ALTHOUGH INFERTILE MEN MAY FATHER CHILDREN WITH ASSISTED CONCEPTION, FERTILIZATION WITH DNA-DAMAGED SPERMATOZOA MAY INCREASE RISK OF GENETIC DISEASE

Fertil Steril. 2001 Apr;75(4):674-7. Links
Correlations between two markers of sperm DNA integrity, DNA denaturation and DNA fragmentation, in fertile and infertile men.Zini A, Bielecki R, Phang D, Zenzes MT.
Division of Urology, Department of Surgery, University of Toronto, Ontario, Toronto, Canada. azini@mtsinai.on.ca

OBJECTIVE: To evaluate two different assays of human sperm DNA integrity, DNA denaturation (DD) and DNA fragmentation (DF), and to correlate these with standard semen parameters. DESIGN: Prospective, observational study. SETTING: University infertility clinic.Patient(s): Forty consecutive semen samples from 33 nonazoospermic men presenting for infertility evaluation and 7 fertile men presenting for vasectomy. Intervention(s): Assessment of sperm concentration, motility, morphology, DD and DF. MAIN OUTCOME MEASURE(S): Sperm DD and DF in fertile and infertile men. RESULT(S): The mean (+/-SE) rates of DD and DF were significantly higher in infertile subjects compared to fertile controls, respectively: 25.4 +/- 3.0 vs. 10.2 +/- 2.3 (P=.028) and 27.6 +/- 2.5 vs. 13.3 +/- 2.5% (P=.016). DF and DD correlated strongly (r = 0.71, P<.0001). Also, DD and DF correlated negatively with standard semen parameters (concentration, motility, and morphology), the strongest correlation being with sperm motility. CONCLUSION(S): The strong correlation between sperm DD and DF, and the higher levels of sperm DNA damage in infertile compared with fertile men, indicate that male infertility is associated with poor sperm DNA integrity. Although infertile men may father children with assisted conception, fertilization with DNA-damaged spermatozoa may increase the risk of genetic disease in the offspring.




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PEDIATRICS Vol. 113 No. 5 May 2004, pp. e472-e486


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The Genetics of Autism
Rebecca Muhle, BA*, Stephanie V. Trentacoste, BA* and Isabelle Rapin, MD

* Class of 2004, Albert Einstein College of Medicine, Bronx, New York
Saul R. Korey Department of Neurology, Department of Pediatrics, and Rose F. Kennedy Center for Research in Mental Retardation and Human Development, Albert Einstein College of Medicine, Bronx, New York




Epilepsy has the highest association with autism, reported in up to a third of individuals with an ASD by adulthood.25–27,33–35 The epilepsy may be subclinical, yielding an electroencephalogram that is epileptiform but without clinical seizures, and is particularly frequent in disintegrative disorder.36 Like autism, epilepsy is a disorder of the brain with multiple genetic and nongenetic causes and a broad range of phenotypes. Infantile spasms are particularly likely to result in autism with nondevelopment of language and mental retardation, especially when the epileptiform activity involves both temporal lobes.37 An occasional nonverbal child with mental retardation, autism, and epilepsy has exhibited early bilateral hippocampal sclerosis.38,39

Behavioral symptoms of autism are frequent in tuberous sclerosis complex (TSC) and fragile X syndrome (FXS), but these 2 disorders nevertheless account for only a minority of the total cases of autism.40,41 Given the high rate of epilepsy in children with TSC and the association between autism and epilepsy, it is perhaps not surprising that as many as 25% of patients with TSC have autism.42,43 An autosomally dominant neurocutaneous disorder, TSC arises from genetic mutations of either TSC1 on 9q or TSC2 on 16p and is characterized by ash-leaf depigmented or other cutaneous manifestations and hamartomatous lesions in multiple organs. In the brain, these lesions are termed tubers, and they are thought to cause the epilepsy seen in more than three quarters of children with TSC.44,45 Furthermore, it is the haphazard distribution of these tubers, together with other metabolic changes, that influences the phenotype of TSC, giving rise in some individuals to autism or epilepsy (often infantile spasms).37 In the population of patients with autism, numerous studies have quoted TSC rates of 1.1% to 1.3%,25–27,46 rates that, although low, are 30% higher than the prevalence of TSC in the general population.

