Anders Helander1, Jaak Jaeken2, Gert Matthijs3, Gösta Eggertsen4. 1. Karolinska Institutet, Department of Laboratory Medicine, Stockholm, Sweden; Karolinska University Laboratory, Clinical Chemistry, Stockholm, Sweden. Electronic address: anders.helander@ki.se. 2. Center for Metabolic Disease, University Hospital Gasthuisberg, Leuven, Belgium. 3. Center for Human Genetics, University Hospital Gasthuisberg, Leuven, Belgium. 4. Karolinska Institutet, Department of Laboratory Medicine, Stockholm, Sweden; Karolinska University Laboratory, Clinical Chemistry, Stockholm, Sweden.
Abstract
CASE REPORT: In a routine company health check-up, a 32-year-old woman presented a highly elevated serum level of carbohydrate-deficient transferrin (CDT), a biomarker for excessive alcohol consumption. The test result (~17% disialotransferrin, reference interval <2.0%; ~3% asialotransferrin, reference 0%) was confirmed by analysis of a second sample, while another alcohol biomarker, phosphatidylethanol (PEth) in whole-blood, was negative. This suggested that her elevated CDT may be unrelated to heavy drinking. The abnormal "type-1" transferrin glycoform pattern indicated a defect in N-glycan assembly occurring in congenital disorders of glycosylation (CDG), a family of rare inherited metabolic disorders. Probing for the underlying enzyme defect(s) using cultured skin fibroblasts demonstrated normal activity of phosphomannomutase, whereas the activity of phosphomannose isomerase (MPI) was reduced (0.64 mU/mg protein, reference 2.1-6.9), pointing to CDG of the MPI subtype (formerly called CDG-Ib). The diagnosis was confirmed by sequence analysis of the MPI gene revealing a homozygous missense mutation (c.656G>A) causing replacement of arginine by glutamine (p.R219Q). However, the woman had never experienced any clinical manifestations associated with MPI-CDG. 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 and had a highly elevated CDT and no clinical symptoms. CONCLUSION: The finding of MPI-CDG adults without clinical manifestations suggests that this type of the disorder may be underdiagnosed. If asymptomatic MPI-CDG subjects undergo CDT screening, their highly elevated test results may be wrongly interpreted as caused by excessive alcohol consumption.
CASE REPORT: In a routine company health check-up, a 32-year-old woman presented a highly elevated serum level of carbohydrate-deficient transferrin (CDT), a biomarker for excessive alcohol consumption. The test result (~17% disialotransferrin, reference interval <2.0%; ~3% asialotransferrin, reference 0%) was confirmed by analysis of a second sample, while another alcohol biomarker, phosphatidylethanol (PEth) in whole-blood, was negative. This suggested that her elevated CDT may be unrelated to heavy drinking. The abnormal "type-1" transferrin glycoform pattern indicated a defect in N-glycan assembly occurring in congenital disorders of glycosylation (CDG), a family of rare inherited metabolic disorders. Probing for the underlying enzyme defect(s) using cultured skin fibroblasts demonstrated normal activity of phosphomannomutase, whereas the activity of phosphomannose isomerase (MPI) was reduced (0.64 mU/mg protein, reference 2.1-6.9), pointing to CDG of the MPI subtype (formerly called CDG-Ib). The diagnosis was confirmed by sequence analysis of the MPI gene revealing a homozygous missense mutation (c.656G>A) causing replacement of arginine by glutamine (p.R219Q). However, the woman had never experienced any clinical manifestations associated with MPI-CDG. 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 and had a highly elevated CDT and no clinical symptoms. CONCLUSION: The finding of MPI-CDG adults without clinical manifestations suggests that this type of the disorder may be underdiagnosed. If asymptomatic MPI-CDG subjects undergo CDT screening, their highly elevated test results may be wrongly interpreted as caused by excessive alcohol consumption.
Authors: Donald M Dougherty; Nathalie Hill-Kapturczak; Yuanyuan Liang; Tara E Karns; Sharon E Cates; Sarah L Lake; Jillian Mullen; John D Roache Journal: Drug Alcohol Depend Date: 2014-07-11 Impact factor: 4.492
Authors: Donald M Dougherty; Tara E Karns; Jillian Mullen; Yuanyuan Liang; Sarah L Lake; John D Roache; Nathalie Hill-Kapturczak Journal: Drug Alcohol Depend Date: 2014-12-31 Impact factor: 4.492
Authors: Megan S Kane; Mariska Davids; Christopher Adams; Lynne A Wolfe; Helen W Cheung; Andrea Gropman; Yan Huang; Bobby G Ng; Hudson H Freeze; David R Adams; William A Gahl; Cornelius F Boerkoel Journal: Am J Hum Genet Date: 2016-01-21 Impact factor: 11.025