Tuesday, March 27, 2007

Advancing Paternal Age, Risk of Male Infertility and the Risk of Genetic Diseases Not Taught In School

Women seem to be more attuned to their biological clocks," he said. "With men the clock seems to tick more slowly, but often I don't think they hear it at all."

Dr Pacey said the government should tackle the problem by broadening sexual education to include advice on starting families. "What we're very good at in schools is getting the message across about sexually transmitted diseases and early pregnancy, but what we're not so good at is explaining when is the best time to have family."

Dr. Allan Pacey
Allan Pacey, the secretary of the British Fertility Society and senior lecturer at Sheffield University, said the evidence for male fertility dropping with age was beginning to stack up. A previous study had revealed a greater risk of Down's syndrome in children born to older fathers.

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Thursday, March 22, 2007

"Spontaneous Copy Number Mutations in Sporadic Cases of Autism

CSHL Scientists Confirm Genetic Distinction Between Heritable and Sporadic Cases of Autism

Science Publishes "Strong association of de novo copy number variation with autism"

“Sporadic autism is the more common form of the disease, and even the inherited form might derive from a mutation that occurred in a parent or grandparent,” explained Wigler. Using a high-resolution method for analyzing DNA called microarray technology, the researchers found that spontaneous copy number mutations occur primarily in sporadic cases. The study reports that these new mutations were found less frequently in families that have more than one child with autism.

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Monday, March 19, 2007

Father's Age is a Major Risk Factor for Schizophrenia

Primary Psychiatry

Dr. Dolores Malaspina interviewed by Dr. Norman Sussman

What is the most irrefutable finding that you and your colleagues have made?
"The most irrefutable finding is our demonstration that a father’s age is a major risk factor for schizophrenia. We were the first group to show that schizophrenia is linearly related to paternal age and that the risk is tripled for the offspring of the oldest groups of fathers.This finding has been born out in every single cohort study that has looked at paternal age and the risk for schizophrenia. The only other finding that has been as consistently replicated in schizophrenia research is that there is an increased risk associated with a family history of schizophrenia. Since only 10% to 15% of schizophrenia cases have a family history, family history does not explain much of the population risk for schizophrenia. However, we think that approximately one third or one quarter of all schizophrenia cases may be attributable to paternal age. Paternal age is the major source of de novo genetic diseases in the human population, which was first described by Penrose in the 1950s. He hypothesized that this was due to copy errors that arose in the male germ line over the many cycles of sperm cell replications. These mutations accumulate as paternal age advances. After the Penrose report, medical researchers identified scores of sporadic diseases in the offspring of older fathers, suggesting that these could occur from gene mutations. Particular attention was paid to conditions in last-born children."

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Autism Risk Rises With Age Of Father

Part of the article in the Washington Post published when the Reichenberg et al. study was published last September.

Large Study Finds Strong Correlation

By Shankar Vedantam
Washington Post Staff Writer
Tuesday, September 5, 2006; Page A01

Children born to fathers of advancing age are at significantly higher risk of developing autism compared with children born to younger fathers, according a comprehensive study published yesterday that offers surprising new insight into one of the most feared disorders of the brain.

With every decade of advancing age starting with men in their teens and twenties, the new study found, older fathers pose a growing risk to their children when it comes to autism -- unhappy evidence that the medical risks associated with late parenthood are not just the province of older mothers, as much previous research has suggested.

Of special concern is the finding that the risk for autism not only increases with paternal age but also appears to accelerate.

When fathers are in their thirties, children have about 1 1/2 times the risk of developing autism of children of fathers in their teens and twenties. Compared with the offspring of the youngest fathers, children of fathers in their forties have more than five times the risk of developing autism, and children of fathers in their fifties have more than nine times the risk

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Delayed parenthood and the risk of cesarean delivery--is paternal age an independent risk factor?

Tang CH, Wu MP, Liu JT, Lin HC, Hsu CC.
Associate Professor at the School of Health Care Administration, Taipei Medical University, Taiwan.

BACKGROUND: Between 1995 and 2001, the average cesarean section rates in Taiwan were as high as 33.34 percent. This study set out to determine the independent effects of paternal age on the likelihood of cesarean delivery among a sample of Taiwanese women. METHODS: Logistic regressions were used to analyze 310,574 singleton deliveries by nulliparous women in Taiwan between 1999 and 2001, linking data abstracted from birth certificates and from the National Health Insurance claims database. After controlling for socioeconomic, pregnancy, and obstetric complications, as well as institutional factors, we investigated both maternal and paternal ages simultaneously, using the single category variable "parental age" to determine the differential age effects on the risk of cesarean delivery. RESULTS: Taking 20- to 29-year-old couples as the reference group, we observed that the relative risks of cesarean delivery become progressively higher with advancing age of the mother. At the same time, within each maternal group, positive and significant variations in cesarean rates occurred for different paternal age groups. The respective increases in the relative risks of cesarean delivery for men aged 20-29, 30-34, 35-39, and 40 years or more, in conjunction with women aged 20-29, 30-34 and 35 or over, are 34 percent from 1.00 to 1.34, 18 percent from 1.51 to 1.69, and 16 percent from 2.03 to 2.19. Other confounding variables are also taken into account. CONCLUSIONS: Irrespective of maternal age, advancing paternal age also appears to be an additional independent factor that has a strong association with the increase in cesarean section rates.

