Kennedy disease (KD) or X-linked spinal-bulbar muscle atrophy 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. more...
As a sex-linked disease, KD affects males, while females are carriers. The gene for the AR is located on the X chromosome (Xq11-q12).
The distinctive AR mutation of Kennedy disease, reported in 1991, involves multiplied CAG repeats in the first exon (trinucleotide repeats). Such a CAG repeat encodes a polyglutamine tract in a part of the androgen receptor outside of the binding sites. The more CAG repeats are present, the more severe the disease. The mechanism by which this type of mutation causes neuromuscular disease is not completely understood, specifically as complete AIS does not affect neuromuscular activity. KD may share mechanistic features with other neurodegenerative disorders that are caused by polyglutamine expansion, such as Huntington'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:
Early signs often include weakness of tongue and mouth muscles, fasciculations, and gradually increasing weakness of proximal 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.
Endocrine manifestations of this disorder are variable and rarely include underdevelopment of internal or external genitalia. In other words, most people affected with Kennedy disease are relatively normal XY men with normal fertility. However, exaggerated and persistent gynecomastia is common and often the only symptom, while in more severe forms testicular atrophy and infertility have been described. Many affected men have the mildly high LH, testosterone, and estradiol levels characteristic of other forms of the androgen insensitivity syndrome.
Homozygous females, whose both X chromosomes have a mutation leading to CAG expansion of the AR gene, show only mild symptoms of muscle cramps and twitching. No endocrinopathy has been described.
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 KS are may be misdiagnosed to have amyotrophic lateral sclerosis (ALS, also Lou Gehrig's disease).
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