Muscular Dystrophy-Dystroglycanopathy (Congenital With Brain And Eye Anomalies), Type A, 5

A number sign (#) is used with this entry because this form of congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A5; MDDGA5), previously designated Walker-Warburg syndrome (WWS) or muscle-eye-brain disease (MEB), is caused by homozygous mutation in the FKRP gene (606596), which encodes a fukutin-related protein, on chromosome 19q13.3.

Mutation in the FKRP gene can also cause a less severe congenital muscular dystrophy-dystroglycanopathy with or without mental retardation (type B5; MDDGB5; 606612) and a limb-girdle muscular dystrophy-dystroglycanopathy (type C5; MDDGC5; 607155).

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' (Beltran-Valero de Bernabe et al., 2004).

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.

FKRP-Related Walker-Warburg Syndrome

Cormand et al. (2001) reported a patient, born of consanguineous Pakistani parents, with WWS. The diagnosis was based on clinical findings of muscular dystrophy, anterior chamber abnormalities, and characteristic brain anomalies, including hydrocephalus, agyria, and absence of the corpus callosum and cerebellar vermis. The patient died at age 3 years. Beltran-Valero de Bernabe et al. (2004) provided detailed clinical features of the patient reported by Cormand et al. (2001). She presented at birth with marked hypotonia, feeding difficulties, and congenital hydrocephalus associated with a Dandy-Walker-like malformation. She had right-sided microphthalmia, corneal clouding, and coloboma, and left-sided retinal pigmentary changes. Serum creatine kinase was markedly elevated. Brain MRI showed a large cyst within the posterior fossa of the brain, with splaying of the cerebellar hemispheres. There was absence of the cerebellar vermis, pontine hypoplasia, ventricular dilatation, absence of the corpus callosum, white matter abnormalities, and absence of cortical sulci, consistent with lissencephaly.

Van Reeuwijk et al. (2010) reported a boy, born of consanguineous parents, with a clinical diagnosis of Walker-Warburg syndrome. He was born with severe hydrocephalus and showed limited spontaneous movements. He had microphthalmia, asymmetric pupils, absent pupillary light reflexes, and cataracts. Brain MRI showed aqueductal stenosis and small cerebellum and pons with kinking of the brainstem. Muscle biopsy showed muscular dystrophy. The infant died of respiratory distress at 6 days of age. Severe hydrocephalus was diagnosed at about 17 weeks' gestation in a subsequent pregnancy, and the pregnancy was terminated. Autopsy was not performed.

FKRP-Related Muscle-Eye-Brain Disease

Beltran-Valero de Bernabe et al. (2004) reported a German patient with FKRP-related MEB. He showed respiratory distress and hypotonia in the neonatal period, and developed roving eye movements at age 6 weeks. Serum creatine kinase was markedly elevated, and muscle biopsy showed dystrophic changes. He had severe psychomotor retardation, never gained the ability to control his head, sit, or roll over, and never learned to speak. Electrocardiography at 3.6 years of age showed left ventricular hypertrophy. He was blind, and funduscopic examination showed extreme rarefaction of pigment epithelium, no demarcation of the macula, and a severe myopia. At age 6 years, he developed bilateral retinal detachment. Brain MRI at age 7 years showed cobblestone lissencephaly, pachygyria, hypoplastic brainstem, dysplastic and hypoplastic cerebellum, a Dandy-Walker-like malformation, and cerebellar cysts. He had recurrent pneumonias and died at age 7 years.

Molecular Genetics

In a patient with WWS previously reported by Cormand et al. (2001), Beltran-Valero de Bernabe et al. (2004) identified a homozygous mutation in the FKRP gene (C318Y; 606596.0017).

In a German patient with muscle-eye-brain disease, Beltran-Valero de Bernabe et al. (2004) identified a homozygous mutation in the FKRP gene (Y307N; 606596.0016).

In 2 sibs, the offspring of consanguineous parents, with a clinical diagnosis of Walker-Warburg syndrome, van Reeuwijk et al. (2010) identified a homozygous mutation in the FKRP gene (M1V; 606596.0019). The mutation was found by homozygosity mapping combined with candidate gene sequencing. The unaffected parents were heterozygous for the mutation. Van Reeuwijk et al. (2010) predicted that the M1V mutation would result in a null allele, which correlated with the severe phenotype seen in these sibs.