PMID: 16499528 [PubMed - indexed for MEDLINE]

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Parental Age As A Risk Factor of Childhood Leukemia and Brain Cancer in Offspring

: Epidemiology. 1999 May;10(3):271-5.
Hemminki K, Kyyronen P, Vaittinen P.
Department of Biosciences at Novum, Karolinska Institute, Huddinge, Sweden.

We use here the Swedish Family-Cancer Database to analyze the time trends in childhood leukemia and brain cancer between 1960 and 1994 and the effect of parental age on childhood leukemia and brain cancer of some 1500 cases each. The database includes all persons born in Sweden after 1940 with their biological parents, over 6 million individuals, whose cancers were retrieved from the Swedish Cancer Registry from years 1958-1994. Incidence in cancer increased from 1960 to 1994; low grade astrocytoma accounted for most of the increase, whereas high grade astrocytoma has not increased in incidence. There has been a moderate increase in leukemia to about 1980. We found a parental age effect for both leukemia and brain cancer, with the former (of about 50% excess in those over 35 years) being mediated by maternal age and the latter (of about 25% excess) by paternal age. Accumulation of chromosomal aberrations and mutations during the maturation of germ cells is a likely mechanism for these findings. They can help to explain partially the secular trends of these malignancies and the excess risks in offspring of the well educated.

PMID: 10230837 [PubMed - indexed for MEDLINE]

No abstract available unfortunately, if interested you have to buy the article.

1: Int J Epidemiol. 2007 Jun;36(3):691-2. Epub 2007 Jun 5.
Comment on:
Int J Epidemiol. 2006 Dec;35(6):1495-503.
Parental age and risk of acute lymphocytic leukaemia and embryonal tumours in the Piedmont Region, Italy.
Maule MM, Vizzini L, Merletti F, Magnani C, Pastore G, Richiardi L.
PMID: 17550942 [PubMed - indexed for MEDLINE]

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Sunday, March 18, 2007

Paternal age and intelligence: implications for age-related genomic changes in male germ cells.

Malaspina D, Reichenberg A, Weiser M, Fennig S, Davidson M, Harlap S, Wolitzky R, Rabinowitz J, Susser E, Knobler HY.
New York State Psychiatric Institute and Columbia University, New York, NY 10032, USA. dm9@columbia.edu

BACKGROUND: A robust association between advancing paternal age and schizophrenia risk is reported, and genetic changes in the germ cells of older men are presumed to underlie the effect. If that is so, then the pathway may include effects on cognition, as those with premorbid schizophrenia are reported to have lower intelligence. There are also substantial genetic influences on intelligence, so de novo genetic events in male germ cells, which accompany advancing paternal age, may plausibly influence offspring intelligence.............................

with later paternal age lowering non-verbal IQ scores more than verbal IQ scores. CONCLUSION: We found independent effects of maternal and paternal age on offspring IQ scores. The paternal age effect may be explained by de novo mutations or abnormal methylation of paternally imprinted genes, whereas maternal age may affect fetal neurodevelopment through age-related alterations in the in-utero environment. The influence of late paternal age to modify non-verbal IQ may be related to the pathways that increase the risk for schizophrenia in the offspring of older fathers.

PMID: 15900226 [PubMed - indexed for MEDLINE

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The Quality of Conceptus as a Function of Father's Age

: J Urol (Paris). 1993;99(1):29-34. Links
[The quality of conceptus as a function of father's age][Article in French]
Auroux M.
Biologie de la Reproduction et du Developpement, CHU Bicetre, Le Kremlin-Bicetre.

Testicular ageing affects at the same time the individual and his lineage. In the individual, vascular, endocrine, blood testis barrier and Sertoli cells changes because of age lead a decrease of spermatozoa number and an alteration in their form and motility. These changes lead a gradual decrease of fertility. In the progeny, paternal ageing is responsible for new dominant autosomic mutations which themselves cause different malformations and perhaps for certain chromosome X linked recessive mutations. Moreover, in animal and man, paternal ageing seems responsible for a gradual lowering in the level of progeny cerebral functions. In man, very youthful age was also related to these effects. Maternal age did not appear to play a part in this event. On the whole, these results pose the problem of the optimum age for fatherhood.

PMID: 8515089 [PubMed - indexed for MEDLINE]

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Paternal Age and Mental Functions of Progeny in Man

Hum Reprod. 1989 Oct;4(7):794-7. Links
Paternal age and mental functions of progeny in man.Auroux MR, Mayaux MJ, Guihard-Moscato ML, Fromantin M, Barthe J, Schwartz D.
Biologie de la Reproduction et du Developpement, CHU Bicetre, Le Kremlin-Bicetre, France.

The effects of maternal age on the quality of offspring are well known. Those due to the father's age are less obvious, apart from the role of increasing paternal age in the onset of many dominant autosomal disorders. But an experimental model has demonstrated that, in rats, increasing paternal age, without any other anomalies, might produce a decreased learning capacity in progeny. The object of the epidemiological investigation presented here was to verify whether this effect might also occur in man. The study involved the distribution of scores obtained in psychometric tests by 18-year-old male subjects, according to their father's age at the time of their birth. This distribution indicated not only that increasing paternal age is accompanied by effects similar to those observed in animals, but also that very young paternal age was also related to these effects. Thus, the curve of such scores produced an inverted U-shape, with maximum scores obtained when the father was about thirty years of age. Maternal age did not appear to play a part in this event. These results pose the problem of identifying genetic and/or psychosocial factors which might have an impact on the quality of the conceptus.

