A number sign (#) is used with this entry because of evidence that this form of congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A13; MDDGA13) is caused by homozygous mutation in the B3GNT1 gene (605517), which encodes a type II transmembrane protein involved in glycosylation of target proteins, on chromosome 11q13.

Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A) is a autosomal recessive disorder associated with severe neurologic defects and resulting in early infantile death. 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 Buysse et al., 2013).

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

Buysse et al. (2013) reported a family of East Indian descent in which 4 sibs had a clinical diagnosis of Walker-Warburg syndrome. Three pregnancies were terminated and 1 affected son died at 2 years of age. The living patient showed severe hypotonia with increased serum creatine kinase and developed intractable seizures. All patients had retinal dysplasia and severe brain malformations, including hydrocephalus, brainstem and cerebellar hypoplasia, nodular heterotopia, and cobblestone lissencephaly. Other more variable abnormalities included thin corpus callosum, absent septum pellucidum, cortical cysts, and Dandy-Walker malformation. One fetus had dysplastic kidneys and testicular hypoplasia. Muscle biopsies showed decreased glycosylation of DAG.

Shaheen et al. (2013) reported 7 children from a highly consanguineous Saudi Arabian family with MDDGA13. The proband was born with occipital encephalocele, anencephaly, cloudy cornea, proptotic eyes, spasticity, micropenis, and multicystic dysplastic kidneys. Serum creatine kinase was highly elevated; he died on the sixth day of life. The other affected individuals had similar features and died either in utero or shortly after birth, although 1 patient survived to 8 months of age. The longest surviving infant had severe motor and cognitive impairment, seizures, undescended testes, micropenis, severe bilateral hydronephrosis, blindness, and agenesis of the optic nerves.

The transmission pattern of MDDGA13 in the family reported by Buysse et al. (2013) was consistent with autosomal recessive inheritance.

By homozygosity mapping of a family with MDDGA, Buysse et al. (2013) found linkage to a region on chromosome 11q13. Affected individuals shared a 5.24-Mb haplotype.

In 4 sibs of East Indian descent with congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies, Buysse et al. (2013) identified homozygosity for 2 missense mutations in the B3GNT1 gene (605517.0001). The mutations, which were found by homozygosity mapping and candidate gene analysis, segregated with the disorder and were not found in 5,379 control samples or 672 in-house control exomes. Both mutations were located in the conserved glycosyltransferase domain of the protein and were shown to result in reduced glycosylation compared to wildtype when expressed in cells, consistent with a loss of function. Morpholino knockdown of b3gnt1 in zebrafish resulted in little or no glycosylated alpha-dystroglycan, and morphant embryos showed signs of muscular dystrophy. Mutations in B3GNT1 were not found in 57 additional families with dystroglycanopathy, suggesting that it is a rare cause of these disorders.

In an infant, born in a large consanguineous Saudi Arabian family, with MDDGA13, Shaheen et al. (2013) identified a homozygous frameshift mutation in the B3GNT1 gene (605517.0002). The mutation, which was found by exome sequencing, was not found in the dbSNP database or in an in-house database of 250 Saudi exomes. There were 6 similarly affected family members, but DNA was not available for analysis. Functional studies and studies of patient cells were not performed.