Reproducibility of the association between advanced paternal age and schizophrenia is suggestive of a Causal Link

Advanced paternal age associated with an elevated risk for schizophrenia in offspring in a Japanese population
Auteur(s) / Author(s)
TSUCHIYA Kenji J. (1) ; TAKAGAI Shu (1) ; KAWAI Masayoshi (1) ; MATSUMOTO Hideo (2) ; NAKAMURA Kazuhiko (1) ; MINABE Yoshio (1) ; MORI Norio (1) ; TAKEI Nori (1 3) ;
Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)
(1) Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, JAPON
(2) Department of Psychiatry, Tokai University School of Medicine, Isehara, JAPON
(3) Division of Psychological Medicine, Institute of Psychiatry, London, ROYAUME-UNI

Résumé / Abstract
Objective: Advanced paternal age at birth as a risk for schizophrenia in the adult offspring has been reported in previous studies exclusively conducted in Western countries and Israel. The question has arisen whether this finding could be replicated in countries with socially and culturally different attitudes toward marriage, including factors such as age at marriage. To address this question, we conducted a case-control study of a Japanese population. Methods: The subjects were representative inpatients with a DSM-IV diagnosis of schizophrenia. Unrelated healthy volunteers were recruited as control subjects. This study was conducted as one of a series of the projects by use of The Mother and Child Health Handbooks (MCHHs), from which information on parental characteristics around the time of birth, including parental ages at birth, had been extracted and recorded on computer. Results: Ninety-nine subjects with schizophrenia and 381 healthy control subjects enrolled for the study. Advanced paternal, but not maternal, age was associated with an elevated risk for schizophrenia. Reproducibility of the association across different cultures is suggestive of a causal link.
Revue / Journal Title
Schizophrenia research (Schizophr. res.) ISSN 0920-9964
Source / Source
2005, vol. 76, no2-3, pp. 337-342 [6 page(s) (article)] (18 ref.)
Langue / Language
Anglais

Editeur / Publisher
Elsevier Science, Amsterdam, PAYS-BAS (1988) (Revue)


Copyright 2006 INIST-CNRS. All rights reserved

Toute reproduction ou diffusion même partielle, par quelque procédé ou sur tout support que ce soit, ne pourra être faite

New Sporadic Breast Cancer Genes Identified

As more genes are identified, tests will become more predictive.

Douglas Easton, University of Cambridge




They identified 30 differences in single DNA bases that seemed to be linked to the disease. These were then compared in more than 20,000 women with breast cancer and in a similar number of controls. The results are reported in Nature1.





Reviews Genetics 1, 40-47 (2000); doi:10.1038/35049558




Summary

Germline base substitution mutations occur more frequently in males than in females, especially in older males.
The main explanation for the sex and age effect is that a much larger number of germline divisions occurs in the male than in the female, and continues throughout male adulthood.
Point mutations at some loci occur almost exclusively in males, whereas others have a smaller excess, roughly ten times more than in females. Which is more typical remains to be determined.
For mutations other than point mutations, sex biases in the mutation rate are very variable. However, small deletions are more frequent in females.
The total rate of new deleterious mutations for all genes is estimated to be about three per zygote. This value is uncertain, but it is likely that the number is greater than one.
It is suggested that quasi-truncation selection is the principal explanation for how the population can rid itself of a large number of mutations with a relatively low fitness cost.
Since this form of selection is effective only with sexual reproduction, perhaps the fact that humans reproduce sexually has made it possible to have such a long life cycle.


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Almost all cases of HGPS (PROGERIA) studied so far turn out to be new mutations of paternal origin with a paternal age effect by about FIVE YEARS

Origin of de novo mutation. As with de novo mutations in achondroplasia, all informative LMNA mutations have been paternal in origin, though the number of families evaluated is small [Eriksson et al 2003]. A paternal age effect is present as the father's age is significantly increased by about five years on average. There is no increase in consanguinity.



Am J Clin Nutr. 1992 Jun;55(6 Suppl):1222S-1224S. Links
Progeria: a human-disease model of accelerated aging.Brown WT.
Department of Human Genetics, New York State Institute for Basic Research, Staten Island 10314.

Progeria is a rare genetic disease with striking features that resemble accelerated aging. The inheritance pattern, paternal age effect, and lack of consanguinity argue that it is due to a sporadic dominant mutation. We have observed elevated levels of hyaluronic acid (HA) excretion in progeria patients. In several progeria patients we observed normal levels of growth hormone (GH) but very low levels of insulin-like growth factor I along with very high basal metabolic rates (BMRs). A trial of GH treatment was begun, which resulted in a marked increase in linear growth and a paradoxical drop in BMRs in these two patients. We hypothesize that the failure of patients with progeria to thrive may be due to a bioinactive form of GH and a lack of vasculogenesis caused by excess HA. An understanding of the progeria genetic mutation may define a key gene with a major effect on normal aging.






