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ICDO = | OMIM = 313200 | MedlinePlus = | eMedicineSubj = neuro | eMedicineTopic = 421 | MeshID = |'Kennedys disease (KD) or X-linked spinal and bulbar muscular atrophy''' (SBMA) is a neuromuscular disease associated with mutations of the androgen receptor (AR). Because of its endocrine manifestations related to the impairment of the AR, it can be viewed as a variation of the disorders of the androgen insensitivity syndrome (AIS). It is named after WR Kennedy, a neurologist who was among the first to describe this disease.
Genetics The androgen receptor gene that is mutated in Kennedy's disease is located on the X chromosome, and 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.
Pathology Kennedy's disease patients have muscle cramps and progressive weakness due to degeneration of motor neurons in the brainstem and spinal cord. As reported in 1991, Kennedy's disease 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 AIS does not cause motor neuron degeneration. KD may share mechanistic features with other neurodegenerative disorders that are caused by polyglutamine expansion, such as Huntington's disease. There is currently no treatment or cure for Kennedy's disease.
Signs and symptoms 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 latest onset was described in a male of 84 years of age. KD does not usually compromise longevity. The syndrome has neuromuscular and endocrine manifestations:
NeuromuscularEarly signs often include weakness of tongue and mouth muscles, fasciculations, and gradually increasing weakness of limb muscles with muscle wasting. In some cases, premature muscle fatigue begins in adolescence. Neuromuscular management is supportive, and the disease progresses very slowly and often does not lead to extreme disability.Neurological:
Homozygous femalesHomozygous 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.
History This disorder was described by Kennedy in 1968. In 1991 it was recognized that the AR is involved in the disease process. The disease is probably more common than originally thought. A study in Scandinavia suggested a prevalence of 1.3/8,500 making KD the most common form of motor neuron disease in the specific area studied; nobody had been diagnosed before 1995. It has been suggested that some men with KD may be misdiagnosed to have amyotrophic lateral sclerosis (ALS, also Lou Gehrig's disease).
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