Age of the Father and the Health of Future Generations

Age of the Father and the Health of Future Generations

THE AGE OF THE FATHER AND THE HEALTH OF FUTURE GENERATIONS
Age of the Father and the Health of Future Generations

THE AGE OF THE FATHER AND THE HEALTH OF FUTURE GENERATIONS

THE AGE OF THE FATHER AND THE
HEALTH OF FUTURE GENERATIONS
Word Count: 903
　
Leslie B. Raschka M.D., Associate Professor (retired),
Department of Psychiatry, University of Toronto
Address: 27 Edgecombe ave, Toronto, Ontario, Canada
M5N 2Xl, Tel. (416) 783-6938
2
Abstract
Purpose: To assess the role of paternal age in the origin of genetic illness in future generations.
Data Sources: All reference data originated in English language international scientific literature and findings of original research conducted by myself.
Study Selection: Original articles published between 1938 and 1998 were selected according to the stated purpose. One article was written by myself.
Data Extraction: The present paper deals with 4 subtopics: andrology, genetics, pathology, and psychiatry.
Results: Nine articles reporting on 1399 patients described the deterioration of the quality of semen related to ageing. Five articles reported an increased mutation rate in the male germ cells as compared to the female germ cell. Twenty-four articles reported on 1230 patients and related studies described paternal age effect on increased mutation rate causing genetic illness. Eight articles reporting on 10,347 patients described increased prevalence of mental illness as related to older paternal age.
Conclusions: The age of the father is an important determinant of the health of future generations. Children conceived by fathers older than 34 years of age are at increased risk for genetic illness due to recent mutation in the male germ cell.
3The genetic illness of a child could originate in a mutation related to the age of the father or to a mutation in the spermatogenesis caused by ageing in previous generations. The ageing process in the male is an important, probably the most important, cause of genetic illness in human populations.
　Key Words: Age of the father, mutation, genetic illness
4 Demographic changes taking place in the 20th Century have directed attention to all possible determinants of the health of future generations. The relationship between maternal age and Down Syndrome is a currently recognized scientific fact. The study of the reproductive efficiency of the male is also relevant to the health of future generations. Most children are born healthy regardless of paternal age; however, the age of the father is a determinant of ill health for a significant minority in future generations.
　
5 Andrology
Ageing in the male is expressed in a progressive decline both in the quality and quantity of the sperm (1). Changes include a decrease in motility (2), decreased vitality and an increased percentage of malformed sperm (3, 4, 5, 6, 7). The deterioration associated with ageing can be noticed first in men between the ages of 35 to 40 years (8, 9).
　
6 Genetics
The mutation rate is higher in the male than in the female germ cell (10, 11, 12, 13, 14). While the ageing male germ cell is especially sensitive to mutation (15) there is a significant difference in mutation, rates among different genes. There is evidence that mutation frequencies for a number of different genes causing illness increase with advancing paternal age. The rate of increase differs among different genes (16); not all genes are subject to the paternal age effect. Almost all new mutations were reported to occur in the male germ cell; however, paternal age effect is not equally pronounced in all mutations (12). It is operant in recent germline mutations. Inherited illnesses such as hemophilia A have their origins in mutations in earlier generations where, for example, increased maternal grandparental age was found and new germline mutation related to increased paternal age transmitted to future generations can result in hereditary illness. In the development of illness, more than one gene can be involved. The phenotypic expression can be influenced by modifying genes. The importance of mutations for the health of future generations was born out by the Bulletin of the World Health Organization 1986 (17), which states that about 1% of children will be born with a serious genetic disease and another 1% will develop a serious genetic illness later in life.
7 Pathology
