Carbohydrate-deficient glycoprotein syndrome (CDGs) type I are genetic multisystem disorders characterized by abnormal cathodal isoforms of serum transferrin (increased di- and asialo-transferrin), and deficient phosphomannomutase (PMM) activity in the majority of patients.

We report here a novel CDGs variant with milder clinical phenotype and profound deficiency of phosphomannose isomerase (PMI) in fibroblasts.

BA was born at term from nonconsanguineous parents. At age 6 weeks he was hospitalized for recurrent vomiting and poor weight gain. Clinical examination showed lipodistrophy, modest hepatomegaly, and generalized hypotonia. Laboratory investigations revealed disturbed liver function (>ASAT, ALAT, ALP, bilirubin; < CHE, albumin), megaloblastic anemia, and reduced antithrombin III and TBG. Transferrin isoelectrofocusing showed a typical CDGs type I pattern. At 4 m, brain CT scan showed diffuse and marked white matter hypodensity with normal cerebellum.

Remarkably, when solid foods (vegetables, rice, meat, fruits) were added to exclusive breast feeding at age 4 m, the child stopped vomiting, started to gain weight, and normalized muscle tone within a few months. Laboratory abnormalities, serum transferrin isoelectrofocusing and neuroimaging paralleled the clinical course with complete normalization at age 10 m.

A deficiency of PMI (0.2 mU/mg protein; controls 8.0+2.0) was found in cultured fibroblasts, while PMM showed normal activity.

This child, with typical CDGs type I sialotransferrin pattern and profound PMI deficiency, showed a milder phenotype with predominant enterohepatic symptoms. A defect of PMI, which catalyzes the first step of mannose pathway, compromises protein N-glycosilation. However, we hypothesize that the higher mannose content of solid foods, compeared to human milk, was a very efficient therapy for this child. This would be due to the possibility of bypassing the PMI step and forming mannose 6-phosphate through the action of hexokinase directly by mannose from food or from the catabolism of endogenous glycoprotein.