FXS is an X-linked genetic disorder that is significantly associated with autism and that is denoted by unusual facial features, macro-orchidism in adulthood, and cognitive impairment of variable severity. It is caused by an increased number of trinucleotide (CGG) repeats in the gene coding for the fragile X mental retardation protein. Approximately 30% of individuals with FXS are on the autistic spectrum.47,48 There is disagreement, however, over the degree of FXS prevalence in patients with autism. Some early studies reported little or no association between FXS and autism,24,49 whereas others found a high association50 (see41 for additional review). More recent epidemiologic studies have documented rates of FXS between 7% and 8% in populations with autism.26,33,51,52 The discrepancies regarding the prevalence of FXS among individuals with autism may reflect the limited reliability of the cytogenetic tests used in the past compared with the more sensitive molecular tests currently used; as such, the number of girls who receive a diagnosis of FXS has increased.6

Genetic mutations that give rise to a number of additional diagnosable diseases may also be associated with autism. Neurofibromatosis, a common autosomal dominant disorder with neurologic and cutaneous manifestations, is much less frequently associated with autism than is TSC or FXS.53 Angelman syndrome (AS) and Prader-Willi syndrome (PWS) usually result from genetic deletions or uniparental disomy (inheritance of both chromosomes from 1 parent) of the chromosome 15q11-q13 locus,54,55 with abnormal imprinting or genetic mutations found in up to 5.1% of PWS cases and up to 15% of AS cases.55 Loss of paternally derived genes results in PWS, whereas AS, more commonly associated with autism than PWS,56,57 can result from the loss or mutation of the maternally derived ubiquitin protein ligase gene UBE3A or the ATP10C gene.58–60 An unexpectedly large proportion of boys with Duchenne muscular dystrophy are on the autistic spectrum.61 Many other rare single-gene defects have been associated with autism in case studies, including those found in Sotos syndrome,62 Williams syndrome,63 hypomelanosis of Ito,64 Cowden syndrome,65 and Moebius syndrome.66,67 We refer the reader to The Biology of the Autistic Syndromes by Gillberg and Coleman (p. 136–184)9 for a more complete listing of rare genetic conditions that are responsible for autism in occasional individuals.

Finally, autism may also occur in the context of abnormal cellular metabolism, such as mitochondrial disease.




Inherited Autism of Unknown Cause: Family Studies
Epidemiologic studies of autism report a prevalence of 5–10 cases of classic autism per 10 000 (some 3–6 per 1000 if the entire spectrum of autism is included) with a male to female ratio of 3:1.3,9,11 The preponderance of males suggests an X-linked disorder, and recent genome-wide screens by 2 separate groups have found evidence of linkage to the X chromosome,78,79 but the data are inconsistent. Cases of male-to-male transmission of autism in multiplex families, however, rule out X-linkage as the predominant mode of inheritance in these families.80,81 Similarly, analysis of Y haplotypes in patients with autism showed no significant associations,82 although Y chromosome abnormalities have been documented in case reports.83

There is strong and convincing evidence from 2 main sources that autism without a diagnosable cause is a heritable disorder. First, the rate of recurrence in siblings of affected individuals is 2% to 8%, much greater than the prevalence rate in the general population.9,27,46 Second, early twin studies in the United Kingdom and Scandinavia reported that monozygotic (MZ) twins had a rate of concordance >60% for classic autism, with no concordance found between dizygotic (DZ) twins.76,77 The higher rate of MZ concordance provides compelling evidence for the strong influence of genetics in the cause of autism, influence that extends well beyond the aforementioned associated genetic disorders. Furthermore, when the unaffected twin discrepant for autism was reevaluated for broader autistic phenotypes, including communication skills and social disorders, the concordance among the UK twins rose remarkably, from 60% to 92% in MZ twins and from 0% to 10% in DZ pairs.76,84 The existence of a susceptible genetic background is also suggested by the preponderance of traits such as obsessive-compulsive disorder, communication disorders, and social phobias in nonautistic family members of patients with autism.85–87 These crucial observations suggest that the interactions of multiple genes cause autism and that there is variable expression of autism-related traits.


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