Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A), which includes both the more severe Walker-Warburg syndrome (WWS) and the slightly less severe muscle-eye-brain disease (MEB), is an autosomal recessive disorder with characteristic brain and eye malformations, ... Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A), which includes both the more severe Walker-Warburg syndrome (WWS) and the slightly less severe muscle-eye-brain disease (MEB), 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. It represents the most severe end of a phenotypic spectrum of similar disorders resulting from defective glycosylation of DAG1 (128239), collectively known as 'dystroglycanopathies' (Godfrey et al., 2007). For a general phenotypic description and a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type A, see MDDGA1 (236670).
Historically, the most severe forms of the dystroglycanopathies were described as Walker-Warburg syndrome (WWS) and muscle-eye-brain disease (MEB); these designations have been retained here when used in the literature.
- LARGE-Related Walker-Warburg Syndrome
Van ... Historically, the most severe forms of the dystroglycanopathies were described as Walker-Warburg syndrome (WWS) and muscle-eye-brain disease (MEB); these designations have been retained here when used in the literature. - LARGE-Related Walker-Warburg Syndrome Van Reeuwijk et al. (2007) reported 2 Saudi sibs, born of consanguineous parents, with Walker-Warburg syndrome. At birth, both showed severe hypotonia, absent deep tendon reflexes, widened anterior fontanels, and ophthalmic changes, including cataract, optic atrophy, and retinal dysplasia. Both had increased serum creatine kinase and dystrophic muscle biopsies. Brain CT scan showed ventricular dilatation, absence of the inferior cerebellar vermis, and hypoplastic cerebellum; 1 of the sibs had hydrocephalus and Dandy-Walker malformation. The sibs died at age 6 and 2 months, respectively. Godfrey et al. (2007) identified 1 patient with LARGE-related WWS in a larger study of 92 patients with muscular dystrophy and evidence of a dystroglycanopathy. Although clinical details were limited, the patient had prenatal onset, feeding difficulties, increased serum creatine kinase, contractures, retinal dysplasia, low IQ, and death at age 8 weeks. Brain MRI showed hydrocephalus, white matter abnormalities, cerebellar hypoplasia, and lissencephaly. Clement et al. (2008) reported a 4-week-old patient with LARGE-related WWS. The patient had mental retardation and retinal dysplasia. Brain MRI showed ventricular dilatation, diffuse white matter abnormalities, hypoplastic and dysplastic cerebellum, posterior concavity of the brainstem, pontine hypoplasia, and posterior cobblestone lissencephaly. The study was part of a larger study of 27 patients with various genetic forms of muscular dystrophy due to defective dystroglycan glycosylation. - LARGE-Related Muscle-Eye-Brain Disease Clement et al. (2008) reported a patient with LARGE-related MEB. The patient had congenital muscular dystrophy, increased serum creatine kinase, mental retardation, and myopia. Brain MRI showed ventricular dilatation, abnormal white matter changes, cerebellar cysts, dysplastic cerebellar vermis, posterior concavity of the brainstem, pontine hypoplasia with a cleft, and frontoparietal polymicrogyria.
In 2 Saudi sibs with WWS, van Reeuwijk et al. (2007) identified a homozygous 63-kb intragenic deletion in the LARGE gene (603590.0003), including part of intron 8, exon 9, intron 9, exon 10, and most of intron 10. ... In 2 Saudi sibs with WWS, van Reeuwijk et al. (2007) identified a homozygous 63-kb intragenic deletion in the LARGE gene (603590.0003), including part of intron 8, exon 9, intron 9, exon 10, and most of intron 10. The unaffected parents were heterozygous for the deletion. In 1 of 81 Italian patients with congenital muscular dystrophy and defective glycosylation of alpha-dystroglycan, Mercuri et al. (2009) identified a homozygous mutation in the LARGE gene (W495R; 603590.0004). The phenotype was consistent with Walker-Warburg syndrome. The patient had head control, but also had increased serum creatine kinase, absent alpha-dystroglycan on muscle biopsy, and mental retardation. In a patient with MEB, Clement et al. (2008) identified compound heterozygosity for 2 mutations in the LARGE gene (603590.0005 and 603590.0006).