The discovery of the “fukutin-related protein” initially came about because mutant forms caused a severe congenital muscular dystrophy (CMD). It later became apparent that certain mutations also cause a common type of later onset limb-girdle dystrophy. As the designation “2” indicates, it is transmitted in an autosomal recessive manner. This is the most common form of limb-girdle dystrophy in patients of Northern European descent. In a series of 16 patients from 14 families, Poppe and colleagues characterized the main features as having an onset of proximal girdle weakness in the second to fourth decades of life (but as early as age 2 years). The majority of patients eventually had respiratory failure and several displayed varying degrees of congestive heart failure, features that also accompany some of the other limb-girdle dystrophies. In most other ways, this disease reflects the heterogeneity of clinical presentation of the other subtypes of limb-girdle disease. A period of stabilization lasting several to 35 years is common, followed by a decade or more of progression that eventually involves the shoulder muscles. Most patients, particularly those with later onset, remained able to walk into their forties. Other features are variable, for example, dysphagia and ptosis; however, distal weakness is not seen and intelligence is normal.
The defective FKRP gene is related in function to 4 other muscle genes in addition to fukutin (hence its name). All 5 of these genes are glycosyl transferases that attach sugar groups to proteins such as alpha-dystroglycan. The severity of the clinical phenotype is inversely related to the levels of glycosylation of alpha-dystroglycan. Defects in any of the 5 genes can cause developmental lesions in the brain in addition to muscle disease, although those associated with FKRP mutations are less common and less severe.
Severe Childhood Autosomal Recessive Muscular Dystrophy (Sarcoglycanopathies; LGMD 2C, D, E, and F)
These entities comprise the best-defined group of limb- girdle dystrophy. Clinically they resemble severe Duchenne dystrophy in practically all respects, including the presence of calf hypertrophy, cardiomyopathy, and marked elevation of CK in the early stages of the illness. The obvious distinction from Duchenne dystrophy is the autosomal recessive pattern of inheritance (affection of both girls and boys in the same sibship). The largest and best-studied group of this severe, recessive pelvic-pectoral dystrophy (99 children in 28 families) has come from Tunisia (Ben Hamida et al). It also occurs commonly in other Arab countries and has been observed repeatedly in Brazil, but less so in Europe and North America.
The basic defect is in 1 of 4 dystrophin-associated glycoproteins (DAGs)—a-, b-, g-, and d-sarcoglycan (see Fig. 45-2); a-sarcoglycan (designated 50 DAG) is also called adhalin, from the Arabic word adhal, meaning muscle. A primary deficiency of adhalin has been traced adhalin on chromosome 17q21 (Roberds et al). A primary defect in b-sarcoglycan (43 DAG) has been mapped to chromosome 4q12, of g-sarcoglycan (35 DAG) to the pericentromeric region of chromosome 13q, and of b-sarcoglycan (43 DAG) to chromosome 5q. Primary defects in 25 DAG may also lead to a deficiency of adhalin, but the latter is incomplete and represents a secondary effect, possibly explained by the proximity of the defective genes to the adhalin gene.