The expanding phenotype of laminin alpha 2 chain (merosin) abnormalities: case series and review

Initial reports of patients with laminin alpha2 chain (merosin) deficiency had a relatively homogeneous phenotype, with classical congenital muscular dystrophy (CMD) characterised by severe muscle weakness, inability to achie ve independent ambulation, markedly raised creatine kinase, and characteris tic white matter hypodensity on cerebral magnetic resonance imaging. We rep ort a series of five patients with laminin alpha2 deficiency, only one of w hom has this severe classical CMD phenotype, and review published reports t o characterise the expanded phenotype of laminin alpha2 deficiency, as illu strated by this case series. While classical congenital muscular dystrophy with white matter abnormality is the commonest phenotype associated with la minin alpha2 deficiency, 12% of reported cases have later onset, slowly pro gressive weakness more accurately designated limb-girdle muscular dystrophy . In addition, the following clinical features are reported with increased frequency: mental retardation (similar to6%), seizures (similar to8%), subc linical cardiac involvement (3-35%), and neuronal migration defects (4%). A t least 25% of patients achieve independent ambulation. Notably, three pati ents with laminin alpha2 deficiency were asymptomatic, 10 patients had norm al MRI (four with LAMA2 mutations reported), and between 10-20% of cases ha d maximum recorded creatine kinase of less than 1000 U/1. LAMA2 mutations h ave been identified in 25% of cases. Sixty eight percent of these have the classical congenital muscular dystrophy, but this figure is likely to be af fected by ascertainment bias. We conclude that all dystrophic muscle biopsi es, regardless of clinical phenotype, should be studied with antibodies to laminin a2. In addition, the use of multiple antibodies to different region s of laminin alpha2 may increase the diagnostic yield and provide some corr elation with severity of clinical phenotype.