The relationship between increased paternal age and pathological conditions of known genetic origin was reported for achondroplasia in nineteen publications (15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34); for Apert Syndrome in sixteen publications (15, 19, 20, 22, 23, 24, 25, 26, 27, 28, 30, 31, 32, 33, 34, 35); on Marfan Syndrome in thirteen publications (15, 20, 21, 22, 23, 25, 26, 27, 30, 31, 32, 33, 34); on osteogenesis imperfecta in five publications (16, 19, 24, 25, 29); on basal cell naevus syndrome in three publications (22, 26, 32); in Waardenburg Syndrome in five publications (22, 26, 31, 32, 33); on Crouzon Syndrome in seven publications (22, 26, 28, 31, 32, 33, 35); on oculo-denta; digital syndrome in four publications (22, 26, 31, 32); on thanatophoric dysplasia in three publications (28, 29, 35); on Pfeiffer Syndrome in three publications (28, 32, 35); on tuberous sclerosis in three publications (31, 33, 36); on multiple endocrine neoplasm in three publications (32, 34, 37); on myositis ossificans in nine publications (15, 19, 21, 22, 24, 30, 31, 32, 33); and on Treacher Collins disease, four publications (22, 26, 31, 33). All of these illnesses are transmitted in an autosomal dominant fashion. Increased risk for X-linked conditions associated with increased maternal grand-parental age is known to exist regarding classical hemophilia and was reported in nine publications (15, 17, 23, 25, 26 31, 32, 34, 38). This is also true for Lesch-Nyhan syndrome, reported in five publications (10, 17, 27, 31, 38). The mutation is transmitted to the child through carrier mothers.
8Psychiatry
Mutations occurring in the course of gametogenesis in the male and the association of psychosis was described in one article (39). Older maternal and paternal age in schizophrenia was reported in four articles (39, 40, 41, 42). My own study involving 574 patients has shown that the increased age of the father is a causative factor in a sub-group of the schizophrenic population (43). Two other articles, reporting on 662 and 8000 patients respectively, confirmed my conclusions, as well as indicating that increased maternal age was secondary to increased paternal age (41, 42). Three articles reporting on 1081 patients described increased paternal age in Alzheimer’s disease (44, 45, 46).
　
9 Discussion
All genetic illnesses have their origin in a distant or recent mutation. Paternal age is an important determinant of mutation frequency in new germ cell mutation, causing both autosomal dominant and X-linked recessive illnesses. The role of other mutagenic factors is not the subject of this study. The results of my own research are supported by other information which indicates that the leading cause of genetic illness present in human populations is the ageing process in the male. Conceiving children by men younger than 35 years of age would prevent many genetic illnesses in future generations.
　
10 Bibliography
1. Johnson L, Nguyen H B, Petty C S, et al. Quantification of Human Spermatogenesis: Germ Cell Degeneration during Spermatocytogenesis and Meiosis in Testes from Younger and Older Adult Men. Biol Reprod 1987; 37: 739.
2. Nieschlag E, Lammers U, Freischem C W, et al. Reproductive Functions in Young Fathers and Grandfathers. J Clin Endocrinol Metab 1982; 55: 676.
3. Holstein A F. Spermatid Differentiation In Man During Senescence. In. : Andre J, ed. Proceedings of the Fourth International Symposium on Spermatology; 1982 June; The Hague. Martinus Nijhoff, 1983: 15-18.
4. Homonnai Z T, Fainman N, David M P, et al. Semen Quality and Sex Hormone Pattern of 39 Middle Aged Men. Andrologia 1982; 14(2): 164.
5. Bacetti B, Renieri T, Selmi M G, et al. Sperm Structure and Function in 70 Year Old Humans. In: Andre J, ed. Proceedings of the Fourth International Symposium on Spermatology; 1982 June; The Hague. Martinus Nijhoff, 1983: 19-23.
6. Spira A, Ducot B. Variations physiologiques du spermatogramme. Ann Biol Clin (Paris) 1985; 43: 55.
7. Sternbach H. Age-Associated Testosterone Decline in Men: Clinical Issues for Psychiatry. Am J Psychiatry 1998; 155: 1310.
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8. Bishop M W H. Aging and Reproduction in the Male. J Reprod Fert 1970; (Suppl. 12): 65.
9. Schwartz D, Mayaux MJ, Spira A, et al. Semen characteristics as a function of age in 833 fertile men. Fertil Steril, 1983; 39: 530.
10. Vogel F. Editorial. A probable sex difference in some mutation rates. Am J Hum Genet, 1977; 29: 312.
11. Haldene J B S. The Mutation Rate of the Gene for Haemophilia and it’s Segregation Ratios in Males and Females. Ann Hum Genet 1947; 13: 261.
12. Vogel F, Motulsky AG. Human Genetics, Problems and Approaches. Berlin: Heidelberg: New York: Springer Verlag, 1979; 282.
13. Crow J F, Denniston C. Mutation in Human Populations. In: Harris H, Hirschhorn K, eds. Advances in Human Genetics. New York: London: Plenum Press, 1985; 14: 59-123.
14. Shimmin L C, Chang B H, Li W. Male-driven evolution of DNA sequences. Nature 1993; 362: 745.
15. Vogel F, Rathenberg R. Spontanious Mutation in Man. In: Harris H, Hirschhorn K, eds. Advances in Human Genetics. New York: London: Plenum Press, 1975; 5: 223-318. 12

