Paternal Age Effect: How Old is Too Old?

Delaying parenthood has serious medical risks for both men and women, study warns

2012-01-17T15:15:00.001-08:00

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Delaying parenthood has serious medical risks for both men and women, study warns

Postmedia News Jan 17, 2012 – 9:48 AM ET

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Babies born to fathers of “advanced paternal age” — defined as 40 and older at the time of conception — are at increased risk of genetic disorders, as well as schizophrenia, autism and some forms of cancer, according to the authors

By Sharon Kirkey
Men, and not just women, need to be aware of the “reproductive consequences” of postponing parenthood, new national guidelines on the risks of delayed child-bearing warn.
Though women especially should recognize that their “fecundity and fertility” starts to decline precipitously after 32, a man’s semen quality and fertility also worsens with age, according to guidelines endorsed by the Society of Obstetricians and Gynaecologists of Canada.

Postponing parenthood could have serious consequences, warns new study

2012-01-17T09:36:00.000-08:00

Postponing parenthood could have serious consequences, warns new study

By Sharon Kirkey, Postmedia News January 17, 2012 10:13 AM

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The new guideline to doctors comes amid growing concerns about the number of women delaying childbearing. In Canada, 11 per cent of first births now occur in women aged 35 and older, up from five per cent in 1987.

Photograph by: Thinkstock, canada.com

Men, and not just women, need to be aware of the "reproductive consequences" of postponing parenthood, new national guidelines on the risks of delayed child-bearing warn.

Though women especially should recognize that their "fecundity and fertility" starts to decline precipitously after 32, a man's semen quality and fertility also worsens with age, according to guidelines endorsed by the Society of Obstetricians and Gynaecologists of Canada.

Read more: http://www.canada.com/health/Postponing+parenthood+could+have+serious+consequences+warns+study/6007363/story.html#ixzz1jjoxmhNe

James Crow Dies

2012-01-11T10:11:00.000-08:00

James Crow Dies

January 11, 2012

James Crow, who was a population geneticist at the University of Wisconsin-Madison, has died, reports The New York Times. He was 95. Crow studied mutational load, and was part of on a National Academy of Sciences committee that assessed mutational damage to the populations of Hiroshima and Nagasaki following the use of atomic bombs there. He also was on a committee that paved the way for using DNA forensics in court. The Times notes that when Crow began teaching in the 1940s and 1950s, the field of genetics underwent rapid changes. "When anxious students asked Dr. Crow what would be in the exams, he would tell them that the questions were the same every year but that the answers were different," the Times says.

Neuron. 2011 Dec 22;72(6):951-63. High Frequencies of De Novo CNVs in Bipolar Disorder and Schizophrenia.

2012-01-07T09:37:00.000-08:00

Neuron. 2011 Dec 22;72(6):951-63.

High Frequencies of De Novo CNVs in Bipolar Disorder and Schizophrenia.

Malhotra D, McCarthy S, Michaelson JJ, Vacic V, Burdick KE, Yoon S, Cichon S, Corvin A, Gary S, Gershon ES, Gill M, Karayiorgou M, Kelsoe JR, Krastoshevsky O, Krause V, Leibenluft E, Levy DL, Makarov V, Bhandari A, Malhotra AK, McMahon FJ, Nöthen MM, Potash JB, Rietschel M, Schulze TG, Sebat J.

Source

Beyster Center for Genomics of Psychiatric Diseases, University of California, San Diego, La Jolla, CA 92093, USA; Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA; Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 12824, USA.

Abstract

While it is known that rare copy-number variants (CNVs) contribute to risk for some neuropsychiatric disorders, the role of CNVs in bipolar disorder is unclear. Here, we reasoned that a contribution of CNVs to mood disorders might be most evident for de novo mutations. We performed a genome-wide analysis of de novo CNVs in a cohort of 788 trios. Diagnoses of offspring included bipolar disorder (n = 185), schizophrenia (n = 177), and healthy controls (n = 426). Frequencies of de novo CNVs were significantly higher in bipolar disorder as compared with controls (OR = 4.8 [1.4,16.0], p = 0.009). De novo CNVs were particularly enriched among cases with an age at onset younger than 18 (OR = 6.3 [1.7,22.6], p = 0.006). We also confirmed a significant enrichment of de novo CNVs in schizophrenia (OR = 5.0 [1.5,16.8], p = 0.007). Our results suggest that rare spontaneous mutations are an important contributor to risk for bipolar disorder and other major neuropsychiatric diseases.

Copyright © 2011 Elsevier Inc. All rights reserved.

Influence of paternal age in schizophrenia].

2012-01-04T08:46:00.000-08:00

Influence of paternal age in schizophrenia].

Encephale. 2011 Jun;37(3):199-206. Epub 2011 Apr 2.

[Influence of paternal age in schizophrenia].

[Article in French]

Hubert A, Szöke A, Leboyer M, Schürhoff F.

Source

Pôle de psychiatrie du CHU de Créteil, groupe hospitalier Henri-Mondor-Albert-Chenevier, AP-HP, 40, rue Mesly, 94000 Créteil, France.

Abstract

BACKGROUND:

Schizophrenia is an aetiologically heterogeneous syndrome, with a strong genetic component. Despite a reduced fertility in this disorder, its prevalence is maintained and could be explained by de novo genetic mutations. Advanced paternal age (APA) is a major source of new mutations in human beings and could thus be associated with an increased risk of developing schizophrenia in offspring. New mutations related to APA have been implicated as a cause of sporadic cases in several autosomal dominant diseases and also in neurodevelopmental diseases, autism, intellectual disabilities, and social functioning. The aim of the present study was to summarize the results of studies investigating the role of APA, and to discuss some interpretations.

METHODS:

All relevant studies were identified through the National Library of Medicine (PubMed(®) database). Keywords used for research were "age" and "schizophrenia" linked to "paternal or father". We have identified and analysed eight cohort studies, five case-control studies, two meta-analyses, and one review concerning different father's mutations potentially transmitted, two studies comparing paternal age at conception between sporadic versus familial cases of schizophrenia. All studies selected have been published between 2000 and 2009.

RESULTS:

After controlling for several confounding factors including maternal age, the relative risk of schizophrenia increased from 1.84 to 4.62 in offspring of fathers with an older age of fatherhood. Mother's age showed no significant effects after adjusting for paternal age. There was a significant association between paternal age and risk of developing schizophrenia, there was a weaker association with psychosis.

DISCUSSION:

The results of these different studies are confirmed by two recent meta-analyses which found an increased risk of schizophrenia in offspring of fathers older than 35 years. Two main hypotheses could explain these results. The first one is based on the presence of new mutations in the spermatogonia, possibly because of accumulating replication errors in spermatogonial cell lines. This hypothesis is confirmed by Malaspina et al. (2002) [19], who found that patients without a family history of schizophrenia had significantly older fathers than probands with a positive family history of schizophrenia. However, this result has not been confirmed by other studies, and paternal age effect could be also explained by a mechanism called imprinting, which is a form of gene regulation. The second hypothesis is based on the fact that fathers with schizophrenia spectrum personality disorder, known to be genetically related to schizophrenia, could have an advanced age at conception. However, regarding this hypothesis, advanced maternal age at conception should be a risk factor for schizophrenia, and this is not the case. Thus, the first hypothesis seems more plausible than the second. APA has been identified as a risk factor for other psychiatric disorders such as autism, bipolar disorder, obsessive-compulsive disorder, and phobia, and thus seems to be a non-specific risk factor. Furthermore, its association with impaired neurocognitive outcomes during infancy and childhood in normal populations raises the question of the phenotype linked to APA.

CONCLUSION:

APA at conception appears to be a risk factor for schizophrenia. This risk factor probably interacts with genetic factors in a gene-environment interaction. To date, there is no validated cut-off at which the risk is significantly increased in offspring. In the future, studies could benefit from analyzing the phenotype related to APA.

Copyright © 2010 L'Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.

PMID: 21703435 [PubMed - indexed for MEDLINE]

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Mutation risk associated with paternal and maternal age in a cohort of retinoblastoma survivors.

2011-12-29T11:59:00.000-08:00

Hum Genet. 2011 Dec 28. [Epub ahead of print]

Mutation risk associated with paternal and maternal age in a cohort of retinoblastoma survivors.

Mills MB, Hudgins L, Balise RR, Abramson DH, Kleinerman RA.

Source

Department of Genetics, Stanford University School of Medicine/Lucile Packard Children's Hospital, 300 Pasteur Drive, Boswell Building A097, Stanford, CA, 94304, USA, mmills@lpch.org.

Abstract

Autosomal dominant conditions are known to be associated with advanced paternal age, and it has been suggested that retinoblastoma (Rb) also exhibits a paternal age effect due to the paternal origin of most new germline RB1 mutations. To further our understanding of the association of parental age and risk of de novo germline RB1 mutations, we evaluated the effect of parental age in a cohort of Rb survivors in the United States. A cohort of 262 Rb patients was retrospectively identified at one institution, and telephone interviews were conducted with parents of 160 survivors (65.3%). We classified Rb survivors into three groups: those with unilateral Rb were classified as sporadic if they had no or unknown family history of Rb, those with bilateral Rb were classified as having a de novo germline mutation if they had no or unknown family history of Rb, and those with unilateral or bilateral Rb, who had a family history of Rb, were classified as familial. We built two sets of nested logistic regression models to detect an increased odds of the de novo germline mutation classification related to older parental age compared to sporadic and familial Rb classifications. The modeling strategy evaluated effects of continuous increasing maternal and paternal age and 5-year age increases adjusted for the age of the other parent. Mean maternal ages for survivors classified as having de novo germline mutations and sporadic Rb were similar (28.3 and 28.5, respectively) as were mean paternal ages (31.9 and 31.2, respectively), and all were significantly higher than the weighted general US population means. In contrast, maternal and paternal ages for familial Rb did not differ significantly from the weighted US general population means. Although we noted no significant differences between mean maternal and paternal ages between each of the three Rb classification groups, we found increased odds of a survivor being in the de novo germline mutation group for each 5-year increase in paternal age, but these findings were not statistically significant (de novo vs. sporadic ORs 30-34 = 1.7 [0.7-4], ≥35 = 1.3 [0.5-3.3]; de novo vs. familial ORs 30-34 = 2.8 [1.0-8.4], ≥35 = 1.6 [0.6-4.6]). Our study suggests a weak paternal age effect for Rb resulting from de novo germline mutations consistent with the paternal origin of most of these mutations

Autism. 2011 Dec 16. [Epub ahead of print]Advancing paternal age and simplex autism.

2011-12-20T08:39:00.000-08:00

Autism. 2011 Dec 16. [Epub ahead of print]

Advancing paternal age and simplex autism.

Puleo CM, Schmeidler J, Reichenberg A, Kolevzon A, Soorya LV, Buxbaum JD, Silverman JM.

Source

Temple University, Philadelphia, PA, USA.

Abstract

De novo events appear more common in female and simplex autism spectrum disorder (ASD) cases and may underlie greater ASD risk in older fathers' offspring. This study examined whether advancing paternal age predicts an increase in simplex (n = 90) versus multiplex ASD cases (n = 587) in 677 participants (340 families). Whether or not controlling for maternal age, results support a significant interaction of linear paternal age and sex of the child on simplex family type. Female ASD cases were significantly more likely to be simplex as paternal age increased, but the increase for males was not significant. Findings suggest that ASD arising from non-familial, de novo events may be far less prominent in males than in females, even if more prevalent in males, due to the substantially larger number of male cases attributable to other, more strongly male-biased risk factors.

Poor sperm quality and advancing age are associated with increased sperm DNA damage in infertile men.

2011-11-02T08:55:00.001-07:00

Andrologia. 2011 Nov 1. doi: 10.1111/j.1439-0272.2011.01243.x. [Epub ahead of print]
Poor sperm quality and advancing age are associated with increased sperm DNA damage in infertile men.
Varshini J, Srinag BS, Kalthur G, Krishnamurthy H, Kumar P, Rao SB, Adiga SK.
Source Clinical Embryology, Division of Reproductive Medicine, Department of Obstetrics and Gynecology, Kasturba Medical College, Manipal University, Manipal, India National Centre for Biological Sciences, Tata Institute for Fundamental Research UAS-GKVK Campus, Bangalore, India Department of Radiation Biology and Toxicology, Manipal Life Science Centre, Manipal University, Manipal, India.

Abstract
With increasing evidence for faulty paternal contribution to reproduction, there has been a steady increase in studies highlighting an association between sperm DNA damage, failed/delayed fertilisation and aberrant embryo development. Owing to prevailing ambiguity, the aims of the study were to analyse the genetic integrity of the male gamete and then to understand its association with age, standard semen parameters, lifestyle and occupational factors. The study included 504 subjects, attending university infertility clinic for fertility evaluation and treatment. Semen characteristics were analysed by standard criteria; terminal deoxynucelotidyl transferase-mediated nick end-labelling assay was employed for DNA damage assessment. The average incidence of sperm DNA damage in patients with normozoospermic semen parameters was <10%. Patients with oligozoospermia, severe oligozoospermia, oligoasthenoteratospermia, asthenoteratozoospermia and necrozoospermia had significantly higher level of sperm DNA damage (P < 0.001). Patients above 40 years of age had significantly high levels of DNA damage (P < 0.001) compared with their counterparts. Patients with varicocele and a history of alcohol consumption had higher incidence of spermatozoa with DNA damage (P < 0.01). Poor sperm characteristics in the ejaculate are associated with increased sperm DNA damage. Age-related increase in sperm DNA damage and association of the same with varicocele and alcohol consumption are also demonstrated.

© 2011 Blackwell Verlag GmbH.

Parental age as a risk factor for non-syndromic oral clefts: A meta-analysis.

2011-10-25T10:01:00.001-07:00

J Dent. 2011 Oct 13. [Epub ahead of print]
Parental age as a risk factor for non-syndromic oral clefts: A meta-analysis.
Herkrath AP, Herkrath F, Rebelo MA, Vettore MV.
SourceInstituto Leônidas e Maria Deane, Fundação Oswaldo Cruz, Rua Terezina, 476 - Adrianópolis, Manaus, AM, CEP: 69.057-070, Brazil.

Abstract
OBJECTIVES: A meta-analysis was conducted to assess the relationship between parental age and the occurrence of non-syndromic oral clefts. The questions addressed if younger or older mothers and fathers have an increased risk of having a child with non-syndromic oral clefts.

DATA: Data from cohort studies, case-control, cross-sectional and prevalence studies in which the association between parental age and oral clefts was investigated were analysed. Only studies on oral clefts not associated with syndromes or other anomalies were considered.

SOURCES: An electronic literature search were conducted in Medline, Embase, LILACS, SciELO, SCOPUS and the Cochrane library databases to identify original research published until November 2010. References of the selected articles were also searched.

STUDY SELECTION: The initial database search identified 4623 citations and according to eligibility criteria 80 articles were submitted to quality assessment. In 13 studies measures of association could be extracted for meta-analysis.

CONCLUSION: Our findings suggest that fathers forty years of age or older had a 58% higher probability of having a child with cleft palate compared to those aged between 20 and 39 years. The probability of mothers aged between 35 and 39 years having a child with cleft palate was 20% higher in comparison with those between 20 and 29 years-old, whilst for those aged 40 years or more this probability was 28% higher compared to those aged between 20 and 29 years. Mothers aged 40 years or over were 1.56 times more likely to have a newborn with cleft lip with or without palate compared to those aged between 20 and 29 years. No evidence of association between early maternal and paternal age with occurrence of oral clefts was observed.

Copyright © 2011. Published by Elsevier Ltd.

PMID:22019990[PubMed - as supplied by publisher]

Advanced paternal and grandpaternal age and schizophrenia

2011-10-18T08:21:00.000-07:00

Schizophr Res. 2011 Oct 13. [Epub ahead of print]
Advanced paternal and grandpaternal age and schizophrenia: A three-generation perspective.
Frans EM, McGrath JJ, Sandin S, Lichtenstein P, Reichenberg A, Långström N, Hultman CM.
SourceDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Abstract
BACKGROUND: Advanced paternal age has been linked with an increased risk of schizophrenia in the offspring. If age-related de novo mutations in the male germ line underlie this association, grandpaternal and paternal age would both be expected to influence the risk of schizophrenia. The aim of the current study was to explore the links between both paternal and grandpaternal age with respect to the risk of schizophrenia in a large, national register-based cohort.

METHOD: We linked the Swedish Multi-Generation and Hospital Discharge Registers and compared parents' ages at offspring birth for 20,582 schizophrenia-affected and 100,176 non-affected individuals. Grandparents' ages at the birth of the parent were compared between 2511 affected and 15,619 non-affected individuals. The risk of schizophrenia was examined with logistic regression when the predictor variable (parent or grandparent age) varied across age strata.

RESULTS: After adjusting for maternal age, birth year and proband sex, we confirmed that offspring of older fathers had an increased risk of schizophrenia. Compared to those with paternal age 20-24years, those with fathers >55years had a two-fold increased risk of schizophrenia. With respect to grandparent age, older maternal (but not paternal) grandfather age was associated with an increased risk of schizophrenia. Compared to maternal grandfather age 20-24years, those with maternal grandfathers >55years had a significantly increased risk of schizophrenia (adjusted odds ratio and 95% confidence intervals; 2.79, 1.71-4.56). The pattern of results was essentially unchanged when we examined male and female probands separately.

CONCLUSION: This is the first study to report an association between grandpaternal age and risk of schizophrenia. The selective effect of advanced maternal grandfather age suggests that the biological mechanisms involving the X-chromosome may differentially contribute to the association between paternal age and offspring risk of schizophrenia.

Copyright © 2011. Published by Elsevier B.V.

Probable association between preeclampsia/eclampsia and paternal age: a pilot study

2011-10-05T09:03:00.001-07:00

Ginecol Obstet Mex. 2011 Apr;79(4):190-5.
[Probable association between preeclampsia/eclampsia and paternal age: a pilot study].
[Article in Spanish]
García-Ortiz L, Gutiérrez-Salinas J, Galaviz-Hernández C, Chima-Galán Mdel C, Hilton-Cáceres JM, Escobedo-Aguirre F, de la Peña-Gutiérrez M, Iniesta-Mejía A, Miranda-Murillo J.
SourceLaboratorio de Medicina Genómica, Centro Médico Nacional 20 de Noviembre, ISSSTE, México. garortiz@yahoo.com

Abstract
BACKGROUND: The preeclampsia is a multisystemic syndrome that occupied the first cause of maternal and fetal mortality around the world. Epidemiologic studies shown both mother and father contribute at the same risk for preeclampsia.

OBJECTIVE: To determinate if there is an association between preeclampsia and paternal age.

MATERIAL AND METHOD: Preeclampsia-eclampsia patients and couples were analyzed in agree to "National High Blood Pressure Education Program Working Group" classification, and a control group constituted by normal pregnant women and couples was included.

RESULTS: There were 27 cases with mild preeclampsia and her couples, 13 cases with severe preeclampsia and her couples and 40 controls conformed by normal pregnant women and her couples. The statistical analysis of variance of the ages shown that men from preeclamptic group had a greater variance in contrast with man of control group (p < 0.001; valor of F = 5.084).

CONCLUSIONS: Although is not clear how paternal age interview in preeclampsia risk, the interaction between paternal-maternal imprinting and spermatic senescence, followed by shortened telomeres of chromosome, could be produce the inactivity of a whole network of signals implicated in disease aetiology.

De novo copy number variants associated with intellectual disability have a paternal origin and age bias.

2011-10-05T08:43:00.001-07:00

J Med Genet. 2011 Oct 3. [Epub ahead of print]
De novo copy number variants associated with intellectual disability have a paternal origin and age bias.
Hehir-Kwa JY, Rodríguez-Santiago B, Vissers LE, de Leeuw N, Pfundt R, Buitelaar JK, Pérez-Jurado LA, Veltman JA.
Source1Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

Abstract
BackgroundDe novo mutations and structural rearrangements are a common cause of intellectual disability (ID) and other disorders with reduced or null reproductive fitness. Insight into the genomic and environmental factors predisposing to the generation of these de novo events is therefore of significant clinical importance.MethodsThis study used information from single nucleotide polymorphism microarrays to determine the parent-of-origin of 118 rare de novo copy number variations (CNVs) detected in a cohort of 3443 patients with ID.ResultsThe large majority of these CNVs (76%, p=1.14×10(-8)) originated on the paternal allele. This paternal bias was independent of CNV length and CNV type. Interestingly, the paternal bias was less pronounced for CNVs flanked by segmental duplications (64%), suggesting that molecular mechanisms involved in the formation of rare de novo CNVs may be dependent on the parent-of-origin. In addition, a significantly increased paternal age was only observed for those CNVs which were not flanked by segmental duplications (p=0.02).ConclusionThis indicates that rare de novo CNVs are increasingly being generated with advanced paternal age by replication based mechanisms during spermatogenesis.

PMID:21969336[PubMed - as supplied by publisher]

The prevalence of spontaneous mutations increases with age in the male germline; consequently, older men have an increased risk of siring children with genetic disease due to de novo mutations.

2011-09-16T13:18:00.000-07:00

Mol Reprod Dev. 2011 Aug 5. doi: 10.1002/mrd.21374. [Epub ahead of print]
Age-related instability in spermatogenic cell nuclear and mitochondrial DNA obtained from Apex1 heterozygous mice.
Vogel KS, Perez M, Momand JR, Acevedo-Torres K, Hildreth K, Garcia RA, Torres-Ramos CA, Ayala-Torres S, Prihoda TJ, McMahan CA, Walter CA.
SourceDepartment of Cellular and Structural Biology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas.

Abstract
The prevalence of spontaneous mutations increases with age in the male germline; consequently, older men have an increased risk of siring children with genetic disease due to de novo mutations. The lacI transgenic mouse can be used to study paternal age effects, and in this system, the prevalence of de novo mutations increases in the male germline at old ages. Mutagenesis is linked with DNA repair capacity, and base excision repair (BER), which can ameliorate spontaneous DNA damage, decreases in nuclear extracts of spermatogenic cells from old mice. Mice heterozygous for a null allele of the Apex1 gene, which encodes apurinic/apyrimidinic endonuclease I (APEN), an essential BER enzyme, display an accelerated increase in spontaneous germline mutagenesis early in life. Here, the consequences of lifelong reduction of APEN on genetic instability in the male germline were examined, for the first time, at middle and old ages. Mutant frequency increased earlier in spermatogenic cells from Apex1(+/-) mice (by 6 months of age). Nuclear DNA damage increased with age in the spermatogenic lineage for both wild-type and Apex1(+/-) mice. By old age, mutant frequencies were similar for wild-type and APEN-deficient mice. Mitochondrial genome repair also depends on APEN, and novel analysis of mitochondrial DNA (mtDNA) damage revealed an increase in the Apex1(+/-) spermatogenic cells by middle age. Thus, Apex1 heterozygosity results in accelerated damage to mtDNA and spontaneous mutagenesis, consistent with an essential role for APEN in maintaining nuclear and mtDNA integrity in spermatogenic cells throughout life. Mol. Reprod. Dev. Published 2011. This article is a U.S. Government work and is in the public domain in the USA.

Published 2011 Wiley-Liss, Inc. This article is a U.S. Government work and is in the public domain in the USA.

breast cancer risk in the offspring: the relations with father's age at birth.

2011-09-07T08:55:00.000-07:00

Mech Ageing Dev. 2011 Apr;132(4):149-53. Epub 2011 Feb 25.
Leukocyte telomere length, breast cancer risk in the offspring: the relations with father's age at birth.
Arbeev KG, Hunt SC, Kimura M, Aviv A, Yashin AI.
SourceCenter for Population Health and Aging, Duke University, Durham, NC 27708-0408, USA. konstantin.arbeev@duke.edu

Abstract
Recent studies have reported that leukocyte telomere length (LTL) is longer in offspring of older fathers. Longer telomeres might increase cancer risk. We examined the relation of father's age at the birth of the offspring (FAB) with LTL in the offspring in 2177 participants of the Family Heart Study and the probability of developing breast cancer in 1405 women from the Framingham Heart Study (offspring cohort). For each year of increase in FAB (adjusted for mother's age at birth), LTLs in the daughters and sons were longer by 19.4bp and 12.2bp, respectively (p<0.0001). Daughters of older fathers were less likely to stay free of breast cancer compared to daughters of younger fathers in empirical (p=0.014) and Cox regression analyses (p=0.0012) adjusted for relevant covariates. We conclude that older fathers endow their offspring with a longer LTL and their daughters with increased susceptibility to breast cancer. These independent observations cannot provide evidence for a causal relationship, mediated by telomere length, between FAB and increased breast cancer risk in daughters. However, with couples delaying having children in today's society, studies exploring the LTL association with increased breast cancer risk in daughters of older fathers might be timely and relevant.

Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Fertility concerns for the aging male.

2011-09-03T09:36:00.000-07:00

Urology. 2011 Sep;78(3):496-9.
Fertility concerns for the aging male.
Stewart AF, Kim ED.
SourceDivision of Urology, Department of Surgery, University of Tennessee, Graduate School of Medicine, Knoxville, TN.

Abstract
Because of many societal factors, the number of men over the age of 35 desiring to conceive children has increased over the past 40 years. The purpose of this review is to identify the mechanisms of aging on male fertility, to evaluate the genetic risk for the offspring, and to provide counseling for the older male. Most evidence suggests trends that increased paternal age has negative effects on fertility and some genetic risk for offspring, but the age at which the risk develops and the magnitude of risk are poorly defined.

Copyright © 2011 Elsevier Inc. All rights reserved.

Father Time: Children with Older Dads at Greater Risk for Mental Illness

2011-08-29T14:45:00.001-07:00

Father Time: Children with Older Dads at Greater Risk for Mental Illness

Biol Reprod. 2011 Aug 24. [Epub ahead of print]

2011-08-26T09:14:00.000-07:00

Biol Reprod. 2011 Aug 24. [Epub ahead of print]
Aging Results in Differential Regulation of DNA Repair Pathways in Pachytene Spermatocytes in the Brown Norway Rat.
Paul C, Nagano M, Robaire B.
Abstract
The present trend of increasing paternal age is accompanied by concerns for the development of complex multi-gene diseases, e.g. autism and schizophrenia, in progeny. Recent studies have established strong correlations between male age, increased oxidative stress, decreased sperm quality and structural aberrations of chromatin and DNA in spermatozoa. We tested the hypothesis that increasing age would result in altered gene expression relating to oxidative stress and DNA damage/repair in germ cells. To test this hypothesis, pachytene spermatocytes and round spermatids were isolated from Brown Norway (BN) rats at 4 (young) and 18 (aged) months of age. Microarray analysis was used to compare gene expression between the groups. The probe sets with significantly altered expression were linked to DNA damage/repair and oxidative stress in pachytene spermatocytes but not in round spermatids. Further analysis of pachytene spermatocytes demonstrated that genes involved in the base excision repair (BER) and nucleotide excision repair (NER) pathways were specifically altered. Quantitative RT-PCR confirmed that NER genes were upregulated (>1.5 fold) whereas BER genes were downregulated (>1.5 fold). At the protein level the members of the BER pathway were also altered by up to 2.3 fold; levels of NER proteins remained unchanged. Furthermore there was an increase in 8-oxo-2'-deoxyguanosine (8-oxodG) immunoreactivity in testes from aged males and in the number of spermatozoa positive for 8-oxodG. In conclusion, aging is associated with differential regulation of DNA repair pathways with a decrease in the BER pathway leading to deficient repair of 8-oxo-dG lesions in germ cells and spermatozoa.

Parental Age Effects on Cortical Morphology in Offspring.

2011-08-06T10:18:00.000-07:00

Cereb Cortex. 2011 Aug 4. [Epub ahead of print]
Parental Age Effects on Cortical Morphology in Offspring.
Shaw P, Gilliam M, Malek M, Rodriguez N, Greenstein D, Clasen L, Evans A, Rapoport J, Giedd J.
SourceChild Psychiatry Branch, Intramural Program of the National Institute of Mental Health.

