Congenital disorders of glycosylation – a second patient of CDG type Id deficiency: different clinical phenotype, molecular analysis and prenatal diagnosis

Congenital disorder of glycosylation type Id has been described so far in only a single patient. The disorder is caused by a defect of the first mannosyltransferase involved in N-glycan biosynthesis inside the endoplasmic reticulum. We have identified a second patient suffering from this type of CDG presenting with a different clinical phenotype resembling much more type Ie and not the previously described Id patient: our patient presented at birth with arthrogryposis multiplex congenita including bilateral club feet and several dysmorphic features. He developed epileptic seizures during his first year of life as well as secondary microcephaly, profound psychomotor retardation and severe vision impairment. The most distinctive clinically available difference to type Ie is a normal creatine phosphokinase (CK) in our patient while type Ie patients very often have elevated levels.

The molecular basis in this patient is a homozygous mutation in exon 1 of the ALG3 gene activating a cryptic splice site and resulting in the subsequent predominant formation of a truncated, presumably non-functional enzyme. We were able to offer prenatal diagnosis to this family in two subsequent pregnancies. The first fetus was affected but – most interestingly – showed at 19 weeks of gestation no obvious glycosylation abnormalities of transferrin in IEF and SDS-PAGE. Likewise, plasma proteins showed only minor signs of hypoglycosylation at this stage of pregnancy when compared to the living index patient. We propose that maternal or placental factors are partially compensating the glycosylation defect in the fetal stage.