Kennedy disease

Kennedy's 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.

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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:

Neuromuscular

Early 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:

• Bulbar Signs The Bulbar muscles are those supplied by the motor nerves coming off the brain stem which control breathing, swallowing, talking and other functions of the throat. Bulbar signs are problems with these functions.
• Dysphagia Trouble swallowing. (One of the Bulbar signs.)
• Intention Tremor Hand tremors when trying to do something.
• Normal Babinski Normal plantar response, ie., when the bottom of the foot is scraped, the toes bend down. An abnormal response would be an upward bendings of the toes indicating a problem in the brain itself.
• Lower Motor Neuropathy The lower motor nerves are those that run from the spinal cord to the muscles that they stimulate to move. Loss of that nerve leads to weakness and wasting of the muscle.
• Primary Sensory Neuropathy Numbness over certain areas. Loss of sensation.
• Decreased or Absent Deep Tendon Reflexes. (When a doctor taps the knee with his hammer and nothing happens.)

Muscular:

• Fasciculations Twitching of small muscles without purposeful movement that can be seen through the skin.
• Cramps Large muscle spasms.
• Postural Tremor Shaky muscles with certain positions.
• Muscular Atrophy Wasting and shrinkage of muscles that occurs when the lower motor nerve does not stimulate the muscle adequately.
• Hypertrophied Calves Calf muscles that become thicker because of cramps.

Thoracic:

• Gynecomastia (breast enlargement).

Endrocrine

• Androgen Deficiency Loss of masculinizing effect.
• Estrogen Excess More of an apparent estrogen effect because of the lost of masulinizing effect.

Genito-Urinary:

• Impotence
• Erectile dysfunction
• Reduced Fertility
• Low sperm count
• Testicular Atrophy Testicles become smaller and less functional.

Miscellaneous Characteristics:

• Late Apparent Onset Usually show symptoms late 30's and after
• Slow Progression Near-normal lifespan
• Asymmetry of Clinical Signs Muscles of one side may be more affected than the same muscles on the other side.

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.

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).

References

• Kennedy WR, Alter M, Sung JH. Progressive proximal spinal and bulbar muscular atrophy of late onset: a sex-linked recessive trait. Neurology 1968;18:671-680. PMID 4233749.
• La Spada A, Wilson EM, Lubahn DB, Harding AE, Fischbeck KH. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 1991;352:77-79.
• Fischbeck KH, Lieberman A, Bailey CK, Abel A, Merry DE. Androgen receptor mutation in Kennedy's disease. Phil Trans R Soc Lond B 1999;354:1075-1078.
• Chen CJ, Fischbeck KH: Clinical aspects and the genetic and molecular biology of Kennedy's disease. In: Wells RD, Ashizawa T (eds.): Genetic Instabilities and Neurological Diseases, Second Edition. San Diego, Academic Press/Elsevier, 2006