Broad Phenotypic Spectrum of A-Dystroglycanopathies due to POMT1 Mutations in 16 Families

Introduction: Congenital muscular dystrophies with defective O-glycosylation of α-dystroglycan (α-dystroglycanopathies) are a heterogeneous group of autosomal recessive inherited disorders explained by mutations in an increasing number of related genes. Among those, POMT1 was initially associated with Walker-Warburg syndrome (WWS) at the most severe end of the disease spectrum. Subsequently, milder POMT1-associated phenotypes such as congenital muscular dystrophy (CMD) or limb girdle muscular dystrophy (LGMD) have been described. In an ongoing study, we aim to further characterize the genotype-phenotype correlation and genotype-dependent long-term course of patients with genetically confirmed forms of those dystroglycanopathies and here present the wide clinical spectrum of POMT1-associated phenotypes.

Methods: Evaluation of the patients’ medical reports and MRI as available were done. Linkage analysis for suitable families, Sanger sequencing, and more recently targeted or exome next generation sequencing were evaluated.

Results: POMT1 mutations were identified in 22 patients from 16 families including 12 patients or fetal samples from 7 families with suspected WWS, 9 patients from 8 families with suspected LGMD2K, and 1 patient clinically classified as CMD. Interestingly, among WWS patients exclusively homozygous or compound heterozygous truncating mutations were observed. Three WWS families had two or more affected offspring showing a uniformly fatal prenatal presentation with severe hydrocephalus. In three WWS families, prenatal diagnosis was requested in subsequent pregnancies. Two patients with LGMD2K and the CMD patient were compound heterozygous for one missense mutation and one truncating POMT1 mutation. A rather uniform LGMD2K phenotype with proximal muscle weakness and cognitive impairment was observed in patients from six families homozygous for the POMT1 mutation p.Ala200Pro. The CMD patient had a neonatal disease onset with muscular hypotonia and subsequently delayed motor development and substantial cognitive impairment without brain MRI abnormalities. During the first decade of life, his phenotype was suggestive of Duchenne muscular dystrophy with creatine kinase values above 5,000 U/L. However, he had an unusually slow progression of his proximally pronounced CMD and a preserved ability to walk into his early thirties. His genetic diagnosis was finally confirmed at the age of 32 years.

Conclusion: Our data suggest a genotype-phenotype correlation for POMT1 with homozygous or compound heterozygous truncating mutations resulting in WWS while the presence of at least one missense mutation is associated with a milder phenotype. Mutations in POMT1 and other related genes should also be considered in adult LGMD and CMD patients, in particular, in those with associated cognitive and psychomotor delay with or without structural brain abnormalities.