POMGnT1 mutation and phenotypic spectrum in muscle-eye-brain disease.

M uscle-eye-brain disease (MEB; OMIM 253280) was first described in 1977 in Finland, where it is enriched because of founder effect and genetic isolation. MEB is now known to occur throughout the world, but Finland remains the country with the largest group of MEB patients. MEB patients present as floppy infants with visual problems and severe mental retardation. The hypotonia is partly caused by muscular dystrophy and partly by cerebral dysfunction. Hypotonia is replaced by spasticity and contractures with increasing age. 3 Visual failure is the result of progressive myopia, retinal degeneration, and congenital glaucoma. Juvenile cataracts develop by the age of 10 years. The presence of giant visual evoked potentials is an important diagnostic feature. The typical central nervous system malformation revealed by magnetic resonance imaging (MRI), referred to as ‘‘cobblestone complex’’, consists of cobblestone cortex, midline deformities, flat brain stem, mild cerebellar hypoplasia, and cerebellar cortical cysts. Microscopically the cortex is disorganised, with an overgrowth of glia forming a thick membrane on the brain surface. The combination of muscular dystrophy and a severe neuronal migration defect is not exclusive for MEB, but is also seen in Walker–Warburg syndrome (WWS; OMIM 236670) and Fukuyama congenital muscular dystrophy (FCMD; OMIM 253800). The recent molecular genetic findings have provided an explanation as to why the distinct clinical features are partially shared in these three diseases. The MEB gene encodes a protein O-mannose b-1, 2-Nacetylglucosaminyltransferase (POMGnT1). Mutations in another enzyme involved in O-mannosylation, the O-mannosyltransferase (POMT1), were recently found in a group of WWS patients. Fukutin, encoded by the FCMD gene, is strongly suspected to play a role in glycosylation. The unifying feature in all these disorders is deficient posttranslational glycosylation of a-dystroglycan, 14–16 suggesting that impaired function of a-dystroglycan plays a critical role in their pathogenesis. Recently, mutations in the LARGE gene were reported in a patient with congenital muscular dystrophy, profound mental retardation, white matter changes, and subtle structural abnormalities on brain MRI, suggesting abnormal neuronal migration. LARGE is the human homologue of mouse Large, which is mutated in the myodystrophy mouse. Compatible with findings in the mouse, the human patient showed reduced immunolabelling of a-dystroglycan, adding a new member to the group of disorders characterised by congenital muscular dystrophy and a neuronal migration defect caused by deficient glycosylation of a-dystroglycan. Thirteen MEB causing mutations covering the whole POMGnT1 gene have previously been reported. 19 Ten of these predict protein truncation, while three are missense mutations. Expression studies of mutant POMGnT1 proteins harbouring patient mutations suggest that MEB is inherited as a loss of function of POMGnT1. 20 We screened the exons and exon–intron boundaries of POMGnT1 in 16 MEB patients from 14 families. We identified nine new mutations and found that the mutation affecting the splice donor site in intron 17, reported previously in three patients, is the prevalent mutation in the Finnish MEB patients.