Classification

Historically, the muscular dystrophies have been defined as progressive myopathies in which muscle biopsies demonstrate replacement of muscle fibers by adipose and connective tissue. The clinical onset of the dystrophy may be evident at birth, as in congenital muscular dystrophies, or may not develop until late adulthood. The dystrophies were felt to differ from congenital myopathies by the presence of specific ultrastructural abnormalities apparent in muscle biopsies in the latter (e.g., nemaline rods, cores, or minicores). However, with advances in molecular genetics the distinction between what constitutes a muscular dystrophy and a congenital myopathy has become blurred. For example, myofibrillar abnormalities and inclusions such as nemaline rods, cytoplasmic bodies, and reducing bodies that initially led to categorization as a congenital myopathy have been noted in disorders known to carry similar genetic defects that have been considered forms of dystrophy.

Dystrophies have been classified according to age of onset, mode of inheritance, and pattern of weakness (Table 1.1). For example, those that present at birth have been termed congenital muscular dystrophies (MDC). Dystrophies have also been named based on the patterns of muscle involvement, including limb-girdle muscular dystrophy (LGMD), facioscapulohumeral dystrophy (FSHD), oculopharyngeal muscular dystrophy (OPMD), distal myopathy/dystrophies, and scapuloperoneal dystrophy. Within the distal muscular dystrophies, subclassifications have been based on inheritance pattern, age of onset, and the specific muscle groups initially affected; for example, the Markesbery–Griggs, Udd, and Laing types of distal myopathy have preferential involvement of the anterior tibial muscles, Miyoshi myopathy the gastrocnemius, and Welander myopathy the extensor forearm muscles. Dystrophies associated with proximal greater than distal weakness are called limb-girdle dystrophies (LGMD). The LGMD, inherited in an autosomal dominant fashion, are termed LGMD type 1 (LGMD1), whereas autosomal recessive dystrophies are called LGMD2. Further subclassifications of the LGMDs are based on genotype differences (e.g., LGMD1A, LGMD1B).

There are problems with this traditional classification of muscular dystrophies. We now know that most of the genetic defects previously found to be associated with congenital muscular dystrophy can all be associated with milder, adult-onset dystrophy (see Table 1.1). In addition, clinical heterogeneity is sometimes evident within family members with specific mutations such that some may manifest with a limb-girdle pattern of weakness, whereas other members in the family have distal weakness (e.g., Miyoshi myopathy, anterior tibial myopathy, LGMD2B are all associated with dysferlin mutations). Thus, it may be more appropriate to classify the dystrophies by the genetic defect (e.g., dysferlinopathies, calpainopathy) and to understand the specific clinical phenotype, including age of onset and patterns of weakness that may be associated with the specific disorders. However, the classic terminology (e.g., LGMD) is so ingrained that it is likely to persist until a new generation of clinical investigators armed with the explanations for divergent phenotypes writes its textbooks.

Figure 1.1 Sarcolemmal membrane and enzymatic proteins. This schematic shows the location of various sarcolemmal and enzymatic proteins associated with muscular dystrophies. The diseases caused by these molecules when mutated are shown in boxes. Dystrophin, via its interaction with the dystroglycan complex, connects the actin cytoskeleton to the extracellular matrix. Intracellularly, it interacts with dystrobrevin (α-DTN) and syntrophins (Syn) (shown in blue). Extracellularly, the sarcoglycan complex (orange) interacts with biglycan, which connects this complex to the dystroglycan complex and the extracellular matrix collagen. Intracellularly, δ- and γ-sarcoglycans interact with filamin C. The four proteins shown in the Golgi complex have been demonstrated to affect the glycosylation state of the α-dystroglycan and mediate its binding to the extracellular matrix. Fukutin and fukutin-related protein (FKRP) have been shown to localize to the medial Golgi. The localization of POMT1 (protein O-mannosyltransferase), POMGnT1 (protein O-linked mannose β-1,2-N-acetylglucosaminyltransferase), and LARGE (another putative glycosyltransferase) is unknown but believed to be in the Golgi complex as these enzymes are involved in the glycosylation process. BMD, Becker muscular dystrophy; DMD, Duchenne muscular dystrophy; ITGA7, integrin-α7; LGMD, limb-girdle muscular dystrophy; MDC, congenital muscular dystrophy; MEB, muscle–eye–brain; SEPN, selenoprotein N; TRIM, E3 ubiquitin ligase.

(From Amato AA, Russell J (2008) p. 530. Neuromuscular Disease. McGraw-Hill, New York, with permission.)

Figure 1.2 Sarcomeric and nuclear proteins involved in the muscular dystrophies. The schematic for the sarcomere and the nucleus showing the localization of the proteins involved in muscular dystrophies. The diseases they give rise to are shown in boxes. EDMD, Emery–Dreifuss muscular dystrophy; h-IBMPFD, hereditary inclusion body myopathy with Paget disease of bone; IBM, inclusion body myopathy; LGMD, limb-girdle muscular dystrophy; MD, muscular dystrophy; OPMD, oculopharyngeal muscular dystrophy; PABN, polyadenylate binding nuclear protein; VCP, valosin-containing protein; ZASP, Z-band alternately spliced PDZ motif-containing protein.

(From Amato AA, Russell J (2008) p. 531. Neuromuscular Disease. McGraw-Hill, New York, with permission.)