Biology of Disease

disorders called muscular dystrophies (MDs). Defects in these proteins

compromise the mechanical strength of the muscle fibers leading to their

rupture and death during years of contraction, hence MDs are characterized

by a progressive wasting of the muscle tissues (Table 16.5). The two best

described MDs are Duchenne muscular dystrophy (DMD also called

pseudohypertrophic muscular dystrophy), which was first described by the

French neurologist Duchenne (1806–1875) in the 1860s, and Becker’s muscular

dystrophy (BMD, or benign pseudohypertrophic muscular dystrophy), named

after the German doctor, Becker (1908–2000), who described this variant of

DMD in the 1950s.

X]VeiZg&+/ MEMBRANE, ORGANELLE AND CYTOSKELETAL DISORDERS

W^dad\nd[Y^hZVhZ

Muscular dystrophy Proteins involved (Figure 16.16)

Autosomal recessive muscular dystrophy (ARMD) Asarcoglycan

Bsarcoglycan

Becker’s muscular dystrophy (BMD) dystrophin

Congenital muscular dystrophy (CMD) A2 laminin

Duchenne muscular dystrophy (DMD) dystrophin

Limb girdle muscular dystrophy (LGMD) Asarcoglycans

Bsarcoglycans

Gsarcoglycans

Severe childhood autosomal recessive muscular

dystrophy (SCARMD)

Gsarcoglycan

Table 16.5Muscular dystrophies

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)+- W^dad\nd[Y^hZVhZ

The incidences of MDs vary depending on the specific type. Duchenne MD is

the commonest with an incidence of three in 10 000 live-born males. Becker’s

MD is the second most common form, at one per 30 000 live male births.

Other types of MD are rare. For example, limb-girdle dystrophy occurs in only

about 1% of patients with MDs.

Duchenne and Becker’s MDs are caused by different mutations in the gene for

dystrophin. Mutations that produce STOP codons or deletions of even rela-

tively small portions that change the reading frame lead to DMD. Surprisingly,

BMD is the result of much larger deletion mutations but the reading frame of

the rest of the gene is unaltered, leading to the production of defective dys-

trophin. This, apparently, is sufficient to protect the muscles from degenerat-

ing as badly or as quickly as is the case with DMD. The gene for dystrophin is

located at Xp21 (Chapter 15). Thus both DMD and BMD are inherited in an

X-linked recessive manner although up to 30% of cases of DMD are the result

of a de novo mutation. Like all X-linked recessive characters, the presence of

the gene in a male will lead to the development of symptoms because of the

absence of a homologous, normal gene on the Y chromosome. Heterozygous

females will be carriers and generally symptomless, although a number do

show mild symptoms. Only in the unlikely event of a female being a homozy-

gote, with two X chromosomes carrying a mutated gene, will females present

with the disease.

Duchenne MD is a rapidly progressive disease characterized by loss of mus-

cle functions that are associated with the muscle tissue wasting. This begins

in the legs and pelvis and progresses to the shoulders and neck followed by

the respiratory muscles. The course of DMD is fairly predictable, in that it

follows an aggressive and progressive course. Symptoms usually appear in

male children aged one to six years. Boys with the disorder are often late in

learning to walk. In toddlers, it may present with enlarged calf muscles and

a clumsy, unsteady gait. The initial enlarged muscle mass of the calf muscles