Duchenne and Becker Muscular Dystrophy

Arising from nonsense or frame-shifting mutations in the dystrophin gene that typically preclude synthesis of a functional gene product, Duchenne muscular dystrophy (DMD) is the most common, serious form of childhood muscular dystrophy (Koenig et al. 1987; Koenig et al. 1988; Monaco 1989). This is an X-linked recessive condition that occurs at a cited frequency of about 1 in 3,800 live male births (Emery 1991 ; Mostacciuolo et al. 1987), with one in three cases arising from a de novo mutation. Becker muscular dystrophy, a milder allelic disorder has a much lower cited incidence of 1 in 14,000 (Mostacciuolo et al. 1993). It has been postulated that the lower frequency of BMD may be due in part to undiagnosed, asymptomatic cases.

The normal dystrophin gene product is thought to function much like a girder, with a primary role in stabilizing myotube structure. Although affected males appear normal at birth, the muscle fibres are compromised by the absence of a functional dystrophin. In these young patients, muscle repair and regeneration keeps pace with the loss of damaged fibres, which occurs in a relentless, progressive, and predictable manner. Eventually the regenerative capacity is overwhelmed and DMD patients begin to show signs of muscle weakness between the ages of 3 and 5 years. Affected individuals may appear clumsy, are unable to keep up with their peers, and are typically restricted to a wheelchair by 12 years. Recent improvements in care management include steroid treatment, physiotherapy, and surgery. Substantial benefit is provided by nocturnal mechanical assisted ventilation, and with combined interventions DMD patients are now living into their mid to late twenties (Eagle et al. 2002).

Becker muscular dystrophy also arises from mutations in the dystrophin gene, but these are typically in-frame deletions producing internally deleted proteins, with intact amino and carboxyl domains. A study of Italian BMD patients characterised mutations in detail and found 35 out of 37 cases were in-frame and the majority of the mutations occurred in the distal part of the rod domain (exons 45-60; Comi et al. 1994). These authors noted that BMD patients with mutations towards the 5' end of the gene tended to have a more severe clinical phenotype, with faster progression and lower dys-trophin expression, leading to earlier presentation. Depending upon the nature and position of the mutations, BMD may manifest from borderline DMD (intermediate) to almost asymptomatic. Some BMD patients have remarkably mild symptoms, despite deletions involving almost half the gene encoding the central rod domain (England et al. 1990; Winnard et al. 1993). Deletions in the dystrophin gene involving exon 45-47 and 45-48 have been reported to be consistently associated with very mild BMD (Bushby 1992).

There are reports of dystrophin deletions being identified indirectly. Melis and colleagues (Melis et al. 1998) reported three unrelated cases, after more detailed dystrophin molecular studies were undertaken, subsequent to an incidental finding of elevated serum creatine kinase levels. Dystrophin exon deletions of 32-44, 48-51, and 48-53 were identified, and adult male relatives from each family found to carry one of these deletions were either normal, or had very mild muscle involvement. In another chance diagnosis, a four-year-old female was found to be a carrier of a dystrophin exon 48 deletion, after she was originally referred for evaluation for a persistent elevation of aspartate aminotransferase (Morrone et al. 1997). Four male relatives, aged between 8 and 58 years, were found to carry the same mutation and as yet had exhibited no clinical symptoms.

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