Muscular Dystrophy-Dystroglycanopathy (Congenital With Mental Retardation), Type B, 14

A number sign (#) is used with this entry because this form of congenital muscular dystrophy-dystroglycanopathy with mental retardation (type B14; MDDGB14) is caused by homozygous or compound heterozygous mutation in the gene encoding the beta subunit of GDP-mannose pyrophosphorylase (GMPPB; 615320) on chromosome 3p21.

Mutation in the GMPPB gene can also cause a more severe congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A14; MDDGA14; 615350) and a less severe limb-girdle muscular dystrophy-dystroglycanopathy (type C14; MDDGC14; 615352).

Description

MDDGB14 is an autosomal recessive congenital muscular dystrophy characterized by severe muscle weakness apparent in infancy and mental retardation. Some patients may have additional features, such as microcephaly, cardiac dysfunction, seizures, or cerebellar hypoplasia. It is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies' (summary by Carss et al., 2013).

For a discussion of genetic heterogeneity of congenital muscular dystrophy-dystroglycanopathy type B, see MDDGB1 (613155).

Clinical Features

Carss et al. (2013) reported 4 unrelated patients, 2 of Mexican descent and 2 girls of southern Italian descent, with congenital muscular dystrophy (CMD) with mental retardation. The patients presented between birth and 4 months of age with severe hypotonia. Three had shown decreased fetal movements in utero. There was some variation in additional features. The 2 Mexican patients had mild mental retardation, delayed walking at about 3 years, cataracts, strabismus, ptosis, and cardiac anomalies. One had long QT syndrome (see LQT1, 192500) and the other had left ventricular dilatation. One also had microcephaly, ileal atresia, and torticollis. Brain MRI in both patients was normal. The 2 Italian patients, previously reported by Messina et al. (2009), had severe hypotonia, microcephaly, generalized muscle weakness, feeding difficulties, drug-resistant epilepsy, and severe mental retardation. One was unable to sit, and 1 could sit at age 2 years. Brain MRI of both girls showed cerebellar hypoplasia. One died at age 14 years and the other was bedridden and unable to speak at age 10 years. All patients had increased serum creatine kinase and muscle biopsies consistent with muscular dystrophy showing hypoglycosylation of DAG1. Isoelectric focusing of serum transferrin was normal.

Inheritance

The transmission pattern of MDDGB14 in the families reported by Carss et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 Mexican patients with MDDGB14, Carss et al. (2013) identified a homozygous mutation in the GMPPB gene (615320.0004). Two unrelated Italian girls with the disorder were compound heterozygous for mutations in the GMPPB gene (615320.0005 and 615320.0006). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder.