Fig. 22.5 Duchennemusculardystrophy.Histologicimagesofmusclebiopsyspecimensfromtwobrothers.(A–B)Specimensfroma3-year-oldboy.(C)Specimenfromhisbrother,9yearsofage.Asseenin(A),atayoungeragefascicularmusclearchitectureismaintained,butmyofibersshowvariationinsize.Additionally,thereisaclusterofbasophilicregeneratingmyofibers(left side) andslightendomysialfibrosis,seenasfocalpink-stainingconnectivetissuebetweenmyofibers.In(B),immunohistochemicalstainingshowsacompleteabsenceofmembrane-associateddystrophin,seenasabrownstaininnormalmuscle(inset).In(C),thebiopsyfromtheolderbrotherillustratesdiseaseprogression,whichismarkedbyextensivevariationinmyofibersize,fattyreplacement,andendomysialfibrosis.
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Both DMD and BMD are caused by mutations disrupting the function of the dystrophin gene located on the short arm of the X chromosome (Xp21). Dystrophin is a very large protein (427 kD in molecular weight) found in skeletal and cardiac muscle, brain, and peripheral nerves; it is part of the dystrophin-glycoprotein complex (
Fig. 22.3 ). This complex stabilizes the muscle cell during contraction and may be involved in cell signaling through interactions with other proteins. Dystrophin-glycoprotein complex defects are thought to make muscle cells vulnerable to transient membrane tears during contraction that lead to calcium influx, and they may also disrupt intracellular signaling. The result is myofiber degeneration that with time out-paces the capacity for repair. The dystrophin-glycoprotein complex also is important for cardiac muscle function; this explains why cardiomyopathy eventually develops in many patients.
The dystrophin gene spans roughly 2.4 megabases (about 1% of the X chromosome), making it one of the largest human genes. Its enormous size may make it more prone to sporadic mutations, which all things being equal are more likely by chance to affect large genes. The most common mutations are deletions, followed by frameshift and point mutations. Patient with DMD usually have either of the first two and show complete absence of dystrohpin on a muscle biopsy. Patients with BMD often have point mutations and make residual but defective forms. The severity of disease therefore correlates with genotype and extent of dystrohpin deficiency.
Often the first symptoms of DMD are clumsiness and an inability to keep up with peers because of muscle weakness. The weakness typically begins in the pelvic girdle and next involves the shoulder girdle. Enlargement of the calves, termed pseudohypertrophy, is an early physical finding. The increased muscle bulk initially stems from myofiber hypertrophy, but as myofibers progressively degenerate, an increasing part of the muscle is replaced by adipose tissue and endomysial fibrosis. Cardiac muscle damage and fibrosis may lead to heart failure and arrhythmias, which may prove fatal. Although no structural abnormalities in the central nervous system have been described, cognitive impairment also may occur and may be severe enough to be classified as mental retardation. Owing to ongoing muscle degeneration, high serum creatine kinase levels are present at birth and persist through the first decade of life but fall as muscle mass is lost as the disease progresses. Death results from respiratory insufficiency, pneumonia, and cardiac decompensation.
BMD becomes symptomatic later in childhood or adolescence and progresses at a slower and more variable rate. Many patients live well into adulthood and have a nearly normal life span. Cardiac involvement may be the dominant clinical feature and may result in death, even in the absence of significant skeletal muscle weakness.