DPM2-CDG: a muscular dystrophy-dystroglycanopathy syndrome with severe epilepsy

Area of Science:

• Biochemistry
• Genetics
• Neurology

Background:

• Congenital disorders of glycosylation (CDG) are rare metabolic diseases affecting protein and lipid glycosylation.
• Severe neurological phenotypes, including developmental delay and epilepsy, are observed in some CDG patients.
• Clinical presentation suggested a muscular dystrophy-dystroglycanopathy syndrome with deficient O-mannosylation.

Purpose of the Study:

• To investigate the underlying genetic defect in three children from two families with a severe neurological and muscular phenotype.
• To identify the specific defect in the glycosylation pathway responsible for the observed clinical manifestations.

Main Methods:

• Combined biochemical and molecular analyses to investigate the endoplasmic reticulum glycosylation pathway.
• Fibroblast analysis of lipid-linked oligosaccharides.
• DNA sequencing to identify mutations in relevant genes.

Main Results:

• Metabolic investigations indicated a defect in protein N-glycosylation, consistent with CDG-I.
• Accumulation of Dol-PP-GlcNAc(2)-Man(5) in patient fibroblasts was observed.
• Mutations in the DPM2 gene, encoding a subunit of dolichol-phosphate-mannose synthase, were identified in all affected individuals.

Conclusions:

• A novel form of CDG, DPM2-CDG, resulting from DPM2 gene deficiency, is described.
• This finding establishes a link between congenital disorders of glycosylation and congenital muscular dystrophies.
• Mutations are now known in all three subunits of the DPM synthase (DPM1, DPM2, DPM3), underscoring its critical role in glycosylation.