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 ... 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 ... 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.
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 ... 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.