The expanding spectrum of LAMA2 gene mutations : from congenital muscular dystrophy 1A to limb girdle muscular dystrophy 2R

OBJECTIVE: To expand the clinical and molecular spectrum of LAMA2 gene mutations, suggesting the classification of adulthood cases as a separate form of LGMD, which should be defined as LGMD2R. BACKGROUND: Mutations in LAMA2 gene, encoding laminin-α2, are generally responsible for congenital muscular distrophy 1A (CMD1A). Few cases presenting with milder limb girdle muscular dystrophy (LGMD) phenotype have been described and are generally characterized by early onset of muscular involvement, partial laminin-α2 deficiency at Western-blot analysis, white matter abnormalities at brain MRI. DESIGN/METHODS: We studied 5 CMD patients and 2 LGMD subjects showing laminin-α2 deficiency at Western-blot analysis. All probands underwent neurological examination, brain MRI and muscle biopsy. Analysis of LAMA2 gene through direct sequencing of all exons and intron boundaries was performed in all patients. RESULTS: We found mutations in 4 CMD and 1 LGMD patient. Five mutations were novel. Patients with CMD phenotype carried the following mutations: p.Gly3067CysfsX5, IVS54+5G>C, p.Pro2693ValfsX12, p.Ser2437AspfsX11, p.Arg744X. They had classical phenotype and laminin-α2 absence at Western-blot analysis. The LGMD patient carried the compound heterozygosis p.Leu2248TrpfsX23/p.His2848Gln and showed mild muscular involvement with late onset at 30 years of age, no tendon retraction and marked alteration of brain white matter. In the second LGMD patient, a heterozygous missense substitution (p.Gly1584Ser) was found. Interestingly only LGMD patients carried missense mutations. CONCLUSIONS: Our data confirm the existence of a wide clinical spectrum associated with LAMA2 gene mutations which is a continuum ranging from typical and late-onset CMD to childhood and adulthood LGMD. LAMA2 study should be considered as an essential part in the diagnostic work-up of undiagnosed LGMD patients, especially if other suggestive features, such as brain white matter abnormalities, are present. LGMD forms associated with LAMA2 mutations should be considered as a separate new form of LGMD, which should be classified as LGMD2R.