Abstract
The age at which a parent has a child impacts the child's cognition and risk for mental illness. It appears that this risk is curvilinear, with both age extremes associated with lower intelligence and increased prevalence of some neuropsychiatric disorders. Little is known of the neural mechanisms underpinning this phenomenon. We extracted lobar volumes, surface areas, and cortical thickness from 489 neuroanatomic magnetic resonance images acquired on 171 youth. Using linear mixed model regression, we determined the association between parental age and offspring's neuroanatomy, adjusting for offspring's age, sex, intelligence, and parental socioeconomic class. For gray matter volumes, quadratic paternal and maternal age terms contributed significantly (maternal quadratic age effect: t = -2.2, P = 0.03; paternal quadratic age effect: t = -2.4, P = 0.02) delineating an inverted "U" relationship between parental age and gray matter volume. Cortical volume increased with both advancing paternal and maternal age until around the early 30s after which it fell. Paternal age effects were more pronounced on cortical surface area, whereas maternal age impacted more on cortical thickness. There were no significant effects of parental age on white matter volumes. These parental age effects on cerebral morphology may form part of the link between parental age extremes and suboptimal neurocognitive outcomes.

PMID:21817090[PubMed - as supplied by publisher]

Exome Sequences Reveal Role for De Novo Mutations in Schizophrenia

2011-07-11T14:13:00.000-07:00

Exome Sequences Reveal Role for De Novo Mutations in Schizophrenia
July 11, 2011
Type size:
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+EmailPrinter-friendly versionRSS FeedBy a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – Individuals with sporadic schizophrenia tend to carry more new, potentially deleterious, genetic changes than individuals in the general population, according to an exome sequencing study of schizophrenia-affected families that appeared online in Nature Genetics yesterday.

"The occurrence of de novo mutations, as observed in this study, may in part explain the high worldwide incidence of schizophrenia," co-senior author Guy Rouleau, a researcher at the University of Montreal and director of its CHU Sainte-Justine Research Center, said in a statement.

Researchers from Canada and France did exome sequencing on individuals from 14 parent-child trios, each comprised of an individual with schizophrenia and his or her unaffected parents. In the process, they found 15 de novo mutations in coding sequences from eight individuals with the psychiatric condition, including four nonsense mutations predicted to abbreviate protein sequences.

"Our study supports the notion that [de novo mutations] may account for some of the heritability reported for schizophrenia," Rouleau and his co-authors wrote, "while providing a list of genes possibly involved in disease pathogenesis."

Recent exome sequencing studies involving parent-child trios have implicated de novo mutations in other brain-related conditions, including autism spectrum disorder and mental retardation.

For the current study, researchers used this approach to look at schizophrenia, a psychiatric condition with a range of symptoms and severity that's thought to have complex genetic underpinnings.

After isolating DNA from blood samples taken from individuals in 14 parent-child trios, the team used Agilent SureSelect Human All Exome kits to capture coding sequences that were subsequently sequenced with the Illumina GAIIx.

The families included in the study each had an affected child but no other close relatives with a history of schizophrenia or other conditions characterized by psychoses.

To detect de novo genetic changes specific to schizophrenia, the team compared coding sequences from affected individuals with the human reference genome, with both of his or her parents, and with 26 unrelated control individuals.

Using this approach, researchers found 73 potential de novo mutations, 15 of which were verified by Sanger sequencing. Of these, 11 were missense mutations predicted to alter the amino acid sequence of the resulting protein and four were nonsense mutations predicted to truncate it.

Among the genes containing nonsense mutations were the zinc finger protein-coding gene ZNF480, the karyopherin alpha 1 gene KPNA1, the low-density lipoprotein receptor-related gene LRP1, and the ALS-like protein-coding gene ALS2CL.

The 15 mutations were found in coding sequences from eight of the individuals with schizophrenia, hinting at a higher de novo mutation rate in individuals with sporadic schizophrenia than is predicted in the population overall.

This difference seems to be specific to exomes, researchers reported, noting that de novo mutation rates across the entire genome are likely comparable in those with or without schizophrenia.

"Our study strongly suggests that the enrichment of [de novo mutations] within the coding sequence of individuals with schizophrenia may underlie the pathogenesis of a substantial number of these individuals," they wrote.

By looking at the genes affected by these mutations and the consequences of the genetic changes, researchers say, it may be possible to learn more about brain development and function, in general, and about some of the biological processes that are altered in schizophrenia specifically.

"Because the mutations are located in many different genes, we can now start to establish genetic networks that would define how these gene mutations predispose to schizophrenia," first author Simon Girard, a University of Montreal graduate student, said in a statement. "Most of the genes identified in this study have not been previously linked to schizophrenia, thereby providing new potential therapeutic targets."

Down the road, some of the genes identified in the study may also prove useful in schizophrenia screening, researchers noted, though they conceded that more research is needed to see how findings from the current study relate to other schizophrenia cases.

"Although sporadic cases are not necessarily representative of all individuals with schizophrenia," they concluded, "these new candidates should be further investigated as potentially implicated in this disease."

A Strategy to Identify de Novo Mutations in Common Disorders such as Autism and Schizophrenia.

2011-06-30T08:46:00.000-07:00

J Vis Exp. 2011 Jun 15;(52). pii: 2534. doi: 10.3791/2534.
A Strategy to Identify de Novo Mutations in Common Disorders such as Autism and Schizophrenia.
Julie G, Hamdan FF, Rouleau GA.
SourceCentre of Excellence in Neuromics, CHUM Research Center and the Department of Medicine, Universite de Montreal.

Abstract
There are several lines of evidence supporting the role of de novo mutations as a mechanism for common disorders, such as autism and schizophrenia. First, the de novo mutation rate in humans is relatively high, so new mutations are generated at a high frequency in the population. However, de novo mutations have not been reported in most common diseases. Mutations in genes leading to severe diseases where there is a strong negative selection against the phenotype, such as lethality in embryonic stages or reduced reproductive fitness, will not be transmitted to multiple family members, and therefore will not be detected by linkage gene mapping or association studies. The observation of very high concordance in monozygotic twins and very low concordance in dizygotic twins also strongly supports the hypothesis that a significant fraction of cases may result from new mutations. Such is the case for diseases such as autism and schizophrenia. Second, despite reduced reproductive fitness(1) and extremely variable environmental factors, the incidence of some diseases is maintained worldwide at a relatively high and constant rate. This is the case for autism and schizophrenia, with an incidence of approximately 1% worldwide. Mutational load can be thought of as a balance between selection for or against a deleterious mutation and its production by de novo mutation. Lower rates of reproduction constitute a negative selection factor that should reduce the number of mutant alleles in the population, ultimately leading to decreased disease prevalence. These selective pressures tend to be of different intensity in different environments. Nonetheless, these severe mental disorders have been maintained at a constant relatively high prevalence in the worldwide population across a wide range of cultures and countries despite a strong negative selection against them(2). This is not what one would predict in diseases with reduced reproductive fitness, unless there was a high new mutation rate. Finally, the effects of paternal age: there is a significantly increased risk of the disease with increasing paternal age, which could result from the age related increase in paternal de novo mutations. This is the case for autism and schizophrenia(3). The male-to-female ratio of mutation rate is estimated at about 4-6:1, presumably due to a higher number of germ-cell divisions with age in males. Therefore, one would predict that de novo mutations would more frequently come from males, particularly older males(4). A high rate of new mutations may in part explain why genetic studies have so far failed to identify many genes predisposing to complexes diseases genes, such as autism and schizophrenia, and why diseases have been identified for a mere 3% of genes in the human genome. Identification for de novo mutations as a cause of a disease requires a targeted molecular approach, which includes studying parents and affected subjects. The process for determining if the genetic basis of a disease may result in part from de novo mutations and the molecular approach to establish this link will be illustrated, using autism and schizophrenia as examples.

PMID:21712793[PubMed - in process]

Influence of paternal age in schizophrenia.

2011-06-28T08:59:00.000-07:00

Encephale. 2011 Jun;37(3):199-206. Epub 2011 Apr 2.
[Influence of paternal age in schizophrenia.]
[Article in French]
Hubert A, Szöke A, Leboyer M, Schürhoff F.
SourcePôle de psychiatrie du CHU de Créteil, groupe hospitalier Henri-Mondor-Albert-Chenevier, AP-HP, 40, rue Mesly, 94000 Créteil, France; Inserm unité 955, IMRB, département de génétique, équipe 15, 94000 Créteil, France; Faculté de médecine, université Paris-Est Créteil, IFR10, 94000 Créteil, France; Fondation Fondamental, fondation de coopération scientifique, hôpital Chenevier, 40, rue Mesly, 94000 Créteil, France.

Abstract
BACKGROUND: Schizophrenia is an aetiologically heterogeneous syndrome, with a strong genetic component. Despite a reduced fertility in this disorder, its prevalence is maintained and could be explained by de novo genetic mutations. Advanced paternal age (APA) is a major source of new mutations in human beings and could thus be associated with an increased risk of developing schizophrenia in offspring. New mutations related to APA have been implicated as a cause of sporadic cases in several autosomal dominant diseases and also in neurodevelopmental diseases, autism, intellectual disabilities, and social functioning. The aim of the present study was to summarize the results of studies investigating the role of APA, and to discuss some interpretations.

METHODS: All relevant studies were identified through the National Library of Medicine (PubMed(®) database). Keywords used for research were "age" and "schizophrenia" linked to "paternal or father". We have identified and analysed eight cohort studies, five case-control studies, two meta-analyses, and one review concerning different father's mutations potentially transmitted, two studies comparing paternal age at conception between sporadic versus familial cases of schizophrenia. All studies selected have been published between 2000 and 2009.

RESULTS: After controlling for several confounding factors including maternal age, the relative risk of schizophrenia increased from 1.84 to 4.62 in offspring of fathers with an older age of fatherhood. Mother's age showed no significant effects after adjusting for paternal age. There was a significant association between paternal age and risk of developing schizophrenia, there was a weaker association with psychosis.

DISCUSSION: The results of these different studies are confirmed by two recent meta-analyses which found an increased risk of schizophrenia in offspring of fathers older than 35 years. Two main hypotheses could explain these results. The first one is based on the presence of new mutations in the spermatogonia, possibly because of accumulating replication errors in spermatogonial cell lines. This hypothesis is confirmed by Malaspina et al. (2002) [19], who found that patients without a family history of schizophrenia had significantly older fathers than probands with a positive family history of schizophrenia. However, this result has not been confirmed by other studies, and paternal age effect could be also explained by a mechanism called imprinting, which is a form of gene regulation. The second hypothesis is based on the fact that fathers with schizophrenia spectrum personality disorder, known to be genetically related to schizophrenia, could have an advanced age at conception. However, regarding this hypothesis, advanced maternal age at conception should be a risk factor for schizophrenia, and this is not the case. Thus, the first hypothesis seems more plausible than the second. APA has been identified as a risk factor for other psychiatric disorders such as autism, bipolar disorder, obsessive-compulsive disorder, and phobia, and thus seems to be a non-specific risk factor. Furthermore, its association with impaired neurocognitive outcomes during infancy and childhood in normal populations raises the question of the phenotype linked to APA.

CONCLUSION: APA at conception appears to be a risk factor for schizophrenia. This risk factor probably interacts with genetic factors in a gene-environment interaction. To date, there is no validated cut-off at which the risk is significantly increased in offspring. In the future, studies could benefit from analyzing the phenotype related to APA.

Copyright © 2010 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.

PMID:21703435[PubMed - as supplied by publisher]

Are Caucasian-European men delaying fatherhood? Results of a 7 year observational study of infertile couples with male factor infertility.

2011-06-24T11:13:00.000-07:00

Int J Androl. 2011 Jun 22. doi: 10.1111/j.1365-2605.2011.01197.x. [Epub ahead of print]
Are Caucasian-European men delaying fatherhood? Results of a 7 year observational study of infertile couples with male factor infertility.
Salonia A, Matloob R, Saccà A, Ferrari M, Gallina A, Castiglione F, Abdollah F, Raber M, Brigante C, Candiani M, Rigatti P, Montorsi F.
SourceDepartment of Urology, University Vita-Salute San Raffaele, Milan Department of Obstetrics and Gynecology, University Vita-Salute San Raffaele, Milan, Italy.

Abstract
This study was aimed at assessing presence and predictors of a trend towards more advanced paternal age at presentation in a cohort of 1283 Caucasian-European infertile couples with male factor infertility (MFI) over a short time frame. Multivariate linear regression analysis tested the association between predictors [namely, partners' age, length of infertility at first presentation, patients' comorbidities as scored with the Charlson Comorbidity Index (CCI) and educational status] and patient's age at presentation. Using anova, patient's age at presentation (F ratio: 2.43; p = 0.024) and patients' educational status (χ(2) trend: 142.38; p < 0.001) significantly increased over time. In contrast, length of infertility at first presentation, CCI and partners' age did not significantly change over time (all p ≥ 0.05). Linear regression analyses showed that CCI, educational status and year of presentation were not correlated with patients' age at presentation (all p ≥ 0.05), whereas partners' age (β = 0.170; p < 0.001) and length of infertility (β = 0.123; p = 0.004) were independent predictors of delayed fatherhood. These results showed a significant shift towards advanced paternal age, but a non-significant increase of maternal age at first presentation among Caucasian-European infertile couples with MFI over a short time frame.

© 2011 The Authors. International Journal of Andrology © 2011 European Academy of Andrology.

Advanced paternal age is a risk factor for schizophrenia in Iranians.

2011-04-26T08:02:00.000-07:00

Ann Gen Psychiatry. 2011 Apr 24;10(1):15. [Epub ahead of print]
Advanced paternal age is a risk factor for schizophrenia in Iranians.
Naserbakht M, Ahmadkhaniha HR, Mokri B, Smith CL.
Abstract
ABSTRACT:

BACKGROUND: Since 1958 many, but not all studies have demonstrated that paternal age is a risk factor for schizophrenia. There may be many different explanations for differences between studies, including study design, sample size, collection criteria, heterogeneity and the confounding effects of environmental factors that can for example perturb epigenetic programming and lead to an increase in disease risk. The small number of children in Western families makes risk comparisons between siblings born at different paternal ages difficult. In contrast, more Eastern families have children both at early and later periods of life. In the present study, a cross-sectional population study in an Iranian population was performed to compare frequency of schizophrenia in younger offspring (that is, older paternal age) versus older offspring.

METHODS: A total of 220 patients with the diagnosis of schizophrenia (cases) from both psychiatric hospitals and private clinics and 220 individuals from other hospital wards (controls), matched for sex and age were recruited for this study. Patients with neurological problem, substance abuse, mental retardation and mood disorder were excluded from both groups.

RESULTS: Birth rank comparisons revealed that 35% vs 24% of the cases vs the controls were in the third or upper birth rank (P = 0.01). Also, the mean age of fathers at birth in case group (30 +/- 6.26 years) was significantly more than the control group (26.45 +/- 5.64 years; P = 0.0001). The age of 76 fathers at birth in case group was over 32 versus 33 fathers in control group. Individuals whose fathers' age was more than 32 (at birth) were at higher risk (2.77 times) for schizophrenia versus others (P <0.0001, 95% CI 1.80 to 4.27). The maternal age at parturition of the case versus controls groups was 26.1 +/- 5.41 vs 25.07 +/- 4.47 (P = 0.02). Logistic regression analysis suggests that maternal age is less likely to be involved in the higher risk of schizophrenia than advanced parental age.

DISCUSSION: This study demonstrates a relationship between paternal age and schizophrenia in large families of an Iranian population. Arguments have been put forth that DNA bases changes or epigenetic changes in sperm account for the increased risk associated with older fathers. However, it would not be surprising that both de novo germline mutations and epigenetic changes contribute to disease occurrence because DNA replication and DNA methylation are closely linked at both the macromolecular level (that is, methylation closely follows replication), and at the metabolic level (both processes require folate), and susceptible to modulation by the environment. Further research on samples such as those collected here are needed to sort out the contributions of de novo mutations versus epigenetic changes to schizophrenia.

Parental ages and levels of DNA methylation in the newborn are correlated.

2011-04-03T18:42:00.001-07:00

Parental ages and levels of DNA methylation in the newborn are correlated.
Adkins RM, Thomas F, Tylavsky FA, Krushkal J.

Abstract
ABSTRACT:

BACKGROUND: Changes in DNA methylation patterns with age frequently have been observed and implicated in the normal aging process and its associated increasing risk of disease, particularly cancer. Additionally, the offspring of older parents are at significantly increased risk of cancer, diabetes, and neurodevelopmental disorders. Only a proportion of these increased risks among the children of older parents can be attributed to nondisjunction and chromosomal rearrangements.

RESULTS: Using a genome-wide survey of 27,578 CpG dinucleotides in a cohort of 168 newborns, we examined the relationship between DNA methylation in newborns and a variety of parental and newborn traits. We found that methylation levels of 144 CpGs belonging to 142 genes were significantly correlated with maternal age. A weaker correlation was observed with paternal age. Among these genes, processes related to cancer were over-represented, as were functions related to neurological regulation, glucose/carbohydrate metabolism, nucleocytoplasmic transport, and transcriptional regulation. CpGs exhibiting gender differences in methylation were overwhelmingly located on the X chromosome, although a small subset of autosomal CpGs were found in genes previously shown to exhibit gender-specific differences in methylation levels.

CONCLUSIONS: These results indicate that there are differences in CpG methylation levels at birth that are related to parental age and that could influence disease risk in childhood and throughout life.

Paternal age related schizophrenia (PARS): Latent subgroups detected by k-means clustering analysis.

2011-03-01T08:53:00.000-08:00

Schizophr Res. 2011 Feb 25. [Epub ahead of print]

Paternal age related schizophrenia (PARS): Latent subgroups detected by k-means clustering analysis.
Lee H, Malaspina D, Ahn H, Perrin M, Opler MG, Kleinhaus K, Harlap S, Goetz R, Antonius D.

Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY, USA.

Abstract
BACKGROUND: Paternal age related schizophrenia (PARS) has been proposed as a subgroup of schizophrenia with distinct etiology, pathophysiology and symptoms. This study uses a k-means clustering analysis approach to generate hypotheses about differences between PARS and other cases of schizophrenia.

METHODS: We studied PARS (operationally defined as not having any family history of schizophrenia among first and second-degree relatives and fathers' age at birth ≥35years) in a series of schizophrenia cases recruited from a research unit. Data were available on demographic variables, symptoms (Positive and Negative Syndrome Scale; PANSS), cognitive tests (Wechsler Adult Intelligence Scale-Revised; WAIS-R) and olfaction (University of Pennsylvania Smell Identification Test; UPSIT). We conducted a series of k-means clustering analyses to identify clusters of cases containing high concentrations of PARS.

RESULTS: Two analyses generated clusters with high concentrations of PARS cases. The first analysis (N=136; PARS=34) revealed a cluster containing 83% PARS cases, in which the patients showed a significant discrepancy between verbal and performance intelligence. The mean paternal and maternal ages were 41 and 33, respectively. The second analysis (N=123; PARS=30) revealed a cluster containing 71% PARS cases, of which 93% were females; the mean age of onset of psychosis, at 17.2, was significantly early.

CONCLUSIONS: These results strengthen the evidence that PARS cases differ from other patients with schizophrenia. Hypothesis-generating findings suggest that features of PARS may include a discrepancy between verbal and performance intelligence, and in females, an early age of onset. These findings provide a rationale for separating these phenotypes from others in future clinical, genetic and pathophysiologic studies of schizophrenia and in considering responses to treatment.

Copyright © 2011 Elsevier B.V. All rights reserved.
PMID: 21353765 [PubMed - as supplied by publisher]

Are Advanced Paternal Age and Point Mutation at Chromosome 4 Associated With Schizophrenia

2011-01-30T17:40:00.000-08:00

Prim Care Companion J Clin Psychiatry. 2010;12(5). pii: PCC.10l00952.

Are Advanced Paternal Age and Point Mutation at Chromosome 4 Associated With Schizophrenia?
Phutane VH, Loganathan S, Jhirwal OP, Varghese M, Jain S, Girimaji SC.

Department of Psychiatry, Yale University, School of Medicine, Connecticut Mental Health Center, New Haven ; Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri ; Department of Psychiatry, National Institute of Human Behavior and Allied Science, Delhi, India ; and Department of Psychiatry, Institute of Mental Health and Neurosciences, Bangalore, India.

PMID: 21274353 [PubMed - as supplied by publisher]

The Male Biological Clock

2011-01-13T19:55:00.000-08:00

The Male Biological Clock
by Jessie Agudo, Staff Writer (Ranked #6 expert in Sexual Health & Enhancement)
According to Nebraska Medical Center, ideally, fathers should finish their family by 40. It is quite risky for fathers over forty to have a child with an autosomal dominant mutation. Fathers over fifty were found to have a twenty percent greater incidence of producing a baby born with serious defects.

A research scientist has been looking into male infertility and remains unconvinced by the American findings on sperm quality.

They get men over sixty coming in for semen analysis and their sperm is no different from that of 20-year-old added the scientist. After 55, sperm numbers significantly reduce. Furthermore he takes the traditional view, maintaining that sperm quality is influenced by factors other than age. Alcohol, smoking, stress, diet, and large levels of cadmium and lead can affect sperm, Heavy alcoholics and cocaine users experience the severest drop in sperm production added research scientist.

According to studies, men are productivity better built than women, sperm are produced every minute of the day, each sperm taking 72 days to evolve. A man produces 200-400 million sperm a day- and it only needs one to fertilize an egg. This goes some way to explained why traditionally it has been more socially acceptable for men to "spread their seed"; it’s all in the name of procreation.

Author of the Rites of Man: love, sex and death in the making of the male, believes that encountering paternal death sooner rather than later makes a great deal of difference to a child. So, if the father is approaching that age, it’s likely that parental loss will occur just when the child is supposed to having the best time of her or his life. This can lead to awful emotional difficulties, apart from the understandable grief. It can result in terrible feelings of guilt and anger.

Nowadays, economic factors like money, jobs, maternity leave and child care play as even greater part in determining when is the right time to reproduce.

The older father will often become "Big Daddy", showering gifts on the daughter and spoiling her. Treating her as "his baby". The relationship will either be intensely paternalistic or lover-like. The more the older father invests in his daughter, the more difficult it will be for her daughter to become independent.

An older father only grows older and, as his daughter’s life is expanding, he is contracting. When he is post-menopausal, she is becoming a woman.

Beating the clock

Nowadays, economic factors like jobs, maternity leave, money and child care play an even greater part in determining when it is right time to reproduce. As women, it can be galling to feel there is a further pressing factor: the biological clock. The facts that biology may not be so favorable to men either is one that, curiously, has been all but ignored up to now. According to psychology adviser, as long as women are conscious of their biological clock, while men regard themselves as immune, this will remain a potential source of conflict and of women’s resentment. But if men start to become more conscious of their own internal ticking the two sexes will gain understanding of each other.

Image

Resource: Woman Today

Paternal age and common mental disorders.

2011-01-12T08:23:00.000-08:00

World J Biol Psychiatry. 2009;10(4 Pt 2):518-23.

Paternal age and common mental disorders.
Krishnaswamy S, Subramaniam K, Indran H, Ramachandran P, Indran T, Indran R, Aziz JA.

Department of Psychiatry, Penang Medical College, Penang, Malaysia. Saroja54@hotmail.com

Abstract
INTRODUCTION: There is evidence in the literature that there are associations between advancing paternal age and psychosis or more specifically schizophrenia, but not enough to support a strong link between advancing paternal age and common mental disorders.

OBJECTIVE: This study aims to explain the association between paternal age at birth and common mental disorders in progeny during their adulthood.

METHODOLOGY: This is a sub-study from a larger survey which was planned to study the epidemiology of mental disorders in Malaysia. Respondents who could remember the age of parents at birth were included in the study. The diagnosis of common mental disorders (CMD) was made using the CIS-R (Clinical Interview Schedule-Revised) instrument in the PROQSY (Programmed Questionnaire System) format. Association between paternal age at birth and CMD was studied using logistic regression, after controlling for age, gender, ethnicity and presence of family history of mental disorders.

RESULTS: Respondents with paternal age at birth of 19 and below and 50 above and had higher rates of 10 and 25% for common mental disorders (chi(2)=7.007, P=0.072) with odds ratios of 2.89 (95% CI of OR = 1.1-7.6) and 4.28 (1.4-12.7).

DISCUSSION: Progenies of fathers under 20 and over 50 had higher risk for mental disorders. Factors such as immaturity in sperm of teenage fathers, mutation in germ line of older fathers, environmental and psychosocial factors could have contributed to increased prevalence of common mental disorders in the progeny.

PMID: 19191074 [PubMed - indexed for MEDLINE]

Delayed fathering and risk of mental disorders in adult offspring.

2011-01-12T08:01:00.000-08:00

Early Hum Dev. 2011 Jan 8. [Epub ahead of print]

Delayed fathering and risk of mental disorders in adult offspring.
Krishnaswamy S, Subramaniam K, Ramachandran P, Indran T, Abdul Aziz J.

University of New England, Locked bag 4, NSW 2351, Australia.

Abstract
INTRODUCTION: Delayed parenting and child bearing at a very young age impose various risks to development of the offspring.

OBJECTIVE: This study aims to investigate the association between disparities in parental age and increased risk factor for common mental disorders in the progenies during adulthood.

METHODOLOGY: The Malaysian Mental Health Survey (MMHS) was analysed for this study. Respondents were asked to estimate the age of their parents at their birth. Presence of common mental disorders (CMD) was determined by referring to the diagnosis given by the Clinical Interview Schedule-Revised (CIS-R) instrument in the Programmed Questionnaire System (PROQSY) format. The association between parental age disparities and CMD was studied using logistic regression.

RESULT: Fifty three percent (n=1972) of the MMHS respondents (N=3666) knew the age of both parents and were included in the study. Three percent (n=53) had significant disparity in parental age, or a difference of 11years or more. Respondents born to parents with significant age disparity had a prevalence rate of 24% (95% CI=22.12-25.89) for CMD in comparison to 6% (95% CI=5.99-6.11) in their counterparts and 3.4 times higher risk for CMD, after adjusting for demographic factors, paternal age at birth and presence of family history of mental disorders. Amongst those born to older fathers aged 50 and above, the presence of disparity increased the rate for CMD to 42% (95% CI=39.82-44.18).

DISCUSSION: Disparity in parental age was significantly associated with increased risk for CMD. Various psychosocial factors contributing to age disparity in both the father and the mother could predispose to stress and mental health problems.

Copyright Â© 2010 Elsevier Ltd. All rights reserved.

Prader- Willi syndrome A genetic defect seen in advanced paternal age offspring

2011-01-06T09:01:00.000-08:00

Indian J Hum Genet. 2010 Sep;16(3):172-4.

Prader-Willi syndrome: Methylation study or fluorescence in situ hybridization first?
Hamzi K, Itto AB, Nassereddine S, Nadifi S.

Laboratory of Human Genetics, Faculty of Medicine, Casablanca, Morocco.

Abstract
Prader-Willi syndrome (PWS) is neurogenetic disorder involving the imprinting mechanism at 15q11-13 region. We report a 4-year-old girl who was referred to our laboratory to be investigated for clinical obesity, mental deficiency and respiratory problems. The patient was born for non-consanguineous and healthy biological parents. After normal pregnancy, the patient was delivered by cesarean section at full term, with a birth weight of 2500 g, and the height and head circumference were unknown. In neonatal stage, she presented severe hypotonia with feeding problems. Her developmental progress was delayed. She walked and developed speech at the age of 3 years. Since the age of 3 years, she presented severe dental problems. Methylation study had confirmed the diagnosis, and for detecting etiology, fluorescence in situ hybridization using probes for small nuclear ribonucleoprotein polypeptide N (SNRPN), which map inside the chromosomal region 15q11-15q13, was necessary to confirm the 15q11-15q13 deletion of paternal chromosome 15, which is the predominant genetic defect in PWS. In conclusion, we report this case with an objective to reinforce the necessity of analysis of DNA methylation within the 15q11-13 region, which is an important tool for the correct diagnosis among children presenting with neonatal hypotonia, mental deficiency and obesity.

PMID: 21206709 [PubMed - in process]

Advancing paternal age and risk of autism: new evidence from a population-based study and a meta-analysis of epidemiological studies.

