Because of clinical similarities, there may be difficulty in distinguishing limb-girdle dystrophies (formerly termed severe childhood autosomal recessive muscular dystrophy [SCARMD]) from a dystrophinopathy (except that the former occur in females). In addition to the difference in inheritance, they can be readily diagnosed by showing a loss of sarcolemmal immunostaining for any of the dystrophin-associated glycoproteins but with preservation of staining for dystrophin itself. However, it is not possible on clinical grounds to distinguish one sarcoglycanopathy from another; this can be accomplished only by specific immunostaining.
These forms of limb-girdle dystrophies have been described in large kindreds, in Indiana (among the Amish people), on the island of Réunion in the Indian Ocean, in Brazil, Great Britain, Italy and Spain, and elsewhere, affecting males and females equally. Both the shoulder and pelvic girdles are involved. The degree of weakness has varied considerably. In one form of the disease, called LGMD 2A, the abnormal gene codes for a calcium-activated neutral protease, or calpain (see Fig. 45-3). This “calpainopathy” is currently believed to account for approximately 40 percent of patients with LGMD. Frequently, and early in the course of disease, there are Achilles tendon contractures and very high serum CK levels (at least 10 times normal), features that may permit distinction from the sarcoglycanopathies.
Yet another fairly common recessive limb-girdle dystrophy of slow progression is caused by a mutation in the gene for the protein dysferlin, which localizes to the muscle fiber membrane. Noteworthy is the fact that this same protein is involved in the distal form of Miyoshi muscular dystrophy described further on. Early involvement of the gastrocnemius muscle (inability to walk on tiptoe) and extraordinarily high levels of CK, as in calpainopathy, are clues to the latter disease.
Several dystrophies with the LGMD phenotype are inherited as autosomal dominant traits. For example, LGMDA 1A is an autosomal dominant limb-girdle dystrophy of late onset that was described in a large North Carolina family (49 affected members in a pedigree of 218 persons). The mean age at onset was 27 years. Proximal leg weakness, with or without proximal arm weakness, and elevated CK values were the main clinical characteristics. Speer and colleagues have documented that the primary defect is in a gene encoding the protein myotilin (see Fig. 45-3). LGMDA 1A is allelic to a form of myofibrillar myopathy.
LGMD 1B is a dominantly inherited disorder arising from mutations in the gene encoding the nuclear membrane protein lamin A/C (Fig. 45-3). Mercuri and colleagues note that the phenotypes of these mutations vary widely. The muscle disorders range from severe cases that mimic CMD to milder ones with features of limb girdle dystrophy or Emery-Dreifuss muscular dystrophy. The diverse, nonmuscular manifestations of lamin A/C mutations include a cardiomyopathy, a form of lipodystrophy, a syndrome of accelerated aging (Hutchinson-Gilford progeria), and a recessively inherited axonal neuropathy.
Progressive External Ophthalmoplegia (Kearns-Sayre Syndrome) (See Also “Progressive External Ophthalmoplegia [PEO] and Kearns-Sayre Syndrome” Under Mitochondrial Myopathies in Chap. 36)