16. Evans HJ. Mutation as a cause of genetic disease. Phil Trans R Soc Lond 1988; 319: 325.
17. Berg K, Bochkov N P, Coutelle C, et al. Bull WHO 1986; 64(2): 205.
18. Penrose L S. Parental Age and Mutation. The Lancet 1955; 2: 312.
19. Modell B, Kuliev A. Changing paternal age distribution and the human mutation rate in Europe. Hum Genet 1990; 86:198.
20. Murdoch J L, Walker B A, Hall J G, et al. Achondroplasia-a genetic and statistical survey. Ann Hum Genet 1970; 33: 227.
21. Rogers J G, Danks D M. Birth defects and the father. Med J Austr 1983; 2: 3.
22. Karp L E. Older Fathers and Genetic Mutations. Am J Med Genet 1980; 7: 405.
23. Tunte W. Human Mutations and Paternal Age. Hum Genet 1972; 16: 77.
24. Modell B, Kuliev A. Impact of public health on human genetics. Clin Genet 1989; 36: 286.
　
　
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25. Carothers A D, McAllion S J, Paterson C R. Risk of dominant mutation in older fathers: evidence from osteogenesis imperfecta. J Med Genet 1986; 23: 227.
26. Jones K L, Smith D W, Sedgwick Harvey M A, et al. Older paternal age and fresh gene mutation: Data on additional disorders. J Ped 1975; 86: 84.
27. Hook EB. Paternal Age and Effects on Chromosomal and Specific Locus Mutations and on Other Genetic Outcomes in Offspring. In: Mastroianni L Jr, Paulsen C A, eds. Aging, Reproduction and the Climacteric. New York and London: Plenum Press, 1986: 117-145.
28. Wilkin D J, Szabo J K, Cameron R, et. al. Mutations in Fibroblast Growth -Factor Receptor 3 in Sporadic Cases of Achendroplansia Occur Exclusively on the Paternally Derived Chromosome. Am J Hum Genet 1998; 63: 711.
29. Orioli J M, Castilla E E, Scarano G, et. al. Effect of Paternal Age in Achondroplasia, Thanatophoric Dysplasia and Osteogenesis Imperfecta. Am J Med Genet 1995; 59: 209.
30. Erickson D, Cohen M M Jr., A Study of parental age effects on the occurrance of fresh mutations for the Apert syndrome. Ann Hum Genet 1974; 38: 89.