: Nature. 2003 May 15;423(6937):293-8. Epub 2003 Apr 25. Links
Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome.Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, Erdos MR, Robbins CM, Moses TY, Berglund P, Dutra A, Pak E, Durkin S, Csoka AB, Boehnke M, Glover TW, Collins FS. Department of Human Genetics, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314, USA.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by features reminiscent of marked premature ageing. Here, we present evidence of mutations in lamin A (LMNA) as the cause of this disorder. The HGPS gene was initially localized to chromosome 1q by observing two cases of uniparental isodisomy of 1q-the inheritance of both copies of this material from one parent-and one case with a 6-megabase paternal interstitial deletion. Sequencing of LMNA, located in this interval and previously implicated in several other heritable disorders, revealed that 18 out of 20 classical cases of HGPS harboured an identical de novo (that is, newly arisen and not inherited) single-base substitution, G608G(GGC > GGT), within exon 11. One additional case was identified with a different substitution within the same codon. Both of these mutations result in activation of a cryptic splice site within exon 11, resulting in production of a protein product that deletes 50 amino acids near the carboxy terminus. Immunofluorescence of HGPS fibroblasts with antibodies directed against lamin A revealed that many cells show visible abnormalities of the nuclear membrane. The discovery of the molecular basis of this disease may shed light on the general phenomenon of human ageing.

PMID: 12714972 [PubMed - indexed for MEDLINE]



1: Clin Genet. 2004 Jan;65(1):52-4. Links
Paternal origin of LMNA mutations in Hutchinson-Gilford progeria.D'Apice MR, Tenconi R, Mammi I, van den Ende J, Novelli G.
PMID: 15032975 [PubMed - indexed for MEDLINE]



FRANCIS COLLINS


"Almost all cases of HGPS studied so far turn out to be new mutations of paternal origin. Consistent with this, the age of fathers of children with HGPS is on the average slightly older than the general population of fathers. You can read more about this in the entry on progeria in GeneClinics.org"

paternal age effect is present as the father's age is significantly increased by about five years on average. There is no increase in consanguinity.




: Proc Natl Acad Sci U S A. 2007 Mar 20;104(12):4949-54. Epub 2007 Mar 14. Links
A lamin A protein isoform overexpressed in Hutchinson-Gilford progeria syndrome interferes with mitosis in progeria and normal cells.Cao K, Capell BC, Erdos MR, Djabali K, Collins FS.
Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by dramatic premature aging. Classic HGPS is caused by a de novo point mutation in exon 11 (residue 1824, C --> T) of the LMNA gene, activating a cryptic splice donor and resulting in a mutant lamin A (LA) protein termed "progerin/LADelta50" that lacks the normal cleavage site to remove a C-terminal farnesyl group. During interphase, irreversibly farnesylated progerin/LADelta50 anchors to the nuclear membrane and causes characteristic nuclear blebbing. Progerin/LADelta50's localization and behavior during mitosis, however, are completely unknown. Here, we report that progerin/LADelta50 mislocalizes into insoluble cytoplasmic aggregates and membranes during mitosis and causes abnormal chromosome segregation and binucleation. These phenotypes are largely rescued with either farnesyltransferase inhibitors or a farnesylation-incompetent mutant progerin/LADelta50. Furthermore, we demonstrate that small amounts of progerin/LADelta50 exist in normal fibroblasts, and a significant percentage of these progerin/LADelta50-expressing normal cells are binucleated, implicating progerin/LADelta50 as causing similar mitotic defects in the normal aging process. Our findings present evidence of mitotic abnormality in HGPS and may shed light on the general phenomenon of aging.

PMID: 17360355 [PubMed - indexed for MEDLINE]

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

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]

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]

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.

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
Abstract:
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.

Retinitis Pigmentosa Significant Increase in Mean Paternal Age In One form

http://www.springerlink.com/content/g32l40643n4xw567/


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.

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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.

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]

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

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=10732803&query_hl=8&itool=pubmed_DocSum

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]

Excepts from the Harvard Mental Health Letter September 2006

Minding Your Mind



New Key to Autism


September 25, 2006


By Michael Craig Miller, M.D.
Harvard Medical School

Convincing Evidence
What Causes These Genetic Errors?
Should Older Men Stop Fathering Babies?
A study published in the September, 2006 issue of the Archives of General Psychiatry may give older prospective fathers pause before plunging into biological parenthood. The authors found a significant increase in the risk of autism and similar disorders as fathers got older


This is not the first discovery of its type. Healthcare professionals have long known that as parents age, the risk of giving birth to a child with certain illnesses goes up. Older mothers, for example, are more likely to have a child with Down syndrome. In recent years, studies have revealed a link between aging fathers and schizophrenia.

