Spinal and bulbar muscular atrophy
|Spinal and bulbar muscular atrophy|
|Synonyms||spinobulbar muscular atrophy, bulbo-spinal atrophy, X-linked bulbospinal neuropathy (XBSN), X-linked spinal muscular atrophy type 1 (SMAX1), Kennedy's disease (KD), and many other names|
|SBMA is inherited in an X-linked recessive pattern.|
|Classification and external resources|
Spinal and bulbar muscular atrophy (SBMA) is a debilitating neurodegenerative disorder resulting in muscle cramps and progressive weakness due to degeneration of motor neurons in the brainstem and spinal cord.
The condition is associated with mutation of the androgen receptor (AR) gene and is inherited in an X-linked recessive manner. As with many genetic disorders, no cure is known, although research continues. Because of its endocrine manifestations related to the impairment of the AR gene, SBMA can be viewed as a variation of the disorders of the androgen insensitivity syndrome (AIS). It is also related to other neurodegenerative diseases caused by similar mutations, such as Huntington's disease.
This condition is rare with an estimated incidence of 1/40,000 males. Although this condition is not normally fatal eventually 20% of those affected may need a wheelchair.
Signs and symptoms
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.
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:
- Bulbar signs: bulbar muscles are those supplied by the motor nerves from the brain stem, which control swallowing, speech, and other functions of the throat.
- Lower motor neuron signs: lower motor neurons are those in the brainstem and spinal cord that directly supply the muscles, loss of lower motor neurons leads to weakness and wasting of the muscle.
- Respiratory musculature weakness
- Action tremor
- Babinski response: when the bottom of the foot is scraped, the toes bend down (an abnormal response would be an upward movement of the toes indicating a problem with higher-level (upper) motor neurons).
- Decreased or absent deep tendon reflexes 
- Cramps: muscle spasms
- Muscular atrophy: loss of muscle bulk that occurs when the lower motor neurons do not stimulate the muscle adequately
- Gynecomastia: breast enlargement
- Erectile dysfunction
- Reduced fertility
- Testicular atrophy: testicles become smaller and less functional
- Late onset: individuals usually develop symptoms in their late 30s or afterwards (rarely is it seen in adolescence) 
Homozygous 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.
The genetics of spinal and bulbar muscular atrophy have to do with the mutated androgen receptor gene located on the X chromosome. The effects of the mutation may be androgen-dependent, thus only males are fully affected. Females are rarely affected; female carriers tend to have a relatively mild expression of the disease if they show symptoms at all.
The mechanism behind SBMA is caused by expansion of a CAG repeat in the first exon of the androgen receptor gene (trinucleotide repeats). 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.
In regards to the diagnosis of spinal and bulbar muscular atrophy, the AR Xq12 gene is the focus. Many mutations are reported and identified as missense/nonsense, that can be identified with 99.9% accuracy. Test for this gene in the majority of affected patients yields the diagnosis.
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 be wheelchair-bound 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.
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 (12 in their data).
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. The disease is probably more common than originally thought, SBMA prevalence has been estimated at 1:50,000 males.
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