Muscular Dystrophy-Dystroglycanopathy (Congenital With Brain And Eye Anomalies), Type A, 12

A number sign (#) is used with this entry because of evidence that this form of congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A12; MDDGA12) is caused by homozygous or compound heterozygous mutation in the POMK gene (615247), which encodes protein-O-mannose kinase, on chromosome 8p11.

Mutation in the POMK gene can also cause a limb-girdle muscular dystrophy-dystroglycanopathy (type C12; MDDGC12; 616094).

Description

Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A) is an autosomal recessive disorder with congenital muscular dystrophy resulting in muscle weakness early in life and brain and eye anomalies. It is usually associated with delayed psychomotor development and shortened life expectancy. 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 Stevens et al., 2013).

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

Clinical Features

Jae et al. (2013) identified a girl, born to nonconsanguineous parents (Family 40), who was delivered after a pregnancy complicated by polyhydramnios. Her birth weight was 3,820 grams and her head circumference was 48 cm. Brain MRI showed triventricular hydrocephalus with a very thin cortex, compression of the cerebellar hemispheres and brainstem, and an Arnold-Chiari malformation. She received a ventriculoperitoneal shunt. Ophthalmologic evaluation showed persistent hypoplastic primary vitreous in both eyes, high myopia of the right eye, and microphthalmia of the left eye. The child had severe hypotonia and muscle weakness with a creatine kinase level of 7,000 U/L. A CT scan at 17 months showed dilated cerebral ventricles with agyria, and hypoplasia of the cerebellum and brainstem. The right eye lens showed cataract. Muscle biopsy at 18 months revealed muscular dystrophy, and immunohistochemistry demonstrated the presence of merosin, dystrophin, and alpha-, beta- and gamma-sarcoglycans. The girl died at the age of almost 3 years. In the couple's second pregnancy, ultrasound at 17 weeks' gestation showed cerebral ventriculomegaly and a small occipital encephalocele. The pregnancy was terminated at 19 weeks. Autopsy showed cerebral anomalies, absence of the falx cerebri, and cerebellar tentorium. Both eyes had cortical cataract and retinal coloboma.

Von Renesse et al. (2014) reported 2 sibs, born of consanguineous parents, with progressive congenital muscular dystrophy and severe psychomotor retardation. The patients were 21 and 15 years old, respectively, at the time of the report. Both showed severe hypotonia with feeding problems and delayed psychomotor development from infancy. Laboratory studies showed increased serum creatine kinase, and muscle biopsy showed dystrophic changes with lack of alpha-dystroglycan and secondary decreases in merosin and desmin immunostaining. Additional features included mild sensorineural hearing loss and large eyes with decreased visual acuity. Brain MRI showed hypomyelination in the periventricular regions. Both patients were severely affected and required a wheelchair as well as help with daily needs. One had progressive microcephaly, and the other developed scoliosis and hypoventilation syndrome. Von Renesse et al. (2014) noted that the phenotype in their patients differed somewhat from that reported by Jae et al. (2013).

Di Costanzo et al. (2014) reported an Italian boy, born of unrelated parents, with MDDGA12 manifest as WWS. Macrocephaly and hydrocephalus were observed on prenatal ultrasound at 32 weeks' gestation. After delivery by cesarean section at 34 weeks, the infant showed hypotonia, glaucoma of the right eye, bilateral retinal degeneration, and severe bilateral sensorineural hearing loss. He had severely delayed psychomotor development, seizures, increased serum creatine kinase, and absent muscle fibers on skeletal muscle biopsy. Brain MRI showed cobblestone lissencephaly, agenesis of the corpus callosum, and severe cerebellar vermis hypoplasia. The child died at age 4 years.

Inheritance

The transmission pattern of MDDGA12 in the family reported by von Renesse et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a child and a fetus with MDDGA12, born of a nonconsanguineous couple, Jae et al. (2013) identified compound heterozygosity for missense mutations in the SGK196 gene (L137R, 615247.0001; Q258R, 615247.0002).

In 2 sibs, born of consanguineous parents, with MDDGA12, von Renesse et al. (2014) identified a homozygous truncating mutation in the POMK gene (Q109X; 615247.0003). The mutation was found by a combination of homozygosity mapping and whole-exome sequencing.

In an Italian boy with MDDGA12, Di Costanzo et al. (2014) identified compound heterozygosity for 2 POMK mutations (c.286delT, 615247.0004 and V302D, 615247.0005). The patient was ascertained from a larger cohort of 28 patients with a similar severe dystroglycanopathy phenotype.

Animal Model

Di Costanzo et al. (2014) found that morpholino knockdown of the pomk gene in zebrafish embryos resulted in a small head, delayed ocular development, shortened thicker tail, U-shaped somites, motility defects, and increased mortality. Analysis of the tail muscle showed dystrophic features and decreased DAG1 glycosylation.