Spinal and bulbar muscular atrophy (SBMA) is an hereditary, adult-onset,
lower motor neuron disease caused by an aberrant elongation of a trinucleotide CAG repeat, which encodes the
polyglutamine tract, in the first exon of the
androgen receptor (AR) gene. The main symptoms are slowly progressive
muscle weakness and
atrophy of bulbar, facial and limb muscles. The cardinal histopathological findings of SBMA are an extensive loss of lower motor neurons in the anterior horn of the spinal cord as well as in brainstem motor nuclei and intranuclear accumulations of mutant AR
protein in the residual motor neurons.
Androgen deprivation
therapy rescues neuronal dysfunction in animal models of SBMA, suggesting that the molecular basis for motor neuron degeneration in this disorder is
testosterone-dependent nuclear accumulation of the mutant AR. Suppression of
disease progression by
leuprorelin acetate has also been demonstrated in a phase 2 clinical trial. In addition, the clarification of pathophysiology leads to appearance of candidate drugs to treat this devastating disease:
heat shock protein (HSP) inducer, Hsp90 inhibitor, and
histone deacetylase inhibitor. Advances in basic and clinical research on SBMA are now paving the way for clinical application of pathogenesis-targeting
therapeutics.