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 A9; MDDGA9) is caused by homozygous mutation in the DAG1 gene (128239) on chromosome 3p21.

Mutation in the DAG1 gene can also cause the less severe disorder limb-girdle muscular dystrophy-dystroglycanopathy (type C9, MDDGC9; 613818).

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, and congenital muscular dystrophy. The phenotype includes the alternative clinical designation Walker-Warburg syndrome (WWS), which is associated with death in infancy. The disorder represents the most severe end of a phenotypic spectrum of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1), collectively known as 'dystroglycanopathies' (summary by Geis et al., 2013 and Riemersma et al., 2015).

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

Geis et al. (2013) reported sisters, born of presumably unrelated Libyan parents, with apparent onset of severe developmental delay and hypotonia at age 4 months. Examination at ages 2 years 8 months and 3 years 7 months, respectively, showed severe mental retardation and muscular hypotonia without any ability to sit or walk. While there was a lack of head control in the younger girl, the other sib had gained some limited ability to balance the head. Neither girl was able to speak. Ophthalmic examinations revealed several abnormalities, including cataract, retinal dystrophy, severe myopia, and buphthalmos. Serum creatine kinase was increased, and muscle biopsy showed a dystrophic myopathy with moderate fiber size variability and absence of immunostaining for alpha-dystroglycan. Brain imaging performed in 1 of the patients showed multiple abnormalities consistent with muscle-eye-brain disease: there was flattening and kinking of the pons and brainstem, hypoplastic cerebellar vermis, subcortical cysts in the cerebellar hemispheres, polymicrogyria with frontal agyria, ventricular dilatation, and thinning of the corpus callosum. In addition, there were severe white matter abnormalities with T2-weighted hyperintensities and multiple large cystic lesions in a somewhat radial orientation from the frontal to parietal subcortical regions and well as smaller subcortical cysts in an anterior-temporal distribution.

Riemersma et al. (2015) reported a consanguineous Israeli-Arab family in which 5 female infants were born with multiple severe abnormalities consistent with WWS and died within a few hours to 3.5 months of life. Features included hydrocephalus, eye anomalies such as microphthalmia, buphthalmos, corneal opacities, and glaucoma, hypotonia with absent reflexes and lack of spontaneous movements, and respiratory failure. One patient had holoprosencephaly. Two patients had increased serum creatine kinase, and muscle biopsy of 1 patient showed marked variation in fiber size. Brain imaging in 3 patients showed scattered intracranial calcifications, but intrauterine infections were excluded.

The transmission pattern of MDDGA9 in the families reported by Geis et al. (2013) and Riemersma et al. (2015) was consistent with autosomal recessive inheritance.

In 2 sisters, born of presumably unrelated Libyan parents, with MDDGA9, Geis et al. (2013) identified a homozygous missense mutation in the DAG1 gene (C669F; 128239.0004). The mutation was found by whole-exome sequencing and confirmed by direct sequencing. The unaffected mother was heterozygous for the mutation. The cys669 residue, postulated to form a covalent disulfide bond with cys713 within beta-dystroglycan, is important for the structure of beta-dystroglycan and thus most likely also for the function of the alpha- and beta-dystroglycan complex. Functional studies of the variant were not performed.

In 5 female infants from a consanguineous Israeli-Arab family with MDDGA9 resulting in death soon after birth, Riemersma et al. (2015) identified a homozygous truncating mutation in the DAG1 gene (128239.0005). The mutation was found by a combination of homozygosity mapping and whole-exome sequencing. Patient fibroblasts that were transformed to myoblasts showed no detectable properly glycosylated alpha-dystroglycan and no detectable alpha- or beta-dystroglycan protein, consistent with complete absence of both protein isoforms.

Moore et al. (2002) showed that brain-selective deletion of dystroglycan in mice is sufficient to cause congenital muscular dystrophy-like brain malformations, including disarray of cerebral cortical layering, fusion of cerebral hemispheres and cerebellar folia, and aberrant migration of granule cells. Dystroglycan-null brain loses its high affinity binding to the extracellular matrix protein laminin (see 150240) and shows discontinuities in the pial surface basal lamina (glia limitans) that probably underlie the neuronal migration errors. Furthermore, mutant mice have severely blunted hippocampal long-term potentiation with electrophysiologic characterization, indicating that dystroglycan might have a postsynaptic role in learning and memory. Moore et al. (2002) concluded that these data strongly supported the hypothesis that defects in dystroglycan are central to the pathogenesis of structural and functional brain abnormalities seen in congenital muscular dystrophies.