Variable clinical phenotype in merosin-deficient congenital muscular dystrophy associated with differential immunolabelling of two fragments of the laminin alpha 2 chain

Approximately half the cases of classical congenital muscular dystrophy (CMD) have a pronounced deficiency or absence of the laminin alpha 2 chain of laminin-2 (merosin). This is caused by mutations in the LAMA2 gene that codes for laminin alpha 2, and all informative cases so far studied show linkage to the appropriate region on chromosome 6q. Most CMD patients with a deficiency of laminin alpha 2 have a severe phenotype that involves skeletal muscle, and the central and peripheral nervous system. We have identified four cases that have minimal reduction of laminin alpha 2 using a commercial antibody that only recognises a C-terminal 80 kDa fragment, but show a pronounced reduction using an antibody to the 300 kDa fragment. Haplotype analysis is compatible with linkage to the LAMA2 locus in three informative families, whilst the fourth family was not informative. Two of the affected children are ambulant and have a mild phenotype. The third case is unusual in having severe muscle weakness but does not show the white matter changes on magnetic resonance imaging of the brain that is usually seen in merosin-deficient cases of CMD; the fourth case has a severe phenotype, typical of merosin-deficient patients but shows good immunolabelling of the 80 kDa fragment of laminin alpha 2, corresponding to the C-terminal region. Our data show that there is a broad spectrum of phenotype and protein expression associated with a primary deficiency in laminin alpha 2, and that a wider range of clinical cases need to be screened for a deficiency of merosin. It is also important to study the expression of laminin alpha 2 with more than one antibody.