Long-term betaine therapy in a murine model of cystathionine beta-synthase deficient homocystinuria: decreased efficacy over time reveals a significant threshold effect between elevated homocysteine and thrombotic risk

Mol Genet Metab. 2012 Mar;105(3):395-403. doi: 10.1016/j.ymgme.2011.11.190. Epub 2011 Dec 2.


Classical homocystinuria (HCU) is caused by deficiency of cystathionine β-synthase and is characterized by connective tissue disturbances, mental retardation and cardiovascular disease. Treatment for pyridoxine non-responsive HCU typically involves lowering homocysteine levels with a methionine-restricted diet and dietary supplementation with betaine. Compliance with the methionine-restricted diet is difficult and often poor. Investigating optimization of the efficacy of long-term betaine treatment in isolation from a methionine-restricted diet is precluded by ethical considerations regarding patient risk. The HO mouse model of HCU developed in our laboratory, exhibits constitutive expression of multiple pro-inflammatory cytokines and a hypercoagulative phenotype both of which respond to short-term betaine treatment. Investigation of the effects of long-term betaine treatment in the absence of methionine-restriction in HO HCU mice revealed that the ability of betaine treatment to lower homocysteine diminished significantly over time. Plasma metabolite analysis indicated that this effect was due at least in part, to reduced betaine-homocysteine S-methyltransferase (BHMT) mediated remethylation of homocysteine. Western blotting analysis revealed that BHMT protein levels are significantly repressed in untreated HCU mice but are significantly induced in the presence of betaine treatment. The observed increase in plasma homocysteine during prolonged betaine treatment was accompanied by a significant increase in the plasma levels of TNF-alpha and IL-1beta and reversion to a hypercoagulative phenotype. Our findings are consistent with a relatively sharp threshold effect between severely elevated plasma homocysteine and thrombotic risk in HCU and indicate that the HO mouse model can serve as a useful tool for both testing novel treatment strategies and examining the optimal timing and dosing of betaine treatment with a view toward optimizing clinical outcome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Betaine / administration & dosage
  • Betaine / pharmacology
  • Betaine / therapeutic use*
  • Betaine-Homocysteine S-Methyltransferase / biosynthesis*
  • Betaine-Homocysteine S-Methyltransferase / metabolism
  • Blood Coagulation
  • Cystathionine beta-Synthase / deficiency
  • Cystathionine beta-Synthase / metabolism*
  • Diet
  • Dietary Supplements
  • Disease Models, Animal
  • Homocysteine / blood*
  • Homocysteine / metabolism
  • Homocystinuria / blood
  • Homocystinuria / drug therapy*
  • Homocystinuria / genetics
  • Interleukin-1beta / blood
  • Male
  • Methionine
  • Methylation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Thrombosis / etiology*
  • Tumor Necrosis Factor-alpha / blood


  • Interleukin-1beta
  • Tumor Necrosis Factor-alpha
  • Homocysteine
  • Betaine
  • Methionine
  • Betaine-Homocysteine S-Methyltransferase
  • Cystathionine beta-Synthase