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2. Bordson B L, Leonardo VS. The appropriate upper age limit for semen donors: a review of the genetic effects of paternal age. Fertil Steril 1991; 56: 397.
1. Sankaranarayanan K. Ionizing radiation and genetic risks IX. Estimates of the frequencies of mendelian diseases and spontaneous mutation rates in human populations: a 1998 perspective. Mutat Res 1998; 411: 129.
2. Friedman J M. Genetic Disease in the Offspring of Older Fathers. Obstet Gynecol 1981; 57: 745.
3. Carlson K M, Bracamontes J, Jackson C E, et al. Parent-of-Origin Effects in Multiple Endocrine Neoplasia Type 2B. Am J Hum Genet 1994; 55: 1076.
4. Moloney D M, Slaney S F, Oldridge M, et al. Exclusive paternal origin of new mutations in Apert syndrome. Nat Genet 1996; 13: 48.
5. Osborne J P, Fryer A, Webb D. Epidemiology of Tuberous Sclerosis. Ann NY Acad Sci 1991; 615: 125.
6. Schuffenecker I, Ginet N, Goldgan D, et al. Prevalence and Parental Origin of De Novo RET Mutations in Multiple Endocrine Neoplasia Type 2A and Familial Medullary Thyroid Carcinoma. Am J Hum Genet 1997; 60: 233.
　
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7. Crow J F. How Much Do We Know About Spontaneous Human Mutation Rates? Environ Mol Mutagen 1993; 21: 122.
8. Crow T J. Editorial. Mutation and psychosis: A suggested explanation of seasonality of birth. Psychol Med 1987; 17: 821.
9. Gordon A. The Incidence of Psychotic Disorders in Individuals Whose Parents Married at an Advanced Age. Med Records 1938; 148: 109.
10. Kinnell H G. Parental Age in Schizophrenia. Br J Psychiatry 1983; 142: 204.
11. Hare E H, Moran PAP. Raised Parental Age in Psychiatric Patients: Evidence for the Constitutional Hypothesis. Br J Psychiatry 1979; 134: 169.
12. Raschka L B. Parental Age and Schizophrenia. Magyar Andrologia-Hungarian Andrology 1998/2; III: 47.
13. Bertram L, Busch R, Spiegl M, et al. Paternal age is a risk factor for Alzheimer disease in the absence of a major gene. Neurogenetics 1998; 1: 277.
14. Whalley L J, Thomas B M, Starr J M. Epidemiology of Presenile Alzheimer’s Disease in Scotland (1974-88). 11. Exposures to Possible Risk Factors. Br J Psychiatry 1995; 167: 732.
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3. Urikami K, Adachi Y, Takahashi K. A Community-Based Study of Parental Age in Alzheimer-Type Dementia in Western Japan. Arch Neurol 1988; 45: 375.
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Labels: Age of the father and the Health of Future Generations Leslie B. Raschka


posted by concerned heart @ 8:37 PM 0 Comments

Tuesday, April 24, 2007
Leslie B.Raschka REALLY TRIED TO GET PEOPLE TO KNOW AND PUBLICIZE THIS RISK HE WAS TRYING TO GET THE WORLD HEALTH ORGANIZATION TO ANNOUNCE IT

this letter was published a year before Dr. Raschka's death. He sounded like a broken record trying to mention paternal age.


Journal of Psychiatry
November 2002


--------------------------------------------------------------------------------
La revue canadienne
de psychiatrie
2002 novembre


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Letters to the Editor
(PDF)


Paternal Age as a Risk Factor



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
Labels: prevention of avoidable mutational disease, Schizophrenia


posted by concerned heart @ 7:00 PM 0 Comments

LESLIE B. RASCHKA M.D. TRIED TO WARN OTHERS ABOUT THE PATERNAL AGE EFFECT BEFORE DR. MALASPINA'S 2001 PAPER

Abstract
Purpose: To assess the role of paternal age in the origin of genetic illness in future generations.
Data Sources: All reference data originated in English language international scientific literature and findings of original research conducted by myself.
Study Selection: Original articles published between 1938 and 1998 were selected according to the stated purpose. One article was written by myself.
Data Extraction: The present paper deals with 4 subtopics: andrology, genetics, pathology, and psychiatry.
Results: Nine articles reporting on 1399 patients described the deterioration of the quality of semen related to ageing. Five articles reported an increased mutation rate in the male germ cells as compared to the female germ cell. Twenty-four articles reported on 1230 patients and related studies described paternal age effect on increased mutation rate causing genetic illness. Eight articles reporting on 10,347 patients described increased prevalence of mental illness as related to older paternal age.


Conclusions: The age of the father is an important determinant of the health of future generations. Children conceived by fathers older than 34 years of age are at increased risk for genetic illness due to recent mutation in the male germ cell.
3The genetic illness of a child could originate in a mutation related to the age of the father or to a mutation in the spermatogenesis caused by ageing in previous generations. The ageing process in the male is an important, probably the most important, cause of genetic illness in human populations.
Labels: children conceived by older fathers are at increased risk of genetic illness due to a recent mutation in the male germ line, Leslie B. Raschka, M.D.