Muscular Dystrophy-Dystroglycanopathy (Congenital With Brain And Eye Anomalies), Type A, 11

A number sign (#) is used with this entry because this form of congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A11; MDDGA11) is caused by homozygous or compound heterozygous mutation in the B3GALNT2 gene (610194), which encodes an enzyme that transfers N-acetyl galactosamine (GalNAc) in a beta-1,3 linkage to N-acetylglucosamine (GlcNAc), on chromosome 1.

Description

Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A) is an autosomal recessive disorder with congenital muscular dystrophy resulting in muscle weakness early in life and brain and eye anomalies. It is usually associated with delayed psychomotor development and shortened life expectancy. The phenotype includes the alternative clinical designations Walker-Warburg syndrome (WWS) and muscle-eye-brain disease (MEB). The disorder represents the most severe end of a phenotypic spectrum of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies' (summary by Stevens et al., 2013).

For a general phenotypic description and a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type A, see MDDGA1 (236670).

Clinical Features

Stevens et al. (2013) reported 6 unrelated patients with MDDGA11. The phenotype was slightly variable, but overall very severe with brain involvement consistent with a clinical diagnosis of WWS or MEB. The patients were identified from 2 cohorts of patients with dystroglycanopathy totaling 102 patients. The patients presented between birth and 17 months with hypotonia, hydrocephalus, or delayed psychomotor development. All eventually showed severe or absent cognitive development and achieved only few or no motor milestones; at least 1 patient had axial hypotonia and spasticity. Most patients had variable eye involvement, including optic nerve hypoplasia, myopia, microphthalmia, or cataracts, and all had some form of brain abnormality, including polymicrogyria, hydrocephalus, cerebellar cysts, pontocerebellar hypoplasia, frontotemporal leukoencephalopathy, and cobblestone lissencephaly. Serum creatine kinase was markedly increased. Muscle biopsy performed on 2 patients showed dystrophic changes and reduced staining of alpha-DAG with the monoclonal antibody IIH6. Flow cytometric analysis of patient fibroblasts also showed a decrease in functionally glycosylated alpha-DAG compared to controls.

Inheritance

The transmission pattern of MDDGA11 in the families reported by Stevens et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 6 unrelated patients with MDDGA11, Stevens et al. (2013) identified homozygous or compound heterozygous mutations in the B3GALNT2 gene (see, e.g., 610194.0001-610194.0006). The mutations were found by exome sequencing or Sanger sequencing. Most of the mutations resulted in a truncated protein, consistent with loss of function, but 2 of the 3 missense mutations were shown to disrupt proper intracellular localization of the protein to the endoplasmic reticulum. Biallelic loss-of-function mutations were associated with the most severe phenotype. Studies of patient cells showed reduced functional glycosylation of alpha-dystroglycan, suggesting that B3GALNT2 plays a role in that process. Knockdown of the b3galnt2 gene in zebrafish recapitulated aspects of the human phenotype.