Congenital disorders of glycosylation (CDG) are rare genetic defects mainly in the post-translational modification of proteins via attachment of carbohydrate chains. We describe an infant with the phenotype of a congenital muscular dystrophy, with borderline microcephaly, hypotonia, camptodactyly, severe motor delay, and elevated creatine kinase. Muscle biopsy showed muscular dystrophy and reduced α-dystroglycan immunostaining with glycoepitope-specific antibodies in a pattern diagnostic of dystroglycanopathy. Carbohydrate deficient transferrin testing showed a pattern pointing to a CDG type I. Sanger sequencing of DPM1 (dolichol-P-mannose synthase subunit 1) revealed a novel Gly > Val change c.455G > T missense mutation resulting in p.Gly152Val) of unknown pathogenicity and deletion/duplication analysis revealed an intragenic deletion from exons 3 to 7 on the other allele. DPM1 activity in fibroblasts was reduced by 80%, while affinity for the substrate was not depressed, suggesting a decrease in the amount of active enzyme. Transfected cells expressing tagged versions of wild type and the p.Gly152Val mutant displayed reduced binding to DPM3, an essential, non-catalytic subunit of the DPM complex, suggesting a mechanism for pathogenicity. The present case is the first individual described with DPM1-CDG (CDG-Ie) to also have clinical and muscle biopsy findings consistent with dystroglycanopathy.
Keywords: CDG; CDG-Ie; CGH; CK; Congenital disorder of glycosylation; Congenital muscular dystrophy; DLO; DPM; DPM1; DPM1-CDG; Dol-P; Dol-P-Man; Dystroglycanopathy; EEG; ER; GDP-Man; GDP-mannose; GPI; GlcNAc; MRI; N-acetylglucosamine; comparative genomic hybridization; congenital disorder of glycosylation; creatine kinase; dolichol-P-mannose; dolichol-P-mannose synthase; dolichol-linked oligosaccharides; dolichol-phosphate; electroencephalogram; endoplasmic reticulum; glycophosphatidyl inositol; magnetic resonance imaging.
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