Muscular Dystrophy-Dystroglycanopathy (Congenital With Brain And Eye Anomalies), Type A, 7

A number sign (#) is used with this entry because this form of congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A7; MDDGA7) is caused by homozygous or compound heterozygous mutation in the ISPD gene (614631) on chromosome 7p21. ISPD encodes an isoprenoid synthase domain-containing protein.

Mutation in the ISPD gene can also cause a less severe limb-girdle muscular dystrophy-dystroglycanopathy without brain and eye anomalies (type C7; MDDGC7; 616052).

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 alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies' (summary by Roscioli et al., 2012).

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

Clinical Features

Chitayat et al. (1995) reported a 37-week-old fetus who was found to have hydrocephalus and retinal detachment on prenatal ultrasound, leading to a diagnosis of WWS. Fetal movements were weak. After delivery, the baby was hypotonic, in a 'frog leg' position, and did not move or cry. He had large fontanels, frontal bossing, deep-set eyes, retrognathia, and small, simple, low-set ears. The eyes had central circular defects in the posterior cornea with abnormal adhesions and anterior segment anomalies consistent with a variant of Peters anomaly. Brain MRI showed hydrocephalus, type II lissencephaly, and cerebellar hypoplasia. He died at age 3 months. Vajsar et al. (2000) performed skeletal muscle studies of the patient reported by Chitayat et al. (1995). Skeletal muscle biopsy showed dystrophic changes and disruption in the basal lamina. Laminin alpha-2 (LAMA2; 156225) immunostaining was normal.

Kanoff et al. (1998) reported a male infant with WWS. He had macrocephaly, low-set ears, unilateral microphthalmia, cataract, and optic nerve hypoplasia. He had a weak cry, facial weakness, and generalized profound hypotonia with absent reflexes. Brain MRI showed ventriculomegaly, a Dandy-Walker malformation, and agyria. Serum creatine kinase was increased, and skeletal muscle biopsy showed necrotic fibers and variation in myofiber diameter, consistent with muscular dystrophy. He died at age 6 months of respiratory impairment. Postmortem examination showed lissencephaly, absence of the posterior cerebellar vermis, atrophy of the corpus callosum, and subcortical heterotopia. There was a decrease in LAMA2 expression in muscle fibers.

Willer et al. (2012) reported 7 patients, including 2 sibs, with MDDGA7 confirmed by genetic analysis. All had a diagnosis of Walker-Warburg syndrome. Two of the patients were those reported by Chitayat et al. (1995) and Kanoff et al. (1998). One additional patient was described in detail by Willer et al. (2012). Brain MRI performed at 3 days and at 5 months of age showed hydrocephalus, cobblestone lissencephaly of the cerebral cortex, and severe brainstem and cerebellar hypoplasia. The patient also had severe muscular dystrophy with increased serum creatine kinase, bilateral microphthalmia, cataracts, and arrested retinal development. Immunofluorescence and protein blot analysis of skeletal muscle showed a typical alpha-dystroglycan glycosylation defect, with loss of both functional glycosylation and receptor function. Fibroblasts from 5 other patients showed a complete loss of functional glycosylation and laminin binding, as well as hypoglycosylation of core alpha-dystroglycan. All patients had a similar phenotype, with muscular dystrophy and brain and eye anomalies. Most died by age 2 years.

Roscioli et al. (2012) reported 9 families with WWS/MEB. One large consanguineous family had 3 affected members. All affected individuals had a severe phenotype, with cobblestone lissencephaly, hydrocephalus, cerebellar hypoplasia, and hypoplasia of the corpus callosum, as well as eye anomalies, such as microphthalmia, cataract, anterior chamber defects, and glaucoma. All had hypotonia and increased serum creatine kinase, and muscle histology showed dystrophic changes and a reduction of glycosylated alpha-dystroglycan. Most died by age 2 years, but 2 patients survived past age 2 and were thus categorized as having MEB.

Vuillaumier-Barrot et al. (2012) reported 8 fetuses from 5 unrelated families with MDDGA7. The probands were ascertained from a larger study of patients with severe diffuse cobblestone lissencephaly. Additional more variable clinical features included neural tube defects (in 4 patients), limb deformations (in 3), visceral malformations (in 2), brain vascular anomalies (in 2), and retinal dysplasia (in all 5 that were examined). One patient had gonadal dysgenesis.

Molecular Genetics

In 7 patients, including a pair of sibs, with congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A7, Willer et al. (2012) identified homozygosity or compound heterozygosity for point mutations in or deletions involving the ISPD gene (see, e.g., 614631.0001-614631.0004). All mutations were predicted to damage or abolish protein function. The mutations were identified by using a cell fusion complementation assay in fibroblasts followed by linkage analysis and targeted exome sequencing within the candidate region on chromosome 7p. Expression of wildtype ISPD in patient-derived cells restored functional glycosylation, confirming that the mutations have pathogenic relevance. Studies of skeletal muscle and fibroblasts from the patients showed a typical alpha-dystroglycan glycosylation defect, with loss of both functional glycosylation and laminin binding.

Roscioli et al. (2012) identified homozygous or compound heterozygous mutations in or deletions involving the ISPD gene in 9 (10%) of 94 families with MDDGA7 (see, e.g., 614631.0005-614631.0008). The gene was initially found by homozygosity mapping of 30 consanguineous families combined with array CGH for copy number variations, as well as exome sequencing of the candidate region in 1 family.

Vuillaumier-Barrot et al. (2012) identified 9 different biallelic mutations or deletions in the ISPD gene (see, e,g., 614631.0009-614631.0013) in 8 fetuses from 5 unrelated families with MDDGA7. The mutations in the first family were found by linkage analysis combined with exome sequencing. ISPD mutations accounted for 5 (9%) of 58 families with cobblestone lissencephaly in whom a genetic defect was found.