A Very Thoughtful and Brave Posting from an Older Dad.

Was father's age a factor in Va. Tech shootings?
I've struggled this week about just how to write this. Several news outlets have reported that the father of Virginia Tech gunman Cho Seung-Hui is 61. The shooter was 23, which would mean the father was in his late 30s when his son was born. Not old by the standards around here, but it does bring home the seriousness of what the decision to delay childbearing can mean. It's unclear to me what exactly Cho was diagnosed with in the past, but two things I have seen have been schizophrenia and autism.

The link between advanced paternal age and schizophrenia has been recognized for a long time now. And just what is advanced paternal age in this case? Late last year, a French researcher concluded that while "no threshold can be precisely defined," there did seem to be a difference in risks for those younger than 35 and those older than 35. There also studies that show an association between both maternal and paternal age in autism. In fathers, there may be an increased risk with each advanced decade of the father's age. Without knowing anything more than the father's age and the son's reported behaviors and ultimate violent act, it's impossible to say here if the father's age had any effect whatsoever. But I think we can conclude it was one, and only ONE, of the potential risk factors involved in this tragic case.

That said, it's important to note that Cho's actions could not be explained away by either a diagnosis of schizophrenia or autism. Obviously, most people with those disorders never do anything like he did. I don't think we'll ever know what got in him to do what he did. To say "he did this because he was autistic" - or whatever - does more to stigmatize those with disorders than it does to satisfy the need to explain why it happened.

It also doesn't mean that older dads are destined to have violent, angry kids. As I've stated many times before, the vast majority of our kids will turn out to be just as quote-unquote normal as our younger-parenting counterparts, though there are some increased risks. Those risks are real and should be taken seriously when making family-planning decisions.

Thanks to concerned heart for posts about the research on advanced paternal age.

Disorders Linked to Advancing Paternal Age Begin To Increase Rapidly 33-35

.."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. Until now, the only evidence for paternal age effects has come from determining how many children with these diseases are born to fathers of various ages.

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.
.....................................................................

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.


Note: This story has been adapted from a news release issued by Johns Hopkins Medical Institutions

YET ANOTHER STUDY CONFIRMS REICHENBERG'S FINDING THAT AUTISM RISK IS ASSOCIATED WITH INCREASING PATERNAL AGE

: Mol Psychiatry. 2007 May;12(5):419-421.Paternal age and autism are associated in a family-based sample.Cantor RM, Yoon JL, Furr J, Lajonchere CM.
[1] 1Department of Human Genetics, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA [2] 2Department of Pediatrics, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA [3] 3AGRE Consortium, Los Angeles, CA, USA.

PMID: 17453057 [PubMed - as supplied by publisher]


The paternal age distribution of the AGRE fathers, whose first child is autistic differs significantly from that of the 'control' sample (P=0.005). A 2 goodness-of-fit test with 2 degrees of freedom was conducted using percents in the 'control' group age categories to calculate the expected values in the AGRE sample. The shift toward higher paternal ages in those with an affected first-born is seen most dramatically in the group of AGRE fathers who are 30–39 years inclusive, which is 54.7% of the distribution compared with the 41.9 % that is expected. We interpret this shifted age distribution to provide support for the recently reported finding by Reichenberg and co-workers that autism risk is associated with advancing paternal age.

Men Have A Biological Clock, Too By: Judy Foreman, 07/03/2001

Judy Foreman is a Lecturer on Medicine at Harvard Medical School. Her column appears every other week. Past columns are available on www.myhealthsense.com

07/03/2001

For years, many prospective parents - and doctors as well - have blithely assumed that, if an older couple's baby has birth defects, it's most likely because of the woman's advancing age.



But, increasingly, scientists are discovering that, by focusing almost exclusively on mothers-to-be, they might have been barking up the wrong genome. A man, or more accurately his sperm, also has a biological clock. And it's ticking can be just as spooky as a woman's, perhaps even more so because its virtually impossible to do prenatal tests to pick up all the possible genetic mutations in sperm.

"There's always been this myth that fathers can be fathers until they die, and that would be fine. It's always the mother who had to be young," said Dr. Eric Vilain, a geneticist and pediatrician at the University of California at Los Angeles. But that's because the risks associated with advancing paternal age have been routinely "underestimated."
Over the years, geneticists have linked a number of other diseases to advancing paternal age, including achondroplasia, or dwarfism; Marfan's syndrome, which can lead to the fatal rupture of a major blood vessel; and Apert's syndrome, or the malformation of the skull, hands and feet.

