An unusually high plasma concentration of homocysteine resulting from a combination of so-called "secondary" etiologies.

Abstract The metabolism of homocysteine is complex and involves many enzymes as well as vitamin-derived cofactors. Any dysregulation of this metabolism may lead to hyperhomocysteinemia (HHCy) which is responsible for many clinical disorders including thromboembolic events. HHCy may result from very different etiologies and is generally classified into three groups according to homocysteine concentrations: moderate ( 100 μmol/L). Major HHCy cases are generally due to monogenic defects of key enzymes involved in homocysteine metabolism, such as cystathionine-β-synthase or 5,10-methylene-tetrahydrofolate reductase, or to any defect in vitamin B12 absorption, transport or metabolism. By contrast, moderate and intermediate HHCy tend to result from so-called “secondary” etiologies (e.g. tobacco, drugs, alcohol, vitamin deficiencies or pathological contexts). Here we describe the case of a patient with an unusually high plasma homocysteine concentration (1562 μmol/L) which was only explained by a combination of such secondary etiologies, among them chronic renal failure, hypothyroidism, the homozygous C677T MTHFR variant, a novel heterozygous variant of the MSR gene, and a vitamin deficiency. In addition, this patient exhibited a spectacular decline in homocysteine concentrations (returning to normal) after betaine and vitamin administration. In conclusion, this case highlights that major HHCy may also result from the association of secondary etiologies, with vitamin deficiency as a triggering factor.