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

Abstract

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.

Take Home Message

Cystathionine is low in patients with cystathionine beta-synthase deficiency except during pregnancy when fetal exposure to high homocysteine results in fetal synthesis of cystathionine and transfer to the mother’s circulation, which may confound the specific diagnosis of hyperhomocysteinemia.

Contributions of Authors

Sally Stabler, Janet Thomas, and Renata Gallagher were responsible for planning the details in the manuscript. Sally Stabler and Robert Allen were involved in the conduct of the laboratory measures in the manuscript. Janet Thomas, Cynthia Freehauf, and Renata Gallagher were involved in the conduct of obtaining the clinical measures. Sally Stabler and Renata Gallagher wrote the bulk of the manuscript with contributions from the other authors.

Guarantor for Chapter

Sally P Stabler serves as the guarantor for this chapter, accepting full responsibility for the work. She had access to all the data and controlled the decision to publish.

Conflict of Interest

Sally Stabler and Robert Allen and the University of Colorado have competing interests because a company has been formed at the University of Colorado to assay homocysteine, methylmalonic acid, and cystathionine. Cynthia Freehauf, Janet Thomas, and Renata Gallagher declare that they have no conflict of interest.

Funding for Research

There was no funding for the research.

Informed Consent

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Written informed consent was obtained from all patients and their children for being included in the study.