Muscular Dystrophy-Dystroglycanopathy (Congenital With Brain And Eye Anomalies), Type A, 1

A number sign (#) is used with this entry because this form of congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A1; MDDGA1), previously designated Walker-Warburg syndrome (WWS) or muscle-eye-brain disease (MEB), is caused by homozygous or compound heterozygous mutation in the gene encoding protein O-mannosyltransferase-1 (POMT1; 607423) on chromosome 9q34.

Mutation in the POMT1 gene can also cause a less severe congenital muscular dystrophy-dystroglycanopathy with mental retardation (type B1; MDDGB1; 613155) and a limb-girdle muscular dystrophy-dystroglycanopathy (type C1; MDDGC1; 609308).

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 a genetically heterogeneous autosomal recessive disorder with characteristic brain and eye malformations, profound mental retardation, congenital muscular dystrophy, and early death. The phenotype commonly includes cobblestone (type II) lissencephaly, cerebellar malformations, and retinal malformations. More variable features include macrocephaly or microcephaly, hypoplasia of midline brain structures, ventricular dilatation, microphthalmia, cleft lip/palate, and congenital contractures (Dobyns et al., 1989). Those with a more severe phenotype characterized as Walker-Warburg syndrome often die within the first year of life, whereas those characterized as having muscle-eye-brain disease may rarely acquire the ability to walk and to speak a few words. These are part of a group of disorders resulting from defective glycosylation of DAG1 (128239), collectively known as 'dystroglycanopathies' (Godfrey et al., 2007).

Genetic Heterogeneity of Congenital Muscular Dystrophy-Dystroglycanopathy with Brain and Eye Anomalies (Type A)

Muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A) is genetically heterogeneous and can be caused by mutation in other genes involved in DAG1 glycosylation: see MDDGA2 (613150), caused by mutation in the POMT2 gene (607439); MDDGA3 (253280), caused by mutation in the POMGNT1 gene (606822); MDDGA4 (253800), caused by mutation in the FKTN gene (607440); MDDGA5 (613153), caused by mutation in the FKRP gene (606596); MDDGA6 (613154), caused by mutation in the LARGE gene (603590); MDDGA7 (614643), caused by mutation in the ISPD gene (614631); MDDGA8 (614830) caused by mutation in the GTDC2 gene (POMGNT2; 614828); MDDGA9 (616538), caused by mutation in the DAG1 gene (128239); MDDGA10 (615041), caused by mutation in the TMEM5 gene (RXYLT1; 605862); MDDGA11 (615181), caused by mutation in the B3GALNT2 gene (610194); MDDGA12 (615249), caused by mutation in the SGK196 gene (POMK; 615247); MDDGA13 (615287), caused by mutation in the B3GNT1 gene (B4GAT1; 605517); and MDDGA14 (615350), caused by mutation in the GMPPB gene (615320).

Nomenclature

The phenotypic variation of dystroglycanopathies covers a wide spectrum, and mutations in different genes known be involved in the glycosylation process have been reported. These phenotypes, here referred to as the 'MDDG' series, range from severe MDDGA, to milder forms of congenital muscular dystrophy (see, e.g., MDDGB1, 613155), to even milder limb-girdle muscular dystrophy (see, e.g., MDDGC1, 609308). The crucial aspect in determining phenotypic severity in patients with a dystroglycanopathy is not necessarily which gene is involved, but to what extent the mutation affects glycosylation of DAG1 (reviewed by Muntoni and Voit, 2004; Muntoni et al., 2008; Mercuri et al., 2009).

Walker-Warburg syndrome was the generally used designation for MDDGA, and appropriately so, since Walker (1942) probably first reported a syndrome of lissencephaly, hydrocephalus, microphthalmia, and retinal dysplasia. Although others, particularly Krause (1946) and Chemke et al. (1975), reported cases, the writings of Warburg (1971, 1976, 1978) have made the syndrome particularly well known.

WWS has also been referred to as the HARD +/- E syndrome, for hydrocephalus (H), agyria (A), retinal dysplasia (RD), with or without encephalocele (+/-E) (Dobyns et al., 1989).

Clinical Features

Historically, the most severe forms of the dystroglycanopathies were described as Walker-Warburg syndrome and muscle-eye-brain disease; these designations have been retained here when used in the literature.

