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

► BHMT expression is repressed in homocystinuric mice and induced by betaine. ► Homocystinuric mice exhibit a decreased biochemical response to betaine over time. ► Decreased efficacy of betaine was due at least in part, to reduced BHMT activity. ► Higher Hcy causes TNF-a, IL-1a induction and a hypercoagulative phenotype. ► There is a sharp threshold effect between Hcy and thrombotic risk in homocystinuria.