Broad phenotypic spectrum of neuromuscular disorders associated with defective O-glycosylation of alpha-dystroglycan

Aims: Defects in O-glycosylation of alpha-dystroglycan result in a group of autosomal recessive disorders with congenital muscular dystrophy (CMD) and brain and/or eye abnormalities. Muscle-eye-brain disease (MEB) is characterized by early onset muscular hypotonia, severely compromised motor development and mental retardation. MR imaging reveals a lissencephaly type II with hypoplasia of brain stem and cerebellum. MEB is caused by mutations in the human POMGnT1 gene. POMT1 and POMT2 mutations result in the more severe phenotype of Walker-Warburg syndrome (WWS). Recently, we could identify a distinct POMT1 missense mutation A200P in patients with limb girdle muscular dystrophy with mental retardation (LGMD2K).

Methods: Clinical examination, evaluation of brain MR images and sequence analysis of the genes POMT1, POMT2 and POMGnT1 in patients with lissencephaly type II and/or suspected MEB, WWS or LGMD2K.

Results: We report about 9 MEB patients with POMGnT1 mutations, including two patients with additional severe autistic features and one patient with an unusually mild phenotype, initially diagnosed as CMD. Consistent cerebral findings included hydrocephalus, predominant frontal pachygyria, occipital polymicrogyria as well as a severe hypoplasia of the brainstem with a characteristic kinking. A severe hydrocephalus had prompted elective termination of a previous pregnancy in two of those MEB families, pronouncing the phenotypic overlap with WWS. Clinical data and MR images of three cases of WWS, resulting from homozygous truncating POMT1 mutations, are demonstrated. MR imaging of two WWS patients in addition to severe hydrocephalus confirmed a cortical malformation with cobblestone lissencephaly and hypoplasia of brainstem as well as cerebellum. Furthermore, we report the clinical data of 5 Turkish families with LGMD2K. Muscle weakness started after achievement of the first motor milestones, serum CK levels were increased more than 20fold, the IQ ranged between 50 and 65. For four patients a normal brain CT/MRI without any structural abnormalities could be obtained.

Conclusions: MEB results from truncating and missense mutations throughout the entire POMGnT1 gene. A broad phenotypic variability even among affected individuals of one family is observed. In contrast, for POMT1 mutations a clear genotype-phenotype correlation is emerging, with WWS resulting from truncating mutations, while distinct missense mutations account for the mild phenotype of LGMD2K.