2010-12-01T11:07:00.000-08:00

Mol Psychiatry. 2010 Nov 30. [Epub ahead of print]

Advancing paternal age and risk of autism: new evidence from a population-based study and a meta-analysis of epidemiological studies.
Hultman CM, Sandin S, Levine SZ, Lichtenstein P, Reichenberg A.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Abstract
Advanced paternal age has been suggested as a risk factor for autism, but empirical evidence is mixed. This study examines whether the association between paternal age and autism in the offspring (1) persists controlling for documented autism risk factors, including family psychiatric history, perinatal conditions, infant characteristics and demographic variables; (2) may be explained by familial traits associated with the autism phenotype, or confounding by parity; and (3) is consistent across epidemiological studies. Multiple study methods were adopted. First, a Swedish 10-year birth cohort (N=1 075 588) was established. Linkage to the National Patient Register ascertained all autism cases (N=883). Second, 660 families identified within the birth cohort had siblings discordant for autism. Finally, meta-analysis included population-based epidemiological studies. In the birth cohort, autism risk increased monotonically with increasing paternal age. Offspring of men aged 50 years were 2.2 times (95% confidence interval: 1.26-3.88: P=0.006) more likely to have autism than offspring of men aged 29 years, after controlling for maternal age and documented risk factors for autism. Within-family analysis of discordant siblings showed that affected siblings had older paternal age, adjusting for maternal age and parity (P<0.0001). Meta-analysis demonstrated advancing paternal age association with increased risk of autism across studies. These findings provide the strongest evidence to date that advanced paternal age is a risk factor for autism in the offspring. Possible biological mechanisms include de novo aberration and mutations or epigenetic alterations associated with aging.Molecular Psychiatry advance online publication, 30 November 2010; doi:10.1038/mp.2010.121.

looked into the relationship between a father’s age and his adult offspring’s likelihood of developing certain cancers.

2010-11-12T14:49:00.000-08:00

Study could change the way doctors understand certain cancers

Dr. Yani Lu’s latest research discovery at City of Hope could change the way doctors understand and treat certain cancers.

Lu, a postdoctoral fellow in the Division of Cancer Etiology, looked into the relationship between a father’s age and his adult offspring’s likelihood of developing certain cancers.

Dr. Yani Lu discovered a connection between a father’s age and his children’s chances to develop certain cancers.
Dr. Lu concluded that the children of older fathers face an increased risk of non-Hodgkin’s lymphoma later in life.

“As a man, you may think you can have a baby at 50 or 60” with no real repercussions, Lu says. “But there may be other risks for your child down the line.”

The idea of a “biological clock” is commonly associated with women alone, but Lu’s research challenges that double standard. In the study, Lu points out that older parents are prone to passing on undesirable genetic traits.

Lu believes the male biological clock might relate to mutations that can accumulate in a man’s reproductive cells over the course of a lifetime. Such cells divide more rapidly than a woman’s reproductive cells. More divisions lead to more chances for abnormalities.

But because many non-Hodgkin’s lymphoma patients are well into their 60s or 70s at the time of diagnosis, most research on the disease has failed to consider genetic effects at all.

Lu and her research team recognized that being born to older parents can have consequences extending well into adulthood.

“For adult-onset malignancies, people seldom think back to factors early in life,” Lu says.

SED congenita

2010-10-02T13:58:00.000-07:00

Chinese Medical Journal, 2010, Vol. 123 No. 19 : 2727-2731

SED congenita is transmitted as an autosomal dominant trait,7 and both men and women are therefore affected equally. The gene for SED congenita has been mapped to the long arm of chromosome 12 (12q14.3). Advanced paternal age is recognized as a risk factor.

A rare genetic disease — spondyloepiphyseal dysplasia

RISKY BUSINESS

2010-09-27T20:48:00.001-07:00

RISKY BUSINESS
Men aged 50 or over are three times more likely to father a child with schizophrenia than men under 25

Read more: http://www.dailymail.co.uk/femail/article-1315456/Women-arent-ones-biological-clocks-says-wannabe-dad.html#ixzz10nCPNhOp

This introduction considers the possibility that epigenetic change that may occur as paternal age advances...

2010-09-25T09:26:00.000-07:00

Ann N Y Acad Sci. 2010 Sep;1204 Suppl:E8-13.

Critical periods and the developmental origins of disease: an epigenetic perspective of schizophrenia.
Perrin M, Kleinhaus K, Messinger J, Malaspina D.

New York University School of Medicine, Social and Psychiatric Initiatives (InSPIRES), New York, New York 10016, USA.

Abstract
Epigenetics holds promise to explain some puzzles concerning the risk and course of psychiatric disorders. Epigenetic information is essential as a set of operating instructions for the genome, which is heritable with DNA. The epigenetic regulation of gene expression can plausibly be influenced by the environment of one's ancestors, prenatal exposures, and by early life events. Some epigenetic mechanisms may alter neurophysiology throughout life by programming gene expression, perhaps in anticipation of certain life experiences. These epigenetic signals are only meta-stable and may be perturbed by stochastic events, errors, or by environmental toxins. This introduction considers the possibility that epigenetic change that may occur as paternal age advances or during fetal adversity may be causally related to the susceptibility for schizophrenia.

PMID: 20840164 [PubMed - in process]

These results support the claim that increased paternal age is associated with a birth of a child with autism spectrum disorder

2010-09-15T08:04:00.000-07:00

Pediatr Neurol. 2010 Oct;43(4):300-302.

Paternal Age in Autism Spectrum Disorders and ADHD.
Gabis L, Raz R, Kesner-Baruch Y.

Weinberg Child Development Center, Safra Children's Hospital, Sheba Medical Center (affiliated with the Sackler School of Medicine, Tel-Aviv University, Israel), Tel Hashomer, Israel.

Abstract
Increased paternal age has been associated with an increased risk for autism spectrum disorders. The present study compared the paternal age distribution in autism spectrum disorders children with that of the general population and among children with attention deficit hyperactivity disorder. Study participants were drawn from the records of children diagnosed with one of these conditions in the years 1998-2006 at the Weinberg Child Development Center, Israel. Data regarding paternal age distribution in the general Israeli population were drawn from the yearly official publications of the Central Bureau of Statistics, Israel. Paternal age at the child's birth was found for autism spectrum disorders children (n = 268) and attention deficit hyperactivity disorders children (n = 320). Paternal age distribution of the attention deficit hyperactivity disorder children was similar to that of the general population in Israel, whereas autism spectrum disorders children were born to older fathers, compared with either the general population (P < 0.001) or children with attention deficit hyperactivity disorder (P = 0.04). These results support the claim that increased paternal age is associated with a birth of a child with autism spectrum disorders, but indicate that this finding cannot be generalized to attention deficit hyperactivity disorder.

In cases of sporadic achondroplasia as well as in fibrodysplasia ossificans progressiva, there is a strong association with paternal age,

2010-09-09T08:21:00.000-07:00

Adv Exp Med Biol. 2010;686:335-48.

Osteochondral diseases and fibrodysplasia ossificans progressiva.
Morales-Piga A, Kaplan FS.

Jefe de Servicio de Proyectos Clínicos del Instituto de Investigación de Enfermedades Raras, Instituto de Salud Carlos III, Sinesio Delgado, 6, 28029, Madrid, Spain, amorales@isciii.es.

Abstract
Osteochondrodysplasias like thanatophoric dysplasia, osteogenesis imperfecta, achondroplasia, and other genetic skeletal disorders like fibrodysplasia ossificans progressiva are infrequently seen in clinical practice. In cases of sporadic achondroplasia as well as in fibrodysplasia ossificans progressiva, there is a strong association with paternal age, a relationship that is less evident in other genetic osteochondral diseases. No other constitutional or environmental factor has proven to be associated with these disorders. The use of prenatal ultrasonography as a routine component of prenatal care is crucial in the early suspicion of osteochondrodysplasias whereas definitive diagnosis is usually obtained by pre-natal molecular analysis. In the case of fibrodysplasia ossificans progressiva, recognition of congenital great toe malformations associated with rapidly-appearing soft tissue swelling is sufficient to make the proper clinical diagnosis, which can be confirmed by genetic testing. Large regional centres will improve diagnosis performance, provide accurate genetic counselling, and ensure an integral assistance for these often severe and incapacitating conditions.

Father's age increase miscarriage, malformation, risk of autism, schizophrenia, and bipolar troubles in children.

2010-09-04T08:14:00.000-07:00

J Gynecol Obstet Biol Reprod (Paris). 2010 Apr;39(1 Suppl):36-8.

[Influence of paternal age]
[Article in French]

Velez de la Calle JF, Broussin B, Lelaidier C, Fallet C.

Unité FIV, Clinique Pasteur, 34, Rue du Moulin à Poudre, Brest, France.

Abstract
Father's age increase miscarriage, malformation, risk of autism, schizophrenia, and bipolar troubles in children.

PMID: 20728806 [PubMed - in process]

Paternal age increases the risk for autism in an Iranian population sample.

2010-08-04T09:33:00.001-07:00

Mol Autism. 2010 Feb 22;1(1):2.

Paternal age increases the risk for autism in an Iranian population sample.
Sasanfar R, Haddad SA, Tolouei A, Ghadami M, Yu D, Santangelo SL.

Department of Psychiatry, Harvard Medical School, Boston, MA, USA. ssantangelo@pngu.mgh.harvard.edu.

Abstract
ABSTRACT: BACKGROUND: Autism is a neurodevelopmental disorder which is known to have a strong genetic component and is most likely oligogenic. However, the necessary role of environmental factors has been well documented. Prior research suggests that parental characteristics, such as age and level of education, may be associated with a risk of autism. Parental age has been shown to be associated with many disorders, such as schizophrenia, childhood cancer and fetal death. However, results from studies of parental age and autism are inconsistent. METHODS: In the present study, we investigated the association of autism with parental age in 179 autism cases and 1611 matched cohort children from Iran. Each case was matched with nine cohort controls on parental education, sex, order of birth, consanguineous marriage, urbanism and province of residence. The Cox regression model was used to carry out conditional logistic regression on the matched data. RESULTS: There was a significant association between higher paternal age, but not maternal age, and an increasing risk of autism. An analysis of the combined effect of parental age and education also revealed that parents with higher education had an increased risk of having autistic children, with a dose-response effect of parental age. CONCLUSIONS: This study, which is the first epidemiological study of autism in Iran, provides evidence of the association of paternal age and risk of autism.

PMID: 20678245 [PubMed - in process]

This case represents de novo origin of two disorders that both may be parental-age related

2010-07-22T06:43:00.000-07:00

Birth Defects Res A Clin Mol Teratol. 2010 Apr;88(4):228-31.

Co-occurrence of achondroplasia and Down syndrome: Genotype/phenotype association.
de Azevedo Moreira LM, Matos MA, Schiper PP, Carvalho AF, Gomes IC, Rolemberg JC, Ferreira de Lima RL, Toralles MB.

Laboratory of Human Genetics and Mutagenesis, Biology Institute, Federal University of Bahia, Barão de Geremoabo, Salvador, Bahia, Brazil. lazevedo@ufba.br

Abstract
BACKGROUND: This report describes the sixth case of an unusual association: Down syndrome with achondroplasia. It also analyzes the effects of both of these disorders on patient phenotype. METHODS: A male infant was evaluated for Down syndrome. His appearance also suggested a diagnosis of achondroplasia. The child was evaluated by physical examination, radiography, cytogenetic study, and mutation analysis. RESULTS: Chromosome analysis showed a karyotype of 47,XY,+21 in all 30 cells analyzed. Radiographic examination showed typical findings of achondroplasia, such as disproportionately large skull, shortening of limb segments, and lumbar lordosis. FGFR3 screening showed a heterozygous G1138A mutation. CONCLUSIONS: The interaction of these two distinct genetic disorders in the same patient produces a phenotype typical of each syndrome with some overlapping signs. This case represents de novo origin of two disorders that both may be parental-age related. (c) 2010 Wiley-Liss, Inc.

Missing heritability: paternal age effect mutations and selfish spermatogonia.

2010-07-17T07:09:00.000-07:00

Nat Rev Genet. 2010 Aug;11(8):589.

Missing heritability: paternal age effect mutations and selfish spermatogonia.
Goriely A, Wilkie AO.

Anne Goriely and Andrew O.M. Wilkie are at the Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.

PMID: 20634812 [PubMed - in process]

Germline and somatic mosaicism for FGFR2 mutation in the mother of a child with Crouzon syndrome:

2010-07-17T07:07:00.000-07:00

Am J Med Genet A. 2010 Jul 15. [Epub ahead of print]

Germline and somatic mosaicism for FGFR2 mutation in the mother of a child with Crouzon syndrome: Implications for genetic testing in "paternal age-effect" syndromes.
Goriely A, Lord H, Lim J, Johnson D, Lester T, Firth HV, Wilkie AO.

Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.

Abstract
Crouzon syndrome is a dominantly inherited disorder characterized by craniosynostosis and facial dysostosis, caused by mutations in the fibroblast growth factor receptor 2 (FGFR2) gene; it belongs to a class of disorders that mostly arise as de novo mutations and exhibit a near-exclusive paternal origin of mutation and elevated paternal age ("paternal age effect"). However, even if this is the major mode of origin of mutations in paternal age-effect disorders, germline mosaicism may also occur. Here we describe the first molecularly documented evidence of germline and somatic mosaicism for FGFR2 mutation, identified in the mother of a child with Crouzon syndrome caused by a heterozygous c.1007A>G (p.Asp336Gly) substitution. Levels of maternal somatic mosaicism for this mutation, estimated by pyrosequencing, ranged from 3.3% in hair roots to 14.1% in blood. Our observation underlines the importance of parental molecular testing for accurate genetic counseling of the risk of recurrence for Crouzon, and other paternal age-effect syndromes. (c) 2010 Wiley-Liss, Inc.

PMID: 20635358 [PubMed - as supplied by publisher]

Conclusions: This research reports the association between blood group system and macrosomia as well as parental age and GDM simultaneously.

2010-07-16T22:04:00.000-07:00

Pediatr Int. 2010 Jul 4. [Epub ahead of print]

MACROSOMIA, TOP OF THE ICEBERG: THE CHARM OF UNDERLYING FACTORS.
Donma MM.

DEPARTMENT OF NEONATOLOGY UNIT, PEDIATRICS CLINICS, MINISTRY OF HEALTH, SULEYMANIYE MATERNITY AND CHILDREN'S DISEASES EDUCATION AND RESEARCH HOSPITAL, ISTANBUL, TURKEY.

Abstract
Background: Macrosomia is associated with childhood obesity. Gestational diabetes mellitus(GDM) is a risk factor for macrosomia. The aim of this large scaled investigation is to determine the incidence, risk factors, characteristic features, and perinatal outcome of macrosomic infants. Methods: This prospective study was carried out on 6,385 newborns. Demographic data included maternal age, paternal age, type of delivery, sex, parity and gestational age at delivery. Anthropometric measurements were recorded. ABO/Rh typing was performed and GDM was diagnosed. Results: Out of 6,385 term deliveries, 477 infants(7.47%) were macrosomic. Incidence of GDM was 0.6% and 4.8% in control group and among macrosomic births, respectively. Incidence of GDM(+) cases was 4% among macrosomic infants weighing 4000 g. < n < 4500 g. GDM(+) cases were densely populated(11%), among macrosomic infants weighing >/=4500 g.(p /=4500 g. than those weighing 4000 g. < n < 4500 g.(p
PMID: 20626633 [PubMed - as supplied by publisher]

There was a statistically significant increase in the odds of Klinefelter syndrome with increasing paternal age.

2010-06-30T08:45:00.000-07:00

Arch Dis Child. 2010 Jun 28. [Epub ahead of print]

Case-control analysis of paternal age and trisomic anomalies.
De Souza E, Morris JK; EUROCAT Working Group.

Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Wolfson Institute of Preventive Medicine, Charterhouse Square, London, UK.

Abstract
Objectives To determine whether older paternal age increases the risk of fathering a pregnancy with Patau (trisomy 13), Edwards (trisomy 18), Klinefelter (XXY) or XYY syndrome. Design Case-control: cases with each of these syndromes were matched to four controls with Down syndrome from within the same congenital anomaly register and with maternal age within 6 months. Setting Data from 22 EUROCAT congenital anomaly registers in 12 European countries. Participants Diagnoses with observed or (for terminations) predicted year of birth from 1980 to 2005, comprising live births, fetal deaths with gestational age >/=20 weeks and terminations after prenatal diagnosis of the anomaly. Data include 374 cases of Patau syndrome, 929 of Edwards syndrome, 295 of Klinefelter syndrome, 28 of XYY syndrome and 5627 controls with Down syndrome. Main outcome measures Odds ratio (OR) associated with a 10-year increase in paternal age for each anomaly was estimated using conditional logistic regression. Results were adjusted to take account of the estimated association of paternal age with Down syndrome (1.11; 95% CI 1.01 to 1.23). Results The OR for Patau syndrome was 1.10 (95% CI 0.83 to 1.45); for Edwards syndrome, 1.15 (0.96 to 1.38); for Klinefelter syndrome, 1.35 (1.02 to 1.79); and for XYY syndrome, 1.99 (0.75 to 5.26). Conclusions There was a statistically significant increase in the odds of Klinefelter syndrome with increasing paternal age. The larger positive associations of Klinefelter and XYY syndromes with paternal age compared with Patau and Edwards syndromes are consistent with the greater percentage of these sex chromosome anomalies being of paternal origin.

PMID: 20584846 [PubMed - as supplied by publisher]

Scientists show children of older fathers face a higher risk of a type of lymphoma

2010-06-26T15:07:00.000-07:00

Scientists show children of older fathers face a higher risk of a type of lymphoma

By Wayne Lewis

Risk of non-Hodgkin’s lymphoma is higher for children of older men, according to City of Hope researchers — a finding that adds to a growing body of evidence suggesting that men, too, may have a biological clock.

The study is one of the first to examine the relationship between parents’ age and their adult offspring’s likelihood of facing cancers of the blood and immune system. Yani Lu, Ph.D., a postdoctoral fellow in the Division of Cancer Etiology, led the study, which was released online in the American Journal of Epidemiology on June 3.

Yani Lu (Photo by p.cunningham)

“As a man, you may think, ‘I can have a baby at 50 or 60 and live long enough to see him go through college.’ But there may be other risks for your child down the line, and you may want to be conscious of those risks,” said Lu.

Lu’s research drew upon data from the California Teachers Study. Initiated in 1995, this project tracks the health, lifestyle choices and demographic information of nearly 133,500 female teachers and administrators in the California public schools’ retirement system. The teachers study is led by Leslie Bernstein, Ph.D., director of the Division of Cancer Etiology in the Department of Population Sciences and Lu’s mentor.

In the latest project, researchers focused on 110,999 women, 819 of whom had been diagnosed with a hematological malignancy. The study revealed that participants born to fathers older than age 40 faced a 59 percent greater risk of non-Hodgkin’s lymphoma compared to similar women born to fathers younger than 25.

“For adult-onset malignancies, people seldom think back” to factors early in life, Lu said. “Diagnosis for non-Hodgkin’s lymphoma occurs closer to the age of 70, so why would in utero factors be related to risk?”

In the study, the fathers’ age had no effect on risk for acute myeloid leukemia or multiple myeloma. Maternal age did not significantly influence risk for blood cancers.

Science has shown that the ticking biological clock is associated with a higher incidence of health issues in children of older mothers. These women face greater risk of miscarriage and increased risks of bearing children with low birth weight or serious health issues such as Down’s syndrome. A recent, large study suggested that children of women over 40 have a greater chance of having autism.

Similar findings among older fathers are scanty, although research going back almost 100 years suggests that these men are more likely to produce children with certain rare birth defects. Numerous studies also show that offspring of older men have a greater risk of developing schizophrenia.

As Lu noted, however, a burgeoning field of research suggests a father’s age at conception may play a more significant role in his progeny’s health than once thought. Recent investigations indicate that children of older fathers have a greater chance of prostate and breast cancers in adulthood as well as some blood cancers during childhood.

Lu believes the male biological clock might relate to mutations that can accumulate in a man’s reproductive cells over the course of a lifetime. Such cells divide more rapidly than a woman’s reproductive cells. More divisions lead to more chances for abnormalities to arise.

Older parental age also appears to be associated with longer length of offspring’s telomeres, the end caps on chromosomes, which might be linked to non-Hodgkin’s lymphoma risk, Lu suggested.

Because non-Hodgkin’s lymphoma is actually a cluster of related diseases with about 30 subtypes, Lu plans to examine how paternal age and other health factors during the early years of life influence risk for specific disease subtypes.

Sophia S. Wang, Ph.D., associate professor of population sciences, was the paper’s senior author. The National Institutes of Health and the California Breast Cancer Research Fund funded the research.

The relation between maternal schizophrenia and low birth weight is modified by paternal age.

2010-06-15T07:17:00.000-07:00

Can J Psychiatry. 2010 Jun;55(6):377-85.

The relation between maternal schizophrenia and low birth weight is modified by paternal age.
Lin HC, Lee HC, Tang CH, Chen YH.

Professor, School of Health Care Administration, Taipei Medical University, Taipei, Taiwan.

Abstract
Objective: Paternal characteristics have never been considered in the relation between maternal schizophrenia and adverse pregnancy outcomes. The aim of our study was to consider different paternal ages while investigating the relation between maternal schizophrenia and low birth weight (LBW), using a nationwide population-based dataset. Method: Our study used data from the 2001 to 2003 Taiwan National Health Insurance Research Dataset and birth certificate registry. A total of 543 394 singleton live births were included. We performed multivariate logistic regression analyses to explore the relation between maternal schizophrenia and the risk of LBW, taking different paternal age groups into account (aged 29 years or younger, 30 to 39 years, and 40 years and older), and after adjusting for other characteristics of infant, mother, and father as well as the difference between the parent's ages. Results: Mothers with schizophrenia had a higher percentage of LBW infants than mothers who did not (11.8%, compared with 6.8%). For infants whose mothers had schizophrenia, the adjusted odds ratios of LBW were 1.47 (95% CI 1.02 to 2.27, P < 0.05) and 2.80 (95% CI 1.42 to 5.51, P < 0.01) times greater than for infants whose mothers did not have schizophrenia, for paternal age groups of 30 to 39 years and 40 years or older, respectively. However, maternal schizophrenia was not a significant predictor of LBW for infants whose fathers were aged 29 years and younger. Conclusions: The relation between LBW and maternal schizophrenia is modified by paternal age. More attention should be paid to the interaction of paternal characteristics and maternal psychiatric disorders in producing adverse pregnancy outcomes.

[Age of the father and health status of the children (2)]

2010-06-11T08:58:00.000-07:00

Rev Med Suisse. 2010 Mar 31;6(242):694-5.

[Age of the father and health status of the children (2)]
[Article in French]

Nau JY.

jeanyves.nau@gmail.com

PMID: 20440994 [PubMed - indexed for MEDLINE]

In females but not in males, increasing paternal age was associated with a linear increased risk of suicide (hazard ratio [HR] = 1.13, 95% confidence

2010-06-10T10:54:00.000-07:00

J Nerv Ment Dis. 2010 Jun;198(6):404-411.

Advanced Paternal Age, Mortality, and Suicide in the General Population.
Miller B, Alaräisänen A, Miettunen J, Järvelin MR, Koponen H, Räsänen P, Isohanni M, Kirkpatrick B.

*Department of Psychiatry and Health Behavior, Medical College of Georgia, Augusta, Georgia; daggerDepartment of Psychiatry, University of Oulu, Oulu, Finland; double daggerDivision of Epidemiology, Public Health, and Primary Care, Imperial College, London, United Kingdom; section signDepartment of Public Health and General Practice, University of Oulu, Oulu, Finland; and paragraph signDepartment of Psychiatry, University of Kuopio, Kuopio, Finland.

Abstract
Advanced paternal age is a risk factor for adverse health outcomes in the offspring. In a population-based birth cohort from Finland, 10,965 singleton offspring born in 1966 and alive at age 1 were followed to age 39. Hazard ratios were calculated, adjusting for maternal age, gender, paternal social class, and maternal parity. In females but not in males, increasing paternal age was associated with a linear increased risk of suicide (hazard ratio [HR] = 1.13, 95% confidence interval [CI] = 1.04-1.24, p < 0.01) and all-causes mortality (HR = 1.06, 95% CI = 1.01-1.10, p = 0.02). Increasing maternal age was associated with a significantly decreased risk of suicide (HR = 0.93, 95% CI = 0.86-1.00, p = 0.04) and all-causes mortality (HR = 0.96, 95% CI = 0.93-1, p = 0.02) in the entire cohort. For paternal age >/=30, the population attributable risk percentage was 13.7% for all deaths and 7.5% for suicides. Parental age at birth may affect suicide and all-causes mortality risk in the offspring in the general population. The causal pathways and specific disorders associated with this increased mortality are largely unknown.

PMID: 20531118 [PubMed - as supplied by publisher]

Advanced paternal age may play a role in non-Hodgkin lymphoma etiology.

2010-05-29T06:43:00.000-07:00

Am J Epidemiol. 2010 May 27. [Epub ahead of print]

Parents' Ages at Birth and Risk of Adult-onset Hematologic Malignancies Among Female Teachers in California.
Lu Y, Ma H, Sullivan-Halley J, Henderson KD, Chang ET, Clarke CA, Neuhausen SL, West DW, Bernstein L, Wang SS.

Abstract
Although advanced parental age at one's birth has been associated with increased risk of breast and prostate cancers, few studies have examined its effect on adult-onset sporadic hematologic malignancies. The authors examined the association of parents' ages at women's births with risk of hematologic malignancies among 110,999 eligible women aged 22-84 years recruited into the prospective California Teachers Study. Between 1995 and 2007, 819 women without a family history of hematologic malignancies were diagnosed with incident lymphoma, leukemia (primarily acute myeloid leukemia), or multiple myeloma. Multivariable-adjusted Cox proportional hazards models provided estimates of relative risks and 95% confidence intervals. Paternal age was positively associated with non-Hodgkin lymphoma after adjustment for race and birth order (relative risk for age >/=40 vs. <25 years = 1.51, 95% confidence interval: 1.08, 2.13; P-trend = 0.01). Further adjustment for maternal age did not materially alter the association. By contrast, the elevated non-Hodgkin lymphoma risk associated with advanced maternal age (>/=40 years) became null when paternal age was included in the statistical model. No association was observed for acute myeloid leukemia or multiple myeloma. Advanced paternal age may play a role in non-Hodgkin lymphoma etiology. Potential etiologic mechanisms include de novo gene mutations, aberrant paternal gene imprinting, or telomere/telomerase biology.

PMID: 20507900 [PubMed - as supplied by publisher]

Male Biological Clock

2010-05-28T06:51:00.000-07:00

Naked Fatherhood
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Select Category Balanced Parenting (3) Early Daze (3) Happy Daze (5) Mad Ramblings (2) The Recent Fathers’ Club (4) Uncategorized (1)
HomeMen’s Biological Clock
by justin on May 24, 2010
in Happy Daze
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There were rumours a while back that Hugh Hefner, the octogenarian founder of the Playboy empire was planning to father a child with Holly Madison (53 years his junior), the alpha female of his three live-in girlfriends. Of course that was before the jam hit the fan and all three moved out of the mansion.

But, apropos the baby – why not? Charlie Chaplin and Picasso both fathered children well into their 70s, with no ill-effects. There are even anecdotal reports in the medical press of men in their 90s becoming fathers. Everyone knows that we men can just carry on having children until very late in life, (although it’s possible that having kids just makes you feel 100 hundred years old).

Photo by: judepics
But is it all true? It seems that medical evidence is mounting that men are not immune from the ticking of the biological clock (although we often battle to hear it quite as loudly as our partners).

The first part of the problem lies with the decline in fertility of men as they age. Testosterone levels fall over time which not only makes it harder for men to hold their tummies in at the beach, but also affects sexual performance. There is also a decline in sperm count and sperm quality which means that it takes men over 45 significantly longer to produce a pregnancy than men under 25 – up to 5 times longer according to some research.

Still, it was thought that even with a decline in fertility, any genetic issues with the pregnancy or resulting child lay with the mother. This was because while a woman is born with her full quota of eggs, men manufacture sperm continually without even having to think about it, so conception between an older couple might be the meeting of a forty-year-old egg with a three-month-old sperm (the time taken to manufacture mature spermatozoa).

However, it now seems that there’s also a deterioration in the quality of the genetic material that each sperm carries. This is first seen in an increase in the number of miscarriages – three times greater where fathers are older than 35 compared to those younger than 25. The incidence of pre-eclampsia also rises with increasing paternal age.

This deterioration of genetic material is thought to arise from a number of causes. The cells which divide to produce sperm cells replicate around 23 times per year starting from puberty, so by the time a man hits 50, those cells have divided about 800 times, increasing the risk of errors.

With age, the frequency of sporadic single-gene mutations also increases four to five times for a person over 45. On top of that, the enzymes that repair faulty DNA decrease in efficiency as one gets older.

All of which means an increase in a list of medical problems now totalling about 20.

A study of data from a huge Israeli health database showed that, for example, schizophrenia is twice as likely to occur in the children of men over forty as in those in their twenties. Men over fifty lead to a three-time increase in risk.

A further study on the same database showed that autism too is six times more frequent where fathers are over forty than those under 30.

