What is bulbospinal muscular atrophy?

Updated: Feb 20, 2018
  • Author: Sridharan Ramaratnam, MD, MBBS; Chief Editor: Helmi L Lutsep, MD  more...
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Bulbospinal muscular atrophy (Kennedy disease)

  • This X-linked recessive disease is associated with an increase in the number of polymorphic tandem CAG repeats in exon 1 of the androgen receptor (AR) gene on the proximal long arm at Xq11 locus.

  • The aggregation of the expanded repeat AR, in the residual motor neurons in the brainstem and spinal cord, rather than playing a pathogenic role, likely reflects the insoluble nature of the misfolded AR protein. [41] Proteolytic processing of the expanded AR protein at various stages of its metabolism may contribute to cellular toxicity through the enhancement of AR protein insolubility, and potentially through the disruption of normal proteolytic degradation processes.

  • Transgenic mice carrying the full-length human AR gene with an expanded polyQ tract demonstrate neuromuscular phenotypes, which are profound in males. Their bulbospinal muscular atrophy–like phenotypes are rescued by castration and aggravated by testosterone administration. Leuprorelin, an LHRH agonist that reduces testosterone release from the testis, inhibits nuclear accumulation of mutant AR proteins, resulting in the rescue of motor dysfunction in the male transgenic mice. However, flutamide, an androgen antagonist promoting nuclear translocation of the AR gene, yielded no therapeutic effect. The degradation and cleavage of the AR protein are also influenced by the ligand, contributing to the pathogenesis. Testosterone appears to be the key molecule in the pathogenesis of Kennedy disease as well as the main therapeutic target of this disease. [42]

  • Muscle cramps on exertion and gynecomastia often precede weakness in the pelvic girdle, which develops between the third and fifth decades. Facial, bulbar, and distal limb involvement may follow.

  • Perioral fasciculations, hand tremors, noninsulin-dependent diabetes mellitus, and infertility are common.

  • Nerve conduction may reveal sensory nerve action potential abnormalities in addition to reduced amplitude of compound muscle action potentials (CMAPs), suggesting degeneration of the dorsal root ganglia in addition to the anterior horn cells.

  • Needle electromyography (EMG) reveals acute and chronic motor axon loss (with the latter predominating). On needle EMG examination of the facial muscles, grouped repetitive motor unit discharges, which are present at rest but become prominent with mild activation of the facial muscles, may occur. [43]

  • The age of onset and clinical severity of the disease often correlate with serum testosterone and gonadotrophin levels and the number of CAG repeats in the AR gene.

  • DNA analysis is now commercially available to help identify singleton males and carrier females.

  • The lifespan is reduced only minimally.

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