Individuals with SBMA have muscle cramps and progressive weakness due to degeneration of motor neurons in the brain stem and spinal cord. Ages of onset and severity of manifestations in affected males vary from adolescence to old age, but most commonly develop in middle adult life. The syndrome has neuromuscular and endocrine manifestations.
Neuromuscular
Early signs often include weakness of tongue and mouth muscles, fasciculations, and gradually increasing weakness of limb muscles with muscle wasting. Neuromuscular management is supportive, and the disease progresses very slowly, but can eventually lead to extreme disability. Further signs and symptoms include:
Homozygous females
females, both of whose X chromosomes have a mutation leading to CAG expansion of the AR gene, have been reported to show only mild symptoms of muscle cramps and twitching. No endocrinopathy has been described.
Genetics
SBMA is a hereditary syndrome, inherited in an X-linked recessive manner. The AR gene, located in the X chromosome, involves a section consisting ofCAG repeats. The number of repeats varies among individuals. Healthy males carry up to 34 repeats. From 35 to around 46 repeats, penetrance gradually increases, approaching a maximum value. Therefore, males bearing 35 to 46 CAG repeats are at intermediate but increasing risk for developing SBMA. Males bearing 47 or more repeats have nearly 100% risk of developing SBMA. Other, still unidentified genetic factors may also play a role in disease manifestation and symptoms’ severity.
Pathophysiology
The mechanism behind SBMA is caused by expansion of a CAG repeat in the first exon of the androgen receptor gene. The CAG repeat encodes a polyglutamine tract in the androgen receptor protein. The greater the expansion of the CAG repeat, the earlier the disease onset and more severe the disease manifestations. The repeat expansion likely causes a toxic gain of function in the receptor protein, since loss of receptor function in androgen insensitivity syndrome does not cause motor neuron degeneration. Spinal and bulbar muscular atrophy may share mechanistic features with other disorders caused by polyglutamine expansion, such as Huntington's disease. No cure for SBMA is known.
Diagnosis
of SBMA is based on identifying the number of CAG repeats in the AR gene using molecular techniques such as PCR. The accuracy of such techniques is nearly 100%.
Management
In terms of the management of spinal and bulbar muscular atrophy, no cure is known and treatment is supportive. Rehabilitation to slow muscle weakness can prove positive, though the prognosis indicates some individuals will require the use of a wheelchair in later stages of life. Surgery may achieve correction of the spine, and early surgical intervention should be done in cases where prolonged survival is expected. Preferred nonsurgical treatment occurs due to the high rate of repeated dislocation of the hip.
Prognosis
A 2006 study followed 223 patients for a number of years. Of these, 15 died, with a median age of 65 years. The authors tentatively concluded that this is in line with a previously reported estimate of a shortened life expectancy of 10–15 years.
History
This disorder was first described by William R. Kennedy in 1968. In 1991, it was recognized that the AR gene is involved in the disease process.
