Defining the phenotype in congenital disorder of glycosylation due to ALG1 mutations

Eva Morava, Julia Vodopiutz, Dirk J. Lefeber, Andreas R. Janecke, Wolfgang M. Schmidt, Silvia Lechner, Chike B. Item, Jolanta Sykut-Cegielska, Maciej Adamowicz, Jolanta Wierzba, Zong H. Zhang, Ivana Mihalek, Sylvia Stockler, Olaf A. Bodamer, Ludwig Lehle, Ron A. Wevers

Research output: Contribution to journalArticle

24 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)e1034-e1039
JournalPediatrics
Volume130
Issue number4
DOIs
StatePublished - Oct 2012

Keywords

  • β-1,4 mannosyltransferase
  • CDG-Ik
  • Microcephaly
  • Seizures
  • Short chain lipid-linked oligosaccharides

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Arts and Humanities (miscellaneous)

Fingerprint Dive into the research topics of 'Defining the phenotype in congenital disorder of glycosylation due to ALG1 mutations'. Together they form a unique fingerprint.

  • Cite this

    Morava, E., Vodopiutz, J., Lefeber, D. J., Janecke, A. R., Schmidt, W. M., Lechner, S., Item, C. B., Sykut-Cegielska, J., Adamowicz, M., Wierzba, J., Zhang, Z. H., Mihalek, I., Stockler, S., Bodamer, O. A., Lehle, L., & Wevers, R. A. (2012). Defining the phenotype in congenital disorder of glycosylation due to ALG1 mutations. Pediatrics, 130(4), e1034-e1039. https://doi.org/10.1542/peds.2011-2711