Missense mutations in the phosphomannomutase 2 gene of two Japanese siblings with carbohydrate-deficient glycoprotein syndrome type I.

Carbohydrate-deficient glycoprotein syndrome type I (CDG1) is an autosomal recessive disorder characterized by severe nervous system involvement and a carbohydrate moiety deficiency in N-linked glycoproteins. Clinical symptoms are psychomotor retardation, stroke-like episodes or hemorrhagic episodes, hepatic dysfunction, polyneuropathy, and cerebellar ataxia. Marked atrophy of the cerebellar hemispheres and pons is recognizable on CT scan or MRI. CDGI has been mapped to human chromosome 16p by linkage studies. Recently, missense mutations in the gene for phosphomannomutase (PMM2) have been detected in Caucasian patients with CDG1. We studied DNA mutations in PMM2 in a Japanese family with CDG1. DNA sequencing of PMM2 in the siblings showed missense mutations of maternal origin in exon 5 and of paternal origin in exon 8. No such mutations were detected in 50 unrelated healthy Japanese. These findings suggest that the PMM2 is responsible for CDG1 in the Japanese as well as in Caucasians, and CDG1 may be the diagnosis in OPCA of neonatal onset, more often than currently thought.