An earlier study by Dr Harry Fisch (author of the book The Male Biological Clock) concluded that parents over 40 have a six-times higher risk of having a child affected by Down Syndrome than where both are under 35. And where a woman over forty has a child affected by Down Syndrome, the genetic blame is now thought to lie 50% with the father.

And the list goes on, with various studies linking advanced paternal age to disorders such as dwarfism, progeria (an extremely rare accelerated aging disease), skeletal disorders, congenital heart defects, certain types of cancer and even reduced scores in nonverbal IQ tests.

All of which helps explain why the cutoff age for sperm donors in The States is set at 40. So that’s another paying hobby limited to the youth – smacks of ageism, doesn’t it?

And yet more and more couples are leaving it later to have children for any number of reasons. Many want to feel like they’ve experienced something of a life and a career before the little tyrants arrive. Some prefer to wait until they’re in a more financially stable phase of their lives before committing. Maybe its just that there are more frogs to kiss nowadays in search of princes. Or even that the kiss-per-frog ratio has risen.

And really, what’s the downside? You may be more likely to spend time in casualty with a back problem from flinging your toddler around and there’s the danger of injuring yourself by tripping over your Zimmer frame when playing cricket with the young ‘uns.

Having kids later probably means that you’re going to have a bit less energy for them, but then again, that depends on how well you’ve looked after yourself in getting to where you are. Also, a decrease in the time available to spend with children can be offset to a certain degree by an increase in the quality of the time spent.

Many parents are finding that they’re having children later without even planning it that way – life often gets in the way of our plans. Then when one’s finally ready to make this life-altering commitment it takes a little while to get everything ready to even start trying (especially when you discover that the whole house has to be remodelled before you can even start).

And then it doesn’t just happen right away, and where there are miscarriages, recovery, both physical and emotional, takes time before you can start again.

All of which means an upswing in the number of parents who battle to remember where they left the children a few minutes before.

Then again, children of older parents should be more independent when they grow up, if only because they’re used to being able to easily outpace their pursuers.

From a selfish point of view, having kids later means that you’ll have someone around who is able to intuitively figure out how to use the new DVD player that has been standing unused because you can’t work out what the instruction manual is trying to tell you.

Also, you don’t resent the loss of your social life to the same degree as those that have their children while they are young (the parents, not the children) – you’re giving up a whole lot less when your idea of a good time is staying in with a good book and listening to Smooth Classics.

And when you’re lucky enough to have your mid-life crisis with small children you’re much less likely to embarrass yourself by running off and buying a convertible or any motorcycle that comes with tassles hanging from the handlebars.

The bottom line? Don’t leave it too late. While it is physiologically possible for a man to produce heirs at a very late stage of life, the risks do rise along the way.

And Hef? I think that at his age, he’s just perfected the art of saying ‘Yes Dear’ without really listening to what anyone is actually saying.

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Tags: fathers, old dads, senior fathers

We conclude that the trend of delaying fatherhood in men undergoing IVF or ICSI treatment is detrimental to sperm quality

2010-05-15T08:16:00.001-07:00

J Androl. 2010 May 13. [Epub ahead of print]

Semen Quality Decline among Men below 60 years of age Undergoing IVF or ICSI Treatment.
Hammiche F, Laven J, Boxmeer J, Dohle G, Steegers E, Steegers-Theunissen R.

Abstract
Due to changes in the society, couples in Western countries are increasingly delaying reproduction. This is accompanied by unhealthy lifestyles that may not only be detrimental to general health but also for reproductive capacity. It is well-known that maternal age has detrimental effects on fertility; the paternal influence on this outcome is largely unknown. This study aims to investigate associations between a paternal age below 60 years of age, lifestyles and sperm quality. In a periconceptional prospective cohort study we included two hundred twenty-seven men undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment. Age at sperm collection, lifestyles, cause of subfertility, ethnicity, sperm DNA fragmentation index (DFI), as marker of sperm DNA damage) and sperm parameters were determined. Linear regression analyses showed a positive association between a rising age from 26 to 59 years and DFI (P
PMID: 20467050 [PubMed - as supplied by publisher]

ANDROLOG SUMMARY: Risks to Offspring Associated with Advanced Paternal Age.

2010-05-15T08:13:00.000-07:00

J Androl. 2010 May 13. [Epub ahead of print]

ANDROLOG SUMMARY: Risks to Offspring Associated with Advanced Paternal Age.
Bhandari A, Sandlow J, Brannigan RE.

Abstract
The exact degree to which advanced paternal age imparts increased risk to offspring as a variety of disorders varies and is not entirely well defined. The following string of Androlog entries summarizes a discussion by several colleagues pondering how best to advise couples regarding the risks of advanced paternal age.

PMID: 20467047 [PubMed - as supplied by publisher]

Association of Paternal Age and Risk for Major Congenital Anomalies From the National Birth Defects Prevention Study, 1997 to 2004

2010-04-16T08:12:00.000-07:00

Titre du document / Document title
Association of Paternal Age and Risk for Major Congenital Anomalies From the National Birth Defects Prevention Study, 1997 to 2004
Auteur(s) / Author(s)
GREEN Ridgely Fisk ; DEVINE Owen ; CRIDER Krista S. ; OLNEY Richard S. ; ARCHER Natalie ; OLSHAN Andrew F. ; SHAPIRA Stuart K. ;
Résumé / Abstract
PURPOSE: The objective of this study was to examine the associations between paternal age and birth defects of unknown etiologies while carefully controlling for maternal age. METHODS: By using 1997 to 2004 data from the National Birth Defects Prevention Study, we fit logistic regression models with paternal and maternal age as continuous variables while adjusting for demographic and other factors. RESULTS: Elevated odds ratios (ORs) for each year increase in paternal age were found for cleft palate (OR. 1.02, 95% confidence interval [95% CI], 1.00-1.04), diaphragmatic hernia (OR, 1.04; 95% CI, 1.02- 1.06), right ventricular outflow tract obstruction (OR, 1.03; 95% CI, 1.01-1.04), and pulmonary valve stenosis (OR, 1.02, 95% CI, 1.01-1.04). At younger paternal ages, each year increase in paternal age correlated with increased odds of having offspring with encephalocele, cataract, esophageal atresia, anomalous pulmonary venous return, and coarctation of the aorta, but these increased odds were not observed at older paternal ages. The effect of paternal age was modified by maternal age for gastroschisis, omphalocele, spina bifida, all orofacial clefts, and septal heart defects. CONCLUSIONS: Our findings suggest that paternal age may be a risk factor for some multifactorial birth defects.
Revue / Journal Title
Annals of epidemiology ISSN 1047-2797 CODEN ANNPE3
Source / Source
2010, vol. 20, no3, pp. 241-249 [9 page(s) (article)]
Langue / Language
Anglais

Editeur / Publisher
Elsevier, New York, NY, ETATS-UNIS (1990) (Revue)

Mots-clés d'auteur / Author Keywords
Congenital Abnormalities ; Maternal Age ; Paternal Age ; Risk Factors ;
Localisation / Location
INIST-CNRS, Cote INIST : 22935, 35400018960899.0090

Nº notice refdoc (ud4) : 22441477

2010-04-03T16:42:00.001-07:00

and advanced paternal age at delivery (greater than 30 year-old).

2010-04-02T09:46:00.000-07:00

J Autism Dev Disord. 2010 Apr 1. [Epub ahead of print]

Prenatal and Perinatal Risk Factors for Autism in China.
Zhang X, Lv CC, Tian J, Miao RJ, Xi W, Hertz-Picciotto I, Qi L.

School of Public Health, Tianjin Medical University, Tianjin, 300070, China.

We conducted a case-control study using 190 Han children with and without autism to investigate prenatal and perinatal risk factors for autism in China. Cases were recruited through public special education schools and controls from regular public schools in the same region (Tianjin), with frequency matching on sex and birth year. Unadjusted analyses identified seven prenatal and seven perinatal risk factors significantly associated with autism. In the adjusted analysis, nine risk factors showed significant association with autism: maternal second-hand smoke exposure, maternal chronic or acute medical conditions unrelated to pregnancy, maternal unhappy emotional state, gestational complications, edema, abnormal gestational age (<35 or >42 weeks), nuchal cord, gravidity >1, and advanced paternal age at delivery (>30 year-old).

PMID: 20358271 [PubMed - as supplied by publisher]

Oh my goodness! Late paternal age starts at 30?

2010-03-30T17:22:00.000-07:00

Speaking of Biological Clocks
Women aren’t the only ones who should pay attention to their biological clocks…

While men can still have kids at 50, it turns out there are increased health and psychological risks to the child:

Is Your Sperm Too Old?

Are you still bearing healthy fruit? Turns out that it’s not just women who have a biological clock—your sperm may be going to seed a lot faster than you think.

By Kevin Conley,
Photographs by Christian Weber

While you’ve never been against the idea of a serious relationship, you are in no particular rush to become a schlub. The attendant trappings of new fatherhood—the preschool viewings, the sleepless nights, the humiliation of carrying a diaper bag—aren’t exactly calling out to you the way, say, another night slinging Pisco sours would. The ever-intensifying din of the proverbial biological clock? That’s for the opposite sex to worry about—you know, like periods, frizz, and whether Mr. Big will dump Carrie in the Sex and the City sequel. As far as you know, your little swim team of DNA carriers will be competing at Olympic level into Letterman age. So what’s the rush?

“I always thought my biological clock was the 36 hours I had left after I took my Cialis pill,” says Zack, a 30-year-old producer in Los Angeles. “That’s the only clock I’ve ever felt ticking.” Turns out, Zack might want to consider the unsung glories of fatherhood.

According to a study released last March in the Public Library of Science Medicine, children born to fathers who were 20 scored an average of 2 points higher on an IQ test than children born to 50-year-old fathers. And that’s not all. Recent studies from Israel, California, and Sweden have connected “late paternal age” with any number of serious medical conditions: The longer you wait, the more likely it is that your kid will be affected by schizophrenia, dwarfism, bipolar disorder, autism, Marfan syndrome, certain childhood cancers, or even, later in life, Alzheimer’s. In some cases, the risk factors skyrocket. A 2005 study conducted by the University of California, Los Angeles, found a fourfold rise in Down syndrome among babies born to men 50 and older. Worse still, those risk factors aren’t limited to your tweed-sporting years: Statistically, “late paternal age” starts at 30, as in Zack’s age. A 2006 study conducted by Mount Sinai School of Medicine found that fathers in their thirties have children with about 1.5 times the risk of developing autism compared with fathers in their teens and twenties. That factor jumps to five times for dads in their forties. The cherry on the cake? The American Society for Reproductive Medicine recommends that sperm banks do not accept specimens from men over 40.

“The biological clock for men and women is really the same,” says Dr. Dolores Malaspina of Bellevue Hospital Center in New York City and New York University, who conducted one of the first studies. “It’s just that men can keep having babies.”

The biology behind this isn’t hard to grasp: Starting in puberty, spermatogonia, the master copies for sperm production, replicate themselves every couple of weeks. After 300 to 500 copies—somewhere in your thirties—a meaningful number of small copy errors, or point mutations, start to emerge, which accumulate over time.

Yet, despite the alarming new science, most men greet parenthood with a sense of urgency that’s more in line with Zack’s than Angelina Jolie’s. The reason is simple: While women are inculcated with the risks of late-age motherhood in sixth-grade sex ed, men remain blissfully ignorant. Since the recent studies have been published, the bad news still doesn’t seem to be making it to the doctor’s office. Scott, a 32-year-old schoolteacher from Babylon, New York, decided to start a family when he was Zack’s age, strictly because he wanted to raise his child while he was young. “For me the doctors were like, ‘Hey, this is going to be good. You’re still active,’” Scott says. “Nobody ever told me about the medical risks of being an older dad.”

That’s because men don’t usually get this news flash until they’re looking through a microscope at a batch of fugly sperm with no sense of direction. Swain, a 37-year-old IT professional in Dallas, wishes he had heard sooner. “Who cares if the baby is born with six fingers we can’t get that far,” he says. “I’d be thrilled to have that problem.” His wife is four years younger than he is, and they decided to wait. “What I did was let her clock be the one in control,” Swain says. “I would have been happy having kids five, six years ago, but she just wasn’t ready. The female clock seems to dominate the conversation.”

But don’t expect sweeping social change anytime soon. “Tell a man he’s got a chance of having kids with genetic abnormalities, and it’s like he’s going through the stages of the acceptance of death,” says Dr. Harry Fisch, a professor of urology and the author of The Male Biological Clock. “They’ll say, ‘I’m losing my manliness, my sexual ability.’ To them it all comes under the same umbrella.”

The good news is that no one, not even Malaspina, is suggesting that older men eschew the joys of fatherhood. But if you’re a younger guy who hasn’t thought twice about postponing it, be forewarned: The female of the species is about to get her just rewards. That bell tolling? It’s for you.

______________________________________________________________

Oh my goodness! Late paternal age starts at 30? I think most men don’t even consider babies until then..

The pathophysiology of neurofibromatosis: IX. Paternal age as a factor in the origin of new mutations

2010-03-29T13:49:00.000-07:00

American Journal of Medical Genetics
Volume 18 Issue 1, Pages 169 - 176
Published Online: 3 Jun 2005

Copyright © 2004 Wiley-Liss, Inc., A Wiley Company

The pathophysiology of neurofibromatosis: IX. Paternal age as a factor in the origin of new mutations
Dr. Vincent M. Riccardi *, Christopher E. Dobson II, Ranajit Chakraborty, Catherine Bontke, John M. Opitz
Neurofibromatosis Program, Baylor College of Medicine, and the Center for Demographic and Population Genetics, Graduate School of Biomedical Sciences, University of Texas Health Science Center, Houston, Texas

*Correspondence to Vincent M. Riccardi, NF Program, Baylor College of Medicine, Texas Medical Center, Houston, TX 77030

Keywords
von Recklinghausen disease • neurofibromatosis • mutation • paternal age • maternal age

Abstract
Von Recklinghausen neurofibromatosis is characterized by a relatively large proportion of apparently nonfamilial cases, presumed spontaneous mutations. This paper analyzes the distribution of paternal and maternal ages for 187 patients with von Recklinghausen disease representing the first definite case in their respective families. Mean paternal age was 32.8 years and mean maternal age was 27.4 years, both being significantly greater than for control populations (P equal to or less than.001). The advanced paternal age was not accounted for by the increase in maternal age. The methodology of controlling the general population paternal ages for each patient's birth year is described.

--------------------------------------------------------------------------------
Received: 17 September 1983; Revised: 21 November 1983

Digital Object Identifier (DOI)

10.1002/ajmg.1320180121 About DOI

Parental Age and Risk of Schizophrenia

2010-03-22T07:06:00.000-07:00

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Vol. 60 No. 7, July 2003 Archives
• Parental Age and Risk of Schizophrenia
A Case-control Study

Majella Byrne, MSc, PhD; Esben Agerbo, MSc; Henrik Ewald, MD, DMSc; William W. Eaton, PhD; Preben Bo Mortensen, MD, DMSc

Arch Gen Psychiatry. 2003;60:673-678.

ABSTRACT

Background Advanced paternal age has been suggested as a possible risk factor for schizophrenia. It is not known whether this is explained by known risk factors for schizophrenia, including sibship characteristics, death of a parent before first hospital admission, season and place of birth, and family history of psychiatric illness, or by socioeconomic factors. We investigated the risk of schizophrenia associated with parental age, adjusting for known risk factors for schizophrenia, including family psychiatric history, and controlling for socioeconomic and demographic factors.

Methods We performed a national population, nested, case-control study based on Danish longitudinal register data. The sample included 7704 patients with an ICD-8 or ICD-10 diagnosis of schizophrenia admitted to a psychiatric facility between 1981 and 1998 in Denmark, and 192 590 individually time-, age-, and sex-matched population controls, their parents, and siblings. The risk of schizophrenia associated with increasing parental age was investigated using conditional logistic regression and controlling for family socioeconomic and demographic factors and family psychiatric history.

Results Advanced paternal and maternal age was associated with increased risk of schizophrenia in univariate analyses. Controlling for socioeconomic factors and family psychiatric history, increased risk of schizophrenia was identified in those with a paternal age of 50 years or older. Sex-specific analyses revealed that the risk of schizophrenia was increased for males with fathers 55 years or older (incidence rate ratio [IRR], 2.10; 95% confidence interval [CI], 1.35-3.28); for females, the risk associated with paternal age was substantial for fathers aged 50 to 54 years (IRR, 2.22; 95% CI, 1.44-3.44) and 55 years or older (IRR, 3.53; 95% CI, 1.82-6.83).

Conclusion Increased risk of schizophrenia was associated with advanced paternal age, particularly in females, lending support to the theory that de novo mutations, possibly X-linked, associated with increased parental age might be responsible for some cases of schizophrenia.

INTRODUCTION
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• Introduction
• Methods
• Results
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ADVANCED PARENTAL age has been suggested to be a risk factor for schizophrenia in some studies. Both advanced maternal1-4 and paternal age2-8 have been reported to be associated with increased schizophrenia risk; however, most of the effect of maternal age has been accounted for by controlling for paternal age. Recently, Malaspina et al8 suggested that de novo spermatogonia mutations that accompany advancing paternal age might be responsible for this association. The authors suggested that as many as two thirds of the cases with fathers older than 50 years could be attributable to paternal age, and the relative risk for schizophrenia increased monotonically with increasing age. For a variety of monogenic diseases, many cases are attributable to de novo mutations associated with advanced paternal age,9-10 but there may also be increased risk for offspring of young fathers.11 The mutation rate of the male germline has recently been estimated to be approximately twice that of the female germline,12 although previous studies13 have suggested it to be 5-fold higher, and it is known to be higher at specific disease loci. De novo mutations might help to account for the persistence of schizophrenia in the population despite reduced fecundity levels in persons with this disorder.14

The aim of our study was 2-fold. First, we wanted to conduct an independent replication of the results of Malaspina and colleagues8 in a national register-based sample. Second, we wanted to investigate whether the association between parental age and risk of schizophrenia could be explained by any of the identified risk factors for schizophrenia, including family psychiatric history,15-16 sibship characteristics,17 death of a parent before admission,5, 18 season of birth,14, 19-20 and place of birth,16, 21 while assessing the possible confounding or modifying effect of socioeconomic factors (parental wealth, education, and marital status).

METHODS
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• Introduction
• Methods
• Results
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The data were based on Danish longitudinal registers that were merged using a unique personal identification number known as the CPR (central person registration) number, which is used across all registration systems in Denmark. All live-born children and new residents in Denmark are assigned a unique personal identification number, and information is kept under this number in all national registers, thus ensuring accurate linkage of information between registers without the necessity to reveal a person's identity. The CPR registry was instigated in 1968.22 Parents' date of birth was identified through the CPR register.

The Danish Psychiatric Central Register has monitored all psychiatric inpatient facilities in Denmark since 1969.23 There are no private psychiatric facilities in Denmark, and all treatment is free of charge. All diagnoses were according to International Classification of Diseases, 8th Revision (ICD-8)24 until December 31, 1993, and according to International Classification of Diseases, 10th Revision (ICD-10)25 beginning January 1, 1994. Parental and sibling psychiatric information relates to the status just before the date of first contact of the case. In this manner, only family members who are affected before this date contribute information to the calculation of the risk associated with family history.

The socioeconomic data were obtained from the Integrated Database for Longitudinal Labour Market Research, which includes linked information on employees and establishments26 and for which there is continuous annual information available from 1980 to 1998. The register covers the total population and includes detailed socioeconomic information. We obtained information on parental education, wealth status, and marital status. We also obtained information on number of siblings as a proxy for family size. For our purposes, a random 5% of this register in addition to the patients and their families was used as the sample base from which the controls and their families were extracted.

STUDY DESIGN

A time-matched, nested, case-control design27 was used to select the control sample. For each case, 25 controls were randomly selected from a subsample of all available controls fulfilling the matching criteria: born in the same calendar year, same age in days, same sex, no admissions to a psychiatric facility in Denmark, and alive on the date that the case was first admitted.

STUDY POPULATION

The study sample was composed of all persons older than 15 years admitted to a Danish psychiatric facility for the first time between 1981 and 1998 with a diagnosis of schizophrenia and known maternal identity. A total of 7704 persons with schizophrenia were identified, 92% had links to a father (that is, paternity was not known or declared in 8%), and 66% were male. The control sample consisted of 192 590 individuals, representing 25 controls per case. Of the controls, 96% had links to a father.

PARENTAL AGE

We defined parental age in a similar manner to Malaspina et al.8 Paternal age was categorized into the following age groups: younger than 20 years, 20 through 24 years, 25 through 29 years, 30 through 34 years, 35 through 39 years, 40 through 44 years, 45 through 49 years, and 50 years or older. Maternal age was defined as younger than 20 years, 20 through 24 years, 25 through 29 years, 30 through 34 years, 35 through 39 years, and 40 years or older. Because we had a substantial number of patients and controls, we were in a position to investigate the effect of paternal and maternal age on the risk for schizophrenia in greater detail than Malaspina et al.8 We extended the age categories to 50 through 54 years and 55 years or older for paternal age and 40 through 45 years and 45 years or older for maternal age.

FAMILY PSYCHIATRIC HISTORY

It was possible to obtain information relating to family history of psychiatric contact for mothers, fathers, and siblings by linking with the Danish Psychiatric Central Register. In line with previous studies using similar data,15-16 history of psychiatric disorders in family members was defined in a hierarchical manner as follows: (1) schizophrenia, schizo-affective disorder, and schizophrenia-like psychosis (ICD-8 codes: 295, 295.7, 297, 298.39, 301.83; ICD-10 codes: F20, F25, F21-F24, F28, F29); (2) bipolar illness and other affective illness (ICD-8 codes: 296.1, 296.3, 296, 300.4; ICD-10 codes: F30, F31, F34.0, F32-F39) and no history of disorders in category 1; and (3) other psychiatric disorder (any other diagnosis) but no history of disorders in either category 1 or 2. In addition, and not included in the hierarchy, we assessed the risk associated with a history of substance abuse disorders (ICD-8 codes: 303, 304; ICD-10 codes: F10.2, F11.2, F12.2, F13.2, F14.2, F15.2, F16.2, F17.2, F18.2, F19.2) and a history of suicide for mother, father, and siblings.

SOCIOECONOMIC AND DEMOGRAPHIC VARIABLES AND SEASON OF BIRTH

Socioeconomic and demographic variables included information about parental education level (organized according to 4 categories: basic/primary education, high school education and vocational training, university level education, and no available information) and information on parental wealth (organized into quartiles based on the distribution of these variables in the 5% sample of the Integrated Database for Longitudinal Labour Market Research). Other variables included were parental marital status, defined as single or married (including cohabiting); death of a parent or sibling before first hospital admission (not due to suicide); reference to father at birth; number of siblings (0, 1, 2, or 3 or more); and place of birth (defined as the capital [Copenhagen], capital suburbs, provincial city [population >100 000], provincial town [population <100 000], rural area, and birth outside Denmark, according to Pedersen and Mortensen16). All variables were treated categorically and entered into the analysis as covariates.

We modeled month of birth as 11 dummy variables, with June as the reference category. The interaction between parental age and season of birth was modeled.

STATISTICAL ANALYSIS

The data were analyzed in a conditional logistic regression model using the PhReg procedure of SAS statistical software version 8.1 (SAS Institute Inc, Cary, NC),28 and asymptotic 95% confidence intervals (CIs) were calculated. Variables were assessed the last full year before the first admission ever to a psychiatric hospital irrespective of whether schizophrenia was diagnosed at first admission or later. The method of sampling controls, that is, risk set sampling, means that the odds ratio estimate in the analyses can be interpreted as an incidence rate ratio (IRR) between exposed and unexposed categories.29 Sex interactions were modeled for each category of paternal and maternal age. We conducted analyses separately for males and females as a result of significant sex interactions with parental age.

RESULTS
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• Introduction
• Methods
• Results
• Comment
• Author information
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PARENTAL AGE

In Table 1, the number and percentage of cases and controls in each category of parental age are presented, along with the mean age at onset of cases in each category and the sex distribution. We conducted a series of models of increasing complexity, the results of which are described in Table 2. In Table 2, the age categories according to Malaspina et al8 are presented along with the extended age categories.

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Table 1. Mean Age at Onset and Sex Distribution for Each Category of Parental Age

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Table 2. Incidence Rate Ratios (IRRs) for Schizophrenia Associated With Parental Age

For all analyses, the reference group was parental age of 20 through 24 years. In Table 2, the IRRs for the unadjusted models are presented, where paternal (model 1a) and maternal (model 1b) age groups were modeled in separate univariate models (all models, including paternal age, controlled for whether there was a reference to a father). A significantly increased risk of schizophrenia was associated with paternal age younger than 20 years and with all age groups 40 years or older (model 1a). A significantly increased risk was associated with maternal age younger than 20 years and with all age groups 30 years or older (model 1b). Paternal age and maternal age were then entered into the same model (model 2) to adjust the IRRs for the effects of age of the other parent. Once paternal age was controlled for in the model, there seemed to be no significant overall association between maternal age and risk of schizophrenia. A significant association remained for the paternal age groups of 40 through 44 years and 50 years or older. The next step was to introduce the psychiatric history of both parents into the model to control for the effect of psychiatric history on the association between parental age and risk of schizophrenia (model 3). For paternal age a significant association remained for the age groups of 40 through 44 years and 50 years or older. We found a weak but significant association between the maternal age group of 30 through 34 years and risk of schizophrenia and a significant association for the maternal age group of 40 years or older. In the next model (model 4), we included the socioeconomic and demographic factors that might independently account for the relationship between parental age and risk of schizophrenia, including parental education, wealth, marital status, history of death before the case was first admitted, place of birth of cases and controls, family size, and, in addition to family psychiatric history, history of suicide and substance abuse in a parent or sibling and reference to father. These data were forced into the model regardless of significance of the estimates. Controlling for this range of factors (possible confounders), there remained a significantly increased risk in those with a paternal age of 50 years or older. We reanalyzed the data to include only those cases (n = 5413) and controls (n = 118 930) without a family history of schizophrenia or other psychiatric admissions, and these are presented in Table 2 (model 5). The results are similar to those of model 4.

When the risks were estimated in the extended parental age groups (paternal age, 50-54 years and 55 years; maternal age, 40-44 years and 45 years), the increased risk was most marked in the oldest paternal age group. The increased risk of schizophrenia associated with paternal age of 55 years or older remained significant after adjustment for the range of familial socioeconomic variables (model 4), although the association for the paternal age category of 50 through 54 years remained relatively unchanged in magnitude. The different models uniformly suggested a thresholdlike effect for the oldest category of fathers rather than a monotonic association as suggested by Malaspina et al,8 and this finding was not modified by any of the other factors included in our study. In fact, it can be seen in Table 2 that the estimates changed little between models. The estimated IRR for any age category within a model was contained within the 95% CIs of the respective estimate from the other models.

EFFECT OF SEX AND AGE AT FIRST ADMISSION

We investigated the interactions between parental age in each category and sex of the patients and between parental age and age at first admission of the patients. We also included a 3-way interaction composed of age group of parent, sex, and age at first admission. Age at first admission was entered into the analysis as a mean-centered variable (the difference between age at first admission and mean age at first admission).15 We did not find any interactions between age at first admission and parental age in this sample. Significant sex interactions were observed for the paternal age groups of 35 through 39 years and 50 years or older, the extended age group of 50 through 54 years, and the maternal age group of 45 years or older. Analyses were conducted separately for males and females and the results are displayed in Table 3. The risk of schizophrenia was significantly increased in the 35- through 39-year age group of paternal age for females only. However, this effect was no longer significant once age of the other parent was controlled for (model 2; the models displayed in Table 3 are named to coincide with those in Table 2; for consistency, model 3 is not presented on this table). The risk associated with paternal age of 50 years or older was significantly increased for females in models 2 and 4. In the paternal age group of 50 through 54 years, the significant effect of paternal age on increased schizophrenia risk was present exclusively for females. The risk was higher for females in the paternal age group of 55 years or older than for males (model 4: IRR, 3.53; 95% CI, 1.82-6.83; vs IRR, 2.10; 95% CI, 1.35-3.28); however, the interaction was not significant. In terms of maternal age, there was a significant increase in the risk for males with mothers 45 years or older but not for females in all models. The estimates associated with the extended maternal age group (age, 45 years) were based on only a few cases (n = 3 females; n = 20 males).

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Table 3. Sex-Specific Estimates of the Incidence Rate Ratios (IRRs) for Schizophrenia by Parental Age

There was no significant increase in the risk of schizophrenia for any month of birth. We did not find any significant interaction between month of birth and parental age.

