P58

Hidden asymptomatic CDG cases may be mistaken for excessive alcohol consumption

Anders Helander1, Jaak Jaeken2, Gert Matthijs3, Gösta Eggertsen1,*

1Dept of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden, 2University Hospital Gasthuisberg, Center for Metabolic Disease, 3University Hospital Gasthuisberg, Center for Human Genetics, Leuven, Belgium

Introduction: An elevated serum level of carbohydrate-deficient transferrin (CDT) is used as a biomarker for detection and follow-up of chronic excessive alcohol use. Elevated CDT levels also appear in congenital disorders of glycosylation (CDG), a family of rare inherited glycosylation disorders usually diagnosed in early childhood.

Objectives: A 32-year-old woman presented a highly elevated CDT level (17%; reference <2%) in a routine company health check-up. Because there were no other indications of heavy drinking, and another alcohol biomarker, phosphatidylethanol (PEth), was negative, this triggered additional examinations to disclose the cause.

Methods: CDT was measured by HPLC and PEth by LC-MS/MS. Enzyme activities were determined in cultivated skin fibroblasts. Mutation analysis was performed by direct sequencing.

Results: The CDT by HPLC analysis revealed an abnormal “type-1” glycoform pattern, indicating a defect in N-glycan assembly of transferrin. Probing for the underlying enzyme defect(s) in skin fibroblasts demonstrated normal activity of phosphomannomutase whereas the phosphomannose isomerase (MPI) activity was reduced (0.64 mU/mg, reference 2.1-6.9), pointing to CDG of the MPI subtype (“CDG-Ib”), despite no present or former clinical manifestations. Sequence analysis of the MPI gene revealed a homozygous missense mutation (c.656G>A), causing replacement of arginine by glutamine (p.R219Q).
Family investigation demonstrated that both parents, being distant relatives, were heterozygous mutation carriers with normal CDT values. Two of three siblings were not affected, whereas one brother was also homozygous for c.656G>A, had a highly elevated CDT level and no clinical symptoms.

Conclusion: The finding of CDG adults without typical clinical manifestations suggests that this type of the disorder may be underdiagnosed. If asymptomatic CDG subjects undergo CDT screening, for example as a pre-employment test, their highly elevated test results may wrongly be interpreted as caused by excessive alcohol consumption.

Keywords: Biomarker, Blood, Inborn error of metabolism