Sixteen different forms of
limb-girdle muscular dystrophies (LGMDs) have emerged from recent molecular genetic studies, six forms with a dominant trait and ten forms with a recessive trait. Among 1,420 Japanese patients with
muscular dystrophy analyzed at NCNP, LGMD is the secondly largest category (19%) following dystrophinopathy (56%). Within LGMDs, the occurrence of
LGMD2A (
calpainopathy),
LGMD2B (
dysferlinopathy), and LGMD2C-F (
sarcoglycanopathy) is 26%, 18%, and 6.6%, respectively, however, causative genes have not been specified in about 50% of the LGMD patients.
LGMD2A patients show
atrophy prominent in shoulder and pelvic girdle muscles without calf muscle
hypertrophy, and abundant lobulated fibers in muscle biopsy. Four major mutations unique to the Japanese population, have been identified. Pathogenesis attributes to a loss of proteolytic activity of mutant calpain-3.
Dysferlin, the defective
protein in
LGMD2B, is a ferlin family molecule possessing six C2 domains probably mediating the resealing mechanism of the damaged sarcolemma. Mutations in the
dysferlin gene result in
Miyoshi distal myopathy and distal anterior compartment
myopathy other than
LGMD2B. Among four sarcoglyconopathies,
LGMD2D is the most common form, whereas
LGMD2F has not yet been reported. In
sarcoglycan-deficient skeletal muscle,
matrix metalloproteinases may be involved in the
beta-dystroglycan processing which underlies the pathogenesis of
sarcoglycanopathy.