Muscular Dystrophy-Dystroglycanopathy (Congenital With Brain And Eye Anomalies), Type A, 14

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 A14; MDDGA14) is caused by compound heterozygous mutation in the GMPPB (615320) on chromosome 3p21. GMPPB encodes the beta subunit of GDP-mannose pyrophosphorylase.

Mutation in the GMPPB gene can also cause a less severe congenital muscular dystrophy-dystroglycanopathy with mental retardation (type B14; MDDGB14; 615351) and a limb-girdle muscular dystrophy-dystroglycanopathy (type C14; MDDGC14; 615352).

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

Clinical Features

Carss et al. (2013) reported an 8-year-old Pakistani boy who presented at birth with increased muscle tone, microcephaly, cleft palate, and feeding difficulties. He later showed severe muscle weakness, delayed walking (only with support at age 3 years), and severe intellectual development with lack of speech. Other features included sensorineural hearing loss, ataxia, and retinal dysfunction. Serum creatine kinase was increased, and muscle biopsy showed dystrophic features with hypoglycosylation of alpha-dystroglycan (DAG1; 128239). Brain MRI revealed pontine and cerebellar hypoplasia. Isoelectric focusing of transferrin was normal. The diagnosis was a muscle-eye-brain- and/or an FCMD (253800)-like disorder.

Inheritance

The transmission pattern of MDDGA14 in the family reported by Carss et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a Pakistani boy with MDDGA14, Carss et al. (2013) identified compound heterozygous mutations in the GMPPB gene (615320.0001 and 615320.0002). The mutations, which were identified by exome sequencing and confirmed by Sanger sequencing, were not found in large control databases. Each unaffected parent was heterozygous for 1 of the mutations.