Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is an x-linked recessive disorder, primarily characterized by progressive muscle weakness and wasting.

The disease results from the absence of dystrophin (DMD; MIM.300377), however the precise molecular mechanisms leading to muscle pathology are poorly understood.

The dystrophin complex has two functions: a structural role in maintaining sarcolemmal integrity during contraction and a scaffolding function that recruits signaling proteins such as neuronal nitric oxide synthase to the membrane.

Dystrophic muscles undergo increased oxidative stress and altered calcium homeostasis, which may contribute to myofiber loss by triggering both necrosis and apoptosis.

Pathogenesis

Duchenne muscular dystrophy is caused by a mutation of the dystrophin gene at locus Xp21.

Dystrophin is responsible for the connection of muscle fibers to the extracellular matrix through a protein complex containing many subunits.

The absence of dystrophin permits excess calcium to penetrate the sarcolemma (cell membrane).

In a complex cascading process that involves several pathways and is not clearly understood, increased oxidative stress within the cell damages the sarcolemma, and eventually results in the death of the cell.

Muscle fibers undergo necrosis and are ultimately replaced with adipose and connective tissue.

Clinical synopsis

Symptoms usually appear in male children before age 6 and may be visible in early infancy. Progressive proximal muscle weakness of the legs and pelvis associated with a loss of muscle mass is observed first. Eventually this weakness spreads to the arms, neck, and other areas.

Early signs may include pseudohypertrophy (enlargement of calf muscles), low endurance, and difficulties in standing unaided or inability to ascend staircases.

As the condition progresses, muscle tissue experiences wasting and is eventually replaced by fat and fibrotic tissue (fibrosis). By age 10, braces may be required to aide in walking but most patients are wheelchair dependent by age 12. Later symptoms may include abnormal bone development that lead to skeletal deformities, including curvature of the spine.

Due to progressive deterioration of muscle, loss of movement occurs eventually leading to paralysis. Intellectual impairment may or may not be present but if present, does not progressively worsen as the child ages.

The average life expectancy for patients afflicted with DMD varies from early teens to age mid 30s. There have been reports of DMD patients surviving past the age of 40 and even 50.

Etiology

 mutations of the DMD gene at Xp21.2

Videos

 muscular dystrophy by Washington Deceit (1)

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 muscular dystrophy by Washington Deceit (2)

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References

 Cossu G, Sampaolesi M. New therapies for Duchenne muscular dystrophy: challenges, prospects and clinical trials. Trends Mol Med. 2007 Dec;13(12):520-6. PMID: 17983835

 van Deutekom JC, van Ommen GJ. Advances in Duchenne muscular dystrophy gene therapy. Nat Rev Genet. 2003 Oct;4(10):774-83. PMID: 14526374

 Froehner SC. Just say NO to muscle degeneration? Trends Mol Med. 2002 Feb;8(2):51-3. PMID: 11815264