Muscular Dystrophy-Dystroglycanopathy (Congenital With Brain And Eye Anomalies), Type A, 8

A number sign (#) is used with this entry because this form of congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A8; MDDGA8) is caused by homozygous mutation in the POMGNT2 gene (614828) on chromosome 3p22. POMGNT2 encodes protein O-mannose beta-1,4-N-acetylglucosaminyltransferase-2.

Description

Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A) is an autosomal recessive disorder with characteristic brain and eye malformations, profound mental retardation, congenital muscular dystrophy, and death usually in the first years of life. The phenotype includes the alternative clinical designation Walker-Warburg syndrome (WWS). 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 Manzini et al., 2012).

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

Clinical Features

Manzini et al. (2012) reported 3 unrelated families with classic features of Walker-Warburg syndrome, including cobblestone lissencephaly, enlarged ventricles, cerebellar hypoplasia, eye abnormalities, and hypotonia. The patients in 2 families died within the first months of life. In the third family, 2 affected pregnancies were terminated at 23 and 20 weeks' gestational age due to severe ventricular enlargement.

Inheritance

The transmission pattern of Walker-Warburg syndrome in the families reported by Manzini et al. (2012) was consistent with autosomal recessive inheritance.

Molecular Genetics

In affected members of 3 unrelated consanguineous families with Walker-Warburg syndrome, Manzini et al. (2012) identified 3 different homozygous mutations in the GTDC2 gene (614828.0001-614828.0003). The first 2 mutations were identified by homozygosity mapping combined with whole-exome sequencing and confirmed by Sanger sequencing.