title: Defining the phenotype in congenital disorder of glycosylation due to ALG1 mutations.
abstract: Deficiency of β-1,4 mannosyltransferase (MT-1) congenital disorder of glycosylation (CDG), due to ALG1 gene mutations. Features in 9 patients reported previously consisted of prenatal growth retardation, pregnancy-induced maternal hypertension and fetal hydrops. Four patients died before 5 years of age, and survivors showed a severe psychomotor retardation. We report on 7 patients with psychomotor delay, microcephaly, strabismus and coagulation abnormalities, seizures and abnormal fat distribution. Four children had a stable clinical course, two had visual impairment, and 1 had hearing loss. Thrombotic and vascular events led to deterioration of the clinical outcome in 2 patients. Four novel ALG1 mutations were identified. Pathogenicity was determined in alg1 yeast mutants transformed with hALG1. Functional analyses showed all novel mutations representing hypomorphs associated with residual enzyme activity. We extend the phenotypic spectrum including the first description of deafness in MT1 deficiency, and report on mildly affected patients, surviving to adulthood. The dysmorphic features, including abnormal fat distribution and strabismus highly resemble CDG due to phosphomannomutase-2 deficiency (PMM2-CDG), the most common type of CDG. We suggest testing for ALG1 mutations in unsolved CDG patients with a type 1 transferrin isoelectric focusing pattern, especially with epilepsy, severe visual loss and hemorrhagic/thrombotic events.
authors.affiliation: Department of Pediatrics at the Institute for Genetic and Metabolic Diseases, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands. e.morava@cukz.umcn.nl
authors.forename: Eva
authors.initials: E
authors.lastname: Morava
authors.forename: Julia
authors.initials: J
authors.lastname: Vodopiutz
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Lefeber
authors.forename: Andreas R
authors.initials: AR
authors.lastname: Janecke
authors.forename: Wolfgang M
authors.initials: WM
authors.lastname: Schmidt
authors.forename: Silvia
authors.initials: S
authors.lastname: Lechner
authors.forename: Chike B
authors.initials: CB
authors.lastname: Item
authors.forename: Jolanta
authors.initials: J
authors.lastname: Sykut-Cegielska
authors.forename: Maciej
authors.initials: M
authors.lastname: Adamowicz
authors.forename: Jolanta
authors.initials: J
authors.lastname: Wierzba
authors.forename: Zong H
authors.initials: ZH
authors.lastname: Zhang
authors.forename: Ivana
authors.initials: I
authors.lastname: Mihalek
authors.forename: Sylvia
authors.initials: S
authors.lastname: Stockler
authors.forename: Olaf A
authors.initials: OA
authors.lastname: Bodamer
authors.forename: Ludwig
authors.initials: L
authors.lastname: Lehle
authors.forename: Ron A
authors.initials: RA
authors.lastname: Wevers
mesh_terms: D002648:Child; D002675:Child, Preschool; D018981:Congenital Disorders of Glycosylation / Q000175:diagnosis / Q000235:genetics*; D017809:Fatal Outcome; D005260:Female; D005819:Genetic Markers; D006801:Humans; D007223:Infant; D008297:Male; D008364:Mannosyltransferases / Q000172:deficiency / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D055815:Young Adult
chemical_list: D005819:Genetic Markers; D008364:Mannosyltransferases; C035777:chitobiosyldiphosphodolichol beta-mannosyltransferase