COMMENT
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• Introduction
• Methods
• Results
• Comment
• Author information
• References

In this national, population-based, epidemiologic sample, controlling for a range of familial socioeconomic and psychiatric factors, advanced paternal age (50 years) was associated with an increased risk of schizophrenia. In addition, we identified a sex effect, in which the increased risk associated with advanced paternal age was particularly prominent for females. A particular strength of our study was the ability to control for the presence of psychiatric disorders in the parents and siblings and for possible confounding due to family socioeconomic factors, family size, and whether a parent had died before the first hospital admission. The data are register based and so are bound by the same limitations of all register-based research, including the fact that the cases represent treated incidence cases.

In our analyses, unlike that of Malaspina et al,8 in which the authors found a monotonic relationship between paternal age and risk of schizophrenia, the increased risk was confined to the older (50 years) paternal ages in our final model (model 4). However, in our study, we were in a position to control for factors that Malaspina et al8 could not control for, namely, parental psychiatric history and information relating to the death of the parents before admission. We identified a U-shaped distribution in the risk for schizophrenia associated with parental age in the initial models; however, after controlling for family psychiatric history and social factors, this U shape was no longer visible for paternal age, and only a weak and nonsignificant effect remained for maternal age. Furthermore, the present study did not find an increased risk in the relatively younger groups of parents. It is possible that environmental and genetic risk factors differ between the Danish population investigated by us and the Israeli population.8 A simple explanation might include the relatively higher ambient temperatures in Israel, since heat exposure may increase the exposure of spermatozoa to mutagenic metabolites,30 leading to more and earlier mutations among Israeli fathers and a paternal effect in younger age groups as well.

A variety of possible explanations for the association between risk of schizophrenia and paternal age have been discussed, including an increase in the rate of de novo genetic mutations in older fathers, attributes of the parents that lead to marriage at an older age than normal that are related to schizophrenia in the offspring,5 and the adverse psychological consequences of losing a parent by death because of the parents' increased age.5

We examined the risk of schizophrenia associated with the death of a parent other than by suicide; however, no increase in risk was identified in the final model. This suggests that the psychological distress caused by the death of an aging parent does not account for the relationship between risk of schizophrenia and advanced paternal age. Although we could not control for birth order in this sample, we controlled for sibship size. In a previous study, sibship size but not birth order was associated with increased risk of schizophrenia.17 We found an independent, small but significant increase in the risk of schizophrenia among those from families with 3 or more siblings compared with being an only child (IRR, 1.15; 95% CI, 1.05-1.26), controlling for family history of psychiatric diagnoses in parents and siblings and socioeconomic factors. This finding suggests that the advanced paternal age effect is independent of factors operating in larger families, such as environmental exposure, perhaps to common infections in childhood, that may increase the risk of schizophrenia.17

We found a sex difference insofar as there was a significant increase in the risk of schizophrenia in females with older fathers in all age groups 50 years or older (50 years, 50-54 years, 55 years) compared with males, for whom the increased risk was confined to the 55-year-or-older age group. Males had an increased risk associated with older mothers (45 years); however, the estimates were based on a small sample size. The de novo mutations that occur with advancing age in parents not only might be point mutations but also could involve trinucleotide repeated expansions, imprinting, or small structural chromosomal rearrangements.13 The data from the present study suggest that the parental effect is particularly related to paternal age in female cases. Therefore, a gene on the X chromosome might be involved, because these are always passed from fathers to daughters. It is well-known that the X chromosome contains a relatively high number of genes expressed in the central nervous system and that the gene for many diseases with cognitive impairment are located on the X chromosomes. Furthermore, a few linkage studies have suggested possible risk loci for schizophrenia on the X chromosome.31 However, the increased mutation rate in males can occur on 2 autosomes in each chromosome pair but only on 1 X chromosome, at least outside the pseudoautosomal region. Imprinted autosomal genes may also explain that an increased risk depends on the sex of the parent.

In our sample, the effect was not restricted to those with a family history of psychiatric illness. When we reanalyzed the data, including only those cases (n = 5413) and controls (n = 118 930) without a family history of schizophrenia or any other psychiatric disorder, the results were similar (Table 2, model 5), indicating that the effect of parental age is not restricted to those with or without a family history of schizophrenia or other psychiatric disorders in this sample and suggesting that family history of psychiatric disorders does not explain the association.

Our findings support the theory that de novo mutations might occur in the offspring of older parents, particularly fathers, leading to an increased risk of schizophrenia and that this might help explain the fact that schizophrenia persists in the population despite reduced fertility levels.14 However, this effect seems to be restricted to fathers older than 50 years. The findings of interactions between sex and age of parent of origin lead to speculation about involvement of de novo genetic mutations occurring on the X chromosome in the etiology of schizophrenia, particularly in the female offspring of older fathers. However, males with older fathers (55 years) also had an increased risk. Focusing efforts on a specific chromosome may facilitate the final identification of risk genes possibly involved in the parental age effect. Such a risk gene might either be a gene of importance for brain development and function or might predispose to de novo mutations in such genes by causing decreased DNA repair and/or increased environmental susceptibility.

AUTHOR INFORMATION
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• Results
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Corresponding author and reprints: Majella Byrne, MSc, PhD, National Centre for Register-based Research, Aarhus University, Taasingegade 1, Aarhus 8000 C, Denmark (e-mail: mb@ncrr.dk).

Submitted for publication May 7, 2002; final revision received December 20, 2002; accepted January 14, 2003.

This study was funded by the Stanley Medical Research Institute and by grant MH53188 from the National Institutes of Mental Health, Bethesda, Md. The National Centre for Register-based Research is supported by the Danish National Research Foundation, Copenhagen, Denmark.

From the National Centre for Register-based Research, Aarhus University, Aarhus, Denmark (Drs Byrne and Mortensen and Mr Agerbo); Institute for Basic Psychiatric Research, Psychiatric Hospital, Aarhus, Risskov, Denmark (Dr Ewald); and Department of Mental Hygiene, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, Md (Dr Eaton).

REFERENCES
Jump to Section
• Top
• Introduction
• Methods
• Results
• Comment
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AN OVERVIEW ON PROGERIA: A RARE DISEASE OF CHILD- Older fathers

2010-03-01T12:47:00.000-08:00

AN OVERVIEW ON PROGERIA: A RARE DISEASE OF CHILD

Kamal Singh Rathore, Sunita P., Khushboo Sharma, R.K.Nema

Â

Progeria is a rare disease, fatal genetic condition that produces rapid aging, beginning in childhood also known as “HutchinsonâGilford progeria syndrome” or “HGPS” and “HutchinsonâGilford syndrome” wherein symptoms resembling aspects of aging are manifested at an early age. Progeria was first described in an academic journal by Dr. Jonathan Hutchinson in 1886, and Dr. Hastings Gilford in 1897 – both in England.

Â Its name is derived from the Greek and means “prematurely old.” Approximately 1 in 4000000 people are diagnosed with this condition. Those born with progeria typically live about 13-20 years, It is a genetic condition that occurs as a new mutation and is not usually inherited, although there is a uniquely inheritable form. This is in contrast to another rare but similar premature aging syndrome, dyskeratosis congenita (DKC), which is inheritable and will often be expressed multiple times in a family line.

Although they are born looking healthy, children with Progeria begin to display many characteristics of accelerated aging at around 18-24 months of age. Progeria signs include growth failure, loss of body fat and hair, aged-looking skin, stiffness of joints, hip dislocation, generalized atherosclerosis, cardiovascular (heart) disease and stroke. The children have a remarkably similar appearance, despite differing ethnic background. Children with Progeria die of atherosclerosis (heart disease) at an average age of thirteen years (with a range of about 8 – 21 years). According to Hayley’s Page “At present there are 53 known cases of Progeria around the world and only 2 in the UK”. There is a reported incidence of Progeria of approximately 1 in every 4 to 8 million newborns. Both boys and girls run an equal risk of having Progeria.

Symptoms

Progeria is a progressive genetic disorder that causes children to age rapidly, beginning in their first two years of life. The condition is rare; since 1886, only about 130 cases of progeria have been documented in the scientific literature. Usually within the first year of life, growth of a child with progeria slows markedly so that height and weight fall below average for his or her age, and weight falls low for height. Motor development and mental development remain normal.

Signs and symptoms of this progressive disorder include:

Limited growth or Growth failure during the first year of life Narrow, shrunken or wrinkled face failure to thrive Baldness (alopecia) Insulin-resistant diabetes (diabetes that does not respond readily to insulin injections) Skin changes similar to that seen in scleroderma (the connective tissue becomes tough and hardened) Loss of eyebrows and eyelashes a distinctive appearance (small face and jaw, pinched nose) Short stature and small, fragile bodies, like those of elderly people Large head for size of face (macrocephaly) Open soft spot (fontanelle) Small jaw (micrognathia) Dry, scaly, thin skin Limited range of motion Teeth – delayed or absent formation Later, the condition causes wrinkled skin, atherosclerosis, and cardiovascular problems. Slowed growth, with below-average height and weight A narrowed face and beaked nose, which makes the child look old Head too large for face Prominent scalp veins Prominent eyes Small lower jaw (micrognathia) High-pitched voice Delayed and abnormal tooth formation Loss of body fat and muscle Stiff joints Hip dislocation

Causes

Progeria usually occurs without cause – it is not seen in siblings of affected children. In extremely rare cases more than one child in the same family may have the condition.

Â It is only very rarely seen in more than one child in a family. Progeria is a childhood disorder caused by a point mutation in position 1824 of the LMNA gene (Lamin A), replacing cytosine with thymine, creating an unusable form of the protein Lamin A. Lamin A is part of the building blocks of the nuclear envelope. 90% of children with progeria have a mutation on the gene that encodes the protein lamin A. a protein that holds the nucleus of the cell together. It is believed that the defective Lamin A protein makes the nucleus unstable. This instability seems to lead to the process of premature aging among Progeria patients.

Diagnosis

Diagnosis is suspected according to signs and symptoms, such as skin changes, abnormal growth, and loss of hair. It can be confirmed through a genetic test. The health care professional will possibly suspect Progeria if the signs and symptoms are there – aging skin, loss of hair, stiffness of joints, etc. This can then be confirmed through a genetic test. The Progeria Research Foundation has created a Diagnostic Testing Program.

No diagnostic test confirms progeria. Doctors typically make a diagnosis based on signs and symptoms, such as failure to grow and hair loss, which typically aren’t fully evident until your child is nearly 2. However, with the discovery of the genetic mutation that causes progeria, it’s possible to use genetic testing for LMNA mutations at the first suspicion of progeria. The sooner you know your child has progeria, the sooner your doctor can recommend treatments that may help ease the signs and symptoms of the disorder.

A blood test may reveal that your child has a low level of high-density lipoprotein (HDL) cholesterol, the so-called good cholesterol that helps keep arteries open. This laboratory finding isn’t diagnostic by itself, but may lend support to a diagnosis of progeria.

Â Treatment

No treatments have been proven effective.

Most treatment focuses on reducing complications (such as cardiovascular disease) with heart bypass surgery or low-dose aspirin. A daily dose may help prevent heart attacks and stroke. Growth hormone treatment has been attempted. Drugs known as farnesyltransferase inhibitors (FTIs), which were developed for treating cancer, have shown promise in laboratory studies in correcting the cell defects that cause progeria. FTIs are currently being studied in human clinical trials for treatment of progeria. it has been proposed, but their use has been mostly limited to animal models. A Phase II clinical trial using the FTI Lonafarnib began in May 2007. Physical and occupational therapy. These may help with joint stiffness and hip problems, and may allow your child to remain active. High-calorie dietary supplements. Including extra calories in your child’s daily diet may help prevent weight loss and ensure adequate nutrition. Feeding tube. Infants who feed poorly may benefit from a feeding tube and a syringe. You can use the syringe to push pumped breast milk or formula through the tube to make it easier for your child to feed. Extraction of primary teeth. Your child’s permanent teeth may start coming in before his or her baby teeth fall out. Extraction may help prevent problems associated with the delayed loss of baby teeth, including overcrowding and developing a second row of teeth when permanent teeth come in.

Prognosis

There is no known cure. Few people with progeria exceed 13 years of age. At least 90% of patients die from complications of atherosclerosis, such as heart attack or stroke.

Mental development is not affected. The development of symptoms is comparable to aging at a rate six to eight times faster than normal, although certain age-related conditions do not occur. Specifically, patients show no neurodegeneration or cancer predisposition. They do not develop physically mediated “wear and tear” conditions commonly associated with aging, like cataracts (caused by UV exposure) and osteoarthritis (caused by mechanical wear).

Epidemiology

Classical Hutchinson-Gilford Progeria Syndrome is almost never passed on from parent to child. It is usually caused by a new (sporadic) mutation during the early division of the cells in the child. It is usually genetically dominant; therefore, parents who are healthy will normally not pass it on to their children. Affected children rarely live long enough to have children themselves.

Research indicates that a chemical (hyaluronic acid) may be found in greatly elevated levels in the urine of Hutchinson-Gilford Progeria Syndrome patients. The same abnormality has been found in Werner Syndrome, which is sometimes called ‘progeria of the adult’.

Lamin A

Nuclear lamin A is a protein scaffold on the inner edge of the nucleus that helps organize nuclear processes such as RNA and DNA synthesis.

Prelamin A contains a CAAX box at the C-terminus of the protein (where C is a cysteine and A is any aliphatic amino acids). This ensures that the cysteine is farnesylated and allows prelamin A to bind membranes, specifically the nuclear membrane. After prelamin A has been localized to the cell nuclear membrane, the C-terminal amino acids, including the farnesylated cysteine, are cleaved off by a specific protease. The resulting protein is now lamin A, is no longer membrane-bound, and carries out functions inside the nucleus.

In 2003, NHGRI researchers, together with colleagues at the Progeria Research Foundation, the New York State Institute for Basic Research in Developmental Disabilities, and the University of Michigan, discovered that Hutchinson-Gilford progeria is caused by a tiny, point mutation in a single gene, known as lamin A (LMNA). Parents and siblings of children with progeria are virtually never affected by the disease. In accordance with this clinical observation, the genetic mutation appears in nearly all instances to occur in the sperm prior to conception. It is remarkable that nearly all cases are found to arise from the substitution of just one base pair among the approximately 25,000 DNA base pairs that make up the LMNA gene. The LMNA gene codes for two proteins, lamin A and lamin C, that are known to play a key role in stabilizing the inner membrane of the cell’s nucleus. In laboratory tests involving cells taken from progeria patients, researchers have found that the mutation responsible for Hutchinson-Gilford progeria causes the LMNA gene to produce an abnormal form of the lamin A protein. That abnormal protein appears to destabilize the cell’s nuclear membrane in a way that may be particularly harmful to tissues routinely subjected to intense physical force, such as the cardiovascular and musculoskeletal systems. Interestingly, different mutations in the same LMNA gene have been shown to be responsible for at least a half-dozen other genetic disorders, including two rare forms of muscular dystrophy. In addition to its implications for diagnosis and possible treatment of progeria, the discovery of the underlying genetics of this model of premature aging may help to shed new light on humans’ normal aging process.

Possible Complications

Heart attack (myocardial infarction)

Stroke

How we can help children with Progeria?

Make a financial contribution. Donations are needed to continue the vital work. No donation is too little or too big â every penny counts in our fight for a cure! Donate your time. Volunteers are also important to Â success. Hold a special event like a bake sale or letter writing campaign; translate documents for the families; help with a mailing â weâll find something for you to do that fits your schedule, location and talents! Donate in-kind services or items. Do you own a printing or office supply business? Do you have a background in non-profit development? These are just some of the many types of talents and connections. The more tasks we can get accomplished on a pro bono basis, the more we can spend on research! Spread the word and tap into your connections. Do you know anyone who can do any of the above.

Care, Coping and support

Learning your child has progeria can be emotionally devastating. Suddenly you know that your child is facing numerous, difficult challenges and a shortened life span. For you and your family, coping with the disorder involves a major commitment of physical, emotional and financial effort. In dealing with a disorder such as progeria, support groups can be a valuable part of a wider network of social support that includes health care professionals, family and friends. In a support group, you’ll be with people who are facing challenges similar to the one that you are. Talking to group members can help you cope with your own feelings about your child’s condition. If a group isn’t for you, talking to a therapist or clergy member may be beneficial. Ask your doctor about self-help groups or therapists in your community. Your local health department, public library, telephone book and the Internet also may be good sources for finding a support group in your area.

Helping the child to cope

If your child has progeria, he or she is also likely to experience fear and grief as awareness grows that progeria shortens life span. Your child eventually will need your help coping with the concept of death, and may have a number of difficult but important questions about God and religion. Your child also may ask questions about what will happen in your family after he or she dies. It’s critical that you are able to talk openly and honestly with your child, and offer reassurance that’s compatible with your belief system. Ask your doctor, therapist or clergy member to help you prepare for such conversations with your child. Friends who you meet through support groups also may be able to offer valuable guidance.

Conclusion and General Discussion

Progeria, or Hutchinson-Gilford progeria syndrome, is a rare, fatal, genetic condition of childhood with striking features resembling premature aging. Children with progeria usually have a normal appearance in early infancy. At approximately nine to 24 months of age, affected children begin to experience profound growth delays, resulting in short stature and low weight. They also develop a distinctive facial appearance characterized by a disproportionately small face in comparison to the head; an underdeveloped jaw (micrognathia); malformation and crowding of the teeth; abnormally prominent eyes; a small, nose; prominent eyes and a subtle blueness around the mouth. In addition, by the second year of life, the scalp hair, eyebrows, and eyelashes are lost (alopecia), and the scalp hair may be replaced by small, downy, white or blond hairs. Additional characteristic features include generalized atherosclerosis, cardiovascular disease and stroke, hip dislocations, unusually prominent veins of the scalp, loss of the layer of fat beneath the skin (subcutaneous adipose tissue), defects of the nails, joint stiffness, skeletal defects, and/or other abnormalities. According to reports in the medical literature, individuals with Hutchinson-Gilford progeria syndrome develop premature, widespread thickening and loss of elasticity of artery walls (arteriosclerosis), which result in life-threatening complications during childhood, adolescence, or early adulthood. Children with progeria die of heart disease (atherosclerosis) at an average age of 13 years, with a range of about eight to 21 years.

Progeria is caused by a mutation of the gene LMNA, or lamin A. The lamin A protein is the scaffolding that holds the nucleus of a cell together. Researchers now believe that the defective lamin A protein makes the nucleus unstable. That cellular instability appears to lead to the process of premature aging in progeria. Because neither parent carries or expresses the mutation, each case is believed to represent a sporadic, new mutation that happens most notably in a single sperm or egg immediately prior to conception.

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D.; Quan, L. : Older paternal age and fresh gene mutation: data on additional disorders. J. Pediat. 86: 84-88, 1975. Khalifa, M. M. : Hutchinson-Gilford progeria syndrome: report of a Libyan family and evidence of autosomal recessive inheritance. Clin. Genet. 35: 125-132, 1989. Kirschner, J.; Brune, T.; Wehnert, M.; Denecke, J.; Wasner, C.; Feuer, A.; Marquardt, T.; Ketelsen, U.-P.; Wieacker, P.; Bonnemann, C. G.; Korinthenberg, R. : p.S143F mutation in lamin A/C: a new phenotype combining myopathy and progeria. Ann. Neurol. 57: 148-151, 2005. Labeille, B.; Dupuy, P.; Frey-Follezou, I.; Larregue, M.; Maquart, F. X.; Borel, J. P.; Gallet, M.; Risbourg, B.; Denceux, J. P. : Progeria de Hutchinson-Gilford neonatale avec atteinte cutanee sclerodermiforme. Ann. Derm. Venerol. 114: 233-242, 1987. Lewis, M. : PRELP, collagen, and a theory of Hutchinson-Gilford progeria. Ageing Res. Rev. 2: 95-105, 2003. Luengo, W. D.; Martinez, A. R.; Lopez, R. O.; Basalo, C. M.; Rojas-Atencio, A.; Quintero, M.; Borjas, L.; Morales-Machin, A.; Ferrer, S. G.; Bernal, L. P.; Canizalez-Tarazona, J.; Pena, J.; Luengo, J. D.; Hernandez, J. C.; Chang, J. C. : Del(1)(q23) in a patient with Hutchinson-Gilford progeria. Am. J. Med. Genet. 113: 298-301, 2002. Maciel, A. T. : Evidence for autosomal recessive inheritance of progeria (Hutchinson Gilford). Am. J. Med. Genet. 31: 483-487, 1988. Mallampalli, M. P.; Huyer, G.; Bendale, P.; Gelb, M. H.; Michaelis, S. : Inhibiting farnesylation reverses the nuclear morphology defect in a HeLa cell model for Hutchinson-Gilford progeria syndrome. Proc. Nat. Acad. Sci. 102: 14416-14421, 2005. McKusick, V. A. : The clinical observations of Jonathan Hutchinson. Am. J. Syph. 36: 101-126, 1952. Merideth, M. A.; Gordon, L. B.; Clauss, S.; Sachdev, V.; Smith, A. C. M.; Perry, M. B.; Brewer, C. C.; Zalewski, C.; Kim, H. J.; and 13 others : Phenotype and course of Hutchinson-Gilford progeria syndrome. New Eng. J. Med. 358: 592-604, 2008. Moulson, C. L.; Fong, L. G.; Gardner, J. M.; Farber, E. A.; Go, G.; Passariello, A.; Grange, D. K.; Young, S. G.; Miner, J. H. : Increased progerin expression associated with unusual LMNA mutations causes severe progeroid syndromes. Hum. Mutat. 28: 882-889, 2007. Ogihara, T.; Hata, T.; Tanaka, K.; Fukuchi, K.; Tabuchi, Y.; Kumahara, Y. : Hutchinson-Gilford progeria syndrome in a 45-year-old man. Am. J. Med. 81: 135-138, 1986. Parkash, H.; Sidhu, S. S.; Raghavan, R.; Deshmukh, R. N. : Hutchinson-Gilford progeria: familial occurrence. Am. J. Med. Genet. 36: 431-433, 1990. Plasilova, M.; Chattopadhyay, C.; Pal, P.; Schaub, N. A.; Buechner, S. A.; Mueller, H.; Miny, P.; Ghosh, A.; Heinimann, K. : Homozygous missense mutation in the lamin A/C gene causes autosomal recessive Hutchinson-Gilford progeria syndrome. J. Med. Genet. 41: 609-614, 2004. Rautenstrauch, T.; Snigula, F.; Krieg, T.; Gay, S.; Muller, P. K. : Progeria: a cell culture study and clinical report of a familial incidence. Europ. J. Pediat. 124: 101-112, 1977. Rava, G. : Su un nucleo familiare di progeria. Minerva Med. 58: 1502-1509, 1967. Rodriguez, J. I.; Perez-Alonso, P. : Diagnosis of progeria syndrome is the only one possible. (Letter) Am. J. Med. Genet. 87: 453-454, 1999. Rodriguez, J. I.; Perez-Alonso, P.; Funes, R.; Perez-Rodriguez, J. : Lethal neonatal Hutchinson-Gilford progeria syndrome. Am. J. Med. Genet. 82: 242-248, 1999. Sagelius, H.; Rosengardten, Y.; Schmidt, E.; Sonnabend, C.; Rozell, B.; Eriksson, M. : Reversible phenotype in a mouse model of Hutchinson-Gilford progeria syndrome. J. Med. Genet. 45: 794-801, 2008. Varela, I.; Pereira, S.; Ugalde, A. P.; Navarro, C. L.; Suarez, M. F.; Cau, P.; Cadinanos, J.; Osorio, F. G.; Foray, N.; Cobo, J.; de Carlos, F.; Levy, N.; Freije, J. M. P.; Lopez-Otin, C. : Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging. (Letter) Nature Med. 14: 767-772, 2008. Viegas, J.; Souza, P. L. R.; Salzano, F. M. : Progeria in twins. J. Med. Genet. 11: 384-386, 1974. Wang, J.; Robinson, J. F.; O’Neil, C. H.; Edwards, J. Y.; Williams, C. M.; Huff, M. W.; Pickering, J. G.; Hegele, R. A. : Ankyrin G overexpression in Hutchinson-Gilford progeria syndrome fibroblasts identified through biological filtering of expression profiles. J. Hum. Genet. 51: 934-942, 2006. Wuyts, W.; Biervliet, M.; Reyniers, E.; D’Apice, M. R.; Novelli, G.; Storm, K. : Somatic and gonadal mosaicism in Hutchinson-Gilford progeria. Am. J. Med. Genet. 135A: 66-68, 2005. Yang, S. H.; Meta, M.; Qiao, X.; Frost, D.; Bauch, J.; Coffinier, C.; Majumdar, S.; Bergo, M. O.; Young, S. G.; Fong, L. G. : A farnesyltransferase inhibitor improves disease phenotypes in mice with a Hutchinson-Gilford progeria syndrome mutation. J. Clin. Invest. 116: 2115-2121, 2006. Brown WT. Progeria. In: Kliegman RM, Behrman RE, Jenson HB, Stanton BF, eds. Nelson Textbook of Pediatrics. 18th Ed. Philadelphia, Pa: Saunders Elsevier; 2007: chap 90. Learning about progeria. National Genome Research Institute. http://www.genome.gov/11007255. Accessed March 5, 2009. Progeria. National Institutes of Health. http://www.nih.gov/about/researchresultsforthepublic/Progeria.pdf. Accessed March 5, 2009. Progeria (Hutchinson-Gilford syndrome). The Merck Manuals Online Medical Library: The Merck Manual for Healthcare Professionals. http://www.merck.com/mmpe/sec19/ch286/ch286d.html. Accessed March 5, 2009. Brown TW. Progeria. In: Kliegman RM, et al. Kliegman: Nelson Textbook of Pediatrics. 18th ed. Saunders Elsevier; 2007. http://www.mdconsult.com/book/player/book.do?method=display&type=bookPage&decorator=header&eid=4-u1.0-B978-1-4160-2450-7..50092-X&uniq=124224571&isbn=978-1-4160-2450-7&sid=812951456. Accessed March 5, 2009. Brown TW. Hutchinson-Gilford progeria syndrome. National Institutes of Health: Gene Reviews. http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=hgps. Accessed March 5, 2009. Hutchison-Gilford progeria syndrome. Genetics Home Reference. http://ghr.nlm.nih.gov/condition=hutchinsongilfordprogeriasyndrome. Accessed March 5, 2009. Anti-cancer drug prevents, reverses cardiovascular damage in mouse model of premature aging disorder. National Institutes of Health. http://www.nih.gov/news/health/oct2008/nhgri-06.htm. Accessed March 5, 2009. Martini R. Helping children cope with chronic illness. American Academy of Child and Adolescent Psychiatry. Accessed March 5, 2009. Paterson, D. : Case of progeria. Proc. Roy. Soc. Med. 16: 42 only, 1922. Brown, W. T. : Personal Communication. Staten Island, N.Y., 1/12/2004.

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Meta-analysis of Paternal Age and Schizophrenia Risk in Male Versus Female Offspring.

2010-02-27T09:33:00.000-08:00

Schizophr Bull. 2010 Feb 25. [Epub ahead of print]

Meta-analysis of Paternal Age and Schizophrenia Risk in Male Versus Female Offspring.
Miller B, Messias E, Miettunen J, Alaräisänen A, Järvelin MR, Koponen H, Räsänen P, Isohanni M, Kirkpatrick B.

1Department of Psychiatry, Medical College of Georgia, Augusta, GA.

Introduction: Advanced paternal age (APA) is a reported risk factor for schizophrenia in the offspring. We performed a meta-analysis of this association, considering the effect of gender and study design. Methods: We identified articles by searching Pub Med, PsychInfo, ISI, and EMBASE, and the reference lists of identified studies. Previously unpublished data from the Northern Finland 1966 Birth Cohort (NFBC 1966) study were also included. Results: There were 6 cohort studies and 6 case-control studies that met the inclusion criteria. In both study designs, there was a significant increase in risk of schizophrenia in the offspring of older fathers (>/=30) compared to a reference paternal age of 25-29, with no gender differences. The relative risk (RR) in the oldest fathers (>/=50) was 1.66 [95% confidence interval (95% CI): 1.46-1.89, P < 0.01]. A significant increase in risk was also found for younger fathers (<25) in males (RR = 1.08, 95% CI: 1.02-1.14, P = 0.01) but not females (RR = 1.04, 95% CI: 0.97-1.14, P = 0.28). The population attributable risk percentage (PAR%) was 10% for paternal age >/=30 and 5% for paternal age <25. Discussion: Both APA (>/=30) and younger paternal age (<25) increase the risk of schizophrenia; younger paternal age may be associated with an increased risk in males but not females. This risk factor increases the risk of schizophrenia as much as any single candidate gene of risk. The mechanism of these associations is not known and may differ for older and younger fathers.

