The congenital muscular dystrophies: recent advances and molecular insights

Abstract

Over the past decade, molecular understanding of the congenital muscular dystrophies (CMDs) has greatly expanded. The diseases can be classified into 3 major groups based on the affected genes and the location of their expressed protein: abnormalities of extracellular matrix proteins (LAMA2, COL6A1, COL6A2, COL6A3), abnormalities of membrane receptors for the extracellular matrix (fukutin, POMGnT1, POMT1, POMT2, FKRP, LARGE, and ITGA7), and abnormal endoplasmic reticulum protein (SEPN1). The diseases begin in the perinatal period or shortly thereafter. A specific diagnosis can be challenging because the muscle pathology is usually not distinctive. Immunostaining of muscle using a battery of antibodies can help define a disorder that will need confirmation by gene testing. In muscle diseases with overlapping pathological features, such as CMD, careful attention to the clinical clues (e.g., family history, central nervous system features) can help guide the battery of immunostains necessary to target an unequivocal diagnosis.

Figure 1

Illustration shows the major components of the dystrophin glycoprotein complex (DGC). Within the cytoplasm of the muscle fiber, the N-terminal of dystrophin links to the actin cytoskeleton. The cysteine-rich C-terminal domain of dystrophin links to the membrane via the dystroglycan complex. Dystroglycan consists of β-dystroglycan, a transmembrane protein, and α-dystroglycan, a highly glycosylated extracellular membrane protein. Several G domains of laminin-2 bind α-dystroglycan to link the complex from the extracellular matrix through the membrane to the actin cytoskeleton. Collagen VI is also a component of the muscle extracellular matrix. The sarcolemmal membrane is additionally anchored by integrin α7β1. Like dystroglycan, integrin α7β1 binds laminin-2 via its G domains, but it links the extracellular matrix to the cytoskeleton via integrin-associated proteins (examples shown are Pa = paxillin; T = talin; Vi = vinculin; FAK = focal adhesion protein).

Figure 2

Axial T-2–weighted image of brain of a 2-year-old patient with laminin α2 deficiency shows high signal intensity in the white matter.

Figure 3

Muscle biopsy from 2-year-old patient with laminin α2 deficiency. The muscle shows marked variability in fiber size. Endomysial connective tissue proliferation surrounds virtually every muscle fiber in the field. Central nucleation is not prominent. H & E stain.

Figure 4

Muscle fibers are not stained for laminin α2 (Vector Laboratories, Inc., Burlington, CA, USA) in a patient with laminin α2-deficient congenital muscular dystrophy (MDC1A) compared with normal control.

Figure 5

(A) Skin biopsy obtained from a normal control shows laminin α2 localized to the basement membrane at the junction of the epidermis and dermis. (B) Biopsy from a patient with laminin α2 deficiency lacks basement membrane staining for laminin α2. Previously published by Sewry et al. in The Lancet 1996;347:582–584. Reproduced with permission of Elsevier [33].

Figure 6

(A) Collagen VI is strongly expressed in the extracellular matrix of muscle fibers and around the blood vessel in a control. In collagen VI deficiency, the staining is reduced (B, C) or completely absent (D). Previously published by Demir et al. in the Am J Hum Genet 2002;70:1446–1458. Reproduced with permission of University of Chicago Press.

Figure 7

Summary of biosynthetic pathway for O-mannosyl glycans on α dystroglycan in mammals. Only steps 1 and 2 are unique to α–dystroglycan glycosylation. The 1st step requires the coexpression of protein-O-mannosyltransferase 1 (POMT1) and protein-O-mannosyltransferase 2 (POMT2). Step 2 requires protein O-linked mannose β1,2-N-acetylglucosaminyltransferase 1 (POMGnT1). The 3rd and 4th steps, which synthesize β1,4-linked galactose and α2,3-linked sialic acid, are found on multiple types of N- and O-linked glycoproteins.

Figure 8

Stain for glycosylated α–dystroglycan (Upstate Cell Signaling Solutions, Lake Placid, NY, USA) in normal muscle compared with marked reduction in a patient with fukutin-related protein (FKRP) deficiency (MDC1C).

Figure 9

Four siblings affected by rigid spine muscular dystrophy type 1 (RSMD1) can be seen in side and frontal views. The loss of muscle bulk is striking, and the presence of scoliosis, varying degrees of lordosis, and joint contractures at elbows and knees can be seen. Previously published by Flanigan et al. in Ann Neurol 2000;47:152–161 with permission of John Wiley & Sons [132].