title: DPM2-CDG: a muscular dystrophy-dystroglycanopathy syndrome with severe epilepsy.
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-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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Pediatric Neurology, Department of Pediatrics, University of Catania, Catania, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Barone
authors.forename: Chiara
authors.initials: C
authors.lastname: Aiello
authors.forename: Valérie
authors.initials: V
authors.lastname: Race
authors.forename: Eva
authors.initials: E
authors.lastname: Morava
authors.forename: Francois
authors.initials: F
authors.lastname: Foulquier
authors.forename: Moniek
authors.initials: M
authors.lastname: Riemersma
authors.forename: Chiara
authors.initials: C
authors.lastname: Passarelli
authors.forename: Daniela
authors.initials: D
authors.lastname: Concolino
authors.forename: Massimo
authors.initials: M
authors.lastname: Carella
authors.forename: Filippo
authors.initials: F
authors.lastname: Santorelli
authors.forename: Wendy
authors.initials: W
authors.lastname: Vleugels
authors.forename: Eugenio
authors.initials: E
authors.lastname: Mercuri
authors.forename: Domenico
authors.initials: D
authors.lastname: Garozzo
authors.forename: Luisa
authors.initials: L
authors.lastname: Sturiale
authors.forename: Sonia
authors.initials: S
authors.lastname: Messina
authors.forename: Jaak
authors.initials: J
authors.lastname: Jaeken
authors.forename: Agata
authors.initials: A
authors.lastname: Fiumara
authors.forename: Ron A
authors.initials: RA
authors.lastname: Wevers
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.forename: Gert
authors.initials: G
authors.lastname: Matthijs
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Lefeber
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D020147:Coagulation Protein Disorders / Q000235:genetics; D018981:Congenital Disorders of Glycosylation / Q000150:complications / Q000235:genetics*; D004252:DNA Mutational Analysis; D004351:Drug Resistance; D049030:Dystroglycans / Q000378:metabolism; D004576:Electromyography; D004721:Endoplasmic Reticulum; D004827:Epilepsy / Q000209:etiology / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D007223:Infant; D007525:Isoelectric Focusing; D008107:Liver Diseases / Q000150:complications / Q000235:genetics; D008297:Male; D008358:Mannose / Q000378:metabolism; D008364:Mannosyltransferases / Q000235:genetics*; D008831:Microcephaly / Q000235:genetics / Q000473:pathology; D008875:Middle Aged; D008969:Molecular Sequence Data; D009136:Muscular Dystrophies / Q000150:complications / Q000235:genetics*; D009154:Mutation / Q000235:genetics / Q000502:physiology; D020125:Mutation, Missense / Q000235:genetics / Q000502:physiology; D011247:Pregnancy; D014786:Vision Disorders / Q000235:genetics / Q000473:pathology; D055815:Young Adult
chemical_list: D049030:Dystroglycans; C115077:DPM2 protein, human; D008364:Mannosyltransferases; D008358:Mannose