PMID: 2606957 [PubMed - indexed for MEDLINE]

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Age of the father and development potential

1: Contracept Fertil Sex (Paris). 1992 Oct;20(10):942-5. Links
[Age of the father and development potential][Article in French]
Auroux MR.
PIP: Testicular aging, like ovarian aging, concerns not just the individual but also the quality of the gametes and hence of the offspring. The 1st signs of testicular aging appear early. Beginning around the age of 30, the vascularization begins to thin, with a progressive decline in the density of the capillaries. The membrane of the seminiferous tubules, an essential element of the hematotesticular barrier, begins to thicken and the number of Sertoli cells begins to decline. Endocrine effects usually appear a decade later, but individual variations are considerable. These modifications are accompanied by a slow decline in the number of sperm and alterations in their morphology and motility. Male fertility declines progressively with age. The quality of the gametes is lower among very young males and increases to a maximum at about age 30. Paternal aging may be responsible for well-defined syndromes in the offspring. Paternal aging has long been recognized as a factor in dominant autosomal mutations causing macroscopic malformations such as achondroplasia, Apert syndrome, Marfan's syndrome, fibrodysplasia ossificans progressiva, and others. The frequency of each disorder is very low, but the total number of recognized disorders of this type exceeds 1000, multiplying the risks so that the .3-.5% risk of anomalies due to paternal aging after 40 is comparable to the risk of trisomy 21 for women aged 35-40. Dominant autosomal mutations can also be responsible for less marked anomalies such as Recklinghausen's neurofibromatosis. Some authors believe that recessive mutations linked to the X chromosome causing hemophilia or Duchenne muscular dystrophy can also result from paternal aging. Some evidence suggests that for a given maternal age, paternal age results in subtle and continuous declines in cerebral functioning. A psychometric study of 1700 military recruits in Nancy, France, in 1985 who were 18 years old showed that sons of very young fathers and of older fathers did less well on the tests. The study is being repeated on 12,000 recruits in the Paris area in 1989-90 to verify the results. Efforts will be made to separate the influence of socioeconomic status and birth order on the results.

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Evolution of male fertility as a function of age and risks in progeny

1: Contracept Fertil Sex (Paris). 1991 Nov;19(11):945-9. Links
[Evolution of male fertility as a function of age and risks in progeny][Article in French]
Auroux MR.
PIP: Testicular aging starts form age 30 with progressive deterioration of vascularization, the density of capillaries, the diminution of the efficacy of the blood-testis barrier, the aging of Sertoli cells, which results in fall of production of androgen-binding protein. These changes lead to a slow reduction of the number of spermatozoa, although it is their quality that is responsible for male fertility. Analysis of the number, morphology, and mobility of spermatozoa of men aged 25-59 showed that the quality varies depending on age: the maximum values are reached between age 25 and 35, decreasing afterwards. The aging finally results in a degradation of the number and especially in the quality of spermatozoa, which is not satisfactory in individuals of very young age either. Whether male of female, parental aging poses a problem, because fertility diminishes and the risk of anomalies of the conceptus increase with the age of parents. It has been demonstrated that the new, autosomal dominant mutations responsible for fetal deaths or the numerous malformation syndromes, such as achondroplasia, Apert's disease, ossifying fibrodysplasia, and Marfan's syndrome, may be linked to paternal aging. The frequency of each of these syndromes is very low: 15-28 cases per million births for achondroplasia. Also, the frequency of anomalies attributable to paternal aging after the 40s reaches .3-.5% of births. Neurofibromatosis or von Recklinghausen's disease, hemophilia A, the myopathy of Duchenne, schizophrenia, and the performance of 18-year-old males on psychometric tests have been associated with paternal aging. The aging of gonads cannot be prevented, but one could avoid the consequences of the aging of gametes by avoiding having children after 35 or 40 years of age. This has been recommended to women for about 15 years, and perhaps should also be recommended to men.

PMID: 12284763 [PubMed - indexed for MEDLINE]

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Origin of mutation in sporadic cases of haemophilia-B. Mutation in carrier mother found to be of paternal origin

: Eur J Haematol. 1992 Mar;48(3):142-5. Links
Origin of mutation in sporadic cases of haemophilia-B.Kling S, Ljung R, Sjorin E, Montandon J, Green P, Giannelli F, Nilsson IM.
Department for Coagulation Disorders, University of Lund, Malmo General Hospital, Sweden.

Of the 45 haemophilia-B patients registered at the haemophilia centre in Malmo, Sweden, 24 are the sole members of their families to be affected, and in 13 of these 24 cases, ascendant relatives are available for study. Detection of the gene defect showed the mutation to be de novo in the proband in 3 of these 13 cases, and inherited from a carrier mother in the remaining 10 cases. All 10 carrier mothers were shown to have de novo mutations, as the patients' grandfathers were phenotypically and/or haematologically normal, and the grandmothers were non-carriers. Seven restriction fragment length polymorphisms (RFLPs) of the factor IX gene were used to determine whether the de novo mutations of the 10 carrier mothers were of paternal or maternal origin. In 6/10 cases, the RFLP patterns were informative, and indicated the mutation to be of paternal origin.

