Wide clinical spectrum in ALG8-CDG: clues from molecular findings suggest an explanation for a milder phenotype in the first-described patient

BSTRACT 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.