Potential Misdiagnosis of Hyperhomocysteinemia due to Cystathionine Beta-Synthase Deficiency During Pregnancy

  • Sally P. Stabler
  • Cynthia Freehauf
  • Robert H. Allen
  • Janet Thomas
  • Renata Gallagher
Research Report
Part of the JIMD Reports book series (JIMD, volume 37)


Extreme hyperhomocysteinemia with low cystathionine and cysteine is virtually diagnostic of cystathionine beta-synthase (CBS) deficiency since remethylation defects and hypermethioninemia due to other inborn errors cause elevated serum cystathionine. However, a pregnant CBS deficient patient was found to have elevated cystathionine in addition to elevated total homocysteine and methionine at 23 weeks of gestation and post-delivery cystathionine decreased to the lower level of normal. A second patient with cystathionine values during gestation also showed a rise from the low pre-pregnant value to massive elevation by delivery. Her infant had severe hyperhomocysteinemia in cord blood with a massive elevation of cystathionine, S-adenosylmethionine, and S-adenosylhomocysteine. The infant corrected her homocysteine value by 2 months and is not affected. This data demonstrates that the fetus when exposed to high homocysteine and methionine has increased synthesis of cystathionine which cannot be cleared because the fetus lacks cystathionine gamma-lyase, and thus cystathionine is returned to the mother’s circulation. This situation could lead to a misdiagnosis of the cause of hyperhomocysteinemia in a previously undiagnosed pregnant CBS deficient patient. Assays combining homocysteine with cystathionine measurements are commonly available from commercial laboratories in the USA. The recognition of CBS deficiency vs. remethylation disorders is important in order to maximize treatment. The cord blood values revealed a major disturbance in methionine metabolism including a potential for impaired transmethylation reactions in the fetus due to the buildup of S-adenosylhomocysteine. It is possible that monitoring maternal cystathionine during gestation could provide another measure of fetal exposure to homocysteine.


Betaine Cavernous sinus thrombosis Cysteine Homocysteine Methionine 



We thank the late S. Harvey Mudd for helpful discussions about the metabolite values, Linda Farb and Carla Ray, the Professional Research Assistants who performed the biochemical assays, and Theresa Martinez for expert administrative support. We thank our colleague David Manchester for the evaluation and referral of patient 1.


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Copyright information

© SSIEM and Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Sally P. Stabler
    • 1
  • Cynthia Freehauf
    • 2
  • Robert H. Allen
    • 1
  • Janet Thomas
    • 2
  • Renata Gallagher
    • 3
  1. 1.Division of Hematology, Department of MedicineUniversity of Colorado School of MedicineAuroraUSA
  2. 2.Department of PediatricsUniversity of Colorado School of MedicineAuroraUSA
  3. 3.Department of PediatricsUniversity of California at San FranciscoSan FranciscoUSA

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