Early Descriptions of Walker-Warburg Syndrome

The first case of Walker-Warburg syndrome is said to be that reported by Walker (1942) and labeled lissencephaly (Greek, 'smooth brain'). In an affected brother and sister, both deceased, Pagon et al. (1978) identified abnormal cerebrocortical cytoarchitecture with no organization into the usual 6 laminations as the histologic finding at autopsy.

Whitley et al. (1983) reported 2 cases with WWS. In the first, hydrocephalus was diagnosed antenatally by ultrasonography. Cataracts and retinal detachments were found in microphthalmic eyes with normal irides. The infant died on the tenth day. The brain showed complete lack of gyral development and massively distended lateral and third ventricles. Microscopic analysis showed markedly disorganized cytoarchitecture with complete lack of lamination and numerous glial heterotopias. Whitley et al. (1983) reviewed 10 cases. Occipital encephalocele was present in 4. Aqueductal stenosis was most frequently the cause of the hydrocephalus.

Burton et al. (1987) reported affected sibs with the additional features of cleft lip, cleft palate, and intrauterine growth retardation, findings not previously noted in this disorder.

Gershoni-Baruch et al. (1990) reported 2 sibs with Walker-Warburg syndrome. The sister had congenital glaucoma and hydrocephalus; the brother had hydrocephalus, microtia, absent auditory canals, and pale retinas.

Dobyns et al. (1986) emphasized congenital muscular dystrophy as a feature of Walker-Warburg syndrome. On the basis of 17 patients, the authors concluded that constant manifestations include type II lissencephaly, retinal abnormalities, and congenital muscular dystrophy. Leopard spot retinopathy was a newly reported finding.

Towfighi et al. (1984) described 7 children from 4 families with a malformation complex characterized by a triad of brain, eye, and muscle abnormalities. They termed the entity cerebro-ocular dysplasia/muscular dystrophy (COD-MD) syndrome. Heggie et al. (1987) reported a brother and sister with COD-MD syndrome, each of whom died at the age of about 1 year. The principal central nervous system (CNS) features were cerebral and cerebellar agyria-micropolygyria, cortical disorganization, glial-mesodermal proliferation within the leptomeninges, neuronal heterotopias, hypoplasia of nerve tracts, and hydrocephalus. Ocular abnormalities included microphthalmia, cataract, immature anterior chamber angle, retinal dysplasia with or without retinal detachment, persistent hyperplastic primary vitreous, optic nerve hypoplasia, and coloboma. Skeletal muscles showed fiber splitting, variable fiber size, and endomysial fibrosis. Heggie et al. (1987) suggested that COD-MD syndrome may be identical to Walker-Warburg syndrome. Dobyns et al. (1989) also suggested that Walker-Warburg syndrome is similar to, if not identical to, cerebrooculomuscular syndrome (Heggie et al., 1987, Korinthenberg et al., 1984).

Cormand et al. (2001) reported 7 patients and 8 fetuses from 8 families who were classified as having WWS based mainly on MRI studies. All of the liveborn probands had cobblestone complex; 3 patients and 2 fetuses had encephaloceles. In 1 family, 3 fetuses with hydrocephalus, severe cobblestone complex, and retinal dysplasia were aborted at 20 to 27 weeks' gestation. Among all patients, ocular changes included microphthalmia, buphthalmos, congenital glaucoma, congenital cataract, corneal clouding, anterior chamber dysgenesis, and retinal dysplasia. Serum creatine kinase was elevated, and muscle biopsies available in 3 infants showed myopathic changes. In 1 patient, the presence of a cobblestone cortex could not be evaluated due to severe hydrocephalus. However, other findings including vermis hypoplasia, flat pons, cerebellar hypoplasia, and a Dandy-Walker malformation together with death in early infancy and high serum creatine kinase, were considered sufficient for a WWS diagnosis. Of the liveborn children with WWS, 1 was living at age 6 months, 2 died at 3 years, and 4 died before age 9 months.

