Kennedy Disease Molecular Basis of Disease

Spinal and bulbar muscular atrophy (SBMA), or Kennedy disease, is a rare X-linked, slowly progressive, adult-onset motor neuropathy.41 The age of onset is usually between 30 and 50 years and is characterized by muscle cramps, proximal and bulbar weakness, and fasciculation. Endocrine abnormalities, including gynecomastia and testicular atrophy, are common. The disease is caused by a CAG trin-ucleotide repeat expansion in the coding region of the androgen receptor gene (AR).42,43 The CAG repeat found within the first exon is polymorphic in normal populations, and ranges in length from 10 to 36 repeats. Patients with SBMA have a CAG repeat expansion that does not overlap with the normal population and ranges from 40 to 62 repeats. Similarly to other trinucleotide repeat disorders, the CAG repeat length correlates with disease severity and age of onset. However, considerable variability in age of onset is seen among family members with similar

CAG repeat lengths, suggesting that factors other than the size of the repeat modulate the onset and severity of the disease. While AR repeats in the unaffected range are stably transmitted, expanded repeats in SBMA patients are transmitted less stably and tend to increase in size by paternal transmission.

The pathogenic mechanism of SBMA expansion involves a gain of a toxic function of the protein product. The mutant allele is both transcribed and translated, arguing against a loss of function mechanism. Individuals with mutations producing a loss of AR protein function have testicular feminization and do not have the motor neuropathy seen in SBMA patients. The exact mechanism by which the expanded polyglutamine tract in the AR protein produces the neuropathy of SBMA is uncertain.

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