PMID: 1348478 [PubMed - indexed for MEDLINE]

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Parental age and risk of childhood cancers: a population-based cohort study from Sweden

International Journal of Epidemiology, doi:10.1093/ije/dyl177

Published by Oxford University Press on behalf of the International Epidemiological Association © The Author 2006; all rights reserved.
Accepted July 10, 2006

Benjamin H. Yip 1, Yudi Pawitan 1, and Kamila Czene 1 *
1 Department of Medical Epidemiology and Biostatistics, Karolinska Institute, 171 77 Stockholm, Sweden

Frequent germ line cells mutations were previously demonstrated to be associated with aging. This suggests a higher incidence of childhood cancer among children of older parents. A population-based cohort study of parental ages and other prenatal risk factors for five main childhood cancers was performed with the use of a linkage between several national-based registries.

Methods In total, about 4.3 million children with their parents, born between 1961 and 2000, were included in the study. Multivariate Poisson regression was used to obtain the incidence rate ratios (IRR) and 95% confidence interval (CI). Children <5 years of age and children 5-14 years of age were analysed independently.

Results There was no significant result for children 5-14 years of age. For children <5 years of age, maternal age were associated with elevated risk of retinoblastoma (oldest age group's IRR = 2.39, 95%CI = 1.17-4.85) and leukaemia (oldest age group's IRR = 1.44, 95%CI = 1.01-2.05). Paternal age was significantly associated with leukaemia (oldest age group's IRR = 1.31, 95%CI = 1.04-1.66). For central nervous system cancer, the effect of paternal age was found to be significant (oldest age group's IRR = 1.69, 95%CI = 1.21-2.35) when maternal age was included in the analysis.

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Effects of male age on the frequencies of germinal and heritable chromosomal abnormalities in humans and rodents.

Fertil Steril. 2004 Apr;81(4):925-43. Links
Sloter E, Nath J, Eskenazi B, Wyrobek AJ.
Biology and Biotechnology Research Program, Lawrence Livermore National Laboratory, Livermore, California 94550, USA.

Sex chromosomal nondisjunction increased with age in both human and rodent male germ cells. Both human and rodent data showed age-related increases in the number of sperm with chromosomal breaks and fragments and suggest that postmeiotic cells are particularly vulnerable to the effects of aging. Translocation frequencies increased with age in murine spermatocytes, at rates comparable to mouse and human somatic cells. Age-related mechanisms of induction may include accumulation of environmental damage, reduced efficiency of DNA repair, increased genomic instability, genetic factors, hormonal influences, suppressed apoptosis, or decreased effectiveness of antioxidants and micronutrients.

CONCLUSION(S): The weight of evidence suggests that the increasing trend toward fathering at older ages may have significant effects on the viability and genetic health of human pregnancies and offspring, primarily as a result of structural chromosomal aberrations in sperm.

PMID: 15066442 [PubMed - indexed

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Writing About a Possible campaign to Lower maternal and paternal age in Spain 1988

1: Am J Med Genet. 1988 Dec;31(4):845-52. Links
Prevalence of dominant mutations in Spain: effect of changes in maternal age distribution.Martinez-Frias ML, Herranz I, Salvador J, Prieto L, Ramos-Arroyo MA, Rodriguez-Pinilla E, Cordero JF.
Estudio Colaborativo Espanol de Malformaciones Congenitas (ECEMC), Facultad de Medicina, Universidad Complutense, Madrid, Spain.

We studied the birth prevalence of autosomal dominant mutations in Spain and estimated how a decrease in maternal age distribution may lead to reduction in dominant mutations. The data were collected by the Estudio Colaborativo Espanol de Malformaciones Congenitas from April, 1976, to December, 1985. Among 553,270 liveborn infants monitored during the period, 66 infants with autosomal dominant conditions were identified. These included Apert, Crouzon, Hay-Wells, Treacher-Collins, Robinow, Stickler, Adams-Oliver, and the blepharophimosis syndromes, achondroplasia, cleidocranial dysostosis, and thanatophoric dysplasia. The overall rate of autosomal dominant conditions was 1.2 per 10,000 liveborn infants. Thirteen (20%) had an affected relative, and 52 (79%) had a negative family history. One case was excluded because of insufficient family data. The rate of autosomal dominant mutations was 0.9 per 10,000 liveborn infants, or 47 per 1 million gametes. A reduction in the maternal age distribution of mothers age 35 years and older from the current 10.8% to 4.9%, as in Atlanta, Georgia, would reduce the rate of Down syndrome in Spain by 33% and through a change in parternal age distribution may lead to a reduction in dominant mutations of about 9.6%. This suggests that a public health campaign to reduce older maternal age distribution in Spain may also lead to a reduction in dominant mutations and emphasizes the potential that a direct campaign for fathers to complete their families before age 35 years may have a small, but measurable, effect in the primary prevention of dominant mutations.

PMID: 3239577 [PubMed - indexed for MEDLINE]

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Parental Age at Child's Birth and Son's Risk of Prostate Cancer: The Framingham Study.

Parental Age at Child's Birth and Son's Risk of Prostate Cancer: The Framingham Study.

