Muscular Dystrophy-Dystroglycanopathy (Congenital With Brain And Eye Anomalies), Type A, 10

A number sign (#) is used with this entry because this form of congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A10; MDDGA10) is caused by homozygous or compound heterozygous mutation in the TMEM5 gene (RXYLT1; 605862), which encodes a transmembrane protein believed to have glycosyltransferase function, on chromosome 12q14.

Description

Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A) 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. The brain shows cobblestone lissencephaly, a cortical malformation. The phenotype includes the alternative clinical designations Walker-Warburg syndrome (WWS) and muscle-eye-brain disease (MEB). The disorder 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 Vuillaumier-Barrot 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

Vuillaumier-Barrot et al. (2012) reported 5 unrelated families in which a total of 9 fetuses were affected with severe cobblestone lissencephaly. Most also had occipital neural tube defects, facial clefts, visceral malformations, retinal dysplasia, and gonadal dysgenesis.

Jae et al. (2013) reported affected members of 2 unrelated consanguineous families with muscular dystrophy-dystroglycanopathy type A10. A newborn male in Family 43 was large for gestational age with macrocephaly and showed occipital encephalocele, right microphthalmia, and bilateral opaque cornea. His muscles were markedly hypotonic, and his creatine kinase levels were sometimes elevated to 3,500 U/L. Cranial ultrasound demonstrated hydrocephalus internus and occipital encephalocele. Ophthalmology evaluation showed bilateral cataracts in addition to the corneal opacification. EEG showed pseudo alpha activity as seen in patients with lissencephaly. Ventriculoperitoneal shunt was necessary at age 6 weeks. He died at age 22 months. In Family 56, 2 sisters, aged 19 and 21 years, had severe intellectual disability with autistic features. Small head circumference was evident. Both were barely mobile and had a broad-based gait. Creatine kinase levels were routinely over 4,000 U/L. MRI of the older sister showed brainstem atrophy, dilated ventricles, widespread pachygyria, and significant white matter involvement with leukodystrophic appearance.

Inheritance

The transmission pattern of MDDGA10 in the families reported by Vuillaumier-Barrot et al. (2012) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 9 fetuses with severe cobblestone lissencephaly consistent with muscular dystrophy-dystroglycanopathy type A, Vuillaumier-Barrot et al. (2012) identified 5 different mutations in homozygous or compound heterozygous state in the TMEM5 gene (605862.0001-605862.0005). The first mutation was identified by homozygosity mapping combined with exome sequencing in a consanguineous family. TMEM5 mutations accounted for 5 (9%) of 58 families with cobblestone lissencephaly in whom a genetic defect was found.

Jae et al. (2013) identified homozygous mutations in the TMEM5 gene in affected members of 2 unrelated consanguineous families with muscular dystrophy-dystroglycanopathy type A. In Family 43, a boy who died at age 22 months had a nonsense mutation (605862.0006); in Family 53, 2 sisters, aged 19 and 21 years, had a frameshift mutation (605862.0007).