engleski

The adult phenotype of congenital muscular dystrophy (MDC1A) due to mutation of LAMA2

Mutations in the laminin alpha 2- chain gene (LAMA2) were originally identified in a subset of patients with autosomal recessive merosin-deficient congenital muscular dystrophy linked to chromosome 6 (MDC1A). The clinical phenotype of these patients is characterized by severe muscle weakness at birth or in the first six months of life, delayed motor milestones, inability to walk, markedly raised creatine kinase, and abnormal white matter signal on brain MRI with normal intelligence. We report a 48-year-old man‚ born to unaffected parents who were second cousins (Fig.1). He had profound hypotonia at birth, started to walk at 6 years and was independently mobile until age 14 years. He could never fully elevate his arms and lost the ability to sit in vertical position from age 17 years. At his current age of 48 he has end-stage muscular atrophy, with his neck in fixed extreme extension, and a severe thoracolumbal scoliosis with torsion. His contractures made it impossible to perform brain MRI. The patient has normal intellect, progressive swallowing difficulties, signs of severe obstructive and restrictive pulmonary disease, and normal CK. Genome-wide SNP analysis of the proband, and close relatives using the Illumina 6000 SNP panel showed a large region of homozygosity around the LAMA2 gene. We confirmed homozygous linkage to LAMA2 by analysis of 8 flanking microsatellite markers and analysed LAMA2 for mutations from genomic DNA by sequencing the 65 exons and flanking intronic regions. We identified a novel homozygous mutation c.IVS15+3A>C (c.2208+3A>G) that is predicted to alter splicing of exon 15. The splicing defect induced by this mutation is unknown (no muscle available) but, as suggested by bioinformatics analysis and previous results in other genes, a reduced level of normal transcript is expected potentially resulting in partial laminin alpha 2 deficiency. This might explain why the patient achieved ambulation.

merosin-deficient congenital muscular dystrophy; MDC1A; laminin alpha 2- chain gene (LAMA2); novel mutation; c.IVS15+3A>C (c.2208+3A>G); adult phenotype; Croatia

DOI: 10.1016/j.nmd.2009.06.098