Spinal and bulbar muscular atrophy

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Spinal and bulbar muscular atrophy (SBMA), popularly known as Kennedy's disease, is a progressive 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.

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.

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:

Ideogram of human X chromosome.

Neurological

• 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

Muscular

• Cramps: muscle spasms
• Muscular atrophy: loss of muscle bulk that occurs when the lower motor neurons do not stimulate the muscle adequately

Endocrine

• Gynecomastia: male breast enlargement
• Erectile dysfunction
• Reduced fertility
• Testicular atrophy: testicles become smaller and less functional

Other

• Late onset: individuals usually develop symptoms in their late 30s or afterwards (rarely is it seen in adolescence)

Homozygous females

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.

Genetics

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.

Pathophysiology

Androgen receptor

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.

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

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.

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 (12 in their data).

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. The disease is probably more common than originally thought, SBMA prevalence has been estimated at 1:300,000 males.

See also

• Spinal muscular atrophies

Further reading

• "Study of Hepatic Function in Patients With Spinal and Bulbar Muscular Atrophy - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2016-03-23.

External links

Classification	ICD-10: G12.1 ICD-9-CM: 335.1 OMIM: 313200 MeSH: D055534 DiseasesDB: 7144
External resources	eMedicine: article/1172604 Orphanet: 481