POMT1-Related Walker-Warburg Syndrome

Beltran-Valero de Bernabe et al. (2002) provided follow-up of 1 of the families reported by Cormand et al. (2001), who was found to have a homozygous mutation in the POMT1 gene (G76R; 607423.0001). The parents were first cousins of Turkish origin. After 3 spontaneous abortions, a male was born with severe hydrocephalus with dilatation of the third and fourth ventricles and minimal cortical development, no visible gyri, bifid cerebellum, and hypoplasia of the vermis and of the cerebellar hemispheres. He also had a cerebellar cyst. Microphthalmia on the left and exophthalmia on the right were noted. The genitalia were hypoplastic. Serum creatine kinase levels were highly elevated at more than 2,000 U/l. The patient died at age 7 months. Another affected child, whose DNA was used for genetic analysis, died 15 minutes after birth. She presented with severe hydrocephaly, encephalocele, and bilateral cleft lip.

Beltran-Valero de Bernabe et al. (2002) also identified a homozygous truncating POMT1 mutation (G76R; 607423.0001) in affected individuals from 2 consanguineous Turkish families previously reported by Cormand et al. (2001). In 1 family, 3 sibs had WWS: a girl who died at age 3 years, and 2 fetuses. The deceased girl had cobblestone lissencephaly, microphthalmia, buphthalmos, megalocornea, glaucoma, and retinal dysplasia. One fetus had an encephalocele. In the second family, there was 1 affected girl who died at age 2 months. She presented with severe hydrocephalic ventricular dilatation, hypoplasia of the cerebellar vermis, cyst formation in the posterior fossa, and a Dandy-Walker-like malformation. Eye malformations included bilateral buphthalmos, bilateral glaucoma, and hypertelorism. Serum creatine kinase levels were significantly increased in all affected patients. Additional patients with POMT1-related WWS had similar features, including hydrocephalus, frontal bossing, ventriculomegaly, cobblestone lissencephaly with agyria and agenesis of the corpus callosum, hypoplasia of the cerebellar vermis, encephalocele, and pachygyria/agyria. Ocular findings included microphthalmia, buphthalmos, retinal dysplasia, and lens opacities. One child had microtia. Serum creatine kinase levels were always significantly increased.

Kim et al. (2004) reported a Japanese boy with Walker-Warburg syndrome. Prenatal studies showed a meningoencephalocele. At birth, he showed hypotonia, hydrocephalus, mild microphthalmia, and corneal clouding. Serum creatine kinase levels were markedly elevated. He had markedly delayed milestones, with inability to control his head, roll over, or sit. Brain MRI showed agyric frontal and temporooccipital lobes mixed with pachygyric parietal cortex, as well as hypoplasia of the brainstem and cerebellum. Muscle biopsy showed marked increase in fatty tissue with evidence of necrosis and regeneration, hypoglycosylation of alpha-dystroglycan, and defective laminin binding. Kim et al. (2004) noted that the patient showed exceptionally long survival for WWS, up to 3.5 years, and thus could be considered to have an intermediate phenotype between WWS and muscle-eye-brain disease (MDDGB1; 613155), but the presence of a meningoencephalocele was more consistent with WWS. Genetic analysis identified a homozygous deletion in the POMT1 gene (1260delCCT; 607423.0004).

POMT1-Related Muscle-Eye-Brain Disease

Godfrey et al. (2007) reported a patient with POMT1-related MEB. Although clinical details were limited, the patient had prenatal onset, increased serum creatine kinase, contractures, congenital glaucoma, microcephaly, and low IQ. Brain MRI showed hydrocephalus, brainstem involvement, white matter abnormalities, cerebellar hypoplasia, and cerebellar cysts. 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 those seen in WWS. 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, MDGDB4; 253800).

Mercuri et al. (2009) reported 2 Italian patients with POMT1-related MEB. Although clinical details were limited, the patients had microcephaly, mental retardation, and increased serum creatine kinase, and 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.

Diagnosis

Crowe et al. (1985) made the diagnosis of Warburg syndrome on the basis of physical features and autopsy findings: congenital hydrocephalus, bilateral microphthalmos, severe developmental retardation, and multiple brain malformations. Dobyns et al. (1989) reviewed the diagnostic criteria for Walker-Warburg syndrome based on 21 of their own patients and an additional 42 patients from the literature. All patients who were examined for type II lissencephaly, cerebellar malformation, retinal malformation, and congenital muscular dystrophy displayed these abnormalities. Two other abnormalities, dilatation of the cerebral ventricles with or without hydrocephalus and malformation of the anterior chamber of the eye, were helpful but not necessary diagnostic criteria.

