GDP-mannose: GlcNAc₂-PP-dolichol mannosyltransferase deficiency (CDG Ik): 5 new patients and 7 novel mutations

Thierry Dupré (1, 2) , Sandrine Vuillaumier-Barrot (1, 2) , Isabelle Chantret (2) , Hassane Sadou Yayé (1) , Christiane Le Bizec (1) , Alexandra Afenjar (3) , Cecilia Altuzarra (4) , Christine Barnérias (5, 6) , Lydie Burglen (3) , Pascale de Lonlay (7) , François Feillet (8) , Silvia Napuri (9) , Nathalie Seta (1) , Stuart E. H. Moore (2)

1 Service de biochimie hormonale, métabolique et génétique
2 CRB3 - Centre de recherche biomédicale Bichat-Beaujon
3 CHU Trousseau [APHP]
4 Service de pédiatrie [CHRU Besançon]
5 Service de neurologie pédiatrique [CHU Necker]
6 Centre de référence des maladies neuromusculaires
7 Service métabolisme
8 MaMEA Nancy-Brabois - Centre de référence des maladies héréditaires du métabolisme
9 Service d'Explorations Fonctionnelles Neurologiques

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 GDP-mannose: GlcNAc-PP-dolichol mannosyltransferase (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 5 new CDG Ik cases and compare these findings with those of the 5 previously described patients. Methods: LLO biosynthesis was examined in skin biopsy fibroblasts, mannosyltransferases were assayed in microsomes prepared from these cells, and -encoding MT-1 was sequenced at both the DNA and cDNA levels. Clinical data for the 5 new patients were collated. Results: Cells from 5 patients with non-typed CDG I revealed accumulations of GlcNAc-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 9 different mutations, 7 of which have not been previously reported. Clinical presentations are severe with CNS involvement and ocular disturbances being prevalent. Conclusions: CDG Ik presents at the severe end of the CDG I clinical spectrum, and in our experience, along with CDG Ib (MPI deficiency: OMIM 602579), is the second most frequently diagnosed CDG I after CDG Ia (PMM2 deficiency: OMIM 601785). Accordingly, we propose that CDG Ik should be given more consideration when diagnostic strategies are prioritised based on apparent CDG I subtype frequencies.

Mots clés: GDP-mannose: GlcNAc2-PP-dolichol mannosyltransferase (MT-1) deficiency; Congenital Disorders of Glycosylation type Ik (CDG Ik); protein N-glycosylation; ALG1-CDG

Thierry Dupré, Sandrine Vuillaumier-Barrot, Isabelle Chantret, Hassane Sadou Yayé, Christiane Le Bizec, et al.. GDP-mannose: GlcNAc₂-PP-dolichol mannosyltransferase deficiency (CDG Ik): 5 new patients and 7 novel mutations. Journal of Medical Genetics, 2010, 47 (11), pp.729. ⟨10.1136/jmg.2009.072504⟩. ⟨hal-00557371⟩