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DPM2‐CDG: A muscular dystrophy–dystroglycanopathy syndrome with severe epilepsy
Author(s) -
Barone Rita,
Aiello Chiara,
Race Valérie,
Morava Eva,
Foulquier Francois,
Riemersma Moniek,
Passarelli Chiara,
Concolino Daniela,
Carella Massimo,
Santorelli Filippo,
Vleugels Wendy,
Mercuri Eugenio,
Garozzo Domenico,
Sturiale Luisa,
Messina Sonia,
Jaeken Jaak,
Fiumara Agata,
Wevers Ron A.,
Bertini Enrico,
Matthijs Gert,
Lefeber Dirk J.
Publication year - 2012
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.23632
Subject(s) - congenital muscular dystrophy , missense mutation , muscular dystrophy , compound heterozygosity , hypotonia , mutation , biology , endoplasmic reticulum , glycosylation , phenotype , microcephaly , genetics , endocrinology , medicine , gene
Objective: Congenital disorders of glycosylation (CDG) are a group of metabolic diseases due to defects in protein and lipid glycosylation. We searched for the primary defect in 3 children from 2 families with a severe neurological phenotype, including profound developmental delay, intractable epilepsy, progressive microcephaly, severe hypotonia with elevated blood creatine kinase levels, and early fatal outcome. There was clinical evidence of a muscular dystrophy–dystroglycanopathy syndrome, supported by deficient O‐mannosylation by muscle immunohistochemistry. Methods: Biochemical and molecular methods were combined to pinpoint the defect in the glycosylation pathway in the endoplasmic reticulum. Results: Metabolic investigations revealed CDG‐I, pointing to a defect in protein N‐glycosylation in the endoplasmic reticulum. Analysis of lipid‐linked oligosaccharides in fibroblasts showed accumulation of Dol‐PP‐GlcNAc 2 ‐Man 5 . DNA analysis revealed mutations in DPM2 , 1 of the subunits of the dolichol‐phosphate‐mannose (DPM) synthase; the patient in the first family is compound heterozygous for 2 mutations (c.68A>G, predicting a missense mutation p.Y23C and c.4‐1G>C, a splice mutation), whereas the patients in the second family are homozygous for the same missense mutation (c.68A>G, p.Y23C). Interpretation: We describe a new CDG, due to a deficiency of DPM2. Hence, mutations have now been described in the genes for the 3 subunits of DPM: DPM1 , DPM2 , and DPM3 , whereby DPM2‐CDG links the congenital disorders of glycosylation to the congenital muscular dystrophies. ANN NEUROL 2012;72:550–558