Muscular Dystrophy-Dystroglycanopathy (Congenital With Brain And Eye Anomalies), Type A, 2

A number sign (#) is used with this entry because this form of congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A2, MDDGA2), previously designated Walker-Warburg syndrome (WWS) or muscle-eye-brain disease (MEB), is caused by homozygous or compound heterozygous mutation in the POMT2 gene (607439) on chromosome 14q24.3. POMT2 encodes an integral membrane protein of the endoplasmic reticulum (ER) that shares significant sequence similarity with a family of protein O-mannosyltransferases of S. cerevisiae.

Mutation in the POMT2 gene can also cause a less severe congenital muscular dystrophy-dystroglycanopathy with mental retardation (type B2, MDDGB2; 613156) and a limb-girdle muscular dystrophy-dystroglycanopathy (type C2, MDDGC2; 613158).

Description

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' (van Reeuwijk et al., 2005).

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

Clinical Features

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.

POMT2-Related Walker-Warburg Syndrome

Van Reeuwijk et al. (2005) reported 3 unrelated patients with POMT2-related WWS. The first girl, born of consanguineous Moroccan parents, had hydrocephalus and cobblestone lissencephaly detected by prenatal ultrasound. At birth, she was severely hypotonic, had bilateral Peters anomaly with cataracts, left-sided microphthalmia, and right-sided buphthalmos. Serum creatine was increased. Brain MRI showed hydrocephalus, cobblestone lissencephaly, and aplasia of the corpus callosum. The second child, born of consanguineous Pakistani parents, showed hydrocephalus on prenatal ultrasound. The patient had cleft lip and palate, bilateral cataracts, and persistent pupillary membrane. MRI showed aplasia of the posterior vermis, hypoplasia of the pons and cerebellum, hydrocephalus, and cobblestone cortex. The third patient, born of a consanguineous Bengali family, showed severe neonatal hypotonia, developmental delay, and poor vision. Ophthalmologic examination showed bilateral lamellar cataracts and buphthalmos. MRI showed hydrocephalus and smooth cortical mantle. Two of the patients died before 1 year of age.

Clement et al. (2008) reported a 5-week-old patient with POMT2-related WWS. Brain MRI showed ventricular dilatation, hypoplastic cerebellum, brainstem hypoplasia, pontine hypoplasia, and a thin lissencephalic cortical mantle.

POMT2-Related Muscle-Eye-Brain Disease

Mercuri et al. (2006) reported an 11-year-old Italian girl with POMT2-related muscle-eye-brain disease. She was found to have ventricular dilatation and hypoplasia of the cerebellar vermis on prenatal ultrasound at 28 weeks' gestation. After birth, she was hypotonic and never achieved independent sitting. She showed poor growth, respiratory insufficiency, severe mental retardation with only a few words, microcephaly, severe muscle weakness, macroglossia, contractures, and muscle hypertrophy of the lower limbs. Brain MRI showed hypoplasia of the cerebellar vermis and pons, as well as periventricular white matter abnormalities. Muscle biopsy showed dystrophic changes, but there was not enough muscle available for alpha-dystroglycan testing.

Godfrey et al. (2007) reported 7 patients with POMT2-related MEB. Age at onset ranged from the neonatal period to 4 years. Three patients never achieved sitting, 2 achieved sitting, 1 never achieved walking, and 1 achieved walking. Most had contractures, increased serum creatine kinase, and muscle hypertrophy and weakness. One patient had rigid spine, another had scoliosis, and a third had both. All had low IQ, and all but 1 had microcephaly. Two patients had myopia and 1 each had hypermetropia and congenital cataracts. Brain MRI findings included hydrocephalus, polymicrogyria, white matter abnormalities, brainstem involvement, cerebellar cysts, cerebellar hypoplasia, and cerebellar dysplasia. One patient had a cerebellar cyst. Seizures and macroglossia were reported in 1 patient each. As part of a larger study involving 92 probands with muscular dystrophy and evidence of a dystroglycanopathy, Godfrey et al. (2007) defined MEB as congenital muscular dystrophy with brain abnormalities less severe than that seen in Walker-Warburg syndrome. MRI findings in MEB included pachygyria with preferential frontoparietal involvement, polymicrogyria, cerebellar hypoplasia, cerebellar dysplasia, and frequent flattening of the pons and brainstem. Eye abnormalities, such as congenital glaucoma, progressive myopia, retinal atrophy, and juvenile cataracts were often seen. Rarely, individuals acquired the ability to walk, although this was delayed, and some rare patients learned a few spoken words. The authors noted phenotypic overlap between MEB and Fukuyama congenital muscular dystrophy (FCMD, MDDGA4; 253800).

Mercuri et al. (2009) reported 2 Italian patients with POMT2-related MEB within a larger study of 81 probands with a dystroglycanopathy. Although clinical details were limited, the patients had microcephaly, mental retardation, and increased serum creatine kinase, and they achieved only sitting. One patient also had myopia and seizures. Mercuri et al. (2009) defined the brain findings of MEB as including pachygyria with preferential frontoparietal involvement, polymicrogyria, cerebellar hypoplasia or dysplasia, and flattening of the pons and brainstem, associated with eye abnormalities.

Yanagisawa et al. (2009) reported 4 patients, including 2 Argentinian sibs, with POMT2-related MEB. All had microcephaly, severe mental retardation, congenital hypotonia, increased serum creatine kinase, and cerebral dysplasia, including pachygyria, polymicrogyria, and heterotopia, as well as cerebellar vermis hypoplasia. Ocular involvement was not present, except in 1 patient with moderate myopia. Maximum motor function achieved was sitting unsupported in 3 patients, and standing in 1. One patient died at age 16 years, and the 2 sibs died at age 15 years; the remaining patient was alive at age 5 years. Genetic analysis identified homozygous or compound heterozygous mutations in the POMT2 gene (see, e.g., 607439.0004; 607439.0018-607439.0019). One patient had an intragenic deletion in the POMT2 gene.

Molecular Genetics

Using a candidate gene approach combined with homozygosity mapping, van Reeuwijk et al. (2005) found possible linkage to the POMT2 locus in 6 of 17 unrelated families with WWS. Sequencing of the POMT2 gene in those 6 families revealed homozygous mutations (607439.0001-607439.0003) in 3 unrelated patients and 1 affected sib, all born of consanguineous parents. Van Reeuwijk et al. (2005) stated that the phenotype observed in these patients was indistinguishable from that of patients with WWS caused by mutations in other genes.

In an Italian girl with MEB, Mercuri et al. (2006) identified compound heterozygosity for 2 mutations in the POMT2 gene (G353S, 607439.0012; G726E, 607439.0013).

In a large study of 92 probands with muscular dystrophy and evidence of a dystroglycanopathy, Godfrey et al. (2007) found that 7 patients with an MEB-like phenotype had homozygous or compound heterozygous mutations in the POMT2 gene (see, e.g., 607439.0004; 607439.0007-607439.0009).