Article Text

This article has a correction. Please see:

other Versions

PDF
Guanosine diphosphate-mannose:GlcNAc2-PP-dolichol mannosyltransferase deficiency (congenital disorders of glycosylation type Ik): five new patients and seven novel mutations
  1. T Dupré1,2,3,
  2. S Vuillaumier-Barrot1,2,3,
  3. I Chantret2,3,
  4. H S Yayé1,
  5. C Le Bizec1,
  6. A Afenjar4,
  7. C Altuzarra5,
  8. C Barnérias6,
  9. L Burglen7,
  10. P de Lonlay8,9,
  11. F Feillet10,
  12. S Napuri11,
  13. N Seta1,8,
  14. S E H Moore2,3
  1. 1Biochimie Métabolique et Cellulaire, Hôpital Bichat-Claude Bernard, AP-HP, Paris, France
  2. 2INSERM U773 CRB3, Paris, France
  3. 3Université Denis Diderot Paris 7, Paris, France
  4. 4Service de Neuropédiatrie et Pathologie du Développement, Hôpital Armand Trousseau, AP-HP, Paris, France
  5. 5Service de Pédiatrie, Hôpital Saint Jacques, Besançon, France
  6. 6Service de Neuropédiatrie and Centre de Référence des Maladies Neuromusculaires, Hôpital Necker—Enfants Malades, AP-HP, Paris, France
  7. 7Service de Génétique, Génétique Clinique-Neurogénétique, Hôpital Armand Trousseau, AP-HP, Paris, France
  8. 8Université Paris Descartes, Paris, France
  9. 9Département de Pédiatrie, Hôpital Necker—Enfants Malades, AP-HP, Paris, France
  10. 10Centre de Référence des Maladies Héréditaires du Métabolisme CHU Brabois Enfant, Vandoeuvre les Nancy, France
  11. 11Service: Explorations Fonctionnelles Neurologiques Hôpital Sud-Rennes , RENNES, France
  1. Correspondence to Dr Thierry Dupré, Laboratoire Biochimie A, INSERM, 3ème étage de la tour, 46 rue Henri Huchard, 75018 Paris, France; thierry.dupre{at}bch.aphp.fr

Abstract

Background In type I congenital disorders of glycosylation (CDG I), proteins necessary for the biosynthesis of the lipid-linked oligosaccharide (LLO) required for protein N-glycosylation are defective. A deficiency in guanosine diphosphate-mannose:GlcNAc2-PP-dolichol mannosyltransferase-1 (MT-1) causes CDG Ik (OMIM 608540), and only five patients, with severe multisystemic clinical presentations, have been described with this disease.

Objective To characterise genetic, biochemical and clinical data in five new CDG Ik cases and compare these findings with those of the five previously described patients.

Methods LLO biosynthesis was examined in skin biopsy fibroblasts, mannosyltransferases were assayed in microsomes prepared from these cells, and ALG1-encoding MT-1 was sequenced at the DNA and complementary DNA levels. Clinical data for the five new patients were collated.

Results Cells from five patients with non-typed CDG I revealed accumulations of GlcNAc2-PP-dolichol, the second intermediate in the biosynthesis of LLO. Assay of MT-1, -2 and -3, the first three mannosyltransferases required for extension of this intermediate, demonstrated only MT-1 to be deficient. DNA sequencing of ALG1 revealed nine different mutations, seven of which have not been previously reported. Clinical presentations are severe, with dysmorphias, CNS involvement and ocular disturbances being prevalent.

Conclusions 5 patients with CDG Ik are described, and their identification reveals that in France, this disease and CDG Ib (mannose phosphate isomerase deficiency: OMIM 602579) are the most frequently diagnosed CDG I after CDG Ia (phosphomannomutase 2 deficiency: OMIM 601785) and substantiate previous observations indicating that this disease presents at the severe end of the CDG I clinical spectrum.

  • GDP-mannose:GlcNAc2-PP-dolichol mannosyltransferase (MT-1) deficiency
  • congenital disorders of glycosylation type Ik (CDG Ik)
  • protein N-glycosylation
  • ALG1-CDG
  • diagnostics
  • metabolic disorders
  • molecular genetics

Statistics from Altmetric.com

Footnotes

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Linked Articles

  • Corrections
    BMJ Publishing Group Ltd