Limb-girdle muscular dystrophies

Louis H Weimer MD (Dr. Weimer of Columbia University has received consulting fees from Roche.)
Salvatore DiMauro MD, editor. (Dr. DiMauro, Director Emeritus of H Houston Merritt Clinical Center for the Study of Muscular Dystrophy and Related Diseases at Columbia University, has no relevant financial relationships to disclose.)
Originally released November 6, 1995; last updated May 30, 2013; expires May 30, 2016
Notice: This article has expired and is therefore not available for CME credit.

This article includes discussion of limb-girdle muscular dystrophies, limb-girdle dystrophy, LGMD, and LGMD2. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

The previously wastebasket term “limb girdle muscular dystrophy” has been transformed into a multitude of specific, genetically defined disorders. Defects are found in diverse cellular components including extracellular matrix, cell membrane and associated proteins (sarcoglycans, caveolin-3, dysferlin, integrins), cellular enzymes (calpain-3), organelle or sarcomere function (telethonin, myotilin, titin), and nuclear envelope (lamins). The group is separated into autosomal recessive and dominant forms. Numerous allelic associations have been made with several gene products. Discovery of the cause of many genes has led to scientific advances in the understanding of muscle function and will hopefully lead to treatment options. Testing for many forms is available on a commercial or research laboratory basis. The author discusses current clinical and scientific knowledge of this rapidly evolving field.

Key points

Historical note and terminology

The history of limb-girdle muscular dystrophy encompasses the history of primary and secondary muscle diseases as a whole (Bell 1943; Levison 1951; Stevenson 1953; 1955; Walton and Nattrass 1954; Bradley 1979; Jerusalem and Sieb 1992; Shields 1994). The cases categorized under the term "limb-girdle dystrophy" have varied over time and among authors. In the older literature, for example, authors tended to lump limb-girdle muscular dystrophy cases with other muscular dystrophies, polymyositis, spinal muscular atrophies, and even poliomyelitis. Recognition of a distinct mode of inheritance and distribution of weakness first helped to differentiate some muscular dystrophies from the limb-girdle syndromes. Modern techniques of investigation then allowed the recognition and separation of the inflammatory myopathies, other acquired myopathies, and neurogenic disorders into separate entities. From the residuum, the cases of congenital myopathies, dystrophinopathies, and mitochondrial and metabolic myopathies have further been culled out based on ultrastructural and biochemical studies. Later, molecular genetics drastically altered the field, initially with linkage of multiple families and syndromes to specific chromosomal loci and over the last decade with a rapid succession of identified genes and gene products for many limb-girdle muscular dystrophy subtypes. Some authors have questioned the existence of limb-girdle muscular dystrophy as a nosologic entity (Sica and McComas 1971; Gardner-Medwin 1980; Walton and Gardner-Medwin 1988). The currently remaining syndromes appear to be a heterogeneous group of disorders with overlapping clinical features but defects in gene products of seemingly disparate function. In some cases, these genes share loci or mutations with other neuromuscular and medical disorders.

Muscular dystrophy was probably known to the ancient Egyptians, as evidenced by wall carvings in pyramids (about 2500 BC). Meryon described an entity in some of his patients that appears to be the first reported description of either limb-girdle muscular dystrophy or benign X-linked muscular dystrophy (Meryon 1852). Duchenne, best known for his description of the childhood dystrophy that bears his name, mentioned dystrophies with onset in later age and with non-X-linked modes of inheritance. In one family reviewed by Nevin, Duchenne described a relatively benign limb-girdle myopathy in a father and son pair, suggesting an autosomal dominant trait; the father's weakness began in his fifth decade (Nevin 1936). Clinical descriptions were long ago characterized by the distribution of weakness based on the predominant involvement of the scapulohumeral (Erb 1884), pelvifemoral (Leyden 1876; Mobius 1879), or quadriceps musculature. In subsequent classifications, these types of muscular dystrophy have maintained their identity and have been traditionally viewed as subtypes of limb-girdle muscular dystrophy. Of note, the terms "muscular dystrophy" and "muscular atrophy" were used interchangeably and without qualification at the time of these early writings. It was not until later that Erb introduced the concept of muscular dystrophy as a hereditary degenerative disease of muscle (Erb 1891).

In the 20th century, an increasing number of cases of upper and lower limb-girdle dystrophy were reported. Levison reviewed 123 personal cases of muscular dystrophy from Denmark, and Stevenson investigated 60 families from Northern Ireland (Levison 1951; Stevenson 1953; 1955). These authors attempted to separate limb-girdle muscular dystrophy from other forms of dystrophies based on clinical, genetic, electrophysiologic, and histologic studies. Walton and Nattrass investigated 105 cases of muscular dystrophy from the northeast of England and proposed the most widely accepted classification of the muscular dystrophies until 1995 (Walton and Nattrass 1954). They grouped the pelvifemoral form of Leyden and Mobius and the juvenile scapulohumeral form of Erb together with the late-onset cases of Nevin under the umbrella term "limb-girdle muscular dystrophy" in order to separate this group from X-linked disorders and fascioscapulohumeral dystrophy. The disorders were lumped because "their observations have not indicated any significant difference in the natural history and mode of inheritance in these cases that could be related to the pattern of muscle affection and the age of onset." However, the diagnosis of limb-girdle muscular dystrophy in some of Nevin's cases has been questioned (Bradley 1979). Moreover, with improved diagnostic methods, limb-girdle muscular dystrophy as described by Walton and Nattrass turned out to include a wide variety of neuromuscular disorders, such as chronic spinal muscular atrophy, polymyositis, endocrine myopathies, and some congenital and metabolic myopathies (Bradley 1979).

The lack of uniformity in the descriptions by various authors has repeatedly raised the broader issue of what constitutes a specific disease entity within the muscular dystrophies. A workshop headed by Bushby reclassified limb-girdle muscular dystrophy based on mode of inheritance and chromosomal localization (Bushby 1995). At the time in 1995, only 1 dominant and 4 recessive loci were identified and only 1 protein product was known (adhalin). In later years, many of the limb-girdle dystrophies have been identified at the molecular level and, in turn, have driven new theories of pathogenesis and refined classification systems based on genetic loci, affected genes, or gene products. At the time of this writing, there are 26 identified genetically distinct limb-girdle muscular dystrophies, and in 22 of these, specific gene defects are identified. An increasing number of neuromuscular, cardiac, and other types of disorders have been linked to limb-girdle muscular dystrophy genes and gene products. Additional forms will probably be recognized as diagnosed families and individuals are tested for known mutations and new cases are identified in light of recent advances.

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