Inherited and progressive myopathy affecting boys.
Presents with muscular, respiratory, and cardiac disease.
DMD; Pseudohypertrophic Muscular Dystrophy; Duchenne Type
of Progressive Muscular Dystrophy; Progressive Muscular Dystrophy Type I.
Approximately 1:3500 boys is affected, which makes it
the most common form of muscular dystrophy. No preferences in race or
nationality have been reported. The disease affects almost exclusively
males, although females rarely can be affected, for example, when they have
a translocation between autosomal chromosomes and the X chromosome,
uniparental disomy (i.e., when the chromosome pair or specific segments of a
chromosome pair are inherited from one parent only), or suffer from Turner
About one third results from spontaneous
mutation (negative family history does not exclude DMD); the rest is
inherited in an X-gonosomal recessive way. Simplified, in DMD a frameshift
mutation results in the absence of dystrophin, whereas in Becker muscular
dystrophy a non-frameshift mutation results in decreased levels of
dystrophin. The responsible gene (with 2400 kbp, one of the largest known
human genes) has been mapped to the short arm of the X chromosome at
position 21 (Xp21).
The DMD gene product, a protein called dystrophin,
is absent or nonfunctional in patients with DMD. Dystrophin, an important
structural part of a large sarcolemmal glycoprotein complex, stabilizes the
sarcolemma and plays an important role in the interaction between sarcoplasm
and extracellular matrix. Dystrophin is expressed in skeletal and cardiac
muscle and in the brain. In the absence of dystrophin (or its function), the
entire function of this sarcolemmal complex appears to be disrupted
(dystrophin links the actin filaments to the glycoprotein complex in the
sarcolemma). This defect may result in either decreased sarcolemmal
stability to the mechanical stress of contraction-relaxation or disturbed
calcium homeostasis with excessive calcium influx into the muscle cell and
pathologic activation of intracellular enzymes. Finally, this results in
destruction and necrosis of muscle fibers, which are eliminated by
macrophages (myophagocytosis) and later replaced by scar and fat tissue with
endomysial and perimysial fibrosis. Although some muscle fibers may show a
compensatory hypertrophy, most often the fibers are atrophic, split, or even
missing in later stages of the disease. The clinically diagnosed
pseudohypertrophy of muscles (particularly the calves) refers to this
phenomenon and is, in fact, the result of scarring and fatty degeneration of
the muscles, which is muscle wasting.
The clinical course, elevated plasma levels of creatine
phosphokinase and other enzymes (e.g., troponin I, lactate dehydrogenase,
and transaminases), and muscle biopsy (fatty degeneration and scarring and
immunostaining confirm the lack of dystrophin) lead to the diagnosis.
Molecular biology allows for intrauterine diagnosis. Age at diagnosis is
before birth (familial context), otherwise between 2 and 5 years
(occasionally later). Female carriers of the disease may have increased
creatine phosphokinase levels, but most often they are clinically
Progressive and symmetrical wasting of muscles of
the legs and pelvis and later of the thorax and upper ...