title: Asymptomatic phosphomannose isomerase deficiency (MPI-CDG) initially mistaken for excessive alcohol consumption.
abstract: METHODS
  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.
  
  
  CONCLUSIONS
  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: Karolinska Institutet, Department of Laboratory Medicine, Stockholm, Sweden; Karolinska University Laboratory, Clinical Chemistry, Stockholm, Sweden. Electronic address: anders.helander@ki.se.
authors: Anders
authors: A
authors: Helander
authors: Center for Metabolic Disease, University Hospital Gasthuisberg, Leuven, Belgium.
authors: Jaak
authors: J
authors: Jaeken
authors: Center for Human Genetics, University Hospital Gasthuisberg, Leuven, Belgium.
authors: Gert
authors: G
authors: Matthijs
authors: Karolinska Institutet, Department of Laboratory Medicine, Stockholm, Sweden; Karolinska University Laboratory, Clinical Chemistry, Stockholm, Sweden.
authors: Gösta
authors: G
authors: Eggertsen
mesh_terms: D000328:Adult; D000437:Alcoholism / Q000175:diagnosis* / Q000378:metabolism; D015415:Biomarkers / Q000032:analysis*; D018981:Congenital Disorders of Glycosylation / Q000097:blood / Q000175:diagnosis; D004247:DNA / Q000235:genetics; D005189:False Positive Reactions; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008359:Mannose-6-Phosphate Isomerase / Q000172:deficiency* / Q000235:genetics; D009154:Mutation / Q000235:genetics; D014168:Transferrin / Q000031:analogs & derivatives* / Q000032:analysis
chemical_list: D015415:Biomarkers; D014168:Transferrin; C056759:carbohydrate-deficient transferrin; D004247:DNA; D008359:Mannose-6-Phosphate Isomerase
keywords: Alcohol biomarkers; Carbohydrate-deficient transferrin (CDT); Congenital disorder of glycosylation (CDG); Human transferrin; Phosphomannose isomerase (MPI)