Spinal and bulbar muscular atrophy is an X-linked, neurodegenerative disease. Clinically, those affected show show proximal muscle weakness and atrophy as well as fasciculations, which mainly affect the perioral muscles. Other frequently occurring characteristics are intention tremor, muscle cramps, difficulty swallowing, peripheral androgen resistance with reduced fertility and gynecomastia. The symptoms usually begin between the age of 30 and 40 and progress slowly. Due to the X-linked inheritance, the disease only affects men. Women who are heterozygous carriers of the causative gene alteration do not show symptoms but can transmit the disease.
The disease is caused by degeneration of spinal and bulbar α-motor-neurons, due to a CAG triplet expansion in the translated region of the androgen receptor gene (AR gene). While a sequence of 12-35 triplets is found in normal individuals, those affected carry 38-53 CAG copies. This results in the incorporation of a sequence of glutamine residues that is too long into the androgen receptor protein. The protein loses its original structure and thus its actual function in the spinal and bulbar motor neurons.
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