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At a glance

X-linked disorder characterized by degeneration of both sensory and lower motor neurons supplying the limb and bulbar musculature caused by a defect in the androgen receptor. Extraocular muscles are spared, possibly because of reduced numbers of androgen receptors in these muscles.

Synonyms

Bulbospinal Neuronopathy; Kennedy Spinal and Bulbar Muscular Atrophy; X-Linked Bulbospinal Muscular Atrophy; Spinal and Bulbar Muscular Dystrophy Syndrome.

History

This medical condition was first described by William R. Kennedy, Professor of Neurology at University of Minnesota since 1964 and Director of the Kennedy Research Laboratory Center since 1968.

Incidence

The incidence is estimated approximately at 1:40,000 to 50,000 males worldwide. It has been diagnosed in the USA, Europe, Asia, South America, and Australia. It seems consistently more frequent in western Finland. This condition is not normally fatal but worsens progressively and in 20% of those affected, become wheelchair bound later in life. In 2006, a study published the observations of 223 patients that were followed for a number of years. Of these, 15 individuals died, with a median age of 65 years. The life expectancy is shortened by 10 to 15 years when compared to the normal population.

Genetic inheritance

X-linked recessive (only males can express the full phenotype). It affects mainly Caucasians and Asians, but not Africans. The genetic defect is located at the DXYS1 marker on the proximal long arm of the X chromosome (Xq11-12). Females are carriers.

Pathophysiology

Degeneration of sensory and motor neurons supplying the limb and bulbar musculature, sparing extraocular muscles (possibly because of reduced numbers of androgen receptors in these muscles). It is caused by an expanded trinucleotide (cytosine-adenine-guanine [CAG]) and repeated in the androgen receptor within the first exon of the gene. The disease mechanism likely involves toxicity of an expanded polyglutamine tract in the androgen receptor protein. Electromyography and muscle histology demonstrate neurogenic atrophy. Necropsy shows diffuse loss and atrophy of anterior horn cells in the spinal cord.

Diagnosis

Laboratory findings include elevated serum creatine kinase, pronounced involutional changes in Leydig cells, hypobetalipoproteinemia, and abnormalities in the androgen receptor gene.

Clinical aspects

This is a slowly progressing muscle atrophy associated with mild androgen insensitivity that affects only males. Muscle atrophy is initially not obvious and usually starts between 20 and 50 years of age. Its onset is insidious and early signs may include difficulties with walking and a tendency to fall. Deep tendon reflexes are decreased and some patients complain about muscle cramps and/or intention tremor. The muscle weakness not only involves the extremities, but also the facial muscles (including facial fasciculations). Calf hypertrophy may occur. Over the following 10 to 20 years, most patients will start to experience difficulties with ...

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