Muscular Dystrophy-Dystroglycanopathy (Limb-Girdle), Type C, 15

A number sign (#) is used with this entry because of evidence that this form of limb-girdle muscular dystrophy-dystroglycanopathy (type C15; MDDGC15) is caused by homozygous mutation in the DPM3 gene (605951) on chromosome 1q22.

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

For a discussion of the classification of CDGs, see CDG1A (212065).

Clinical Features

Lefeber et al. (2009) reported a 27-year-old Greek woman who presented at age 11 years with mild muscle weakness and waddling gait. At age 20, she was diagnosed with a dilated cardiomyopathy after episodes of precordial pain. However, there were no signs of cardiac muscle hypertrophy or outflow obstruction. Laboratory studies showed increased serum creatine kinase and mildly elevated liver function tests. Skeletal muscle biopsy showed moderate muscular dystrophy with variation in fiber size, multiple internal nuclei, necrotic fibers, rimmed vacuoles, fiber splitting, and interstitial fibrosis. At age 21, the patient experienced a stroke-like episode. Cerebral angiography and ophthalmologic evaluation were normal. Metabolic investigations were normal, but results of transferrin isoelectric focusing showed an abnormal profile suggesting a CDG type I pattern. At age 27, she showed low-normal IQ and mild proximal muscle weakness. Further biochemical studies showed defective N-glycosylation of transferrin in the endoplasmic reticulum and decreased dolichol-phosphate-mannose (Dol-P-Man) synthase activity.

Van den Bergh et al. (2017) reported a 57-year-old woman with clinical onset of progressive limb-girdle muscular dystrophy at age 42. She presented with proximal muscle weakness affecting the lower limbs with unsteady gait and difficulty rising from a chair and showed a positive Gowers sign. Serum creatine kinase was elevated, and skeletal muscle biopsy showed nonspecific myopathic changes, a dystrophic pattern, and alpha-DAG deficiency as demonstrated by immunoblotting. Analysis of serum transferrin showed normal N-glycosylation. Brain, eye, cardiac, and respiratory functions were normal, and there was no family history of a similar disorder.

Inheritance

The transmission pattern of MDDGC15 in the family reported by Van den Bergh et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a Greek female patient with MDDGC15, Lefeber et al. (2009) identified a homozygous mutation in the DPM3 gene (L85S; 605951.0001). The authors noted that 4 biosynthetic pathways depend on DPM activity, including O-mannosylation of alpha-dystroglycan (DAG1; 128239), and postulated that the isolated phenotype of muscular dystrophy in this patient most likely resulted from deficient O-mannosylation of DAG1. These findings linked the congenital disorders of glycosylation to the dystroglycanopathies.

In a woman with MDDGC15, Van den Bergh et al. (2017) identified a homozygous missense mutation in the DPM3 gene (L44P; 605951.0002). The mutation, which was found by exome sequencing, segregated with the disorder in the family. DPM synthase activity in patient fibroblasts was reduced by 50% compared to controls.