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  • Updated 06.21.2021
  • Released 11.06.1995
  • Expires For CME 06.21.2024

Limb-girdle muscular dystrophies

Introduction

Overview

The previously wastebasket term “limb girdle muscular dystrophy” has been transformed into a multitude of specific, genetically defined disorders. In 2017, the European Neuromuscular Center LGMD workshop study group met in the Netherlands to reach a consensus on the most useful nomenclature and classification of limb-girdle muscular dystrophy subtypes that is accurate, scientific, and with capacity to accommodate further discoveries of limb-girdle muscular dystrophies. The proposed definition for limb-girdle muscular dystrophy is as follows: “limb girdle muscular dystrophy is a genetically inherited condition that primarily affects skeletal muscle leading to progressive, predominantly proximal muscle weakness at presentation caused by a loss of muscle fibres. To be considered a form of limb girdle muscular dystrophy the condition must be described in at least 2 unrelated families with affected individuals achieving independent walking, must have an elevated serum creatine kinase activity, must demonstrate degenerative changes on muscle imaging over the course of the disease, and have dystrophic changes on muscle histology, ultimately leading to end-stage pathology for the most affected muscles”. As a result of this new classification, some previously cases of limb-girdle muscular dystrophy described in a single family were removed from this classification. Other conditions were reclassified according to the protein affected or phenotype. This review will mention the new classification, with mention of the old classification for clarification purposes.

Historical note and terminology

The history of limb-girdle muscular dystrophy encompasses the history of primary and secondary muscle diseases as a whole (33; 282; 468; 469; 529; 53; 241; 456). 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 subsequently with a rapid succession of identified genes and gene products for many limb-girdle muscular dystrophy subtypes.

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 (328). Duchenne mentioned dystrophies with onset in later age and with non-X-linked modes of inheritance. In 1 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 (356). Clinical descriptions were long ago characterized by the distribution of weakness based on the predominant involvement of the scapulohumeral (134), pelvifemoral (283; 335), 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 (135).

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 (282; 468; 469). 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 (529). 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. However, 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 (53).

A workshop headed by Bushby reclassified limb-girdle muscular dystrophy based on mode of inheritance and chromosomal localization (63). 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. As more information is gained regarding the genes and mechanisms involved for pathogenesis in limb-girdle muscular dystrophies, there has been further exploration into therapeutic targets.

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