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Query: UMLS:C0004352 (autism)
 32,579 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Advanced paternal age has been associated with an increased risk for spontaneous congenital disorders and common complex diseases (such as some cancers, schizophrenia, and autism), but the mechanisms that mediate this effect have been poorly understood. A small group of disorders, including Apert syndrome (caused by FGFR2 mutations), achondroplasia, and thanatophoric dysplasia (FGFR3), and Costello syndrome (HRAS), which we collectively term "paternal age effect" (PAE) disorders, provides a good model to study the biological and molecular basis of this phenomenon. Recent evidence from direct quantification of PAE mutations in sperm and testes suggests that the common factor in the paternal age effect lies in the dysregulation of spermatogonial cell behavior, an effect mediated molecularly through the growth factor receptor-RAS signal transduction pathway. The data show that PAE mutations, although arising rarely, are positively selected and expand clonally in normal testes through a process akin to oncogenesis. This clonal expansion, which is likely to take place in the testes of all men, leads to the relative enrichment of mutant sperm over time-explaining the observed paternal age effect associated with these disorders-and in rare cases to the formation of testicular tumors. As regulation of RAS and other mediators of cellular proliferation and survival is important in many different biological contexts, for example during tumorigenesis, organ homeostasis and neurogenesis, the consequences of selfish mutations that hijack this process within the testis are likely to extend far beyond congenital skeletal disorders to include complex diseases, such as neurocognitive disorders and cancer predisposition.
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PMID:Paternal age effect mutations and selfish spermatogonial selection: causes and consequences for human disease. 2232 59

What are the implications for population health of the demographic trend toward increasing paternal age at conception (PAC) in modern societies? We propose that the effects of older PAC are likely to be broad and harmful in some domains of health but beneficial in others. Harmful effects of older PAC have received the most attention. Thus, for example, older PAC is associated with an increased risk of offspring having rare conditions such as achondroplasia and Marfan syndrome, as well as with neurodevelopmental disorders such as autism. However, newly emerging evidence in the telomere field suggests potentially beneficial effects, since older PAC is associated with a longer leukocyte telomere length (LTL) in offspring, and a longer LTL is associated with a reduced risk of atherosclerosis and with increased survival in the elderly. Thus, older PAC may cumulatively increase resistance to atherosclerosis and lengthen lifespan in successive generations of modern humans. In this paper we: (i) introduce these novel findings; (ii) discuss potential explanations for the effect of older PAC on offspring LTL; (iii) draw implications for population health and for life course; (iv) put forth an evolutionary perspective as a context for the multigenerational effects of PAC; and (v) call for broad and intensive research to understand the mechanisms underlying the effects of PAC. We draw together work across a range of disciplines to offer an integrated perspective of this issue.
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PMID:Leukocyte telomere length and the father's age enigma: implications for population health and for life course. 2347 38

There is robust evidence from epidemiological studies that the offspring of older fathers have an increased risk of neurodevelopmental disorders, such as schizophrenia and autism. The authors present a novel mechanism that may contribute to this association. Because the male germ cell undergoes many more cell divisions across the reproductive age range, copy errors taking place in the paternal germline are associated with de novo mutations in the offspring of older men. Recently it has been recognized that somatic mutations in male germ cells that modify proliferation through dysregulation of the RAS protein pathway can lead to within-testis expansion of mutant clonal lines. First identified in association with rare disorders related to paternal age (e.g., Apert syndrome, achondroplasia), this process is known as "selfish spermatogonial selection." This mechanism favors propagation of germ cells carrying pathogenic mutations, increasingly skews the mutational profile of sperm as men age, and enriches de novo mutations in the offspring of older fathers that preferentially affect specific cellular signaling pathways. This mechanism not only offers a parsimonious explanation for the association between advanced paternal age and various neurodevelopmental disorders but also provides insights into the genetic architecture (role of de novo mutations), neurobiological correlates (altered cell cycle), and some epidemiological features of these disorders. The authors outline hypotheses to test this model. Given the secular changes for delayed parenthood in most societies, this hypothesis has important public health implications.
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PMID:"Selfish spermatogonial selection": a novel mechanism for the association between advanced paternal age and neurodevelopmental disorders. 2363 89

Birth data from developed countries indicates that the average paternal age is increasing. As the trend to older fatherhood has become established, concerns have been raised that this may be linked to adverse outcomes, such as pregnancy complications, congenital anomalies, and long-term health implications for the child. Since the sperm of older fathers may be impaired due to the general effects of ageing, their offspring may be at risk due to defects in sperm quality at conception. A literature search was performed to identify pregnancy complications, fetal anomalies and health issues for the child when the father is in an older age bracket. Evidence for impairment in the sperm and genetic material of older fathers was reviewed. With an older father, there is evidence of an increase in stillbirths and a slightly increased risk of autism, bipolar disorder and schizophrenia in the offspring later in life. The increased risk of achondroplasia has long been recognised. For the mother, there is an increased rate of Caesarean section. Investigations of other possible adverse outcomes have produced mixed findings. Further robust and longitudinal studies are needed to clarify these issues.
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PMID:Delayed fatherhood. 2495 72

Autism spectrum disorder (ASD) and achondroplasia are common disorders on their own. However, this case of co-occurrence in the same patient has not yet been reported in literature except for a hypothesized statistical probability based on prevalence studies stating that two to five in 10 million children could have the probability of having both conditions occurring simultaneously. Achondroplasia typically presents with motor delays and difficulties that are related to musculoskeletal impairments that can affect self-care, mobility, and social cognition; however, the presence of delays in other domains of development, particularly in social communication, raises a suspicion of a co-occurring autism spectrum disorder. The content of this report reviews the common delays and difficulties seen in children with achondroplasia and those with autism spectrum disorder and describes the presence of both in the child presented in this case.
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PMID:Co-Occurrence of Autism Spectrum Disorder and Achondroplasia. 3131 7

Infertility and fecundity problems concern 10-18% of partners in their reproductive years compromising around one million females and males in Poland. Research and analysis of factors that affect male fertility are limited, especially, regarding the age of the father and determining the age at which quality of semen decreases. Age of the father has greater impact than maternal age, on cases of sporadic autosomal dominant congenital diseases such as Apert, Crouzon, Pfeiffer, Noonan and Costello syndromes, multiple endocrine neoplasia (types 2A and 2B) and achondroplasia. However, there are only a few reports taking paternal advanced age into consideration for pre-mature birth, low Apgar scores or admission to a neonatal intensive care department. Paternal age increases the frequency of congenital diseases such as heart malformations as well as oral, palate and lip cleft. Moreover, mental disorders (autism, schizophrenia, bipolar disorder, low IQ level as well as ADHD) also occur more frequently in advanced father's age. Advanced paternal age is defined differently in every research. It depends on disorders in offspring we are talking about. Paternal age has an impact on child's health and development and it is as significant as maternal age, when it comes to reproductive matters.
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PMID:Paternal age is affected by genetic abnormalities, perinatal complications and mental health of the offspring. 3204 16