Greenberg et al. (1992) reported that Walker-Warburg syndrome can give a false-positive test for Duchenne muscular dystrophy (DMD; 310200)/Becker muscular dystrophy (BMD; 300376) on administration of the neonatal test of dried filter paper blood spots to check for creatine kinase. This experience emphasized the importance of the myopathy finding in this syndrome.

Prenatal Diagnosis

By means of ultrasonography, Crowe et al. (1985) prenatally diagnosed WWS in a subsequent pregnancy. Farrell et al. (1987) made the prenatal ultrasonographic diagnosis of this syndrome in a family not known to be at risk of having an affected child: ultrasonography at 28 weeks suggested fetal hydrocephalus; at 30 weeks, marked dilatation of both lateral ventricles and a small encephalocele were demonstrated as well as abnormality of the posterior fossa; at 35 weeks, retinal abnormalities were demonstrated. Prenatal ultrasonographic findings of hydrocephalus and occipital encephalocele were present in a second affected fetus at 18 weeks of gestation.

Rodgers et al. (1994) reported 3 affected sibs whose parents were second cousins once removed. Prenatal diagnosis was made in the 2 latter born sibs. In the first sib, clinical and imaging studies demonstrated hydrocephalus, microphthalmia of the left eye, corneal opacity of the right eye, Dandy-Walker malformation, severe hypoplasia or absence of the cerebellar vermis, and severe hypotonia. The second affected fetus was diagnosed at 20 weeks of gestation by the finding of hydrocephalus. In the third affected fetus, hydrocephalus, cerebellar cyst, and a small occipital meningocele were detected by ultrasonography at 19 weeks of gestation. Type II lissencephaly was demonstrated at autopsy.

By prenatal ultrasonography, Chitayat et al. (1995) detected hydrocephalus and retinal nonattachment consistent with Walker-Warburg syndrome at 37 weeks' gestation. Chitayat et al. (1995) provided a tabulation of conditions associated with congenital nonattachment/detachment of the retina.

Gasser et al. (1998) made the prenatal diagnosis of Walker-Warburg syndrome in 3 sibs. In each of 3 successive pregnancies, the fetus was found to have hydrocephalus by ultrasound. Autopsy of the second infant, a male, showed dilated ventricles, thin cortex, and type II lissencephaly with microscopic evidence of chaotic architecture. Eye examination showed retinal dysplasia. There was no demonstrable muscle change. A third fetus, a female, was found to have hydrocephalus at 13 weeks of gestation. Termination of pregnancy was performed at 20 weeks, and autopsy showed brain, eye, and muscular findings similar to those of the previous case. In addition, cystic changes and stenosis of the pyeloureteral junction were found in the right kidney. Although muscular dystrophy is an additional abnormality in postnatal cases, a lack of demonstrable muscle changes in the fetal period must be emphasized.

Inheritance

The first familial occurrence of WWS was that reported by Chemke et al. (1975); 3 of 7 offspring of third-cousin parents were affected, indicating autosomal recessive inheritance.

Warburg (1976) found reports of 15 cases of the association between hydrocephalus and congenital retinal detachment, and she (Warburg, 1978) observed this association in the son of first-cousin parents. Warburg (1976, 1978) thus proposed autosomal recessive inheritance.

Pagon et al. (1978) reported an affected brother and sister with WWS, and Ayme and Mattei (1983) reported 2 affected sibs.

By studying 17 patients, Dobyns et al. (1986) found parental consanguinity in 1 instance as well as 6 affected sibs among the 19 total sibs of the probands. The authors concluded that their findings supported recessive inheritance of WWS.

Mapping

By genomewide linkage analysis of 15 consanguineous WWS families. Beltran-Valero de Bernabe et al. (2002) found that 5 showed homozygosity for markers, such as D9S64, at the POMT1 locus on chromosome 9q34. Further studies on the remaining 10 families indicated the existence of at least 3 different WWS loci, indicating genetic heterogeneity.

Genetic Heterogeneity

Currier et al. (2005) excluded mutations in the POMT1 gene as the cause of WWS in 28 of 30 unrelated patients of various ethnic and geographic origins. Linkage to the POMT1 locus was excluded in 6 consanguineous families, indicating genetic heterogeneity.