Until recently, health care professionals have focused almost exclusively on the mother's age as a risk factor for health problems in the child. But we now know that the father's age also adds to the risk of potentially devastating diseases. And there is no practical way to detect these illnesses during pregnancy. For those weighing the risks, the decision can be wrenching. Adoption and in some instances a sperm donation may be acceptable alternatives to older fathers wanting to build a healthy family.

Michael Craig Miller, M.D. is Editor in Chief of the Harvard Mental Health Letter. He is also associate physician at Beth Israel Deaconess Medical Center and assistant professor at Harvard Medical School. He has been practicing psychiatry for more than 25 years and teaches in the Harvard Longwood Psychiatry Residency Program.

Paternal Age as A Risk Factor CANADIAN JOURNAL OF PSYCHIATRY NOVEMBER 2002

Letters to the Editor

Paternal Age as a Risk Factor
Dear Editor:

Recent research reports have focused attention on the association between advanced paternal age and increased risk of schizophrenia in offspring (1,2). In addition to schizophrenia, numerous genetic illnesses are reported to have the same association with increased paternal age (3). An increased mutation rate related to increased paternal age has been documented in the male gametogenesis (4). Most of these illnesses are autosomal-dominant disorders (5). Two x-linked recessive illnesses—hemophilia A and Lesch-Nyhan disease—have been frequently found with increased maternal grandpaternal age (6–8). It is proposed that the origin of schizophrenia can in some cases be related to a mutation in the gametogenesis of the father that is related to aging. It is further proposed that, as with hemophilia A and Lesch-Nyhan disease, the mutated gene or genes in some cases of schizophrenia and other genetic illnesses can be transmitted to future generations. In such cases, the illness could be expressed in a distant relative far removed in time from the original mutational event. Further genetic research on germline mutations related to paternal age is needed to establish the significance of paternal age as a risk factor.

References
1. Malaspina D, Harlap S, Fennig S, Heiman D, Nahon D, Feldman D, and others. Advancing paternal age and the risk of schizophrenia. Arch Gen Psychiatry 2001;58:361–7.

2. Raschka LB. Parental age and schizophrenia. Magyar Andrologia [Hungarian Andrology] 1998;111:47–50.

3. Tarin JJ, Brines J, Cano A. Long-term effects of delayed parenthood. Hum Reprod 1998;13:2371–6.

4. Crow JF. How much do we know about spontaneious human mutation rates? Environ Mol Mutagen 1993;21:122–9.

5. Carothers AD, McAllion SJ, Paterson CR. Risk of dominant mutation in older fathers: evidence from osteogenesis imperfecta. J Med Genet 1986;23:227–30.

6. Rimoin DL. Mutation in man. In: Emery AEH, Rimoin DA, editors. Principles and practice of medical genetics. Edinburgh (UK): Churchill Livingstone; 1983. p 32–3.

7. Crow JF. The high spontaneious mutation rate: is it a risk? Proc Natl Acad Sic USA 1997;94:8380–6.

8. Prevention of avoidable mutational disease: memorandum from a WHO meeting. Bull World Health Organ 1986;64:205–16.

Leslie B Raschka, MD, FRCPC
Toronto, Ontario

Diabetes Type 1 and Paternal Age

1: Eur J Pediatr. 1999 May;158(5):362-6. Links
Risk factors for type I diabetes mellitus in children in Austria.Rami B, Schneider U, Imhof A, Waldhor T, Schober E.
University Children's Hospital Vienna, Austria.

The aim of this study was to investigate environmental risk factors in the development of type 1 diabetes mellitus in a population-based case-control study. Parents of all patients with manifestation of type 1 diabetes between 1989 and 1994 in Vienna were asked to complete a questionnaire (n = 114). Control children (n = 495), matched for age and sex, were randomly recruited from all schools in Vienna. Fathers of diabetic children were significantly older at the time their children were born than fathers of control children (P = 0.015). Children with diabetes were more likely to be second- or third-born children (P<0.05) and fewer went to kindergarten than the control group children (P = 0.007). No significant difference in duration of gestation, percentage of delivery by caesarean section, birth weight or length was found. Neonatal jaundice was more often observed in the patient group (P = 0.038). Breast feeding was reported by 82.7% of mothers of diabetic children and by 81% of mothers of control children, and the duration of breast feeding was longer in patients than in controls (n.s.). CONCLUSION: In our study, the development of type 1 diabetes mellitus was associated with higher paternal age and neonatal jaundice. No correlation could be found with dietary intake of cow's milk products in early infancy, vaccination and other environmental factors.

PMID: 10333115 [PubMed - indexed for MEDLINE]