PMID: 20185538 [PubMed - as supplied by publisher]

Paternal age and mortality in nonaffective psychosis.

2010-02-19T07:09:00.000-08:00

Schizophr Res. 2010 Feb 16. [Epub ahead of print]

Paternal age and mortality in nonaffective psychosis.
Miller B, Pihlajamaa J, Haukka J, Cannon M, Henriksson M, Heilä H, Huttunen M, Tanskanen A, Lönnqvist J, Suvisaari J, Kirkpatrick B.

Department of Psychiatry and Health Behavior, Medical College of Georgia, Augusta, Georgia, United States; Department of Psychiatry, University of Oulu, Oulu, Finland.

INTRODUCTION: Advanced paternal age (APA) is associated with an increased mortality in the general population, and is a risk factor for schizophrenia. We aimed to test if APA is associated with increased mortality in people with nonaffective psychosis. METHODS: Subjects with nonaffective psychosis who were born in Helsinki, Finland, between 1951 and 1960 (n=529) were followed until June 2006 (age 46 to 55). Hazard ratios were calculated, adjusting for subject age, age of the other parent, and gender. RESULTS: In females but not males, there was a significant increase in all-causes mortality (HR=7.04, 95% CI 1.60-31.04, p=0.01) and natural deaths (HR=7.64, 95% CI 1.20-48.66, p=0.03) in offspring of fathers age >/=40, after adjustment for potential confounders. In males but not females, there was a significant decrease in suicides (HR=0.89, 95% CI 0.81-0.97, p=0.01) with increasing maternal age (as a continuous variable). In the entire sample, there was also a trend for decreased all-cause mortality (HR=0.96, 95% CI 0.92-1.01, p=0.08) with increasing maternal age (as a continuous variable). DISCUSSION: Both paternal and maternal age may affect mortality risk in offspring with psychosis. The specific disorders and pathway(s) associated with the increase in natural cause mortality remain to be determined. Copyright © 2010 Elsevier B.V. All rights reserved.

PMID: 20163936 [PubMed - as supplied by publisher]

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Tick tock goes the male biological clock

2010-02-18T17:37:00.000-08:00

Tick tock goes the male biological clock
by Raquel on February 18, 2010 · 0 comments

in INFERTILITY

Tick tock tick tock. As soon we women reach the age of 30, we hear the biological ticking away as we try to hold on to our fertility just for another while. But what about men? Don’t they have a biological clock to listen to?

I mean, look at the following oldies celebrity dads who fathered kids beyond their 60th birthday:

David Letterman, at age 61
Donald Trump, 62
Sylvester Stallone, 62
Rod Stewart, 63
Michael Douglas, 64
Mick Jagger, 65
Hugh Hefner, 65
Paul McCartney, 66
Clint Eastwood 66.
Sir Michael John Gambon, 68
Woody Allen, 73
Charlie Chaplin, 73
Larry King, 75
Anthony Quinn, 81
Surely for men, age doesn’t matter for fertility.

However, there is increasing evidence that this is not the case, and that men too, should listen to the ticking clock starting at midlife. Researchers report that the sperm quality of men decreases with age, and that fertility starts to wane when they reach the 30s, and plummets when they reach their 40s. During the time, the overall chance of fathering a child drastically decreases. And if a pregnancy is ever achieved, the likelihood of miscarriage is increased. In addition, the resulting offspring would have a higher likelihood to suffer from genetically related disorders such as autism, schizophrenia, autism and low IQ. This is according to a study by researchers at the Eylau Centre for Assisted Reproduction in Paris, France who looked at more than 1,200 couples.

So what’s reason behind the male biological clock?

Researchers think it is due to some kind of “sperm decay” which is characterized by DNA damage and abnormalities. Men start producing sperms at puberty at a rate of 100 million new sperms per day. During the process, DNA is copied and duplication from one sperm to another. During the countless sperm-copying processes, mistakes occur and DNA mutations happen. These errors accumulate with age, leading to decreasing sperm quality.

According to fertility specialist Dr. Carl Herbert

“These subtle copying defects cause a long list of diseases in the children of older fathers. Lesch Nyhan syndrome, polycystic kidney disease and hemophilia A are among the most well known. For fathers over age 40, the risk of having a child with a disease-causing mutation is similar to the risk the mother has for a child with Down syndrome.”

Aside from age, other health factors, including body weight and diabetes, can also adversely affect sperm quality.

According to Dr. Harry Fisch, urologist at Columbia University, and author of the book The Male Biological Clock

“…couples are waiting longer to have children, and advances in reproductive technology are allowing older men and women to consider having children. The lack of appreciation among both medical professionals and the lay public for the reality of a male biological clock makes these trends worrisome.”

He further advises older dads to “have a thorough history and physical examination focused on their sexual and reproductive capacity. Such examination should entail disclosure of any sexual dysfunction and the use of medications, drugs, or lifestyle factors that might impair fertility or sexual response.”

Read more: http://battlingforhealth.com/2010/02/tick-tock-goes-the-male-biological-clock/#ixzz0fwRmD4mi

Paternal factors and low birthweight, preterm, and small for gestational age births: a systematic review.

2010-02-02T19:16:00.000-08:00

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Am J Obstet Gynecol. 2010 Feb;202(2):103-23.

Paternal factors and low birthweight, preterm, and small for gestational age births: a systematic review.
Shah PS; Knowledge Synthesis Group on determinants of preterm/low birthweight births.

Collaborators (11)Shah PS, Ohlsson A, McDonald SD, Hutton E, Shah V, Beyene J, Frick C, Scott F, Murphy KE, Newburn-Cook C, Allen V.
Department of Pediatrics, Mount Sinai Hospital, and the Departments of Pediatrics and of Health Policy, Management and Evaluations, University of Toronto, Toronto, Ontario, Canada. pshah@mtsinai.on.ca

A systematic review of the risks of a low birthweight (LBW), preterm, and small-for-gestational-age births in relation to paternal factors was performed. Medline, Embase, Cumulative Index of Nursing and Allied Health Literature, and bibliographies of identified articles were searched for English-language studies. Study qualities were assessed according to a predefined checklist. Thirty-six studies of low-to-moderate risk of bias were reviewed for various paternal factors: age, height, weight, birthweight, occupation, education, and alcohol use. Extreme paternal age was associated with higher risk for LBW. Among infants who were born to tall fathers, birthweight was approximately 125-150 g higher compared with infants who were born to short fathers. Paternal LBW was associated with lower birthweight of the offspring. In conclusion, paternal characteristics including age, height, and birthweight are associated with LBW. Paternal occupational exposure and low levels of education may be associated with LBW; however, further studies are needed. Copyright 2010 Mosby, Inc. All rights reserved.

Men: Your Biological Clocks are Ticking

2010-01-30T21:52:00.000-08:00

Men: Your Biological Clocks are Ticking!
by Whitney Rhodes on January 30, 2010

For many years, it was tacitly assumed that while women have a “Sell By” date when it comes to fertility, men become fertile at puberty and remain so until a ripe old age.

Actually, although there is some truth in that myth, to the extent that males do not have a hormonal menopause as women do; the fact is that fertility in men does begin to decline after a certain age.

Men don’t completely stop being fertile at any age.

However, older fathers are prone to problems that younger fathers usually don’t experience.

What are Some of the Problems Experienced by Older Fathers?

A study that was conducted recently at the University of California, Berkeley, on a test group of men aged 22 to 80 showed that the sperm of older men are fewer in number with less mobility, as well as being less able to move in a straight line.

This research also showed an increased risk of achondroplasia, a genetic mutation that produces a kind of dwarfism.

Nor was this the only risk.

Older fathers were shown to have an increased risk of siring children with autism, or who were mentally retarded, or have behavioral problems with conditions such as schizophrenia.

Downs Syndrome, although associated with older mothers, doesn’t seem so far to be one of the risks of older fathers, but testing is still in progress.

It is believed that many times, male fertility problems caused by age and/or a medical condition might be mistaken as a potency issue, and mistakenly treated with a prescription for Viagra or a similar medication.

Investigating male infertility, and research of male sperm is gaining much new ground these days, as specialists recognize that infertility is not any more likely to rest with the female half of a couple than the male.

Today, more than ever, men and women alike are waiting longer to start families. This has given rise to an increasing frequency of fertility problems encountered with older parents.

So, although men are never completely infertile due to age, research has shown that the quality and quantity of sperm decrease with age.

Parental age and birth order in Chinese children with congenital heart disease

2010-01-30T08:33:00.000-08:00

To order reprints of this article go to:
http://journals.bmj.com/subscriptions/
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Downloaded from hwmaint.jmg.bmj.com on 30 January 2010
Journal of Medical Genetics, 1982, 19, 441-443
Parental age and birth order in Chinese children with
congenital heart disease
JOHN S H TAY, WILLIAM C L YIP, AND R JOSEPH
From the Department ofPaediatrics, National University of Singapore, Singapore.
SUMMARY Parental age and birth order were studied in 100 Chinese children with congenital
heart disease (proven by cardiac catheterisation) and in 100 controls. A higher incidence of congenital
heart disease was present in the children with higher birth orders. No relationship was
found between the incidence and the paternal or maternal ages. Using the method of multiple
regression analysis this birth order effect was significant (p <0 01) and independent of parental age.
This finding provides indirect evidence of environmental influence in the causation of congenital
heart disease, which is known to be inherited in a multifactorial manner. Family planning to limit
the size of the family may possibly contribute to the reduction of the incidence of congenital heart
disease.
Parental age and birth order effects have been
demonstrated in a number of genetic diseases and
congenital malformations. Certain chromosomal
disorders such as trisomy 21 (Down's syndrome),
trisomy 13 (Patau's syndrome), trisomy 18 (Edwards's
syndrome), and Klinefelter's syndrome have been
shown to be related to maternal age.1 Some autosomal
dominant disorders such as Apert's syndrome,
Marfan's syndrome, and achondroplasia are related
to paternal age.2 A number of congenital malformations
have been shown to be related to birth order.3
Congenital dislocation of the hip and congenital
pyloric stenosis occur more frequently in first born
children, and anencephaly and spina bifida are
more common among first born children as well
as in high birth orders.4
The rationale of studying parental age and birth
order effects is that the results of such studies may
shed some light on pathogenesis. The presence of a
parental age or birth order effect is presumptive
evidence of an environmental influence in the
causation of the disease.' This kind of information
may also be of help in genetic counselling.
The purpose of this study was to investigate the
parental age and birth order effects in Chinese
children with congenital heart disease.
Materials and methods
The material consisted of 100 consecutive Chinese
children with congenital heart disease proven by
Raceived for publication 9 April 1982.
441
cardiac catheterisation. The parental ages (at the
birth of the child) and the birth order of the children
with congenital heart disease were noted. The
parental age and birth order of 100 consecutive
normal Chinese children born in Singapore during
the same period were similarly recorded.
To distinguish the separate effects of paternal age,
maternal age, and birth order, which are usually well
correlated with one another, the method of Smith,5
using multiple regression analysis, was used.
A computer programme was written specially for
the Apple II microcomputer to compute all the
required calculations.
The method and terminology of Smith5 was
followed closely. The essence of this method is that,
given the matrix of the coefficients of regression
(for the controls),
rmm Pmf Pmb
| 1fm Pff Pfb
-Pbm Pbf 13bb
(where 3mf is the coefficient of regression of mother's
age on father's age and so on), it is possible to test
the hypothesis 'that only the father's age has any
appreciable real influence on the condition, the rises
in the mother's age and birth rank being statistical
consequences of this' (as well as similar hypotheses
involving the mother's age and the birth order).5 The
variance-covariance matrix is given by
rt1nrmnImf ltnib
I "'fill 'ff 'Ifh
i bm t/bf t'bb I
Downloaded from hwmaint.jmg.bmj.com on 30 January 2010
442
(where Vmm denotes the variance of m, the maternal
age, in the sample, Umf, the covariance of m and f,
and so on).
The expected rise in the mother's age (and
similarly for the father's age and the birth order) is
3mf Af, where Am is the observed rise in the mother's
age, and the difference between observed and
expected is Am-3mf Af. The error variance of An,
is vmm/n, where n is the number of observations in the
sample, the error variance of Af is uff/n, and their
covariance is /mf /n. Hence, the error variance of
Am-3mf Af iS given by
("imnm 2-2mf",mf 13 Imf!lff)/n.
Smith's method also allows estimation of the
expected independent changes (dm, df, db) in the
variables m, f, and b. The expected increase in the
mean maternal age m owing to dm, df, db is dm+ Pmf
df+rmfdb. By setting this equal to the observed
increase Am, we have
dnm+pmfdf+P3mbdb - Am.
In all, there are three linear equations for the
three unknowns dmi di., and db, which are written
in matrix form ,d- A where d is the column vector
with elements [dmi df, db]T and A similarly is given
by [Am, Af, Ab]T. This has the solution d -1A.
The error variance matrix is given by var d -IV
(I1)T/n.
The values of dm, df, and db are compared with the
size of their respective standard errors to determine
whether there are independent paternal age, maternal
age,'or birth order effects.
Results
The parental ages and birth order of the 100 Chinese
children with congenital heart disease and the 100
controls are shown in table and the correlation
coefficients listed in table 2. The birth order of the
children with congenital heart disease was significantly
higher than the controls (p<0.01), but there
was no significant difference in the paternal and
maternal ages of the patients and controls (p >0 05).
As expected, the parental ages and birth order were
TABLE 1 Parental age and birth order in congenital
heart disease.
Father's AMother's Birth
age (yr) age (yr) order
Congenital heart
disease (n = 100) Mean 31*51 27-66 2.78
SD 6-10 5.41 2-24
Controls (n = 100) Mean 30-37 26-55 2-09
SD 4.52 3.83 1-01
Observed rise in parental age
or birth order 1.14 1.11 0.69
Significance of difference p>0*05 p>0.05 p<0-01
JSHTay, WCL Yip, andR Joseph
TABLE 2 Correlation coefficients.
Congenital Controls
heart disease
Father's age and mother's age 0.7219 0.5809
Father's age and birth order 0.5612 0-4588
Mother's age and birth order 0.4789 0-4696
all well correlated with one another for both groups
of children, with correlation coefficients ranging
from 0 46 to 0 72 (p <0 0001).
The matrix for the regression coefficients (controls)
are shown below:
0000
p = 0.6863
0-1234
0 4916
1*0000
0-1020
1-7871]
2.0628
I.0000 .
The variance-covariance matrix for the children
with congenital heart disease is as follows:
r29 - 2368
v - 23 8014
5*- 8032
23-8014
37- 1817
7-6689
5.8032]
7-6689
5.0218 .
The error variance matrix is given by
r 04195 -0 1029 -0.0760-
vard- -0 1029 0.4188 --0.0451
-0-0760 -- 0 0451 0.0700].
The values of dm,, df, and db, their standard errors,
and the significance of the parental age and birth
order effects are shown in table 3. There was no
significant paternal or maternal age effect (p>0.05)
but the birth order effect was significant (p<0-01).
The various types of congenital heart disease are
shown in table 4.
TABLE 3 Significance ofparental age and birth order
eftects.
Factor acting independently Standard p value
error (SE)
Maternal age- 0.020 (0.03 x SE) 0.648 p>0.05
Paternal age-O0 348 (0.54 x SE) 0*647 p>0.05
Birth order 0 * 730 (2*75 x SE) 0.265 p<0O01
TABLE 4 Types of congenital heart disease.
Diagnosis Number
Ventricular septal defect 22
Fallot's tetralogy 19
Pulmonary stenosis+ventricular or atrial septal defect 11
Persistent ductus arteriosus 8
Transposition of great vessels ±other lesions 8
Endocardial cushion defect 7
Double outlet right ventricle 6
Pulmonary atresia ±ventricular septal defect 5
Pulmonary valvular stenosis 3
Coarctation of aorta + other lesions 3
Others (including Ebstein's anomaly, aorto-pulmonary
window, persistent truncus arteriosus, total
anomalous pulmonary venous drainage, and cor
triatriatum) 8
Total 100
Downloaded from hwmaint.jmg.bmj.com on 30 January 2010
Parental age and birth order in Chinese children with congenital heart disease
Discussion
This is the first study, as far as we are aware, of the
parental age and birth order effects in Chinese
children with congenital heart disease. A moderate
birth order effect is demonstrated.
Nora6 and Nora et a17 demonstrated a multifactorial
inheritance for congenital heart disease.
They showed that the risk of recurrence of a congenital
heart defect in another child in a family
varies with the frequency the lesion is found in the
general population and the type of lesion in the first
affected child, the recurrence risk ranging from about
1 to 4 %. Applying Falconer's model8 for the
estimation of heritability to their data, it can be
shown that the heritability of various types of
congenital heart disease is in the order of 50 to 80 %.
This measure can give some indication of the
relative importance of heredity and environment
in the causation of the disease.
The presence of a birth order effect in congenital
heart disease is indirect evidence of the presence of
an environmental influence in the causation of the
disease and is thus consistent with what is known
about the multifactorial inheritance of congenital
heart disease. While the exact mechanism of the
birth order effect is at present unclear, this finding
may nevertheless have practical applications. The
increase in the incidence of congenital heart disease
with the higher birth orders would suggest that
family planning to reduce the size of families may
possibly contribute towards the lowering of the
incidence of congenital heart disease.
References
Emery AEH. Methodology in medical genetics. An introduction
to statistical methods. Edinburgh, London, New
York: Churchill Livingstone, 1976.
2 Jones KL, Smith DW, Harvey MAS, Hall BD, Quan L.
Older paternal age and fresh gene mutation: data on
additional disorders. J Pediatr 1975;86:84-8.
3 Carter CO. The inheritance of common congenital
malformations. Prog Med Genet 1965 ;4:59-84.
4 Fedrick J. Anencephalus: variation with maternal age,
parity, social class and region in England, Scotland and
Wales. Ann Hum Genet 1970;34:31-8.
5 Smith CAB. Note on the estimation of parental ageeffects.
Ann Hum Genet 1972;35:337-42.
6 Nora JJ. Multifactorial inheritance hypothesis for the
etiology of congenital heart disease. Circulation 1968;38:
604.
7 Nora JJ, Vargo TA, Nora AH, et al. Dexamphetamine:
a possible environmental trigger in cardiovascular malformations.
Lancet 1970;i :1290.
Falconer DS. The inheritance of liability to certain
diseases, estimated from the incidence among relatives.
Ann Hum Genet 1965;29:51-76.
Requests for reprints to Professor John Tay,
University Department of Paediatrics, Singapore
General Hospital, Outram Road, Singapore 0316.

Advanced paternal age is associated with alterations in discrete behavioural domains and cortical neuroanatomy of C57BL/6J mice.

2010-01-29T07:58:00.000-08:00

Eur J Neurosci. 2010 Jan 25. [Epub ahead of print]

Advanced paternal age is associated with alterations in discrete behavioural domains and cortical neuroanatomy of C57BL/6J mice.
Foldi CJ, Eyles DW, McGrath JJ, Burne TH.

Queensland Brain Institute, The University of Queensland, St Lucia, Qld 4072, Australia.

Abstract Advanced paternal age (APA) is associated with an increased risk of neurodevelopmental disorders such as autism and schizophrenia. A previous study in mice suggested that the offspring of aged sires have altered locomotion and avoidance learning. The aim of the current study was to conduct a comprehensive behavioural screen in adult offspring of mice of APA. We also examined brain morphology in neonate and adult mice. The adult offspring of 12- to18-month-old (APA) and 4-month-old (control) male C57BL/6J mice underwent a behavioural test battery comprising tests for locomotion, anxiety, exploration, social behaviour, learned helplessness and sensorimotor gating. The brains of these mice were collected at 3 months and imaged ex vivo using a 16.4T MRI scanner to assess gross neuroanatomy. Neuroanatomy was also examined at birth in a separate cohort of animals. Overall, the APA mouse model was associated with subtle behavioural changes and altered cortical morphology. The behavioural phenotype of female APA mice included increased anxiety-related behaviour, increased exploration and decreased learned helplessness compared to control females. Male APA mice had thinner cortices at birth and increased cortical volume as adults. This animal model may assist in exploring the mechanism of action linking APA with disorders such as schizophrenia and autism.

PMID: 20105239 [PubMed - as supplied by publisher]

Risk of dominant mutation in older fathers: evidence from osteogenesis imperfecta.

2010-01-15T07:56:00.000-08:00

Journal of Medical Genetics 1986;23:227-230; doi:10.1136/jmg.23.3.227
Copyright © 1986 by the BMJ Publishing Group Ltd.
Risk of dominant mutation in older fathers: evidence from osteogenesis imperfecta.
A D Carothers, S J McAllion, C R Paterson

The mean paternal age at birth of 80 presumed mutant cases of dominant osteogenesis imperfecta (OI) was significantly higher than that of population controls and remained so after adjusting for maternal age. There was also an increase in mean maternal age (not significant) which disappeared after adjusting for paternal age. No significant increase in maternal or paternal age was found in cases having OI either of a dominant type with an affected parent or of a type (Sillence type III) usually regarded as recessive. We conclude that, as in certain other dominant conditions, the risk of mutant OI increases with paternal age. However, the rate of increase of risk with paternal age appears to be considerably lower than, for example, in achondroplasia. The overall risk of fresh dominant mutation in older fathers may therefore be lower than has previously been suggested.

Bipolar Depression: NEW Look at Physiology, Resources and Tips

2010-01-14T07:45:00.000-08:00

January 13, 2010
Bipolar Depression: NEW Look at Physiology, Resources and Tips

A discussion about Paternal Age and Health of Children

2010-01-12T08:41:00.001-08:00

Will our age gap be something to worry about when we decide to get pregnant?
January 11, 2010 3:57 PM Subscribe
Will our age gap be something to worry about when we decide to get pregnant?

My partner and I, a heterosexual couple, are a decade apart in age, and we expect that this relationship will result in marriage and children. It will be years before I am ready for kids, and I'm concerned that by that time, my partner will be an older-than-average father (I will not be an older mother, due to the age gap), and I've read some research that this could contribute to a higher risk of birth defects.

Is this something we should be seriously concerned with, enough so that I should consider having children sooner? Would it be worth it for our peace of mind to store his sperm now, and forgo natural conception for a more clinical, but less risky conception?
posted by anonymous to health & fitness (25 comments total) 3 users marked this as a favorite

Our findings suggest that paternal age may be a risk factor for some multifactorial birth defects

2010-01-09T09:12:00.000-08:00

Ann Epidemiol. 2010 Jan 5. [Epub ahead of print]

Association of Paternal Age and Risk for Major Congenital Anomalies From the National Birth Defects Prevention Study, 1997 to 2004.
Green RF, Devine O, Crider KS, Olney RS, Archer N, Olshan AF, Shapira SK; The National Birth Defects Prevention Study.

National Center on Birth Defects and Developmental Disabilities; Centers for Disease Control and Prevention; Atlanta, GA (R.F.G., O.D., K.S.C., R.S.O., S.K.S.); Texas Department of State Health Services; Austin, TX (N.A.); and Department of Epidemiology; University of North Carolina; Chapel Hill, NC (A.F.O.).

PURPOSE: The objective of this study was to examine the associations between paternal age and birth defects of unknown etiologies while carefully controlling for maternal age. METHODS: By using 1997 to 2004 data from the National Birth Defects Prevention Study, we fit logistic regression models with paternal and maternal age as continuous variables while adjusting for demographic and other factors. RESULTS: Elevated odds ratios (ORs) for each year increase in paternal age were found for cleft palate (OR. 1.02, 95% confidence interval [95% CI], 1.00-1.04), diaphragmatic hernia (OR, 1.04; 95% CI, 1.02-1.06), right ventricular outflow tract obstruction (OR, 1.03; 95% CI, 1.01-1.04), and pulmonary valve stenosis (OR, 1.02, 95% CI, 1.01-1.04). At younger paternal ages, each year increase in paternal age correlated with increased odds of having offspring with encephalocele, cataract, esophageal atresia, anomalous pulmonary venous return, and coarctation of the aorta, but these increased odds were not observed at older paternal ages. The effect of paternal age was modified by maternal age for gastroschisis, omphalocele, spina bifida, all orofacial clefts, and septal heart defects. CONCLUSIONS: Our findings suggest that paternal age may be a risk factor for some multifactorial birth defects. Published by Elsevier Inc.

PMID: 20056435 [PubMed - as supplied by publisher]

Paternal Age and Schizophrenia

2010-01-08T07:42:00.000-08:00

Paternal Age and Schizophrenia
Research Date:
03/23/2006
An Expert Interview with Dolores Malaspina, M.D., M.P.H.

Great Neck, NY - March 23, 2006) — Scientists have linked paternal age to genetic diseases since the 1950s, and some have suggested an association between the age of the father and the risk for schizophrenia. In 2001, Dolores Malaspina, M.D., M.P.H., and her colleagues reported their research identifying a relationship between paternal age and the occurrence of schizophrenia. On behalf of Medscape* Jessica Gould interviewed Dr. Malaspina, Professor of Clinical Psychiatry at Columbia University and Research Psychiatrist at New York State Psychiatric Institute in New York City. Dr. Malaspina elaborates on her research and speaks about new directions in genetic research on schizophrenia. (NARSAD NOTE: Dr. Malaspina was a NARSAD 1993 and 1995 Young Investigator and a 2001 Independent Investigator.)

Medscape: Tell me about your research on paternal age and schizophrenia.

Dolores Malaspina: I have been compelled by the idea that schizophrenia is not a single disease. The consensus in the field is that schizophrenia is a syndrome, and a syndrome is a collection of different disorders. Yet there is still some controversy over whether or not there are variants of schizophrenia that might have separate causes and respond differently to various medications.

Since beginning my research in the late 1980s, I have focused on this heterogeneity, and one way that I've done that is by examining aspects of the disease in people who come from densely affected families, where two or more relatives have schizophrenia, and comparing them with cases of schizophrenia that have no family history of any chronic psychosis.

Now, in genetic research, it's known that for human genetic diseases, when a new case presents itself in a family, the mutation almost always arises during spermatogenesis. We have known for almost 100 years that the late born children in a family have more new genetic diseases. In the 1950s, a scientist named Penrose showed that only the age of the father predicts these genetic diseases. Over the last decade, it was shown that the risk for many complex genetic diseases was also correlated with paternal age. I thought that if schizophrenia cases with no family history were due to new genetic events, maybe they would also be correlated with the father's age.

I have the good fortune to be funded by the National Institutes of Health to study a very special birth cohort in Israel of about 100,000 pregnancies. We have a rich amount of demographic and clinical data on the parents, including the age of the father. The analysis showed what we considered to be a striking effect of the age of the father on the risk for schizophrenia.

Medscape: Could you tell me more about this group of research subjects from Israel?

Dr. Malaspina: The offspring were born between 1964 and 1976, and the original birth cohort was designed to examine the health of women during pregnancy as well as fetal outcomes. Israel maintains a high-quality psychiatric case registry. Working with the people at the Ministry of Health in Israel, my colleagues linked the birth cohort data to the psychiatric case registry data. The results showed that the risk of schizophrenia was tripled for the offspring of the oldest group of fathers.

We found that paternal age explained over a quarter of the risk for schizophrenia in the population. At the time, people were skeptical. But the findings have been replicated many times now, and not a single study has failed to find this strong relationship between father's age and the risk for schizophrenia. And at this point, other explanations for the relationship have been ruled out, including social factors in the family, prenatal care, and parental psychiatric ailments. There simply seems to be a relationship between paternal age and schizophrenia risk.

Medscape: Can you explain why the relationship between paternal age and schizophrenia exists?

Dr. Malaspina: When Penrose found that paternal age predicted new human genetic diseases, he proposed the Copy Error Theory. He said that each time the spermatozoa are copied there's an opportunity for a new mutation. Sperm cells divide every 16 days after puberty, so the DNA in the sperm of a 20-year-old father has been copied 100 times, but sperm DNA from a 50-year-old father has been copied more than 800 times. By comparison, egg cells from the mother only undergo a few dozen cell divisions all together. It is clear that there are many more opportunities for mutations to occur during spermatogenesis and that these increase with the age of the father. That is why new mutations are introduced in mammals in proportion to paternal age.

To further establish that paternal age is associated with schizophrenia risk, we went back to examine if paternal age is related to other factors associated with schizophrenia risk. We looked at intellectual functioning at age 17 in our birth cohort. Those data were available because adolescents in Israel are screened for military service. Working with personnel at the Israeli Defense Force, we examined whether intelligence was related to paternal age. And what we found was a very strong specific effect of paternal age on performance IQ. Very young mothers and very old mothers had offspring with impairments in verbal and performance intelligence. While there was no effect of late fathers' age on verbal IQ, there was a strong effect on performance intelligence, or nonverbal intelligence, which we have published.

In a parallel study, we examined the effect of late paternal age in a mouse model. Working with my colleague, Jay Gingrich, we studied several cohorts of inbred mice to compare offspring with younger and older fathers. The mouse model demonstrated striking effects of paternal age on the behavior of mice.

Those three lines of evidence provide converging data that paternal age does influence neural functioning and that paternal age is a plausible risk factor for schizophrenia.

Medscape: Could you describe what is meant by sporadic schizophrenia and how that relates to paternal age?

Dr. Malaspina: This goes along with the issue of whether schizophrenia is one single disease or several different variants, several different diseases. If it is several diseases, we could make much more progress if we knew how to separate individuals who have one variant of the disease from individuals who have the other variant, such as for treatment studies.

So, we have this finding that father's age predicts schizophrenia, but we don't know if the genetic changes are in the same genes that cause familial schizophrenia or if they occur at a different place. Some of the birth cohorts have actually looked to see how the risk of schizophrenia with paternal age is related to the family history of schizophrenia. The finding is that father's age is not connected to the risk of schizophrenia when it runs in families, but only for cases with no family history. That is called sporadic schizophrenia.

We have also looked at patients, with the help of funding from the National Alliance for Research on Schizophrenia and Depression, and we have examined whether or not cases with late paternal age and no family history have different symptoms and brain abnormalities from those of other cases. That work is under way.

Medscape: You also looked at the duration of the parents' marriage.

Dr. Malaspina: Yes, and we found that the duration of marriage was protective against the risk for schizophrenia. This goes in the opposite direction of paternal age, but it's an independent factor. Couples that have a very long marriage are less likely to have offspring with schizophrenia. One possibility is that parents who have mental disorders themselves may have shorter marriages. Another possibility is that there is an increased risk of schizophrenia when there is a marital separation.

Medscape: A variety of environmental factors can influence the development of schizophrenia. How do you control for that?

Dr. Malaspina: On the one hand, there may be scores of different intrauterine exposures that increase the risk for schizophrenia through different pathways. Another possibility, though, is that there are only a few final common pathways through which various intrauterine adversities are linked to the risk for schizophrenia.

The Barker hypothesis deals with the area of fetal programming. Research shows that the risk for many adult-onset chronic diseases, such as cardiovascular disease, obesity, diabetes, and hypertension, is related to fetal development. The mechanism may be that an adverse fetal environment compromises the development of organs and tissues and changes lifelong gene expression. The fetus survives, but its health is compromised. Effects on the developing nervous system could contribute to schizophrenia risk. So that's a possible pathway for the risk for schizophrenia, through a variety of prenatal exposures.

The benefit of our study in Israel is that we had such a wealth of obstetric data. The birth cohort involved early pregnancy interviews with the mom. It also involved evaluations of the progress of the pregnancy and records of the delivery. Our study was able to show that other prenatal exposures did not explain the linkage of paternal age to the risk of schizophrenia. Also, there have been many excellent studies after ours was conducted that have looked at numerous fetal exposures and found that those also do not explain the risk of paternal age for schizophrenia.

I do, however, believe that many fetal exposures can increase the risk of schizophrenia. I would suggest that the mechanism of these events may be via changes in lifelong gene expression.

Medscape: What about the influence of environmental factors after birth, during childhood and adolescence?

Dr. Malaspina: I think three of the interesting factors that have been linked to the risk of schizophrenia are severe stress in a stress-sensitive person who has underlying genes for schizophrenia, traumatic brain injury in those with underlying genes for schizophrenia, and, very importantly, cannabis exposure in early adolescence.

Medscape: Your research about paternal age became public in 2001. Do you think fewer men over a certain age might choose to have children as a result?

Dr. Malaspina: I haven't heard that. I would personally not discourage anyone from having a child at any age. People weigh their own risks. For the offspring of older fathers, the risk of schizophrenia is about 3 percent. That means that 97percent of the offspring do not have schizophrenia. Other cognitive diseases linked to paternal age include mental retardation of unknown etiology and Alzheimer's disease, and there is a strong relationship between paternal age and autism.

Medscape: What do you expect to be the future of your research in this area?

Dr. Malaspina: The genes for schizophrenia that we have identified lately are very interesting; they explain a large degree of the risk of the disease. Attention probably should turn toward factors that affect the expression of these genes and other genes. This is the area of epigenetics, the code that determines whether or not genes will be expressed.

We're pursuing a gene expression hypothesis for paternal age and schizophrenia. Humans have dozens or hundreds of genes that are expressed, not on the basis of being dominant or recessive, but on the basis of which parent we have inherited them from. So genes that control the growth of the fetus tend to be expressed on the basis of inheritance from the father. Other genes are expressed only on the basis of inheritance from the mother. These are called "parent of origin genes" or "parentally-imprinted genes." In these genes, the father's copy is expressed and the mother's is silenced, or vice versa. We are interested in this mechanism of gene-silencing. For the male parent, the silencing, or the activation/expression of genes from dad, takes place late in spermatogenesis. So our hypothesis and model right now for how paternal age affects the risk for schizophrenia is that it has altered the expression of genes inherited from the father.

Even exposures that interact with genetic susceptibility may act by changing gene expression, such as traumatic brain injury, cannabis, and stress. Maybe we can integrate our understanding of the many exposures tied to schizophrenia and the many genes tied to schizophrenia with the understanding that certain exposures may act by changing gene expression.

Meanwhile, some individuals who develop schizophrenia have a good outcome and stability without much deterioration -- but not as many as we would like. If we can't prevent the disease, perhaps we can learn the risk factors for deterioration and how to prevent it.

Although I see schizophrenia as a syndrome of separate illness variants, I think the field has benefited from considering it as a single disease. From here forwards, we may be diluting our ability to find risk factors and optimize outcome by considering the disease as a whole. To go forward in schizophrenia, we need to better understand how similar symptoms may arise from abnormalities in different neural circuits; that the set of symptoms we call schizophrenia could reflect a common pathway, but that the underlying biology may differ for groups of people, and that those differences may explain which medications they should receive, or which factors are more adverse for them. I think the field needs to move toward a finer understanding of the variants that exist. The identified genes may be clearly explanatory for some cases but not for others.

Funding Information

This interview is published in collaboration with NARSAD: The Mental Health Research Association, and is supported by an educational grant from Pfizer.

Dolores Malaspina, M.D., Professor of Clinical Psychiatry, Columbia University, New York, NY;
Director of Clinical Neurobiology, New York State Psychiatric Institute and Columbia University Medical Center, New York, N.Y.

Disclosure: Jessica Gould has disclosed no relevant financial relationships.

Disclosure: Dolores Malaspina, MD, has disclosed no relevant financial relationships.

*Reprinted with permission from Medscape Psychiatry & Mental Health 2006:11(1) http://www.medscape.com/viewarticle/520009 © 2006, Medscape. Please be advised that Medscape requires free registration to view articles.

Advancing Paternal Age Is Associated with Deficits in Social and Exploratory Behaviors in the Offspring: A Mouse Model

2009-12-30T08:09:00.000-08:00

Research Article

Advancing Paternal Age Is Associated with Deficits in Social and Exploratory Behaviors in the Offspring: A Mouse Model

Accumulating evidence from epidemiological research has demonstrated an association between advanced paternal age and risk for several psychiatric disorders including autism, schizophrenia and early-onset bipolar disorder. In order to establish causality, this study used an animal model to investigate the effects of advanced paternal age on behavioural deficits in the offspring.

C57BL/6J offspring (n = 12 per group) were bred from fathers of two different ages, 2 months (young) and 10 months (old), and mothers aged 2 months (n = 6 breeding pairs per group). Social and exploratory behaviors were examined in the offspring.

The offspring of older fathers were found to engage in significantly less social (p = 0.02) and exploratory (p = 0.02) behaviors than the offspring of younger fathers. There were no significant differences in measures of motor activity.

Given the well-controlled nature of this study, this provides the strongest evidence for deleterious effects of advancing paternal age on social and exploratory behavior. De-novo chromosomal changes and/or inherited epigenetic changes are the most plausible explanatory factors.

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Abstract
Introduction
Results
Discussion
Methods
Author Contributions
References
Rebecca G. Smith1#, Rachel L. Kember1#, Jonathan Mill1, Cathy Fernandes2*, Leonard C. Schalkwyk1, Joseph D. Buxbaum3,4, Abraham Reichenberg1,3

1 Medical Research Council Social Genetic and Developmental Psychiatry Centre, King's College London, London, United Kingdom, 2 Department of Psychological Medicine and Psychiatry, King's College London, London, United Kingdom, 3 Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, United States of America, 4 Laboratory of Molecular Neuropsychiatry, and the Seaver Autism Center for Research and Treatment, Mount Sinai School of Medicine, New York, New York, United States of America

Abstract Top
Background
Accumulating evidence from epidemiological research has demonstrated an association between advanced paternal age and risk for several psychiatric disorders including autism, schizophrenia and early-onset bipolar disorder. In order to establish causality, this study used an animal model to investigate the effects of advanced paternal age on behavioural deficits in the offspring.

Methods
C57BL/6J offspring (n = 12 per group) were bred from fathers of two different ages, 2 months (young) and 10 months (old), and mothers aged 2 months (n = 6 breeding pairs per group). Social and exploratory behaviors were examined in the offspring.

Principal Findings
The offspring of older fathers were found to engage in significantly less social (p = 0.02) and exploratory (p = 0.02) behaviors than the offspring of younger fathers. There were no significant differences in measures of motor activity.

Conclusions
Given the well-controlled nature of this study, this provides the strongest evidence for deleterious effects of advancing paternal age on social and exploratory behavior. De-novo chromosomal changes and/or inherited epigenetic changes are the most plausible explanatory factors.

Citation: Smith RG, Kember RL, Mill J, Fernandes C, Schalkwyk LC, et al. (2009) Advancing Paternal Age Is Associated with Deficits in Social and Exploratory Behaviors in the Offspring: A Mouse Model. PLoS ONE 4(12): e8456. doi:10.1371/journal.pone.0008456

Editor: Kenji Hashimoto, Chiba University Center for Forensic Mental Health, Japan

Received: October 28, 2009; Accepted: December 2, 2009; Published: December 30, 2009

Copyright: © 2009 Smith et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This study was supported by the Beatrice and Samuel A. Seaver Foundation, by a British Medical Association Margaret Temple Award, and National Institute of Health Research (NIHR) Biomedical Research Centre (BRC) for Mental Health at the South London and Maudsley National Health Service (NHS) Foundation Trust and Institute of Psychiatry, King's College London (KCL) Pilot Award to Drs. Jonathan Mill and Abraham (Avi) Reichenberg. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

* E-mail: cathy.fernandes@kcl.ac.uk

# These authors contributed equally to this work.

Introduction Top
Accumulating evidence from epidemiological research has demonstrated an association between advanced paternal age and risk for several psychiatric disorders including autism [1], schizophrenia [2] and early-onset bipolar disorder [3]. Despite the methodological advantages of epidemiological research, a major limitation is that techniques are limited to observation. In order to establish causality, experimental evidence in the form of randomized-controlled trials or the development of animal models is required [4]. Animal models are particularly important as they allow environmental and genetic confounds to be controlled.

The lack of complete specificity in the association between advancing paternal age and psychiatric disorders may suggest that advancing paternal age is related to phenotypes shared across disorders. One phenotype in-common to schizophrenia, autism and bipolar disorder is abnormalities in social cognition broadly defined severe social deficit [5], [6], [7], [8]. A recent epidemiological study found an association between advancing paternal age and impaired social functioning in male offspring in the general population [9].

In this study we examined the effect of older paternal age on social and non-social behavior in mice. To the best of our knowledge this is the first fully-controlled animal study of the effects of paternal age on these behaviors.

Results Top
Social Behavior
Offspring of old fathers engaged in less social activity than the offspring of young fathers, spending less time socially-interacting with the conspecific mice (t = 2.23, d.f. = 22, p = 0.02, one-tailed test, Figure 1). This result was consistently observed across all measures of social behavior. There were no significant differences in overall locomotor activity.

Figure 1. Results of social behavioral data from male offspring of young fathers (n = 12) and old fathers (n = 12).

* shows a p-value of less than 0.05, † shows p-value of 0.06. A. Mean time (±SEM) displaying all social behaviors toward a conspecific mouse (broken down into components in B, C and D). B. Mean time (±SEM) displaying allogrooming behavior towards a conspecific mouse. C. Mean time (±SEM) displaying anogenital sniffing behavior towards a conspecific mouse. D. Mean time (±SEM) displaying sniffing behavior towards a conspecific mouse.

doi:10.1371/journal.pone.0008456.g001
Exploration in the Holeboard
Offspring of old fathers demonstrated reduced exploration in the holeboard, making fewer nose pokes and spending less time nose poking than offspring of young fathers (t = −2.21, d.f. = 22, p = 0.02; Figure 2A). No significant differences were evident in distance moved or time spent in the centre of the Holeboard arena.

Figure 2. Results of holeboard and open field data from male offspring of young fathers (n = 12) and old fathers (n = 12).

* shows a p-value of less than 0.05. A. Mean number of nose pokes (±SEM) into holes in the holeboard trial. B. Mean time spent in each area of arena (±SEM) in the open field task.

doi:10.1371/journal.pone.0008456.g002
Exploration in the Open Field
Offspring of old fathers were less exploratory in the Open Field, taking longer to enter the central zone of the arena (t = 1.7837, d.f. = 22, p = 0.04). However, there were no significant differences inthe time spent in the middle (t = −0.9548, d.f. = 22, p = 0.1785) or central zones (t = −1.3166, d.f. = 22, p = 0.1056) (Figure 2B) or in overall locomotor activity between offspring of old fathers and offspring of young fathers in the open field.

To further explore these findings we examined the same set of behaviors in a small group of mice that were the offspring of very old fathers (aged >12 months, n = 9 male offspring generated from 7 breeding pairs). The behavioral results of reduced social behavior and exploration were seen in the offspring of very old fathers, but the numbers are too small to allow for a reliable statistical test (data not shown).

Discussion Top
Using a mouse model we documented deleterious effects of advancing paternal age on offspring behavior. Male offspring of older fathers engaged in less social behavior and exhibited less exploration in a novel environment. These effects were not confounded by differences in overall locomotor activity. Abnormalities in social behavior characterize psychiatric disorders previously linked to advancing paternal age, suggesting a common phenotype affected by paternal age.

There are several advantages for the mouse model used in this study. First, given the tractable nature of animal work, the environment was tightly controlled, minimizing any environmental confounds. Second, the age of all the mothers of the offspring was standard such that differences observed in the offspring cannot be accounted for by maternal age.

Finally, the most common reference inbred strain of mouse was used (C57BL/6J), reducing genetic variation.

In men, it is thought that the spermatogonial stem cell divisions occurring over the life-course of males result in higher mutational rates and cytogenetic abnormalities in the sperm of older men [10], [11]. Numerous neurological and psychiatric disorders have been related to genomic alterations [12]. A number of studies have uncovered an increased prevalence of de-novo copy-number variants (CNVs), and other forms of genomic alterations in autistic and in schizophrenia cases [13], [14].

An alternative explanation is that epigenetic dysfunction underlies some paternal age effects. Epigenetic dysfunction has been associated with several neuropsychiatric disorders, including schizophrenia and bipolar disorder [15]. A study by Flanagan and colleagues [16] reported intra- and inter-individual epigenetic variability in the male germline, and found a number of genes that demonstrated age-related DNA-methylation changes. Epigenetic signals are generally reprogrammed in the germline, although it appears that such reprogramming may not be fully complete across all regions of the genome [17]. In particular, repetitive and transposable elements in the genome, which are generally hypermethylated, are often not efficiently reprogrammed [18]. It is thus plausible that de novo structural mutations, which are often associated with repetitive DNA sequence motifs, may also be subjected to differential epigenetic reprogramming implicating both mutagenic and epigenetic processes in the phenotypic manifestation of increased paternal age.

Despite the advantages of this model, the results of this study should be interpreted in light of some limitations. We only examined one strain of male mice. This was a-priori decided in order to follow common practice in animal research aimed at limiting variation caused by sex differences in behaviors. Hence, findings should not be generalized across sexes. In addition, behavior was assessed at one developmental stage (12 weeks, young adulthood). Thus, the developmental nature of these differences could not be determined.

In conclusion, this study provides the strongest evidence to date for the behavioral effects of advancing paternal age on the offspring. Studies are ongoing to investigate the role of molecular changes in mediating the effects of advancing paternal age on social and exploratory behaviors in offspring, by assessing de-novo CNV events and alterations in DNA methylation.

Methods Top
Breeding Strategy
C57BL/6J mice were bred and maintained in the Biological Services Unit at the Institute of Psychiatry, Kings College London using stocks purchased from Charles River Laboratories. All housing and experimental procedures were performed in accordance with the UK Home Office Animals (Scientific Procedures) Act 1986. Typical breeding age for mice starts at 2 months. Male breeders are generally retired after 7–8 months. Therefore, females aged 2 months were bred with males of two different ages; young males of 2 months (n = 6 breeding pairs), and old males of 10 months (n = 6 breeding pairs). The average litter size within each age group was 7 (male to female ratio 1:1) and total progeny generated was 40 mice in the young fathers group and 44 mice in the old fathers group. Two males were randomly selected from each litter (n = 12 males per group) and weaned aged 4–5 weeks and pair housed with their siblings and then individually housed for two weeks prior to testing. Mice were housed in standard cages measuring 30.5×13×11 cm, with food and water available ad libitum. The housing room was maintained on a standard light/dark cycle with white lights on from 08:00 to 20:00. Ambient temperature in all rooms was maintained at 21±2°C with 45% humidity.

Offspring Behavioral Testing
Offspring were aged 12 weeks at the start of testing and all testing took place during the light phase with a light level <30 lux in the test room. Each apparatus was wiped clean with 1% Trigene® between subjects to avoid olfactory cueing behaviors. Behaviors for all tests were recorded on videotapes for further detailed analysis. Mice were returned to their home cage at the end of each test.

Social Behavior
The social behavior of the test mice towards a juvenile conspecific was assessed in a 5 minute trial [19]. The test mouse is habituated in an arena (36×20×14 cm) for 5 minutes, after which a male juvenile conspecific of the same strain (aged 4 weeks) was introduced for a further 5 minutes. During this trial, social behavior (including social sniffing, anogenital sniffing and allogrooming) by the test mouse towards the conspecific were scored from videotape by an observer blind to the group factor of paternal age.

Holeboard
The holeboard test is used to measure activity and exploration in a novel arena [20]. The Truscan Photo Beam Activity System (Coulbourn Instruments, Whitehall, PA) was used, which consists of an arena (25.4 cm square) and a nose poke floor with 16 holes (4×4 array) with sensor rings to track movement. The beams are spaced 1.52 cm apart providing a 0.76 cm spatial resolution. Animals were placed in the arena and the movement, the number of nose pokes and the time spent nose poking were recorded automatically by beam breaks for 5 minutes using the Truscan program.

Open Field
The open field [21] used a square white acrylic box with dimensions 72×72×33 cm. The animal was placed in the outer part of the arena facing an outer wall and allowed to freely explore the arena for 5 minutes. A video camera placed above the arena allowed movement to be tracked using an automated tracking system (Ethovision, Noldus Information Technologies). The number of faecal boli and urination were recorded at the end of the test. A square of equal distance from the periphery (36×36 cm) was defined in Ethovision as the ‘outer’, ‘middle’ and ‘central’ zones in order to determine the number of entries into, and time spent in, these zones in the arena. In addition, the latency to enter the inner zones as well as locomotor activity in all three zones of the arena were measured by the tracking system.

Statistical Analysis
Behavioral performances of offspring of young fathers and offspring of old fathers in the social interaction task, holeboard and open field were compared using unpaired, one-tailed Students t-tests. Significance level was set at 0.05.

Author Contributions Top
Conceived and designed the experiments: JM CF LCS AR. Performed the experiments: RGS RLK. Analyzed the data: RGS RLK CF. Contributed reagents/materials/analysis tools: JDB. Wrote the paper: RGS RLK JM CF LCS AR.

References Top
Kolevzon A, Gross R, Reichenberg A (2007) Prenatal and perinatal risk factors for autism: a review and integration of findings. Arch Pediatr Adolesc Med 161: 326–333. Find this article online
Torrey EF, Buka S, Cannon TD, Goldstein JM, Seidman LJ, et al. (2009) Paternal age as a risk factor for schizophrenia: how important is it? Schizophr Res 114: 1–5. Find this article online
Frans EM, Sandin S, Reichenberg A, Lichtenstein P, Langstrom N, et al. (2008) Advancing paternal age and bipolar disorder. Arch Gen Psychiatry 65: 1034–1040. Find this article online
Rothman KJ, Greenland S (1997) Modern Epidemiology: Lippincott Williams and Wilkins.
Geschwind DH (2009) Advances in autism. Annu Rev Med 60: 367–380. Find this article online
Green MF, Penn DL, Bentall R, Carpenter WT, Gaebel W, et al. (2008) Social cognition in schizophrenia: an NIMH workshop on definitions, assessment, and research opportunities. Schizophr Bull 34: 1211–1220. Find this article online
Green MF (2006) Cognitive impairment and functional outcome in schizophrenia and bipolar disorder. J Clin Psychiatry 67: e12. Find this article online
Brotman MA, Skup M, Rich BA, Blair KS, Pine DS, et al. (2008) Risk for bipolar disorder is associated with face-processing deficits across emotions. J Am Acad Child Adolesc Psychiatry 47: 1455–1461. Find this article online
Weiser M, Reichenberg A, Werbeloff N, Kleinhaus K, Lubin G, et al. (2008) Advanced parental age at birth is associated with poorer social functioning in adolescent males: shedding light on a core symptom of schizophrenia and autism. Schizophr Bull 34: 1042–1046. Find this article online
Crow JF (2000) The origins, patterns and implications of human spontaneous mutation. Nat Rev Genet 1: 40–47. Find this article online
Buwe A, Guttenbach M, Schmid M (2005) Effect of paternal age on the frequency of cytogenetic abnormalities in human spermatozoa. Cytogenet Genome Res 111: 213–228. Find this article online
Reichenberg A, Mill J, MacCabe J (In Press) Epigenetics, Genomic Mutations and Cognitive Function. Cognitive Neuropsychitry. Find this article online
Marshall CR, Noor A, Vincent JB, Lionel AC, Feuk L, et al. (2008) Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet 82: 477–488. Find this article online
Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, et al. (2007) Strong association of de novo copy number mutations with autism. Science 316: 445–449. Find this article online
Mill J, Tang T, Kaminsky Z, Khare T, Yazdanpanah S, et al. (2008) Epigenomic profiling reveals DNA-methylation changes associated with major psychosis. Am J Hum Genet 82: 696–711. Find this article online
Flanagan JM, Popendikyte V, Pozdniakovaite N, Sobolev M, Assadzadeh A, et al. (2006) Intra- and interindividual epigenetic variation in human germ cells. Am J Hum Genet 79: 67–84. Find this article online
Lane N, Dean W, Erhardt S, Hajkova P, Surani A, et al. (2003) Resistance of IAPs to methylation reprogramming may provide a mechanism for epigenetic inheritance in the mouse. Genesis 35: 88–93. Find this article online
Waterland RA, Jirtle RL (2003) Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol 23: 5293–5300. Find this article online
Winslow JT (2003) Mouse social recognition and preference. Curr Protoc Neurosci Chapter 8: Unit 8 16. Find this article online
Nolan NA, Parkes MW (1973) The effects of benzodiazepines on the behaviour of mice on a hole-board. Psychopharmacologia 29: 277–286. Find this article online
Hall CS (1951) The genetics of behaviour. In: Steven SS, editor. Handbook of Experimental Psychology. New York: John Wiley & Sons Inc. pp. 304–329.

Older fathers appear to raise risks of genetic disorder

2009-12-26T10:10:00.000-08:00

Older fathers appear to raise risks of genetic disorder - Print Version - International Herald Tribune 19/09/07 20.04
http://www.iht.com/bin/print.php?id=4748536 Page 1 of 2
Older fathers appear to raise risks of genetic disorders
By Roni Rabin
Wednesday, February 28, 2007
When it comes to fertility and the prospect of having normal babies, it has always been assumed
that men have no biological clock — that unlike women, they can have it all, at any age.
But mounting evidence is raising questions about that assumption, suggesting that as men get
older, they face an increased risk of fathering children with abnormalities. Several recent studies
are starting to persuade many doctors that men should not be too cavalier about postponing
marriage and children.
Until now, the problems known to occur more often with advanced paternal age were so rare they
received scant public attention. The newer studies were alarming because they found higher rates
of more common conditions — including autism and schizophrenia — in offspring born to men in
their middle and late 40s. A number of studies also suggest that male fertility may diminish with
age.
"Obviously there is a difference between men and women; women simply can't have children after
a certain age," said Dr. Harry Fisch, director of the Male Reproductive Center at New York-
Presbyterian Hospital/Columbia University Medical Center and the author of "The Male Biological
Clock."
"But not every man can be guaranteed that everything's going to be fine," Fisch said. "Fertility will
drop for some men, others will maintain their fertility but not to the same degree, and there is an
increased risk of genetic abnormalities."
It's a touchy subject. "Advanced maternal age" is formally defined: women who are 35 or older
when they deliver their baby may have "AMA" stamped on their medical files to call attention to
the higher risks they face. But the concept of "advanced paternal age" is murky. Many experts are
skeptical about the latest findings, and doctors appear to be in no rush to set age guidelines or
safety perimeters for would-be fathers, content instead to issue vague sooner-rather-than- later
warnings.
"The problem is that the data is very sparse right now," said Dr. Larry Lipschultz, a specialist in
the field of male infertility and a past president of the American Society for Reproductive Medicine.
"I don't think there's a consensus of what patients should be warned about."
And many men maintain their fertility, said Dr. Rebecca Sokol, president of the Society of Male
Reproduction and Urology. "If you look at males over 50 or 40, yes, there is a decline in the
number of sperm being produced, and there may be a decline in the amount of testosterone,"
Sokol said. But by and large, she added, "the sperm can still do their job."
Some advocates, however, welcome the attention being paid to the issue of male fertility, saying it
is long overdue.
"The message to men is: 'Wake up,'" said Pamela Madsen, executive director of the American
Fertility Association, a U.S. education and advocacy group. "It's not just about women anymore,
it's about you, too."
Analyses of sperm samples from healthy men have found changes as men age, including
increased fragmentation of DNA, and some studies outside the United States have noted
increased rates of some cancers in children of older fathers.
Geneticists have been aware for decades that the risk of certain rare birth defects increases with
the father's age. One of the most studied of these conditions is a form of dwarfism called
achondroplasia, but the list also includes neurofibromatosis, the connective tissues disorder Marfan
syndrome, skull and facial abnormalities like Apert syndrome, and many other diseases and
abnormalities.
Some studies suggest that the risk of sporadic single-gene mutations may be four to five times
higher for fathers who are 45 and older, compared with fathers in their 20s, said Dr. Joe Leigh
Simpson, president-elect of the American College of Medical Genetics. Overall, having an older
father is estimated to increase the risk of a birth defect by 1 percent, against a background 3
percent risk for a birth defect, he said.
Even grandchildren may be at greater risk for some conditions that are not expressed in the
daughter of an older father, according to the American College of Medical Genetics. These include
Duchenne muscular dystrophy, some types of hemophilia and fragile-X syndrome.
A recent study on autism attracted attention because of its striking findings. Researchers analyzed
a large Israeli military database to determine whether there was a correlation between paternal
age and the incidence of autism and related disorders. It found that children of men who became
a father at 40 or older were 5.75 times as likely to have an autism disorder as those whose fathers
were younger than 30.
"Until now, the dominant view has been, 'Blame it on the mother,'" said Dr. Avi Reichenberg, the
lead author of the study, published in September in The Archives of General Psychiatry. "But we
Older fathers appear to raise risks of genetic disorders - Print Version - International Herald Tribune 19/09/07 20.04
http://www

'Effect of advanced paternal age on fertility and pregnancy'

2009-12-26T09:44:00.000-08:00

Medline ® Abstracts for References 7-11
of 'Effect of advanced paternal age on fertility and pregnancy'

--------------------------------------------------------------------------------

7
TI Changes with age in the level and duration of fertility in the menstrual cycle.
AU Dunson DB; Colombo B; Baird DD
SO Hum Reprod 2002 May;17(5):1399-403.