Original Contributions

American Journal of Epidemiology. 150(11):1208-1212, December 1, 1999.
Zhang, Yuqing 1; Kreger, Bernard E. 1,2; Dorgan, Joanne F. 3; Cupples, L. Adrienne 4; Myers, Richard H. 1; Splansky, Greta Lee 5; Schatzkin, Arthur 3; Ellison, R. Curtis 1
The authors examined the relation of parental age at birth to the risk of prostate cancer among sons with the use of data from the Framingham Study. During 42 years of follow-up (1949-1993), 141 prostate cancer cases occurred in 2,164 men. All but six cases were confirmed by histologic report. The incidence rate of prostate cancer increased from 1.70 per 1,000 person-years among sons in the lowest quartile of paternal age (<27 years), to 2.00, 2.32, and 2.74 among those of each increased paternal age category (27-<32, 32-<38, and >=38 years), respectively. After adjustment for age and other covariates, men in the second, third, and oldest quartiles of paternal age had 1.2, 1.3, and 1.7 times increased risk of prostate cancer compared with men in the youngest quartile (p for trend = 0.049). Further adjustment for maternal age did not change the relation materially. The association of older paternal age with risk of early-onset prostate cancer (<65 years) ..........................................................................

Copyright 1999 by The Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland, USA. All rights reserved.

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Retinitis Pigmentosa Significant Increase in Mean Paternal Age In One form


Josseline Kaplan1 , Dominique Bonneau1, Jean Frézal1, Arnold Munnich1 and Jean-Louis Dufier2

(1) Clinique de Génétique Médicale, Unité de Recherches sur les Handicaps Génétiques de l'Enfant, INSERM U.12, Hôpital des Enfants-Malades, 149, Rue de Sèvres, 15 Paris Cedex, France
(2) Consultation d'Ophtalmologie, Unité de Recherches sur les Handicaps Génétiques de l'Enfant, INSERM U.12, Hôpital des Enfants-Malades, 149, Rue de Sèvres, 15 Paris Cedex, France

Received: 12 December 1989 Revised: 14 March 1990

Summary The clinical course of defective vision and blindness has been investigated in relation to different modes of genetic transmission in a large series of 93 families with retinitis pigmentosa (RP). For autosomal dominant RP, two clinical subtypes could be distinguished according to the delay in macular involvement. In the severe form, macular involvement occurred within 10 years, while in the mild form, macular involvement occurred after 20 years. Interestingly, a significant increase of mean paternal age (38.8 years, mean controls in France = 29.1 years, P < 0.001) was found in this form of RP, a feature which is suggestive of new mutations. For autosomal recessive RP, four significantly different clinical subtypes could be recognized, according to both age of onset and the pattern of development (P < 0.001), namely cone-rod dystrophy and early-onset severe forms on the one hand (mean age of onset = 7.6 years), late-onset mild forms and senile forms on the other. Similarly, two significantly different clinical subtypes could be recognized in X-linked RP, according to both mode and age of onset, which were either myopia (mean age = 3.5±0.5 years) or night blindness (mean age = 10.6±4.1 years, P < 0.001). By contrast, no difference was noted regarding the clinical course of the disease, which was remarkably severe whatever the clinical subtype (blindness before 25 years). In addition, all obligate carriers in our series were found to have either severe myopia or pigment deposits in their peripheral retina. Finally, sporadic RP represented the majority of cases in our series (42%). There was a considerable heterogeneity in this group, and at least three clinical forms could be recognized, namely cone-rod dystrophy, early onset-severe forms and late onset moderate forms. At the beginning of the disease, the hereditary nature of the sporadic forms was very difficult to ascertain (especially between 7–10 years) and only the clinical course could possibly provide information regarding the mode of inheritance. However, the high level of consanguinity, and the high sex ratio in early onset and severe sporadic forms (including cone-rod dystrophy), was suggestive of an autosomal or X-linked recessive inheritance, while increased paternal age in late onset forms was suggestive of autosomal dominant mutations.


References secured to subscribers.

What causes Retinitis Pigmentosa?
Retinitis pigmentosa is an inherited disorder, and therefore not caused by injury, infection or any other external or environmental factors. People suffering from RP are born with the disorder already programmed into their cells. Doctors can see the first signs of retinitis pigmentosa in affected children as early as age 10. Research suggests that several different types of gene mutations (changes in genes) can send faulty messages to the retinal cells which leads to their progressive degeneration. In most cases, the disorder is linked to a recessive gene, a gene that must be inherited from both parents in order to cause the disease. But dominant genes and genes on the X chromosome also have been linked to retinitis pigmentosa. In these cases, only one parent has passed the disease gene. In some cases, a new mutation causes the disease to occur in a person who does not have a family history of the disease. The disorder also can show up as part of other syndromes, such as Bassen-Kornzweig disease or Kearns-Sayre syndrome.

