familial als and kennedy’s disease

amyotrophic lateral sclerosis (als) is a progressive neurodegenerative disorder of the motor neurons in the spinal cord, brainstem, and motor cortex. ten percent of als cases are familial with both autosomal dominant and recessive modes of inheritance. mutations in the copper/zinc superoxidedismutase-1 (sod-1) gene, the first gene linked with als, result in sod-1 gene accounting for ~ 20% of familial als cases. to date, 135 mutations have been identified that result in the toxic gain of function of the sod-1 enzyme which normally functions as a free radical scavenger but the mechanisms underlying motor neuron degeneration have not been clearly elucidated. evidence is emerging regarding a complex interaction between genetic and molecular factors, with resultant damage of critical target proteins and organelles within the motor neuron. several important genetic discoveries have been made recently that will bring substantial insight into some of the mechanisms involved in als. mutations in two genes with related functions were recently reported in patients with familial als: the fus/tls gene at the als6 locus on chromosome 16 and the tardbp gene at the als10 locus on chromosome 1. in addition, the first wave of genomewide association studies in als has been published. while these studies clearly show that there is no definitive and common highly penetrant allele that causes als, some interesting candidate genes emerged from these studies. bulbar and spinal muscular atrophy (kennedy‘s disease) is an adult-onset, x-linked recessive trinucleotide polyglutamine disorder caused by expansion of a polymorphic cag tandem-repeat in exon 1 of the androgen-receptor (ar) gene on chromosome xq11-12. patients present with amyotrophic, proximal or distal weakness and wasting of the facial, bulbar and limb muscles, occasional sensory disturbances, and endocrinologic disturbances such as androgen resistance, gynecomastia, elevated testosterone or progesterone, and reduced fertility. there may be mild hyper-ck-emia, abnormal motor and sensory nerve conduction studies, and neuropathic and myopathic alterations on muscle biopsy. the gold standard for diagnosis is genetic analysis, demonstrating a cag-repeat number >40. no causal therapy is available but symptomatic therapy should be provided for tremor, endocrinologic abnormalities, sensory disturbances, and muscle cramps. the course is slowly progressive and the ability to walk is lost only late in life. only few patients require ventilatory support and life expectancy is only slightly reduced.