Muscular Dystrophy-Dystroglycanopathy (Limb-Girdle), Type C, 8

A number sign (#) is used with this entry because this form of limb- girdle muscular dystrophy-dystroglycanopathy (type C8; MDDGC8), also known as LGMDR24, is caused by homozygous or compound heterozygous mutation in the POMGNT2 gene (614828) on chromosome 3p22.

Biallelic mutation in the POMGNT2 gene can also cause congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A8; MDDGA8; 614830), a much more severe disorder.

Description

MDDGC8 is an autosomal recessive muscular dystrophy with onset in childhood. The phenotype is highly variable: some patients may have gait difficulties and impaired intellectual development, whereas others may be clinically asymptomatic. Common features include calf hypertrophy and increased serum creatine kinase, and muscle biopsy often shows dystrophic features (summary by Endo et al., 2015). The disorder is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies' (Godfrey et al., 2007).

For a discussion of genetic heterogeneity of muscular dystrophy- dystroglycanopathy type C, see MDDGC1 (609308).

Clinical Features

Endo et al. (2015) reported 3 unrelated Japanese males, aged 28, 19, and 14 years, with a mild form of limb-girdle muscular dystrophy. The most severely affected individual (P1) presented at age 11 months with delayed motor development after an illness. He had global developmental delay and achieved walking at age 2, but could never run. As an adult, he could not walk up or down stairs without handrails and had difficulty lifting heavy objects due to proximal muscle weakness affecting the lower and upper limbs. Serum creatine kinase was increased, and there was mild calf hypertrophy as well as impaired intellectual development (IQ less than 35 at age 28) with poor speech. The other 2 patients were ascertained due to incidental findings of increased serum creatine kinase. P2 had no muscle symptoms or weakness at age 19, although he did have calf hypertrophy. This patient had congenital biliary atresia necessitating a liver transplant at age 17. P3 had normal motor milestones and calf hypertrophy, but normal muscle power and volume in the limbs. He also had mildly impaired intellectual development, delayed speech, and hyperactivity disorder. None of the patients had facial muscle weakness or eye, heart, kidney, respiratory, or brain abnormalities. Muscle biopsies in all patients showed negative immunostaining with the glycoepitope for alpha-dystroglycan, and Western blot analysis showed 3 bands, confirming the diagnosis, but suggestive of a reduction rather than complete loss of glycosylation. In P1 and P3, muscle biopsy also showed dystrophic changes, including necrotic and regenerating fibers, internal nuclei, and mild endomysial fibrosis; muscle biopsy in P2 was almost normal except for some internal nuclei. The pathologic changes were in proportion to the clinical severity.

Inheritance

The transmission pattern of MDDGC8 in the families reported by Endo et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 unrelated Japanese patients with MDDGC8, Endo et al. (2015) identified homozygous or compound heterozygous missense mutations in the POMGNT2 gene (P253L, 614828.0004 and M165T, 614828.0005) at highly conserved residues in the putative glycosyltransferase domain. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing, but segregation studies in the families were not performed. In vitro functional expression studies showed that the mutant proteins were expressed and localized normally, but the enzymatic activity was greatly reduced to less than 10% of control values. Expression of the mutations into POMGNT2-null cells failed to rescue the glycosylation defects and disrupted laminin binding of DAG1, consistent with a partial loss of function. The findings were consistent with reduced POMGNT2 activity resulting in a mild phenotype. The patients were ascertained from a cohort of 20 patients identified as having a dystroglycanopathy through immunostaining or Western blot analysis.