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Syndromes With Reproductive Misfunction by Dr. Paul Turek



Duchnenes in Boys Whose Mother's Had Older Fathers

Frequency of new mutants among boys with Duchenne muscular dystrophy
K. Bucher 1, Dr. V. Ionasescu 2 *, J. Hanson 2, John M. Optiz
1Department of Preventive Medicine and Environmental Health, College of Medicine, University of Iowa, Iowa City
2Department of Pediatrics, College of Medicine, University of Iowa, Iowa City
*Correspondence to V. Ionasescu, Department of Pediatrics, University of Iowa Hospitals, Iowa City, IA 52242

ribosomal protein synthesis • Duchenne • statistical analysis • mutation


Haldane's rule states that one-third of the cases of an X-linked recessive lethal should represent new mutations. This rule is derived under the assumptions that there is equilibrium between mutation and selection, that mutation rates in ova and sperm are equal, and that heterozygous and homozygous normal women have the same fitness. To test this rule for Duchenne muscular dystrophy (DMD), we have examined the mothers of 55 boys with DMD (16 familial and 39 isolated cases) and classified them as carriers or noncarriers on the basis of measures of ribosomal protein synthesis (RPS). Of the 55 mothers, only nine (16.4%) are classified as noncarriers, a figure significantly different from the expected one-third. When the analysis is limited to the 39 mothers of isolated cases, 23.1% (9/39) are classified as noncarriers, still significantly different than expected under Haldane's rule. Violation of any of the assumptions under which Haldane's rule is derived could lead to deviations from the expected one-third new mutants. We find the most likely explanation to be a higher male than female mutation rate. This is supported also by the finding that maternal grandfathers in whom a mutation occurred had higher mean age at birth of the carrier daughter (33.7 ± 1.6) than did the general population or intrapedigree controls (29.5 ± 1.3).

Received: 3 December 1979; Revised: 28 April 1980
Digital Object Identifier (DOI)

10.1002/ajmg.1320070107 About DOI

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Mothers and Fathers Ages of Patients with Anorexia were much Older


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a paternal age effect was detected in those with athetoid/dystonic cerebral palsy and congenital hemiplegia

: J Med Genet. 1993 Jan;30(1):44-6. Links
Parental age, genetic mutation, and cerebral palsy.Fletcher NA, Foley J.
Department of Neurological Sciences, St Bartholomew's Hospital, London.

Parental age and birth order were studied in 251 patients with cerebral palsy. No parental age or birth order effects were observed in spastic quadriplegia or diplegia, but a paternal age effect was detected in those with athetoid/dystonic cerebral palsy and congenital hemiplegia. These observations indicate that some cases of athetoid/dystonic or hemiplegic cerebral palsy might arise by fresh dominant genetic mutation.

PMID: 8423607 [PubMed - indexed for MEDLINE]


The Effect of Male Age on Sperm DNA Damage

1: Hum Reprod. 2007 Jan;22(1):180-7. Epub 2006 Oct 19. Links
The effects of male age on sperm DNA damage in healthy non-smokers.Schmid TE, Eskenazi B, Baumgartner A, Marchetti F, Young S, Weldon R, Anderson D, Wyrobek AJ.
Lawrence Livermore National Laboratory, Livermore, CA, USA.

BACKGROUND: The trend for men to have children at older age raises concerns that advancing age may increase the production of genetically defective sperm, increasing the risks of transmitting germ-line mutations. METHODS: We investigated the associations between male age and sperm DNA damage and the influence of several lifestyle factors in a healthy non-clinical group of 80 non-smokers (mean age: 46.4 years, range: 22-80 years) with no known fertility problems using the sperm Comet analyses. RESULTS: The average percentage of DNA that migrated out of the sperm nucleus under alkaline electrophoresis increased with age (0.18% per year, P = 0.006), but there was no age association for damage measured under neutral conditions (P = 0.7). Men who consumed >3 cups coffee per day had approximately 20% higher percentage tail DNA under neutral but not alkaline conditions compared with men who consumed no caffeine (P = 0.005). CONCLUSIONS: Our findings indicate that (i) older men have increased sperm DNA damage associated with alkali-labile sites or single-strand DNA breaks and (ii) independent of age, men with substantial daily caffeine consumption have increased sperm DNA damage associated with double-strand DNA breaks. DNA damage in sperm can be converted to chromosomal aberrations and gene mutations after fertilization, increasing the risks of developmental defects and genetic diseases among offspring.

PMID: 17053003 [PubMed - indexed for MEDLINE]

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Saturday, March 10, 2007

Newborns At Risk for Special Ed-Fathers 40 or More at birth

1: Eur J Paediatr Neurol. 2007 Mar 6; [Epub ahead of print]Newborns at risk for special education placement: A population-based study.Mannerkoski MK, Aberg LE, Autti TH, Hoikkala M, Sarna S, Heiskala HJ.
Department of Child Neurology, Hospital for Children and Adolescents, Helsinki University Central Hospital, Helsinki, Finland.

OBJECTIVES: To establish the contributions of birth weight (BW), gender, socioeconomic status (SES), and parental age on risks for special education (SE) placements in school-age children. METHODS: A population-based sample of 900 school-age children attending the following full-time SE groups: at level 1, children had isolated neurodevelopmental, physical, or other impairments; at level 2, borderline to mild intellectual disability (ID); and at level 3, moderate to severe ID. Three hundred and one children enrolled in mainstream education formed the control group (level 0). For all children with siblings, we defined familiar forms of learning disorders as having a sibling in one of the SE groupings. We performed our analysis for the entire cohort as well as comparing risk factors within the familial and non-familial types of SE groupings. RESULTS: In multinomial logistic regression analysis, age of father 40 years, low BW (<2500g or <-2 SD), male sex, and parent's lower SES, all increased the probability of SE placement. In the familial forms of levels 2 and 3, the parental SES was lower and, in addition, in the level 2, the family size was bigger. Furthermore, in the non-familial form of level 2, both the low and the high (4000g) BW were more common. CONCLUSIONS: Among the known risk factors for learning disabilities (LD), our study highlighted the importance of a higher paternal age and a lower SES especially in the familial forms of LD.

