Metabolic Profiling of Total Homocysteine and Related Compounds in Hyperhomocysteinemia: Utility and Limitations in Diagnosing the Cause of Puzzling Thrombophilia in a Family

  • Sally P. StablerEmail author
  • Mark Korson
  • Reena Jethva
  • Robert H. Allen
  • Jan P. Kraus
  • Elaine B. Spector
  • Conrad Wagner
  • S. Harvey Mudd
Research Report
Part of the JIMD Reports book series (JIMD, volume 11)


We describe a family illustrating the diagnostic difficulties occurring when pyridoxine-responsive cystathionine beta-synthase (CBS) deficiency presents with thrombotic disease without associated ocular, skeletal, or CNS abnormalities, a situation increasingly recognized. This family had several thromboembolic episodes in two generations with apparently inconstant elevations of plasma total homocysteine (tHcy). When taking (sometimes even low amounts) of pyridoxine, the affected family members had low-normal tHcy and normal values for cystathionine, methionine, and cysteine. Withdrawal of vitamin therapy was necessary before lower cystathionine, elevated methionine, and decreased cysteine became apparent, a pattern suggestive of CBS deficiency, leading to the finding that the affected members were each compound heterozygotes for CBS p.G307S and p.P49L. To assist more accurate diagnosis of adults presenting with thrombophilia found to have elevated tHcy, the patterns of methionine-related metabolites in CBS-deficient patients are compared in this article to those in patients with homocysteine remethylation defects, including inborn errors of folate or cobalamin metabolism, and untreated severe cobalamin or folate deficiency. Usually serum cystathionine is low in subjects with CBS deficiency and elevated in those with remethylation defects. S-Adenosylmethionine and S-adenosylhomocysteine are often markedly elevated in CBS deficiency when tHcy is above 100 umol/L. We conclude that there are likely other undiagnosed, highly B6-responsive adult patients with CBS deficiency, and that additional testing of cystathionine, total cysteine, methionine, and S-adenosylmethionine will be helpful in diagnosing them correctly and distinguishing CBS deficiency from remethylation defects.


Compound Heterozygote Pyridoxal Phosphate Methylmalonic Acid Case Family Cobalamin Deficiency 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.













Cystathionine B-synthase


Cystathionine gamma-lyase




Methionine adenosyltransferase






Methionine synthase


Methylenetetrahydrofolate reductase


Pyridoxal phosphate


S-adenosylhomocysteine hydrolase


Total Cysteine


Total homocysteine



We would like to acknowledge the expert technical assistance of Carla Ray, Linda Farb, and Bev Raab. Preparation of the manuscript was assisted by Theresa M. Martinez.


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Copyright information

© SSIEM and Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Sally P. Stabler
    • 1
    Email author
  • Mark Korson
    • 2
  • Reena Jethva
    • 3
  • Robert H. Allen
    • 1
  • Jan P. Kraus
    • 4
  • Elaine B. Spector
    • 4
  • Conrad Wagner
    • 5
  • S. Harvey Mudd
    • 6
  1. 1.Division of Hematology, Department of MedicineUniversity of Colorado School of MedicineAuroraUSA
  2. 2.Division of Genetics and Metabolism, Department of PediatricsTufts Medical CenterBostonUSA
  3. 3.Section of Neurology, Department of PediatricsSt. Christopher’s Hospital for ChildrenPhiladelphiaUSA
  4. 4.Department of PediatricsUniversity of Colorado School of MedicineAuroraUSA
  5. 5.Department of BiochemistryVanderbilt UniversityNashvilleUSA
  6. 6.Laboratory of Molecular BiologyNational Institute of Mental HealthBethesdaUSA

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