Kennedy's disease

Abstract

X-linked spinal and bulbar muscular atrophy (SBMA) (Kennedy's disease) is an inherited neuromuscular disorder characterized by lower motor neuron degeneration. Patients exhibit signs of androgen insensitivity, which led to the evaluation of the androgen receptor (AR) gene and identification of cytosine-adeonsine-guanine (CAG) repeat expansions in the first coding exon of the AR gene as the cause of this disorder. Motor neuron degeneration only occurs in males, as female carriers are protected by low levels of testosterone. Studies of disease pathogenesis indicate that a polyglutamine-expanded AR protein promotes accumulation and aggregation of the mutant protein, altering transcription regulation in the central nervous system (CNS) and possibly also in the muscle. Highly representative mouse models have been generated and now provide a proving ground for testing novel therapies, including strategies aimed at reducing the function of the mutant protein (antiandrogens) or decreasing the expression of the mutant protein by targeting the ribonucleic acid for destruction (knockdown).