PMID: 17346999 [PubMed - as supplied by publisher]

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Friday, March 09, 2007

Genetic Diseases related to Advanced Paternal Age


Table II. Long-term effects of paternal ageing on offspring from table on page 2373 of Long –term effects of delayed parenthood by J.J. Tarin, J. Brines, and A. Cano

Dominant disorders
Wilms tumour, thanatophoric dysplasia, retinitis pigmentosa, osteogenisis imperfecta type IIA, acrodysostosis, achondroplasia, Apert’s disease, fibrodysplasia ossificans progressiva, aniridia, bilateral retinoblastoma, multiple exostoses, Marfan’s, Lesch-Nyan’s, Pfeiffer’s, Wardenburg’s, Treacher-Collins, Soto’s, and Crouzon’s syndromes, basel cell nevus, cleidocranial dysostosis, polyposis coli, oculodentodigital syndrome, Costello syndrome , progeria, Recklinghausen’s neurofibromatosis, tuberous sclerosis and renal polycystic kidney disease.

X-linked recessive diseases
Haemophilia A and Duchenne’s muscular dystrophy

Non-cytogenetic congential defects
Congential cataracts, reduction defects of the upper limb, nasal aplasia, pulmonic and urethtal stenosis, perauricular cyst, cleft palate,1 neural tube defects

Athetoid /dystonic cerebral palsy and congenital hemiplegia

Psychotic disorders

Decreased learning capacity and/or mental retardation

Moreover, (i) the activities of antioxidant enzymes within the seminal plasma and spermatozoa from older men may be reduced and so spermatozoa may be more vulnerable to mutational changes than spermatozoa from younger men; and (ii) late spermatids, and immature and mature spermatozoa do not have a DNA repair system.

posted by concerned heart at 8:37 PM | 0 comments

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Thursday, March 08, 2007

Risk for ALL increased with paternal age > or= 35 years

: Cancer. 1991 Sep 15;68(6):1351-5. Links

Maternal reproductive history and birth characteristics in childhood acute lymphoblastic leukemia.Kaye SA, Robison LL, Smithson WA, Gunderson P, King FL, Neglia JP.
Division of Epidemiology, University of Minnesota, Minneapolis 55455.

In a historical cohort study of all singleton live births in Northern Ireland from 1971-86 (n=434,933) associations between early life factors and childhood acute lymphoblastic leukaemia were investigated. Multivariable analyses showed a positive association between high paternal age (> or =35 years) and acute lymphoblastic leukaemia (relative risk=1.49; 95% confidence interval (CI)=0.96--2.31) but no association with maternal age. High birth weight (> or =3500 g) was positively associated with acute lymphoblastic leukaemia (relative risk=1.66; 95% CI=1.18--2.33). Children of mothers with a previous miscarriage or increased gestation (> or =40 weeks) had reduced risks of ALL (respective relative risks=0.49; 95% CI=0.29--0.80, and 0.67; 95% CI=0.48--0.94). Children born into more crowded households (> or =1 person per room) had substantially lower risks than children born into less crowded homes with also some evidence of a lower risk for children born into homes with three adults (relative risks=0.56; 95% CI=0.35-0.91 and 0.58; 95% CI=0.21-1.61 respectively). These findings indicate that several early life factors, including living conditions in childhood and maternal miscarriage history, influence risk of acute lymphoblastic leukaemia in childhood. Copyright 2002 The Cancer Research Campaign

PMID: 11875699 [PubMed - indexed for MEDLINE]

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Paternal Age >39 increases risk for ALL compared to 25-29

Cancer Causes Control. 2002 Feb;13(1):15-25.
Birth characteristics, maternal reproductive history, hormone use during pregnancy, and risk of childhood acute lymphocytic leukemia by immunophenotype (United States).

Ou SX, Han D, Severson RK, Chen Z, Neglia JP, Reaman GH, Buckley JD, Robison LL.
Department of Pediatrics, University of Minnesota, Minneapolis, USA. Xiao-Ou.Shu@mcmail.vanderbilt.edu

