Birth order and the genetics of amyotrophic lateral sclerosis
ABSTRACT The cause of ALS remains largely unknown for the 90% with no known family history, but spontaneous mutation to risk alleles of as yet unidentified genes is possible. It has long been recognized that genetic diseases may be more likely to occur in the last born children of a sibship because increased paternal age is associated with an increased spontaneous point mutation rate in sperm. To test the hypothesis that such a mechanism is responsible for sporadic ALS, we have performed a retrospective analysis of birth order position. We have analyzed sibships of size greater than four using a binomial test for birth position. The 478 pedigrees studied show no birth order effect, suggesting that any genetic contributions to sporadic ALS are more likely to be through deletion in large genes or interactions of common polymorphisms, rather than frequent spontaneous point mutation. This is encouraging for the prospect of finding sporadic ALS susceptibility genes using genome-wide association mapping.
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ABSTRACT: The greatest effect of the birth Dolly, the first cloned animal derived from an adult, has been in prompting biologists to consider ways of reprogramming adult nuclei to a pluripotent state directly. The first procedure depends upon use of viral vectors to introduce selected transcription factors, but this procedure is slow and very inefficient. Research in our laboratory has demonstrated that exposure of differentiated nuclei to an extract of embryo stem cells induces expression of key pluripotency genes within 8 h, suggesting that it may be possible to identify and use other factors to enhance direct reprogramming. A study of mechanisms that bring about changes in DNA methylation in early sheep embryos identified a developmental isoform of Dnmt1, the expression of which was limited to early stages of pregnancy. Reduction in the level of transcript of this isoform at the time of fertilisation caused sheep embryo development to cease at the early morula stage, revealing a key role for the isoform that remains to be characterised. The ability to obtain pluripotent cells from specific patients is providing important new opportunities to study inherited diseases when the causative mutation is not known. The initial objective of this research is not cell therapy, but to use cells with the characteristics of those in a patient who has inherited the disease to establish a high-throughput screen to identify drugs that are able to prevent progression of the symptoms of the disease. Research is in progress with cells from patients with amyotropic lateral sclerosis.Reproduction Fertility and Development 01/2009; 21(1):95-100. DOI:10.1071/RD08216 · 2.58 Impact Factor
Article: Amyotrophic lateral sclerosis[Show abstract] [Hide abstract]
ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by progressive muscular paralysis reflecting degeneration of motor neurones in the primary motor cortex, corticospinal tracts, brainstem and spinal cord. Incidence (average 1.89 per 100,000/year) and prevalence (average 5.2 per 100,000) are relatively uniform in Western countries, although foci of higher frequency occur in the Western Pacific. The mean age of onset for sporadic ALS is about 60 years. Overall, there is a slight male prevalence (M:F ratio approximately 1.5:1). Approximately two thirds of patients with typical ALS have a spinal form of the disease (limb onset) and present with symptoms related to focal muscle weakness and wasting, where the symptoms may start either distally or proximally in the upper and lower limbs. Gradually, spasticity may develop in the weakened atrophic limbs, affecting manual dexterity and gait. Patients with bulbar onset ALS usually present with dysarthria and dysphagia for solid or liquids, and limbs symptoms can develop almost simultaneously with bulbar symptoms, and in the vast majority of cases will occur within 1-2 years. Paralysis is progressive and leads to death due to respiratory failure within 2-3 years for bulbar onset cases and 3-5 years for limb onset ALS cases. Most ALS cases are sporadic but 5-10% of cases are familial, and of these 20% have a mutation of the SOD1 gene and about 2-5% have mutations of the TARDBP (TDP-43) gene. Two percent of apparently sporadic patients have SOD1 mutations, and TARDBP mutations also occur in sporadic cases. The diagnosis is based on clinical history, examination, electromyography, and exclusion of 'ALS-mimics' (e.g. cervical spondylotic myelopathies, multifocal motor neuropathy, Kennedy's disease) by appropriate investigations. The pathological hallmarks comprise loss of motor neurones with intraneuronal ubiquitin-immunoreactive inclusions in upper motor neurones and TDP-43 immunoreactive inclusions in degenerating lower motor neurones. Signs of upper motor neurone and lower motor neurone damage not explained by any other disease process are suggestive of ALS. The management of ALS is supportive, palliative, and multidisciplinary. Non-invasive ventilation prolongs survival and improves quality of life. Riluzole is the only drug that has been shown to extend survival.Orphanet Journal of Rare Diseases 03/2009; 4(1):3. DOI:10.1186/1750-1172-4-3 · 3.96 Impact Factor
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ABSTRACT: Birth order is considered one of the most influential environmental factors in child development, affecting cognitive abilities and behavioral traits. This study investigates the effect of birth order in relation to attention-deficit hyperactivity disorder (ADHD), the most common neuro-behavioral disorder of childhood. The study describes birth order of 598 children aged 6 to 18 years diagnosed due to attention-deficit hyperactivity disorder. The cohort contains relatively large size families because 47.1% of the participants were born in families of more than 4 children. The results show no statistically significant differences in birth order of children among all families. We conclude that the chances of first, middle, or later born children, as well as single children, to suffer from attention-deficit hyperactivity disorder are almost equal. This study provides evidence that birth order has no effect in relation to attention-deficit hyperactivity disorder.Journal of child neurology 03/2009; 24(6):692-6. DOI:10.1177/0883073808330763 · 1.67 Impact Factor