Genotype and Phenotype in 34 Families with Genetically Confirmed Walker-Warburg Syndrome or Muscle Eye Brain Disease

Aims: Walker-Warburg syndrome (WWS) and muscle–eye–brain disease (MEB) comprises the most severe end of congenital muscular dystrophies with defective O-glycosylation of α-dystroglycan. Both are characterized by prenatal or neonatal onset, severe structural brain and eye abnormalities, and profoundly disturbed psychomotor development. the aim of this study is to describe the genotype and phenotype of patients with genetically confirmed WWS or MEB.

Methods: Evaluation of medical records and MR imaging as available for 63 families with suspected WWS or MEB, linkage analysis, and stepwise Sanger sequence analysis of POMT1, POMT2, POMGnT1, Fukutin, FKRP, LARGE, ISPD, or NGS exome sequencing.

Results: Causal mutations could be identified in 34 families (54%).Overall, 15 WWS families with homozygous or compound heterozygous mutations confirming WWS were identified: POMT1 (eight families), POMGnT1 (one), FKRP (one), Fukutin (one), LARGE (three), and ISPD (one). In POMT1-associated WWS families, exclusively truncating mutations were found. In three WWS families, the diagnosis was suspected prenatally with termination of pregnancy, in 11 WWS families with postnatal diagnosis and available clinical information severe neonatal hypotonia and elevated creatinine kinase above 1,800 U/L were reported in eight and drug-resistant epilepsy in six families. In 19 MEB families, we identified causal mutations in POMGnT1 (16), POMT1 (2), or DAG1 (1). Characteristic observed brain malformations included cobblestone lissencephaly, hydrocephalus, brain stem, and cerebellar hypoplasia.

Conclusion: Our data confirm genetic heterogeneity for WWS and MEB with mutations in the seven core genes currently explaining about half of the characteristic families and apparently only minor contribution of additional genes detected by larger NGS algorithms. In our patient cohort, we predominantly identified truncating POMT1 mutations in WWS, and POMGnT1 mutations in the majority of MEB families. Prenatally recognized CNS malformations and/or neonatal muscular hypotonia with elevated CK are commonly observed and may facilitate early genetic diagnosis.

Keywords: Walker-Warburg syndrome, Muscle–eye–brain disease, MEB, WWS, dystroglycanopathie, lissenzephalie.