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The Congenital and Limb-Girdle Muscular Dystrophies Sharpening the Focus, Blurring the Boundaries

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The Congenital and Limb-Girdle Muscular Dystrophies Sharpening the Focus, Blurring the Boundaries NEUROLOGICAL REVIEW SECTION EDITOR: DAVID E. PLEASURE, MD The Congenital and Limb-Girdle Muscular Dystrophies Sharpening the Focus, Blurring the Boundaries Janbernd Kirschner, MD; Carsten G. Bo¨nnemann, MD uring the past decade, outstanding progress in the areas of congenital and limb- girdle muscular dystrophies has led to staggering clinical and genetic complexity. With the identification of an increasing number of genetic defects, individual enti- ties have come into sharper focus and new pathogenic mechanisms for muscular dys- Dtrophies, like defects of posttranslational O-linked glycosylation, have been discovered. At the same time, this progress blurs the traditional boundaries between the categories of congenital and limb- girdle muscular dystrophies, as well as between limb-girdle muscular dystrophies and other clini- cal entities, as mutations in genes such as fukutin-related protein, dysferlin, caveolin-3 and lamin A/C can cause a striking variety of phenotypes. We reviewed the different groups of proteins cur- rently recognized as being involved in congenital and limb-girdle muscular dystrophies, associ- ated them with the clinical phenotypes, and determined some clinical and molecular clues that are helpful in the diagnostic approach to these patients. Arch Neurol. 2004;61:189-199 Muscular dystrophies were first recog- phy. The age at onset may range from early nized as a disease entity with the detailed childhood to late adulthood.5 description of the clinical presentation of During the past decade, exciting Duchenne muscular dystrophy in 1852 and progress has been made in the field of CMD thereafter.1,2 About 50 years later, Batten3 and LGMD, emphasizing differences as published the first case reports of a con- well as commonalities between them. Af- genital form of muscular dystrophy (CMD). ter further careful clinical delineation of Unlike the Duchenne-Becker phenotype,2 phenotypes in particular within CMD, ad- in patients with CMD weakness and dys- vances in genetic and histochemical char- trophic changes in muscle biopsy speci- acterization have led to the identification mens are present at birth, but they tend in of numerous molecularly defined sub- many cases to be considerably less progres- types of muscular dystrophy based on the sive than in patients with the Duchenne involved genes and proteins. This has form. The term limb-girdle muscular dys- brought individual clinical entities into trophy (LGMD) was introduced in the mid- sharper focus, but has also blurred the 20th century when it became obvious that boundaries between the traditional cat- there was an additional major group of non- egories of muscular dystrophy. For ex- congenital muscular dystrophies different ample, it has now been recognized that mu- from the X-linked Duchenne-Becker and tations in the same protein can give rise autosomal dominant facioscapulo- to very different phenotypes. Fukutin- humeral forms.4 Accordingly, LGMD cur- related protein (FKRP) mutations can rently comprises clinical phenotypes with manifest with variable severity ranging progressive weakness, onset in the limb- from a severe CMD (including type 1C, girdle muscles, and histologic evidence of CMD with cerebellar cysts, and Walker- a dystrophin-positive muscular dystro- Warburg syndrome) to a milder adult- onset LGMD (type 2I).6-11 Dysferlinopa- thies can present as a classic LGMD From the Division of Neurology, The Children’s Hospital of Philadelphia and phenotype (type 2B), as a distal muscular University of Pennsylvania School of Medicine, Philadelphia. dystrophy (Miyoshi type), or as mixed phe- (REPRINTED) ARCH NEUROL / VOL 61, FEB 2004 WWW.ARCHNEUROL.COM 189 ©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 Collagen Type VI β1 γ1 Perlecan Laminin-2 Nidogen Integrin α2 α7 β1 Collagen Type IV Biglycan α Sarcoglycan Dystroglycan β Caveolin-3 Plasma Membrane β α δ γ nNOS Sarcospan Dysferlin γ-Filamin Adhesion Complex Syntrophin Actin Dystrobrevin Dystrophin COOH Schematic representation of the dystrophin-associated proteins and other sarcolemmal and extracellular proteins relevant to muscular dystrophy. Proteins for which mutations in the corresponding genes have been shown to cause muscular dystrophies are shown in color. ␣-Dystroglycan (dotted pattern) can be indirectly involved via alterations of its O-linked glycosylation. nNOS indicates neuronal nitric oxide synthase; COOH, carboxy terminus; and NH2, amino terminus. Adapted with permission from Neuromuscular Disorders of Infancy, Childhood, and Adolescence: A Clinician’s Approach.23 Copyright 2003, Elsevier. notypes.12,13 