OBJECTIVE: To investigate the associations of birth characteristics and maternal reproductive factors with risk of childhood acute lymphoblastic leukemia (ALL) by immunophenotypic subtypes. METHODS: Data collected from a case-control study including 1842 ALL cases (age < 15 years) and 1986 individually matched controls were analyzed. Exposure information was obtained through telephone interviews of parents. RESULTS: Factors associated with risk of ALL from all subgroups combined included high birth weight (OR = 1.4, 95% CI = 1.1-1.8), high birth order (OR = 2.0, 95% CI = 1.3-3.0 for fourth-born child compared to first-born child). young maternal age (<20 compared to 25-29, OR = 1.4, 95% CI = 1.1-1.9), advanced paternal age (>39 compared to 25-29, OR = 1.4, 95% CI = 1.0-1.9), induced abortion prior to the index pregnancy (OR = 1.2, 95% CI = 1.0-1.4), and oral contraceptive use during the index pregnancy (OR = 1.5, 95% CI = 1.0-2.2) with children under the age of 2 (OR = 5.1, 95% CI = 1.0-24.7) being the predominantly affected group. Risk of early pre-B-cell ALL increased with advanced paternal age (OR = 1.7, 95% CI = 1.1-2.7) and high birth order (OR = 2.0, 95% CI = 1.1-3.6), while risk of pre-B-cell ALL increased with both younger (OR = 3.4, 95% CI = 1.4-8.4) and advanced maternal age (OR = 2.6, 95% CI = 1.1-5.9). T-cell ALL was associated with high birth weight (OR = 2.4, 95% CI = 1.1-5.5) and history of induced abortion (OR = 2.4, 95% CI = 1.3-4.5). CONCLUSION: This study suggests that the association of ALL with birth characteristics and maternal reproductive factors varies with the immunophenotype of the ALL. Future studies are needed to better understand the effect of maternal hormone in the development of subtype of childhood ALL.

PMID: 11899114 [PubMed - indexed


Tuesday, March 06, 2007

Paternal age is a risk factor for Alzheimer disease in the absence of a major gene.


Bertram L, Busch R, Spiegl M, Lautenschlager NT, Muller U, Kurz A.
Department of Psychiatry, Technical University Munich, Germany.

We compared the parental age at birth of patients with Alzheimer disease (AD) with that of cognitively healthy control subjects. Within 206 carefully diagnosed AD patients, two groups were distinguished according to the likelihood of carrying a major gene for AD (MGAD). This likelihood was calculated by applying a Bayesian approach which incorporates data on aggregation of the disease, age at onset, and "censoring" ages within the family. All AD patients were ranked by MGAD probability. According to the sample's quartiles, two subgroups were defined representing the 52 individuals with the lowest and the 52 with the highest MGAD probability. Age at onset of dementia, education, and apolipoprotein E epsilon4 allele frequencies were not statistically different between the two groups. Fathers of patients with a low MGAD probability were significantly older (35.7+/-8.1 years) than fathers of both other groups (high MGAD probability 31.3+/-6.9 years, P=0.004; controls 32.6+/-6.8 years, P=0.04, n=50). The differences for mothers were less pronounced and not statistically significant. These findings suggest that increased paternal age is a risk factor for AD in the absence of a major gene, whereas increased maternal age and AD are associated only weakly and independently of genetic disposition.

PMID: 10732803 [PubMed - indexed for MEDLINE]

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Disease-Causing Genetic Mutations In Sperm Increase With Men's Age

"It makes sense that the mutations causing these diseases would occur more frequently in older men, and indeed that's what we saw for Apert syndrome," says Ethylin Jabs, M.D., director of the Center for Craniofacial Development and Disorders at Johns Hopkins.

Importantly, disorders linked to advancing paternal age begin to increase rapidly at about the same time as maternal risks increase -- age 33 to 35.

To obtain the first genetic explanation for these effects, the scientists studied sperm from about 60 men of various ages and looked for two genetic changes responsible for 99 percent of the cases of Apert syndrome. They found that men over 50 were, on average, three times as likely as men under 30 to have sperm with at least one of these changes. The mutations were not more common in blood samples as men aged.

The scientists say it's likely that the number of cell divisions that go into making a sperm plays a large role in the link between Apert syndrome and paternal age, and represents a fundamental difference between how aging egg and sperm can impact the health of a child.

"In the men we studied, these mutations had not been inherited, but rather collected over time in the reservoir of primitive cells that become sperm," says first author Rivka Glaser, a graduate student in human genetics at the Johns Hopkins School of Medicine.

Cells that mature into eggs are essentially frozen in time from puberty until the time the egg is signaled to develop. Because of the stage at which they are "frozen," the most likely error in an egg is to have an abnormal partitioning of chromosomes, producing an egg with an extra copy or a missing copy, Glaser says. For example, in Down syndrome, an extra copy of chromosome 21 is inherited from the mother.

Sperm, on the other hand, are continually produced throughout a male's lifetime from a reservoir of primitive cells. These primitive cells, like other kinds of so-called stem cells, can either replicate themselves or take a step closer to becoming a sperm, a process called differentiation. All told, these cells divide every 21 days after puberty, and at each cell division the opportunity exists for an error in copying the DNA.

"Literally hundreds of millions of sperm are made in each batch, so in most cases there are still many normal sperm available," says Jabs, also a professor of pediatrics. Their study showed that "high levels" of mutations among men who had no children with Apert syndrome amounted to roughly 3 sperm with the mutation among 100,000 sperm.

If an error is made in any of the steps toward becoming a sperm, the only cells affected are the resulting sperm for that batch. However, if an error appears in a primitive cell as it replicates itself and the mistake isn't fixed, the mutation will continue to be passed on to all of its progeny, including subsequent primitive cells and other batches of semen.

As men age, more of these primitive cells have collected mutations that cause Apert syndrome, leading to more sperm with the mutations in each batch of semen, the scientists suggest. The risk of having a child with Apert is about six times higher for a man age 52 than for someone who's 27.

Authors on the study are Glaser, Jabs, and Rebecca Schulman, of Johns Hopkins School of Medicine, and Karl Broman, of the Johns Hopkins Bloomberg School of Public Health.

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