Pathogenesis

Gelot et al. (1995) reported detailed neuropathologic studies of 5 unrelated cases of cobblestone lissencephaly (type II) from 3 fetuses and 2 infants in an effort to determine the developmental course of the cerebral lesions. The authors believed that all the features could be related to a primitive meningeal pathology, a type of neurocristopathy. They found evidence for 2 distinct developmental events: first, an early disturbance in cortex formation resulting from a disorder of radial migration and from disruption of the pial barrier; and second, a later perturbation of the organization of the cerebral surface. Muscle pathology was not examined in any of these 5 cases and the eyes were examined in only 1, in which there was evidence of microphthalmia and abnormalities in the anterior chamber.

Voit et al. (1995) demonstrated preserved merosin M chain (see LAMA2, 156225) expression in skeletal muscle specimens from 5 patients with Walker-Warburg syndrome. This preservation distinguished Walker-Warburg syndrome from congenital muscular dystrophy with central hypomyelination (MDC1A; 607855) in which merosin is completely absent. In 2 unrelated children with WWS, Wewer et al. (1995) found decreased expression of laminin-2 in skeletal muscle membranes, with normal expression in smooth muscle and peripheral nerve. They also found severely reduced alpha-sarcoglycan (SGCA; 600119) immunoreactivity. Both deficiencies were believed to be secondary.

In a review, Muntoni and Voit (2004) noted that dystroglycan is an important structural protein that links cells to the extracellular matrix, and is an essential component of the basement membrane. Hypoglycosylation of alpha-dystroglycan results in the disruption of the dystrophin (DMD; 300377)-glycoprotein complex in skeletal muscle and can perturb glial and neuronal interactions, resulting in abnormal migration of neurons in the brain.

Molecular Genetics

By candidate gene analysis in combination with homozygosity mapping in 15 consanguineous families with WWS, Beltran-Valero de Bernabe et al. (2002) identified homozygous or compound heterozygous mutations in the POMT1 gene in 6 of 30 probands (see, e.g., 607423.0001-607423.0003). Three of the families had been reported by Cormand et al. (2001). Immunohistochemical analysis of muscle from patients with POMT1 mutations corroborated the O-mannosylation defect, as judged by the absence of glycosylation of DAG1. The findings suggested that mutations in the POMT1 gene account for approximately 20% of cases of WWS.

In a Japanese boy with Walker-Warburg syndrome, Kim et al. (2004) identified a homozygous 3-bp deletion in the POMT1 gene (607423.0004).

Currier et al. (2005) identified heterozygous POMT1 mutations in 2 of 30 unrelated patients with WWS, but a second POMT1 mutation was not identified in either patient. The authors concluded that mutations in the POMT1 gene are an uncommon cause of WWS, identified in only 7% of their patient sample.

In a large study of 92 probands with muscular dystrophy and evidence of a dystroglycanopathy, Godfrey et al. (2007) found that 1 patient with an MEB-like phenotype had a homozygous 2-bp deletion in the POMT1 gene (2179delTC; 607423.0015).

In a large study of 81 Italian patients with a dystroglycanopathy, Mercuri et al. (2009) found that 2 with MEB had mutations in the POMT1 gene (607423.0016-607423.0018).

History

Williams et al. (1984) reported an affected brother and sister who died on postnatal day 53 and in the third month. Histologic studies showed a myopathy, and brain findings suggested a sclerosing meningoencephalitis active through the second and third trimesters. Indeed, the authors favored a nongenetic cause, i.e., 'an acquired agent...transmitted transplacentally through consecutive pregnancies.'

Karadeniz et al. (2002) reported an infant who had clinical signs of Walker-Warburg syndrome, including congenital muscular dystrophy, lissencephaly, ventricular dilatation and hydrocephalus, hypoplasia of cerebellar vermis, bilateral megalocornea and optic atrophy with buphthalmos, and corneal clouding. An apparently balanced de novo reciprocal translocation, t(5;6)(q35;q21), was detected. However, because Walker-Warburg syndrome is a recessive condition, it would be necessary to have a separate mutation on the other allele if the gene for this disorder is located at 1 of the 2 breakpoints. The authors pointed out that laminin chain alpha-4 (LAMA4; 600133) is located on 6q21.