We report two siblings, an 11-year-old boy and his 7-year-old sister, referred to us with a diagnosis of
muscular dystrophy. The boy presented at 22 months with delay in walking. A very high serum
creatine kinase (CK) level and a dystrophic muscle biopsy lead to a diagnosis of
Duchenne muscular dystrophy prior to the identification of the
dystrophin gene. Two years later his sister presented with similar problems. A diagnosis of
limb-girdle muscular dystrophy was made when they were shown to have inherited different X-chromosomes and normal expression of
dystrophin and all
sarcoglycans. Their conditions remained static. Recently a slowing of the peripheral motor nerve conduction velocities and T2-weighted brain magnetic resonance imaging showed increased signal of the white matter, both of which are features of
merosin-deficient congenital muscular dystrophy. Immunolabelling using a C-terminal
laminin alpha 2 chain antibody showed a reduction in expression, while labelling with another antibody that recognises a 300-kDa fragment showed a very significant reduction. Mutational analysis of the LAMA2 gene showed two mutations: one was a G-->C point mutation at position -1 of intron 28 acceptor splicing site. This mutation induced activation of a cryptic splice at
nucleotide 4429 of exon 29 and partial skipping of this exon, with conservation of the open reading frame. The other was a
nonsense mutation due to a C_T transition at position 5525 of the
cDNA sequence (exon 37), resulting in a stop
codon. These data confirm that mutations of the LAMA2 gene that do not completely disrupt the production of the
protein can give rise to phenotypes considerably milder than classical
merosin-deficient congenital muscular dystrophy. Partial
laminin alpha 2 deficiency should be considered in the differential diagnosis of
limb-girdle muscular dystrophy.