Sandrine Vuillaumier-Barrot1, Manuel Schiff2, Francesca Mattioli3, Elise Schaefer4, Audrey Dupont5, Julia Dancourt6, Thierry Dupré7, Alain Couvineau6, Hélène Ogier de Baulny2, Pascale de Lonlay8, Nathalie Seta7, Stuart Moore6, Isabelle Chantret6. 1. AP-HP, Hôpital Bichat, Biochimie, Paris, France. Sandrine.vuillaumier@aphp.fr. 2. APHP, Robert Debré Hospital, Reference Center for Inborn Errors of Metabolism, UMR1141, PROTECT, Université Paris Diderot, Sorbonne Paris Cité, Paris, France. 3. Institut de Génétique et de Biologie Moléculaire et Cellulaire, INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67400, Illkirch-Graffenstaden, France. 4. Service de Génétique Médicale, CHU de Hautepierre, avenue Molière, Institut de Génétique Médicale d'Alsace, 67098, Strasbourg, France. 5. Intensive Care Unit, CHU Lenval, 57 avenue de la Californie, 06200, Nice, France. 6. INSERM, U1149, Centre de Recherche sur l'Inflammation (CRI) and Université Paris 7 Denis Diderot, BP 416, 75018, Paris, France. 7. AP-HP, Hôpital Bichat, Biochimie, Paris, France. 8. AP-HP, Necker-Enfants Malades Hospital, Reference Center for Inborn Errors of Metabolism, metabERN, G2M, IMAGINE Institute, University Paris Descartes-Sorbonne Paris Cité, Paris, France.
Abstract
BACKGROUND: Congenital disorders of glycosylation (CDG) includes ALG8 deficiency, a protein N-glycosylation defect with a broad clinical spectrum. If most of the 15 previously reported patients present an early-onset multisystem severe disease and early death, three patients including the cas princeps, present long-term survival and less severe symptoms. METHODS: In order to further characterize ALG8-CDG, two new ALG8 patients are described and mRNA analyses of the ALG8-CDG cas princeps were effected. RESULTS: One new patient exhibited a hepato-intestinal and neurological phenotype with two novel variants (c.91A > C p.Thr31Pro; c.139dup p.Thr47Asnfs*12). The other new patient, homozygous for a known variant (c.845C > T p.Ala282Val), presented a neurological phenotype with epilepsy, intellectual disability and retinis pigmentosa. The cas princeps ALG8-CDG patient was reported to have two heterozygous frameshift variants predicted to be without activity. We now described a novel ALG8 transcript variant in this patient and the 3D model of the putative encoded protein reveals no major difference with that of the normal ALG8 protein. CONCLUSION: The description of the two new ALG8 patients affirms that ALG8-CDG is a severe disease. In the cas princeps, as the originally described frameshift variants are degraded, the novel variant is promoted and could explain a milder phenotype.
BACKGROUND: Congenital disorders of glycosylation (CDG) includes ALG8 deficiency, a protein N-glycosylation defect with a broad clinical spectrum. If most of the 15 previously reported patients present an early-onset multisystem severe disease and early death, three patients including the cas princeps, present long-term survival and less severe symptoms. METHODS: In order to further characterize ALG8-CDG, two new ALG8 patients are described and mRNA analyses of the ALG8-CDG cas princeps were effected. RESULTS: One new patient exhibited a hepato-intestinal and neurological phenotype with two novel variants (c.91A > C p.Thr31Pro; c.139dup p.Thr47Asnfs*12). The other new patient, homozygous for a known variant (c.845C > T p.Ala282Val), presented a neurological phenotype with epilepsy, intellectual disability and retinis pigmentosa. The cas princeps ALG8-CDG patient was reported to have two heterozygous frameshift variants predicted to be without activity. We now described a novel ALG8 transcript variant in this patient and the 3D model of the putative encoded protein reveals no major difference with that of the normal ALG8 protein. CONCLUSION: The description of the two new ALG8 patients affirms that ALG8-CDG is a severe disease. In the cas princeps, as the originally described frameshift variants are degraded, the novel variant is promoted and could explain a milder phenotype.
Authors: Daniah Albokhari; Bobby G Ng; Alis Guberinic; Earnest James Paul Daniel; Nicole M Engelhardt; Rita Barone; Agata Fiumara; Livia Garavelli; Gabriele Trimarchi; Lynne Wolfe; Kimiyo M Raymond; Eva Morava; Miao He; Hudson H Freeze; Christina Lam; Andrew C Edmondson Journal: J Inherit Metab Dis Date: 2022-06-30 Impact factor: 4.750