Mild POMGnT1 mutations underlie a novel limb-girdle muscular dystrophy variant

Background: Mutations in protein-O-mannose-beta 1,2-N-acetylglucosaminyltransferase 1 (POMGnT1) have been found in muscle-eye-brain disease, a congenital muscular dystrophy with structural eye and brain defects and severe mental retardation. Objective: To investigate whether mutations in POMGnT1 could be responsible for milder allelic variants of muscular dystrophy. Design: Screening for mutations in POMGnT1. Setting: Tertiary, neuromuscular unit. Patient: A patient with limb-girdle muscular dystrophy phenotype, with onset at 12 years of age, severe myopia, normal intellect, and decreased a-dystroglycan immunolabeling in skeletal muscle. Results: A homozygous POMGnT1 missense mutation (c.1666G > A, p.Asp556Asn) was identified. Enzyme studies of the patient's fibroblasts showed an altered kinetic profile, less marked than in patients with muscle-eye-brain disease and in keeping with the relatively mild phenotype in our patient. Conclusions: Our findings widen the spectrum of disorders known to result from mutations in POMGnT1 to include limb-girdle muscular dystrophy with no mental retardation. We propose that this condition be known as LGMD2M. The enzyme assay used to diagnose muscle-eye-brain disease may not detect subtle abnormalities of POMGnT1 function, and additional kinetic studies must be carried out in such cases.