Refining genotype phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan

Abstract

Muscular dystrophies with reduced glycosylation of alpha-dystroglycan (alpha-DG), commonly referred to as dystroglycanopathies, are a heterogeneous group of autosomal recessive conditions which include a wide spectrum of clinical severity. Reported phenotypes range from severe congenital onset Walker-Warburg syndrome (WWS) with severe structural brain and eye involvement, to relatively mild adult onset limb girdle muscular dystrophy (LGMD). Specific clinical syndromes were originally described in association with mutations in any one of six demonstrated or putative glycosyltransferases. Work performed on patients with mutations in the FKRP gene has identified that the spectrum of phenotypes due to mutations in this gene is much wider than originally assumed. To further define the mutation frequency and phenotypes associated with mutations in the other five genes, we studied a large cohort of patients with evidence of a dystroglycanopathy. Exclusion of mutations in FKRP was a prerequisite for participation in this study. Ninety-two probands were screened for mutations in POMT1, POMT2, POMGnT1, fukutin and LARGE. Homozygous and compound heterozygous mutations were detected in a total of 31 probands (34 individuals from 31 families); 37 different mutations were identified, of which 32 were novel. Mutations in POMT2 were the most prevalent in our cohort with nine cases, followed by POMT1 with eight cases, POMGnT1 with seven cases, fukutin with six cases and LARGE with only a single case. All patients with POMT1 and POMT2 mutations had evidence of either structural or functional central nervous system involvement including four patients with mental retardation and a LGMD phenotype. In contrast mutations in fukutin and POMGnT1 were detected in four patients with LGMD and no evidence of brain involvement. The majority of patients (six out of nine) with mutations in POMT2 had a Muscle-Eye-Brain (MEB)-like condition. In addition we identified a mutation in the gene LARGE in a patient with WWS. Our data expands the clinical phenotypes associated with POMT1, POMT2, POMGnT1, fukutin and LARGE mutations. Mutations in these five glycosyltransferase genes were detected in 34% of patients indicating that, after the exclusion of FKRP, the majority of patients with a dystroglycanopathy harbour mutations in novel genes.

Novel cardiovascular findings in association with a POMT2 mutation: three siblings with α-dystroglycanopathy

“…8 With regard to cardiac findings in patients with mutations in the POMT2 gene, a study of nine patients found one to have right bundle branch block. 6 In a second study of four patients, one patient had left ventricular hypertrophy at the age of 3.5 years. 1 The enlargement of the aortic root is usually asymptomatic and is often found incidentally in the course of imaging studies.…”

“…Fukutin, fukutinrelated protein (FKRP) and LARGE may be involved in glycosylation, but their exact functions remain unknown. 6 The DPM3 gene, encoding a subunit of DOL-P-Man synthase, was recently associated with CMD in a patient with muscular dystrophy and reduced a-dystroglycan staining but without intellectual disabilities. 9 Finally, mutations in DAG1 encoding a-dystroglycan were identified in a patient with a form of limb girdle muscular dystrophy who had normal brain imaging and relatively mild muscular involvement but intellectual disabilities.…”

“…10 POMT2 mutations have been associated with a wide spectrum of phenotypes, including some patients without structural CNS involvement and a more benign course of cognitive impairment and microcephaly. 2 Other more severe forms include structural brain abnormalities such as seen in a WWS-like phenotype, 11 a muscle-eyebrain phenotype, 6 and cerebellar hypoplasia with or without cerebral atrophy. 3 The specific mutant allele found in our patients (Y666C) has previously been reported in the homozygous state in families of Spanish and French origin and appears to be a European founder mutation based on the identification of a single haplotype (PMID: 17634419).…”

“…4,5 Both POMT1 and POMT2 mutations are the most common causes of WWS. 1, 2,6,7 Cardiac involvement among the dystroglycanopathies remains poorly characterized. Whereas dilated and hypertrophic cardiomyopathy have been described, 8 aortopathy in dystroglycanopathies has not been previously reported.…”

B3GALNT2 is a gene associated with congenital muscular dystrophy with brain malformations

“…However, many patients with dystroglycanopathy still remain genetically unidentified. 5 Stevens et al 6 recently reported that mutations in the gene b-1,3-N-acetylgalactosaminyltransferase 2 (B3GALNT2; MIM 610194) cause congenital muscular dystrophy and hypoglycosylation of a-dystroglycan with, in most cases, severe brain involvement.…”