Mutations in lamin A/C have an even wider importantly to laminin-2. Other ligands are known, such spectrum of phenotypes associated with them.14-20 as neurexin, in the nervous system.24 Although muta- In this review, we will focus on entities within the tions of dystroglycan itself in humans have not been found, scope of CMD and LGMD, as progress in these areas has alterations of its posttranslational modification as well as led to staggering clinical and genetic complexity. We will mutations in its main extracellular ligand laminin-2 give briefly introduce the different groups of proteins cur- rise to diverse forms of LGMD and CMD. O-mannose– rently recognized as being involved in CMD and LGMD linked glycosylation is a rare form of posttranslational modi- before we associate them in a second step with the clini- fication of mammalian proteins, but it seems to be spe- cal phenotypes. Finally, we offer some clinical and mo- cifically perturbed in ␣-dystroglycan in a number of lecular clues that are helpful in the diagnostic approach disorders.25 Abnormal glycosylation appears to decrease to these patients. or abolish ␣-dystroglycan’s binding affinity for known in- teracting proteins of the extracellular matrix (eg, laminin THE MOLECULAR PLAYERS and neurexin).24 So far, 5 different known or putative gly- cosyltransferases or proteins involved in these path- Dystrophin-Associated and ways6,25-28 (Table 1) have been shown to cause mainly Membrane-Based Proteins CMDs in humans (for review see Michele and Campbell35). Abnormal ␣-dystroglycan likely is responsible for most of The discovery of dystrophin as the protein deficient in the observed aspects of these disorders, but it is unclear Duchenne and Becker muscular dystrophy21 has led to whether other target proteins could also be underglyco- the recognition of a multimeric protein complex associ- sylated and contribute to the pathogenesis of the disease. ated with dystrophin (dystrophin-associated proteins) (for In contrast, the sarcoglycan-sarcospan complex is review see Blake et al22). This complex can be subdi- mainly involved in the pathogenesis of LGMD pheno- vided further into 2 transmembrane (dystroglycan and types (LGMD2C-F).36 In muscle, the major sarcoglycan sarcoglycan-sarcospan) and 1 intracellular (dystrobrevin- complex consists of the subunits ␣-, ␤-, ␥-, and ␦-sarco- syntrophin) complex (Figure). glycan, all 4 of which can be mutated in forms of The dystroglycan complex forms an important link LGMD.37-41 Additional sarcoglycans (⑀, ␨) are also known from the actin cytoskeleton via dystrophin to the basal to be expressed in other tissues. Mutations in ⑀-sarco- lamina and extracellular matrix proteins, in muscle most glycan cause myoclonus-dystonia syndrome.42 Possible (REPRINTED) ARCH NEUROL / VOL 61, FEB 2004 WWW.ARCHNEUROL.COM 190 ©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 Table 1. The Congenital Muscular Dystrophies (CMDs) Disease Entity Locus, Protein Product Helpful Clinical Features CNS Involvement Laboratory Testing CMD with primary 6q22-q23, Laminin-␣2 Sitting and standing with support as Abnormal white-matter Mostly complete laminin-␣2 laminin-2 maximal motor ability if complete signal (T2 MR imaging), deficiency on IH/WB, (merosin) deficiency, neuropathy, epilepsy in 5% occipital pachygyria secondary reduction of deficiency about 30%, possible subclinical or agyria integrin ␣7 possible, (MDC1A) cardiomyopathy, generally normal mutation analysis* mental development CMD with partial 1q42, Not known Rare, variety of severity, delayed onset Abnormal white-matter and Partial deficiency of laminin-␣2 merosin possible, proximal girdle weakness, structural changes possible on IH/WB, ␣-DG significantly deficiency generalized muscle hypertrophy, reduced on IH, linkage (MDC1B)29 early respiratory failure possible analysis Fukutin-related 19q13.3, Fukutin-related Often reminiscent of MDC 1A, but Generally normal, structural ␣-DG with diminished MW on proteinopathy protein (FKRP, putative severity more variable, from severe abnormalities with WB, or reduction of IH using (MDC1C) phospholigand CMD to LGMD (Table 2), generally cerebellar cysts possible antibodies against transferase) normal mental development, rare glycosylated isotopes, cases with structural brain secondary reductions in involvement and mental retardation laminin-␣2 on IH/WB, mutation analysis* LARGE-related CMD 22q12.3, LARGE (putative So far only 1 patient described; White-matter changes, IH/WB comparable with (MDC1D)27 glycosyltransferase) congenital muscular dystrophy with hypoplastic brainstem, MDC1C, mutation analysis* profound mental retardation mild pachygyria Ullrich CMD 21q22.3 And 2q37, ␣1/2 Distal joint hyperextensibility, proximal No IH for collagen VI with severe to (UCMD) and ␣3 collagen VI contractures, motor abilities
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