Clinical and molecular features of three patients with congenital disorders of glycosylation type Ih (CDG-Ih) (ALG8 deficiency)

Congenital disorder of glycosylation type Ih (CDG-Ih) is caused by a defect in the dolichyl-P-Glc:Glc 1 Man 9 GlcNAc 2 -PP-dolichyl a1,3-glucosyltransferase (ALG8).Thus far, the only patient has been described with a relatively mild clinical picture.N We describe the molecular and clinical features of three patients from two families with an ALG8 deficiency.All three patients presented with severe, life-threatening multi organ failure and died within their first months of life.N Diagnosis of CDG-Ih was based on the accumulation of the lipid-linked oligosaccharyl intermediates dol-PP-GlcNAc 2 Man 9 and dol-PP-GlcNAc 2 Man 9 Glc 1 in patients' fibroblasts.Mutation analysis of the ALG8 gene identified in both families a compound heterozygosity for a splice site mutation and a missense mutation (family 1: c.96-2A.G and p.T47P; family 2: c.672+4A.G and p.G275D).The functional effect of the ALG8 splice mutations was analysed on mRNA and the effect of the missense mutations was assayed in ALG8 deficient yeast strains.N CDG-Ih patients present with severe hepato-intestinal problems, and the clinical spectrum ranges from mild to very severe, including neonatal death.Central nervous system defects have not been observed in the four known patients.