Dismantling Limb-Girdle Muscular Dystrophy

Muscular dystrophy encompasses a diverse group of genetically determined muscle disorders. The first clinical description of the disorder is attributed to Giovanni Semmola, who, in 1829, described 2 boys affected by a disorder with prominent muscular hypertrophy.1 Between 1850 and 1868, Aran, Meryon, and Duchenne described a progressive atrophy of voluntary muscles, ultimately termed pseudohypertrophic muscular paralysis of children by Duchenne.1,2 Other descriptions followed: familial atrophy of the pelvic girdle muscles (Leyden in 1876), scapulohumeral muscular atrophy (Erb in 1884), and myopathy with facial weakness (Landouzy and Dejerine in 1884).1 The term limb-girdle muscular dystrophy (LGMD), suggested by Stevenson in 1953,3 and further detailed by Walton and Nattrass in a seminal article,2 refers to a group of muscular dystrophies with onset of weakness in the shoulder or pelvic girdles.4 The variable clinical course of this disorder was recognized even in these early descriptions.2,3 Traditional neurology emphasizes the role of the history and clinical examination in arriving at a diagnosis. The clinical approach to patients with suspected myopathy includes obtaining a history of symptom evolution, comprehensive pedigree analysis, evaluation of the distribution of weakness, and identification of extramuscular manifestations. Neuromuscular neurologists often use a “pattern recognition” approach, which classifies muscle weakness into specific schema: limb girdle, distal, humeroperoneal, etc. There is value to this clinical approach, which allows one to narrow the diagnosis down to a few conditions, or even a single condition, to inform subsequent confirmatory testing. A young boy with onset of weakness in the first decade, calf hypertrophy, Gowers maneuver, and a similarly affected maternal uncle is likely to have Duchenne muscular dystrophy. For a young adult with myotonia, ptosis, temporalis atrophy, distal limb weakness, and a family history suggesting autosomal dominant inheritance, clinical suspicion of myotonic dystrophy leads to confirmatory genetic testing. However, genetic heterogeneity (ie, the existence of similar phenotypes due to different genetic mutations) limits the diagnostic capacity of phenotypic classifications. In 1987, the discovery of the genetic defect and protein product, dystrophin, in Duchenne muscular dystrophy revolutionized the approach to muscular dystrophies.5 An era of molecular diagnoses was born. As the search for genetic causes for neuromuscular disorders continued, it became apparent that LGMD was not a single disease but likely represented several disorders unified by their phenotype. After reports of autosomal recessive LGMD from the 1950s on, Fardeau and colleagues, in 1989, described an autosomal recessive LGMD on the French island of Réunion; in 1991, this disorder was found to link to chromosome 15q, and in 1995, it was identified as calpainopathy.6 In 1986, a report of autosomal dominant LGMD established the genetic heterogeneity of this syndrome.7 A subsequent family with autosomal dominant LGMD reported in 1988 was found to have a type of LGMD that linked to chromosome 5q in 1992, and in 2000, this family was identified as having a mutation in the myotilin gene.8 A genetic classification of LGMDs was proposed in 1995, based on the inheritance pattern: Type 1 LGMDs are autosomal dominant, and type 2 LMGMDs are autosomal recessive. A letter defining the order of discovery of the chromosomal locus is appended to the numeric designation.9 The list of LGMDs with known genetic loci continues to grow rapidly (8 autosomal dominant LGMDs [LGMD1A1H) and 23 autosomal recessive LGMDs [LGMD2A-2W]).10 A definitive diagnosis of the type of LGMD is important; it avoids repeated testing or empirical, potentially toxic treatments for acquired causes such as inflammatory myopathy; provides patients with a sense of closure; assists genetic counseling; and aids the identification and treatment of complications.11 In the future, knowledge of the underlying genetic mutation will be necessary for enrollment in clinical trials of targeted therapies. However, the genetic heterogeneity of the LGMD phenotype makes establishing a definitive diagnosis challenging. The approach to diagnosis is complex and includes evaluation of the inheritance pattern and identification of specific clinical features that direct further testing.11 Conventional genetic testing for mendelian disorders such as LGMD involve genome-wide linkage to identify mutations that cosegregate within affected individuals, positional cloning, and, finally, targeted candidate gene sequencing.12 In autosomal recessive disorders, autozygosity mapping, which identifies regions of the genome that are homozygous in affected individuals but not in unaffected family members, is followed by gene sequencing to identify the causal mutation.13 These techniques assume the availability of several affected family members and are of limited utility when only a few cases are available or in sporadic cases owing to de novo mutations. In addition, genetic and phenotypic heterogeneity and incomplete penetrance limit these approaches.13 The DNA sequencing technique described by Sanger et al14 was used to sequence the human genome in 2001 (the Human Genome Project).15 In 2004, next-generation sequencing methods (which use high-throughput, massively parallel sequencing platforms) were introduced, making it possible to sequence sevRelated article page 1424 Opinion