Retinoblastoma, an eye cancer; neurofibromatosis, or fleshy growths of abnormal nerve tissue; and some types of prostate cancer also have been linked with older fathers. And some diseases caused by genes on the X-chromosome, among them hemophilia, Duchenne muscular dystrophy and Hunter syndrome, have been linked to advanced age not of a child's father but of his maternal grandfather. In these cases, an older man passes on a defective gene on the X chromosome to his daughter, who, like Queen Victoria, becomes an unaffected carrier who can pass the disease to her sons.

When certain diseases caused by genetic defects show up in a family for the first time, the odds are seven to 10 times greater that the mutation has occurred in the DNA of the father rather than that of the mother, said Dr. Victor McKusick, professor of%2

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


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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

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.

"Sung-Tae Cho, the Killer's father... He was a "Country Bumpkin", and Considerably Older than Cho's Mother"

Sung-Tae Cho, the killer's father, came from a poor rural area. He was a "country bumpkin" and considerably older than Cho's mother, Hyang-Im Kim, the daughter of a refugee, said Cho's great-aunt, Kim Yan-Soon. "We practically forced her to get married

Father's age:


South Korea's largest newspaper Chosun Ilbo reported that Cho's family was poor when they lived in a Seoul suburb and decided to emigrate to seek a better life.

The family lived in a rented, basement apartment - usually the cheapest unit in a multi-apartment building, the newspaper reported quoting building owner Lim Bong-ae, 67. Police identified the shooter's father as Cho Seong-tae, 61.

"I didn't know what (Cho's father) did for a living. But they lived a poor life," Lim told the newspaper. "While emigrating, (Cho's father) said they were going to America because it is difficult to live here and that it's better to live in a place where he is unknown."

Meanwhile, South Korean President Roh Moo-hyun held a special meeting with aides today to discuss the shooting, as the public expressed shame over a South Korean citizen being identified as the gunman.

Rwas to speak publicly about the tragedy later in the day, his office said, without elaborating on what the president discussed at the meeting with aides.

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Sung Cho, 61, and Hyang Cho, 56, kept a low profile in the small town, attending services at the Korean Presbyterian Church and planting lettuce in the backyard of their home.








Journal of Epidemiology amd Community Health 2006;60:851-853

"Average paternal age in the UK is increasing. The public health implications of this trend have not been widely anticipated or debated. .....Accumulated chromosomal aberrations and mutations occurring during the maturation of the male germ cells are thought to be responsible for the increased risk of certain conditions with older fathers. Growing evidence shows that the offspring of older fathers have reduced fertility and an increased risk of birth defects, some cancers and schizophrenia." ......

Is this Information in the Biology Textbooks By Now? This paper is from 1999

It is now 2007 and most of the public has no idea of this. This paper was published before the very large study showing that the risk of schizphrenia increases with rising paternal age and there have been nine more studies showing this in different parts of the world. IS THIS TAUGHT IN HIGH SCHOOLS ALONG WITH THE CURRICULUM TO DISCOURAGE EARLY PREGNANCY? SHOULD IT BE TAUGHT?


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

Epidemiological Studies Find Older Paternal Age and Autism Linked

Several studies13, 34-39 of clinical samples have reported advanced paternal age in individuals with autism or childhood psychosis. The results of this review show that 3 of the 4 population-based studies28-29,32 to examine paternal age reported a significant association with risk of autism and ASDs. The fourth study31 also found that paternal age was older in fathers of case patients with autism compared with fathers of controls, although this relationship was statistically weaker in the adjusted analysis. Thus, advancing paternal age is consistently associated with increased risk of autism and ASDs.
Advanced paternal age has been associated with several congenital disorders, including Apert syndrome,40 craniosynostosis,41 situs inversus,42 syndactyly,43 cleft lip and/or palate,44-45 hydrocephalus,44 neural tube defects,46 and Down syndrome.47 In addition, advanced paternal age has been associated with schizophrenia15 and decreased intellectual capacities in the offspring.48 The most widely proposed mechanism underlying these congenital anomalies is known as the "copy error" hypothesis, first proposed by Penrose.49 After puberty, spermatocytes divide every 16 days, and by the age of 35 years, approximately 540 cell divisions have occurred. As a result, de novo genetic mutations that result from replication errors and defective DNA repair mechanisms are believed to propagate in successive clones of spermatocytes. These mutations accumulate with advancing paternal age and thus help explain how this disorder, which has a large genetic component, can be maintained in the population despite reduced reproduction in affected individuals.

AUTISM OLDER FATHERS AND AUTOIMMUNE DISORDERS

Is Autism an "Auto Immune Disorder"? Are autoimmune disorders due to gene mutations due to increasing paternal age?

DIABETES TYPE 1 ASSOCIATED WITH HIGHER PATERNAL AGE

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.


