Muscular Dystrophies and Allied Disorders II: Limb-Girdle Muscular Dystrophies

History and Background

Heterogeneity in the muscular dystrophies has long been recognized ( ). The wide application of molecular techniques and increasing use of next-generation sequencing have identified a growing number of clinical entities, and their gene and protein defects, described as ‘limb-girdle muscular dystrophies’ (LGMD). This is a diverse group of disorders with either autosomal dominant or autosomal recessive inheritance ( Tables 11.1 and 11.2 ). Dominant forms were classified as LGMD1 and recessive forms as LGMD2. An alphabetical suffix was then assigned for each locus, which allowed for addition of new discoveries. Nomenclature, particularly of the recessives forms, however, is now difficult, as the letter Z has been reached (LGMD2Z). Currently, eight dominant (LGMD1A–H) and 26 recessive forms (LGMD2A–Z) are recognized, plus a few additional forms caused by mutations in various genes, some of which are allelic to, or are part of, the spectra of disorders caused by mutations in the same gene ( ) (see also Neuromuscular Disorders Gene Table at http://www.musclegenetable.fr/ ). In addition, the classification of some LGMDs is confusing (e.g. LGMD1D/1E; ). A new nomenclature for the LGMDs has been proposed, but full international consensus has yet to be reached, although it is used in Online Mendelian Inheritance in Man (OMIM) database ( ). The proposed new nomenclature is based on an LGMD phenotype, mode of inheritance, numbered in order of discovery of the gene, and the defective protein. It allows for the addition of new entities ( Table 11.3 ). Thus, all LGMDs that are inherited in a dominant manner are designated by the letter ‘D’ and those inherited recessively by the letter ‘R’ and numbered in order of their identification. Bethlem myopathies and mild cases with mutations in the gene encoding laminin α2 (see Ch. 12 ) have been included in this new nomenclature, although several patients and muscle pathology do not conform to the definition of LGMD stated in the report and some disorders described as LGMD under the current widely used nomenclature have been excluded either because they are defined as another disorder, e.g. a myofibrillar myopathy, Emery–Dreifuss muscular dystrophy or metabolic myopathy ( ).

The common clinical feature of all LGMDs is progressive weakness of the pelvic and shoulder muscles, although distal wasting in the lower limbs is also a feature of some (e.g. LGMD2A, LGMD2B/Miyoshi myopathy, LGMD2J, LDMD2L, see Table 11.4 ). The facial muscles are not usually involved. Other features are variable, and we have attempted to summarize those that can alert the pathologist to a particular type of LGMD ( Table 11.4 ). Clinical details and the magnetic resonance imaging (MRI) patterns of muscle involvement of each type of LGMD are beyond the scope of this book and can be found in various textbooks and reviews (e.g. ). Difficulties in classification of LGMDs arise because of allelic variations, with clinical extremes or clearly different phenotypes resulting from defects in the same gene. For example, mutations in several genes involved with the glycosylation of α-dystroglycan can cause an LGMD or a severe form of congenital muscular dystrophy (see Ch. 12 ); the gene for dysferlin is responsible for LGMD2B presenting with limb-girdle weakness and for Miyoshi myopathy, which presents with selective distal weakness. Disorders with a limb-girdle phenotype associated with hypoglycosylation of α-dystroglycan have been assigned a nomenclature in OMIM that attempts to take into account the phenotypic variability, particularly in relation to involvement of the brain (see below and Ch. 12 ). Genotype–phenotype correlations and a broadening of our understanding of pathogenesis are beginning to clarify aspects of this, but the mechanisms of gene modification are still far from understood. In this book we have adhered to a clinical classification, rather than one based on the gene/protein defect, as the clinical features are fundamental to diagnosis, and direct molecular analysis and patient management (see Ch. 8 ).

Histology and Histochemistry

The overall pattern of pathology is usually dystrophic, with variation in fibre size, necrosis and regeneration, splitting and branching of fibres, internal nuclei and often an increase in connective tissue and architectural change. As with all muscle disorders, the degree of pathology does not correlate with clinical severity. It is not possible to classify a case of LGMD, or distinguish LGMD from Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD) or a carrier of DMD, based on histology and histochemistry alone, and immunohistochemistry is essential.

Changes in Fibre Size

Fibres may be round in shape, and all forms show an abnormal variation in fibre size that is usually obvious ( Fig. 11.1 ). Hypertrophied fibres are common and this may be marked, especially in some adults. The hypertrophied fibres often show splits or appear branched in longitudinal sections. Some of the size variation seen in transverse sections is due to this branching. In contrast to DMD, the hypertrophied fibres are rarely hypercontracted and heavily stained in LGMD. Groups of small fibres, as in BMD, are not usually seen but can occur. Multiple splitting may sometimes give the impression of a group of small fibres ( Fig. 11.2 ). In cases of LGMD1B, we have noted a tendency for the type 1 fibres to be generally smaller in diameter than type 2 ( ), but this is not a specific feature.