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

Rita Barone, Chiara Aiello, Valérie Race, Eva Morava, Francois Foulquier, Moniek Riemersma, Chiara Passarelli, Daniela Concolino, Massimo Carella, Filippo Santorelli, Wendy Vleugels, Eugenio Mercuri, Domenico Garozzo, Luisa Sturiale, Sonia Messina, Jaak Jaeken, Agata Fiumara, Ron A. Wevers, Enrico Bertini, Gert MatthijsDirk J. Lefeber

Research output: Contribution to journalArticle

Abstract

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-GlcNAc2-Man5. 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

Original languageEnglish
Pages (from-to)550-558
Number of pages9
JournalAnnals of Neurology
Volume72
Issue number4
DOIs
Publication statusPublished - Oct 2012

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Congenital Disorders of Glycosylation
Muscular Dystrophies
Epilepsy
Glycosylation
Mutation
Missense Mutation
Endoplasmic Reticulum
Dolichol Phosphates
Microcephaly
Muscle Hypotonia
Fatal Outcome
Metabolic Diseases
Mannose
Creatine Kinase
Fibroblasts
Immunohistochemistry
Phenotype
Lipids
Muscles
DNA

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Barone, R., Aiello, C., Race, V., Morava, E., Foulquier, F., Riemersma, M., ... Lefeber, D. J. (2012). DPM2-CDG: A muscular dystrophy-dystroglycanopathy syndrome with severe epilepsy. Annals of Neurology, 72(4), 550-558. https://doi.org/10.1002/ana.23632

DPM2-CDG : A muscular dystrophy-dystroglycanopathy syndrome with severe epilepsy. / 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.

In: Annals of Neurology, Vol. 72, No. 4, 10.2012, p. 550-558.

Research output: Contribution to journalArticle

Barone, R, Aiello, C, Race, V, Morava, E, Foulquier, F, Riemersma, M, Passarelli, C, Concolino, D, Carella, M, Santorelli, F, Vleugels, W, Mercuri, E, Garozzo, D, Sturiale, L, Messina, S, Jaeken, J, Fiumara, A, Wevers, RA, Bertini, E, Matthijs, G & Lefeber, DJ 2012, 'DPM2-CDG: A muscular dystrophy-dystroglycanopathy syndrome with severe epilepsy', Annals of Neurology, vol. 72, no. 4, pp. 550-558. https://doi.org/10.1002/ana.23632
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. / DPM2-CDG : A muscular dystrophy-dystroglycanopathy syndrome with severe epilepsy. In: Annals of Neurology. 2012 ; Vol. 72, No. 4. pp. 550-558.
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AU - Morava, Eva

AU - Foulquier, Francois

AU - Riemersma, Moniek

AU - Passarelli, Chiara

AU - Concolino, Daniela

AU - Carella, Massimo

AU - Santorelli, Filippo

AU - Vleugels, Wendy

AU - Mercuri, Eugenio

AU - Garozzo, Domenico

AU - Sturiale, Luisa

AU - Messina, Sonia

AU - Jaeken, Jaak

AU - Fiumara, Agata

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AU - Lefeber, Dirk J.

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