MULTIPLE SCLEROSIS AND ADVANCING PATERNAL AGE


Epidemiology. 2004 Nov;15(6):717-23. Links
Parental age, family size, and risk of multiple sclerosis.Montgomery SM, Lambe M, Olsson T, Ekbom A.
Clinical Epidemiology Unit, Department of Medicine, Karolinska Hospital, Karolinska Institutet, SE-171 76Stockholm, Sweden. Scott.Montgomery@medks.ki.se

BACKGROUND: Family structure, such as having siblings, provides proxy measures for a variety of characteristics relevant to disease risk. The etiology of multiple sclerosis (MS) is not well defined and analysis of family structure may provide etiologic clues. We conducted a case-control study to examine possible associations. METHODS: Using the Swedish Inpatient Register, we identified 4443 patients with a diagnosis of MS. From the general Swedish population, using birth and death registers, we selected 24,194 controls with similar characteristics for year, county of birth, and survival until at least age at diagnosis of the matched cases. The Multi-Generation Register linked data on siblings and parents. The Census provided father's social class based on occupation. RESULTS: Having 3 or more younger siblings, compared with none, produced an adjusted odds ratio (OR) for MS (with 95% confidence interval) of 0.80 (0.70-0.92) (adjusting for number of siblings, twins, maternal and paternal age, parental MS, sex, father's social class, county and year of birth). With 3 or more older siblings, the adjusted OR was 0.83 (0.72-0.96). Different-sex twin pairs compared with singletons had an OR of 0.59 (0.37-0.95) for MS. The risk of MS increased steadily with father's age but not mother's age, up to 2.00 (1.35-2.96) for 51- to 55-year-old fathers (compared with 21- to 25-year-old fathers). CONCLUSIONS: Parents who have offspring with MS may have subtly impaired fertility. The unexpected association with paternal age may be the result of an increased risk of accumulating germ cell mutations among older men.

Why does Autism Speaks Play Down the Paternal Age Issue in the Press and in Their Literature?

Are older parents really "slightly" higher risk to have autistic children? Especially older fathers as I have not been convinced that being an older mother without other risk factors raises the risk of autism.

One thing that does raise the risk of autism, is if you have an autoimmune disorder or you parents or your cousins, aunts, uncles, grandparents do.
Why is this fact not made public?

Research Reveals A Cellular Basis For A Male Biological Clock

In the study, researchers recruited 60 men, age 22 to 60, from laboratory and clinical groups. A computerized semen analysis was performed for each of the subjects, looking for breaks in sperm cell DNA and evidence of apoptosis, or cell suicide. Normally, when something goes irreparably wrong in a cell, that cell is programmed to kill itself as a means of protecting the body.

The researchers found that men over age 35 had sperm with lower motility and more highly damaged DNA in the form of DNA double-strand breaks. The older group also had fewer apoptotic cells an important discovery, Singh said.

"A really key factor that differentiates sperm from other cells in the body is that they do not repair their DNA damage," he said. "Most other cells do."

As a result, the only way to avoid passing sperm DNA damage to a child is for the damaged cells to undergo apoptosis, a process that the study indicates declines with age.

"So in older men, the sperm are accumulating more damage, and those severely damaged sperm are not being eliminated," Singh said. "That means some of that damage could be transmitted to the baby." More research is needed to determine just what the risks are. Other reseachers in the study included Richard E. Berger, UW professor of urology. The work was supported by the Paul G. Allen Foundation for Medical Research.

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. Until now, the only evidence for paternal age effects has come from determining how many children with these diseases are born to fathers of various ages.

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.

If up to 1/3 of all schizophrenia is caused by older paternal age how much autism in the UK is also caused by older fathers?

Advanced Paternal Age: How old is too old?

Journal of Epidemiology and Community Health 2006;60:851-853



Advanced paternal age: How old is too old?
Isabelle Bray, David Gunnell and George Davey Smith
Department of Social Medicine, University of Bristol, UK


Correspondence to:
Dr I Bray
Department of Social Medicine, University of Bristol, Canynge Hall, Whiteladies Road, Bristol BS8 2PR, UK; Issy.Bray@bristol.ac.uk


Average paternal age in the UK is increasing. The public health implications of this trend have not been widely anticipated or debated. This commentary aims to contribute to such a debate. Accumulated chromosomal aberrations and mutations occurring during the maturation of male germ cells are thought to be responsible for the increased risk of certain conditions with older fathers. Growing evidence shows that the offspring of older fathers have reduced fertility and an increased risk of birth defects, some cancers, and schizophrenia. Adverse health outcomes should be weighed up against advantages for children born to older parents, mindful that these societal advantages are likely to change over time.



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Keywords: paternal age; DNA damage; fertility; abnormalities; schizophrenia