BACKGROUND: Most analyses of age-related changes in fertility cannot separate effects due to reduced frequency of sexual intercourse from effects directly related to ageing. Information on intercourse collected daily through each menstrual cycle provides the data for estimating day-specific probabilities of pregnancy for specific days relative to ovulation, and these estimates allow unconfounded analysis of ageing effects. METHODS: A total of 782 healthy couples using natural family planning methods contributed prospective data on 5860 menstrual cycles. Day of ovulation was based on basal body temperature measurements. Estimates of day-specific probabilities of pregnancy and the length of the fertile window were compared across age groups. RESULTS: Nearly all pregnancies occurred within a 6 day fertile window. There was no evidence for a shorter fertile window in older men or women. On average, the day-specific probabilities of pregnancy declined with age for women from the late 20s onward, with probabilities of pregnancy twice as high for women aged 19-26 years compared with women aged 35-39 years. Controlling for age of the woman, fertility was significantly reduced for men aged>35 years. CONCLUSIONS: Women's fertility begins to decline in the late 20s with substantial decreases by the late 30s. Fertility for men is less affected by age, but shows significant decline by the late 30s.

AD Biostatistics Branch, MD A3-03, National Institute of Environmental Health Sciences, National Institutes of Health, P.O.Box 12233, Research Triangle Park, NC 27709, USA. dunson1@niehs.nih.gov

And the real kicker? Men over 35 are twice as likely to be infertile as those under 25.

2009-12-18T14:05:00.000-08:00

Age is a factor in autism

2009-12-16T07:11:00.000-08:00

Age is a factor in autism
December 15, 9:41 PMDouglas County Special Needs Kids Examiner

Gina St. Aubin

(Photo By: Ghutchis / Flickr)We've know for some time that the parent's age at conception and birth plays a large role in the possibility of birth defects for a child. For a woman, researchers indicate that as she reaches her late 30's and 40's the risk of infertility and miscarriage significantly increase. In the United States alone, approximately 1 in 12 first-time births are to women over 35; even while more studies have shown that infertility rates increase by 3% for each year beyond 35.

Now, a recent study from American Journal of Epidemiology indicates that age has more of a factor for birth defects than previously thought. In a study of 7.5 million births in California between 1989 and 2002, researchers identified 23,311 children who received state-sponsored services for autism. Further, through this research, the state's health department found that a child's risk of developing autism increased along with the age of the parents. For each 10-year increase in a mother's age between the ages of 20 and 40, the risk of her child developing autism climbed by 38 percent. Similarly, each 10-year increase in a father's age between the ages of 20 and 60 was associated with a 22-percent increase in autism risk.

Although past studies have indicated that the older age of parents may increase a child's risk of autism, or that it has no impact at all, these latest findings suggest (not prove) that an older age in parents may be an additional risk factor. With studies showing that the number of autism diagnosis' has skyrocketed over the past two decades, along with this new information, it may possible that the concomitant trend toward delaying childbirth could have contributed to that rise." But even if older parental age is a factor, she said, it would be a "relatively minor one."

So what do couples contemplating starting or continuing a family do with this information? What do women and men do as individuals mapping out their life's plan where beginning a family earlier in life is not possible or desired? At this point, with autism and it's research essentially still very young, is it not possible to take this information along with you as you have the previous information? Take it with you, in consideration, but not an end-all as the previous knowledge that increased age can increase the overall risk for birth defects? Could it not be added to the number of issues "listed" as those your possible future child is at risk for?

Or would couples begin their families sooner, beyond the consideration of education, finances and stability, all in the hopes of dodging the chance that their child, too, will be effected by autism?

Increased Bipolar Risk Linked to Father's Age

2009-12-16T07:08:00.000-08:00

Psychiatric News November 7, 2008
Volume 43 Number 21 Page 18
© American Psychiatric Association
Clinical & Research News
Increased Bipolar Risk Linked to Father's Age
Joan Arehart-Treichel
Next Section
Older men are more likely than younger men to father children with autism, schizophrenia, or early-onset bipolar disorder.

Previous Section
Fathering a child later in life seems to increase its risk of having autism or schizophrenia, research has shown. And now it seems to increase a child's risk of having bipolar disorder as well, a new study suggests.

The study was headed by Emma Frans, a doctoral student in epidemiology at the Karolinska Institute in Stockholm. Results were published in the September Archives of General Psychiatry.

Sweden's Multigeneration Register, as well as Sweden's National Hospital Discharge Register, made this new investigation possible. The former, which has been in existence since 1947, gives demographic information about all people living in Sweden as well as about their parents. The latter, which has been in existence since 1973, lists all people living in Sweden who have been hospitalized for various conditions.

Using the hospital discharge register, the researchers identified more than 13,000 persons who had been hospitalized for bipolar disorder at least twice since 1973 when the hospital discharge register was started. Using the Multigeneration Register, the researchers picked out five healthy individuals who matched each of the 13,000 persons on gender and date of birth. In other words, some 13,000 persons with bipolar disorder served as subjects, and 67,000 other individuals served as controls.

The researchers then used the Multigeneration Register to determine the age of each subject's father and of each control's father at the time of the subject's or control's birth. Finally, the researchers used this data to determine whether there was any link between paternal age at the time of birth and an offspring's chances of having bipolar disorder.

A link was found. Even when some possibly confounding factors such as socioeconomic status, family history of mental disorders, or maternal age at time of birth were considered, the offspring of men aged 55 or older were significantly more likely—1.37 times more likely—to have bipolar disorder than were the offspring of men aged 20 to 24. And for early-onset bipolar disorder (defined as occurring before age 20), the impact of paternal age was even more pronounced: the offspring of men aged 50 or older were 2.63 times more likely to have bipolar disorder than were the offspring of men aged 20 to 24.

Thus, paternal age seems to be “an independent risk factor for bipolar disorder,” Frans and her colleagues concluded in their study report. “Furthermore, our results indicate that the paternal age effect might be most evident in patients with an early onset of the disorder.”

Why older men are more at risk of fathering children with bipolar disorder, or autism or schizophrenia, than younger men are is not known. However, Frans and her team suspect that it is genetic, especially since they found a strong link between older paternal age and early-onset bipolar disorder, which has shown greater heritability than bipolar disorder that occurs later in life.

Furthermore, Frans and her group speculated in their report, older men's genetic proneness to father children with bipolar disorder may be due to the fact that “spermatogonial cells replicate every 16th day, resulting in approximately 200 divisions by the age of 20 years and 660 divisions by the age of 40 years [and even more divisions as a man grows older. Thus] disorders associated with advancing paternal age could partially result from de novo mutations.”

Women, in contrast, they explained, “are born with their full supply of eggs that have gone through only 23 replications, a number that does not change as they age. Therefore DNA copy errors should not increase in number with maternal age.”

The study had no outside funding.

An abstract of “Advancing Paternal Age and Bipolar Disorder” is posted at.▪

American Psychiatric Association

Egg and sperm donation rules to be reviewed

2009-12-09T21:42:00.000-08:00

Egg and sperm donation rules to be reviewed

By John von Radowitz, Press Association

Wednesday, 9 December 2009

A major review of the rules regarding sperm, egg and embryo donation will take place over the course of next year.

The most controversial area to be discussed concerns expenses payments made to donors.

Also on the agenda will be age limits for male and female donors, and restrictions on how many families a man can donate his sperm to.

Currently in the UK payments for sperm and egg donations can only be made to reimburse travel costs and loss of earnings.

Some other European countries interpret the rules more liberally to include compensation for "inconvenience".

Under EU law donors cannot be paid directly for their eggs and sperm, as happens in the US where people earn large sums of money helping infertile couples. An EU directive limits compensation to "making good expenses and inconveniences related to the donation".

In the UK expenses payments for donors are broadly in line with those given to jurors. There is an overall limit of £250 for each course of sperm or egg donation.

Four years ago the Human Fertilisation and Embryology Authority (HFEA), which regulates fertility services and research, decided not to allow compensation for "inconvenience". It was felt that paying "inconvenience" money might encourage people to make donations without thinking enough of the consequences.

Since then there have been calls for more flexibility to better reflect the sacrifices made by many donors.

Members of the HFEA agreed to hold the review at a meeting today.

Professor Lisa Jardine, who chairs the authority, said: "The authority had a rewarding and well informed debate across a wide range of important issues and arrived at some significant decisions. I welcome the fact that we are now beyond the implementation of the new legislation and can address issues which have implications for all of our stakeholders.

"There was a general view that the HFEA's policy with regard to reimbursement for donors, which has now been in place for two years since the introduction of the European Tissue and Cell Directive, was one that could usefully be revisited in light of what we have learned over those two years. We will not prejudge the outcome of the review that will now take place."

Other issues to be addressed include whether to change the current lower age limit for egg donation, which currently stands at 18, to take account of potential health risks.

The authority will also look at whether its upper age limit of sperm donors should be brought in line with professional guidelines. The official age limit is now 45, while the professional guidance recommends 40 or younger.

Also under discussion is the 10-family limit for sperm donors. This prevents a man donating his sperm to more than 10 families, irrespective of the number of babies that result.

Egg sharing, donations between family members, and the possibility of allowing people only to donate to certain patient groups will also be considered.

Paternal age as a risk factor for schizophrenia: How important is it?

2009-12-06T05:33:00.000-08:00

Paternal age as a risk factor for schizophrenia: How important is it?
Auteur(s) / Author(s)
FULLER TORREY E. (1) ; BUKA Stephen (2) ; CANNON Tyrone D. (3) ; GOLDSTEIN Jill M. (4) ; SEIDMAN Larry J. (5 6) ; TIANLI LIU (2) ; HADLEY Trevor (7) ; ROSSO Isabelle M. (8) ; BEARDEN Carrie (3) ; YOLLCEN Robert H. (9) ;
Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)
(1) The Stanley Medical Research Institute, 8401 Connecticut Ave., Suite 200, Chevy Chase, MD 20815, ETATS-UNIS
(2) Department of Community Health, Brown University, 121 South Main Street, Providence, RI 02806, ETATS-UNIS
(3) Departments of Psychology and Psychiatry, 1285 Franz Hall, University of California, Los Angeles, Los Angeles, CA 90095, ETATS-UNIS
(4) Departments of Psychiatry and Medicine, Harvard Medical School at Brigham and Women's Hospital, One Brigham Circle, Division of Women's Health, 3rd floor, 1620 Tremont St., Boston, MA 02120, ETATS-UNIS
(5) Harvard Medical School, Department of Psychiatry, Massachusetts Mental Health Center Public Psychiatry Division, Beth Israel Deaconess Medical Center, Boston, MA 02115, ETATS-UNIS
(6) Harvard Medical School, Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114, ETATS-UNIS
(7) Department of Psychiatry, University of Pennsylvania, 3535 Market Street, Philadelphia PA 19104, ETATS-UNIS
(8) McLean Hospital and Harvard Medical School, 115 Mill Street, Belmont, MA 02478, ETATS-UNIS
(9) The Stanley Division of Developmental Neurovirology, Johns Hopkins University, 600 N. Wolfe Street, Blalock 1105, Baltimore, MD 21287-4933, ETATS-UNIS

Résumé / Abstract
Advanced paternal age has been widely cited as a risk factor for schizophrenia among offspring and even claimed to account for one-quarter of all cases. We carried out a new study on 25,025 offspring from the Collaborative Perinatal Project (CPP), including 168 diagnosed with psychosis and 88 with narrowly defined schizophrenia. We also conducted a meta-analysis of this and nine other studies for which comparable age-cohort data were available. The mean paternal age for the CPP cases was slightly, but not significantly, higher than the matched controls (p=0.28). Meta-analyses including these new results were conducted to determine the relative risk associated with alternative definitions of advanced paternal age (35, 45 or 55 years and older). These yielded pooled odds ratios and 95% confidence intervals of 1.28 (1.10, 1.48),1.38 (0.95, 2.01) and 2.22 (1.46, 3.37), respectively. Thus, increased paternal age appears to be a risk factor for schizophrenia primarily among offspring of fathers ages 55 and over. In these 10 studies, such fathers accounted for only 0.6% of all births. Compared with other known risk factors for schizophrenia, advanced paternal age appears to be intermediate in magnitude. Advanced paternal age is also known to be a risk factor for some chromosomal and neoplastic diseases in the offspring where the cause is thought to be chromosomal aberrations and mutations of the aging germline. Similar mechanisms may account for the relationship between advanced paternal age and schizophrenia risk.
Revue / Journal Title
Schizophrenia research ISSN 0920-9964
Source / Source
2009, vol. 114, no1-3, pp. 1-5 [5 page(s) (article)] (3/4 p

Men's biological clocks are ticking, too

2009-12-04T14:16:00.000-08:00

Evidence is piling up that men, or at least our reproductive parts, have a "best before" date. Not only is it harder to create a pregnancy after the age of 35 or 40, researchers are finding that our sperm quality decreases with age. This can result in a higher-than-normal incidence of offspring with schizophrenia, autism and low IQ, as well as an increased chance of miscarriage.

Scientists Believe Your Cell Phone Is a Death Trap

2009-12-01T06:51:00.000-08:00

Scientists Believe Your Cell Phone Is a Death Trap
Articles Home » Scientists Believe Your Cell Phone Is a Death Trap

Dr. Mercola

December 01 2009

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In the video above, ElectromagneticHealth.org founder Camilla Rees presents an overview of an emerging public health issue -- excessive exposures to microwave radiation from wireless technologies.

Illness linked to electromagnetic radiation exposure inclufiede many cancers, neurological conditions, ADD, sleep disorders, depression, autism, cognitive problems, cardiovascular irregularities, hormone disruption, immune system disorders, metabolism changes, stress, fertility impairment, increased blood brain barrier permeability, mineral disruption, DNA damage and much, much more.

Learn how to sensibly protect yourself in high EMF environments, and why it is important you join others in advocating for stricter safety standards for wireless technologies.

The Web site ElectromagneticHealth.org also offers ten free audio interviews with some of the world’s leading experts in the field of EMF.

Click the source link below to hear some of the fascinating information and insights they offer!

Sources:

Electromagnetic Health

Dr. Mercola's Comments
The video above is a great, broad summary of what we now know about the dangers inherent with our wireless revolution. There’s no doubt in my mind that if our society keeps ignoring this issue, we will pay a very steep price in declining health over the coming generations.

However there are a large number of other excellent video interviews on their site, www.ElectroMagneticHealth.org, which is a tremendous resource of EMF knowledge. There is even one from my mentor Dr. Dietrich Klinghardt. If you were to attend a conference that had all these presentations, I am sure you would spend hundreds of dollars, but now you can access them all for free.

Personally, I believe this issue is so important, I’ve created an entire web site dedicated to EMF education and information. Feel free to bookmark EMF.mercola.com, and check back on occasion for the latest news and updates.

Unfortunately, while some countries are taking measures to reduce public radiation, the United States is not one of them. Instead, the US is heading in the exact opposite direction with the introduction of Wi-Max, short for Worldwide Interoperability for Microwave Access.

As infatuating as this type of technology can be to technological geeks and business people alike (myself included), the health ramifications cannot be ignored. We are already seeing increasing numbers of people suffering the very real effects of electrohypersensitivity.

The problem has gotten bad enough that France, for example, has created “EMF refugee zones,” where those who are hypersensitive now live in trailers, doing everything they can to protect themselves in order to be able to function normally.

Do You Experience Electromagnetic Hypersensitivity Symptoms?
The graph below, created by Prof. Magda Havas, PhD, illustrates the frequency of electromagnetic hypersensitivity symptoms based on your distance to a cell phone base station (cell phone tower). It is based on a Spanish study published in 2001 in the journal La Presse Medicale, which clearly showed that the closer you are to the base station, the greater your chances of exhibiting a number of health related symptoms such as fatigue, sleep disturbances, visual and auditory disturbances, and cardiovascular effects, just to name a few.

It’s worth noting that these symptoms are just for ONE type of exposure, at a distance. It does not include the effects of other technologies that are emitting radiofrequency radiation as well, such as cell phones, cordless home phones, and wi-fi networks in your office.

Now we’re even blasted with WiFi on airplanes. Last week I actually used WiFi in the sky to get some work done on a four hour trip to LA. Soon WiFi internet will be on EVERY aircraft.

When you add all sources of exposure together, the potential effects become quite staggering.

The Biological Effects of EMF
There is a significant amount of studies showing the biological effects of electromagnetic fields and radiofrequencies within the microwave range. However, the crux of the issue is that industry claims that since these technologies do not have a thermal (heating) effect on your body, they will not cause biological problems.

There are literally thousands of studies showing that this logic is incorrect. EMF’s DO cause biological harm, even without thermal effects, including:

The truth is that industry, and our regulating agencies, are simply choosing not to look at any of this research…

Scientists across the globe are starting to pay attention to this issue, and they’re seeing the problems. Professor Franz Adelkofer, coordinator of the REFLEX report, has stated:

“This is real evidence that hyperfrequency electromagnetic fields can have geno-toxic effects. And this damaged DNA is always the cause of cancer.

We’ve found these damaging effects on the genes at levels well below the safety limits. That’s why we think it’s urgent to base our safety limits on the biological effects, not the thermic ones.

They should be based on biology, not on physics.”

Two great sources of research into the biological effects of EMF’s and other types of radiation include the BioInitiative Report, which was published in August 2007 (available on www.bioinitiative.org), and the 2009 special EMF issue of the Journal of Pathophysiology.

I also recommend the book Public Health SOS: The Shadow Side of the Wireless Revolution, written by Camilla Rees and Magda Havas, PhD.

The Real Reason Why US Government is So Slow to Protect You
Most people do not realize this, but the US government has significant conflicts of interest on this issue.

For example, the top 20 telecom companies have spent $2.3 billion in political lobbying over the past 10 years to influence government officials, both in the US and in other countries. The US also receives significant federal revenue from individual usage taxes, in addition to the revenue collected directly from the telecom industry.

Last but not least, companies bought spectrum rights with little money down in the late 1990s, with the agreement to pay these loans back with user fees over time. Essentially, the FCC is a mortgage holder for the mobile phone industry!

As is the case any time you’re dealing with conflicts of interest of this magnitude, it will take Herculean efforts to break through the walls of greed to protect human health. But it must be done, and it will require people like you and me to keep pushing for change.

Says Olle Johanson, PhD, from the Karolinska Institute in Sweden:

“It is evident that various biological alterations, including immune system modulation, are present in electrohypersensitive persons.

There must be an end to the pervasive nonchalance, indifference and lack of heartfelt respect for the plight of these persons. It is clear something serious has happened and is happening. Every aspect of electrohypersensitive people’s lives, including the ability to work productively in society, have healthy relations and find safe, permanent housing, is at stake.

The basics of life are becoming increasingly inaccessible to a growing percentage of the world’s population. I strongly advise all governments to take the issue of electromagnetic health hazards seriously and to take action while there is still time. There is too great a risk that the ever increasing RF-based communications technologies represent a real danger to humans.

Governments should act decisively to protect public health by changing the exposure standards to be biologically-based, communicating the results of the independent science on this topic and aggressively researching links with a multitude of associated medical conditions.”

Factors that Influence Your Susceptibility to EMF Damage
Researchers have found that there are a number of factors that influence the degree to which you may be affected by EMF’s and other types of radiowaves. For example, according to the research by Dr. Dietrich Klinghardt, your physical body, such as your body weight, body-mass index, bone density, and water and electrolyte levels can alter the conductivity and biological reactivity to EMFs.

Heavy metals in your brain also act as micro-antennas, concentrating and increasing reception of EMF radiation. Likewise, any kind of metal implants and/or amalgam tooth fillings will significantly increase reception of microwaves, and the mircrocurrents from cell phones and other ambient fields.

This is yet another major reason for having your mercury fillings removed by a trained biological dentist.

Your genes can also play a part, as certain genes regulate metal detoxifying enzymes. So depending on your genetic makeup, you may be more or less predisposed to electromagnetic hypersensitivity.

People who suffer from diseases that causes myelin loss, such as muscular sclerosis, Lyme disease, and other autoimmune diseases are also at greater risk of electro-sensitivity.

Unfortunately, EMFs have been found to cause microorganisms to release higher amounts of potent toxins, which can exacerbate infections and autoimmune diseases.

Your overall risk is also dependent on other sources of EMF, such as the synergistic effect from geopathic earth radiation, metallic objects and furnishings in your home or office, electronic appliances, and household wiring.

Mechanism of Action
According to Dr. Andrew Goldsworthy retired from the Imperial College of London, acute electrohypersensitivity symptoms and diseases stemming from excessive non-thermal radiation exposure could potentially be explained by the effects on the cell wall.

Because as your body absorbs radiation, currents are created that weaken your cells’ walls by removing calcium and other divalent ions.

This creates permeability, or “leakage” in your body, and this is known to happen even in non-thermal fields, and, interestingly, only in certain “amplitude windows.” Low frequencies can be worse than high frequencies, and pulsed waves are worse than sine waves.

One of the most noticeable effects of this permeability in your body is the effect it can have on your brain function. As explained in the video, programmed flow of calcium ions through your cell membranes is a prerequisite for release of neurotransmitters. “Unscheduled” leakage of calcium ions increases background calcium which makes membranes hypersensitive and more likely to transmit random signals.

The end result can be clouded mental activity. It can also activate random thoughts, which naturally makes it more difficult to concentrate.

Much of this effect is characteristic of ADHD…

Also, leakage of digestive enzymes from lysosomes can account for damage to DNA, and may offer yet another explanation for cancer rates and the rise in infertility. The resulting DNA fragmentation may also create genetic mutations that could appear in future generations.

Interestingly, and quite believably, the rise in microwave radiation and EMF exposure may be a significant contributing factor to the skyrocketing increase in autism, as electromagnetically induced membrane leakage leads to brain hyperactivity. A summary of a study conducted by Dr. Dietrich Klinghardt, MD, on the EMF level in the bedrooms of pregnant women whose children were autistic, versus EMF levels of mothers who had healthy children, can be found in the "Media Story Leads" section of www.ElectromagneticHealth.org. Body voltage levels in that location were also measured in the study.

The results suggest an urgent need for further research in the autism-EMF area, especially given the official number of children with autism was recently announced to be 1 in 91, compared to 1 in 150 in 2002.

More research is also needed on the mechanisms of action in general. A summary of all currently known mechanisms of action is expected to be published in 2010.

For example, in addition to Dr. Goldsworthy's theories discussed above, other possible mechanisms of action leading to symptoms and diseases include: increased free radical production, and impact on serotonin and melatonin.

In Defending Itself, Your Body Wears Itself Out…
The good news is that your body can, to a degree, defend itself from these types of radiation damage. It does so by pumping surplus calcium out of your cells, and by activating certain enzymes that protect your DNA, and by making heat shock proteins to protect enzymes.

The bad news is that in doing so, your body becomes fatigued, and the more it has to defend itself, the worse your health will fare. Eventually, it can start interfering with your metabolism; impair your immune system; and lower your resistance to disease and cancer.

Last but not least, EMF exposures have a sensitizing effect, so you will become more and more sensitive over time.

How You Can Help Yourself
Fortunately, you are not completely helpless. There are strategies that can help reduce your exposure and protect your health against the constant onslaught of radiation.

First and foremost, you’ll want to reduce your exposure to as many sources as you can.

For my latest list of safety tips and guidelines on how to reduce your exposure, please see this previous article.

In addition to my recommendations, Camilla Rees mentions a few more in her video above, including:

Intestinal care – mainly by making sure you’re getting plenty of healthy probiotics. The Paracelsus Clinic in Switzerland discovered that symptoms of electrosensitivity can be reduced by providing gut barrier support. For more information, listen to the interview with Dr. Rau, medical director of the Paracelsus Clinic, available at this link.
Regular detoxification programs – Reducing your toxic burden has become far more important than it ever was before. Not only are you dealing with increasing amounts of toxic chemicals in your environment, your body is full of microorganisms that respond to EMFs by generating increased levels of their own toxins, according to a course for physicians on this subject, taught by Dr. Dietrich Klinghardt, MD.
Beware of mold – Mold, just like other microorganisms, can also react in high EMF environments. One study showed 600 times more neurotoxins generated from mold in a high EMF environment. According to Rees, there are also mold legal cases being reviewed, assessing if problems in buildings infested with mold may have actually been related to nearby antenna infrastructure.
Last but not least, please do help spread awareness about this ever increasing problem.

For more information, please see EMF.mercola.com for the latest news and updates.

It’s unfortunate, but the government is not likely to step up and do the right thing to protect your health, and the health of your children and grandchildren. We need you to get involved, at any level you can, to help increase the pressure on industry and industry regulators, to ensure a safer future for everyone, everywhere.

Related Links:

A Cell Phone on Your Hip Weakens Your Bones

Top 'Safe' Cell Phones That Aren't Safe

Secret Link Between Cigarettes and Cell Phones

Differences in maternal and paternal age between Schizophrenia and other psychiatric disorders.

2009-12-01T06:35:00.000-08:00

Schizophr Res. 2009 Nov 27. [Epub ahead of print]

Differences in maternal and paternal age between Schizophrenia and other psychiatric disorders.
Lopez-Castroman J, Gómez DD, Belloso JJ, Fernandez-Navarro P, Perez-Rodriguez MM, Villamor IB, Navarrete FF, Ginestar CM, Currier D, Torres MR, Navio-Acosta M, Saiz-Ruiz J, Jimenez-Arriero MA, Baca-Garcia E.

Department of Psychiatry at Fundacion Jimenez Diaz Hospital and Autonoma University, CIBERSAM, Madrid, Spain.

Advanced parental age has been shown to increase offspring risk for a number of neuropsychiatric disorders including schizophrenia and Down's syndrome. Other psychiatric disorders have been less studied with respect to the effect of parental age on offspring risk. In this study we examine if advanced parental age increased risk for ICD-10 diagnoses. We hypothesized that advanced parental age would increase risk for offspring psychotic disorders and mental retardation but not other ICD-10 diagnoses. We examined follow-up data for 30,965 subjects treated in outpatient psychiatric facilities between 1980 and 2007. Subjects were younger than 18years of age at their first outpatient visit. A comparison group was obtained from data on registered births in Spain from 1975. We compared parental age (maternal, paternal, combined) across diagnostic categories using ANOVA and logistic regression was used to estimate the risk of psychopathology in the offspring with advanced parental age (maternal, paternal, combined). Maternal and paternal ages were higher for subjects diagnosed with mental retardation. Risk for psychotic disorders showed a significant linear increase only with advancing maternal age, and not paternal age as is more often reported.

PMID: 19945257 [PubMed - as supplied by publisher]

2009-11-27T06:14:00.000-08:00

Clin Dysmorphol. 2009 Nov 24. [Epub ahead of print]

Limb malformations with associated congenital constriction rings in two unrelated Egyptian males, one with a disorganization-like spectrum and the other with a probable distinct type of septo-optic dysplasia.
Temtamy SA, Aglan MS, Ashour AM, El-Badry TH.

Departments of aClinical Genetics bOrodental Genetics, Division of Human Genetics and Genome Research, National Research Centre, Cairo, Egypt.
In this report, we describe two unrelated Egyptian male infants with limb malformations and constriction rings.
The first case is developing normally but has severe limb anomalies, congenital constriction rings, scoliosis because of vertebral anomalies, a left accessory nipple, a small tumor-like swelling on his lower back with tiny skin tubular appendages, a hypoplastic scrotum, and an anchored penis. The second case is developmentally delayed with limb malformations, congenital constriction rings, a lumbar myelomeningeocele, hemangioma, and tiny tubular skin appendages on the back. The patient also had bilateral optic atrophy. The constellation of features in our patients cannot be fully explained by the amniotic disruption complex. The first patient may represent an additional case of the human homolog of the mouse disorganization mutant. The presence of bilateral optic atrophy in the second case, although without an absent septum pellucidum nor other brain anomalies resembles the infrequently reported disorder of septo-optic dysplasia with limb anomalies. Both cases were sporadic and could be caused by a new dominant mutation because of the high paternal age of case 1 and the history of paternal occupational exposure to heat for both fathers. We draw attention to the phenotypic overlap between the disorganization-like syndrome and septo-optic dysplasia with limb anomalies.

PMID: 19940763 [PubMed - as supplied by publisher]