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

Betaine treatment of cystathionine β-synthase-deficient homocystinuria; does it work and can it be improved?

“…60 Possible metabolic adaption to long-term betaine treatment in HCU A recent 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 Hcy is significantly diminished over time. 7 One week of betaine treatment significantly lowered the observed mean plasma tHcy level compared to the untreated HO HCU mice (50.14 µM ± 16.4 versus 186.1 µM ± 32.3; P , 0.0001). In a 6-week betaine treatment group, there was an approximate doubling in plasma tHcy compared to the 1-week treatment group (117 µM ± 45.1 versus 50.14 µM ± 16.4; P = 0.0015).…”

“…In a 6-week betaine treatment group, there was an approximate doubling in plasma tHcy compared to the 1-week treatment group (117 µM ± 45.1 versus 50.14 µM ± 16.4; P = 0.0015). 7 The observed increase in plasma Hcy during prolonged betaine treatment was accompanied by a significant increase in the plasma levels of TNF-α and IL-1β and a reversion to a hypercoagulative phenotype. The findings of this analysis are consistent with a relatively sharp threshold effect between severely elevated plasma tHcy and thrombotic risk in HCU.…”

“…2,6 Interestingly, HCU does not exhibit elevated DMG 2 and recent research has indicated that this is due to the fact that untreated HCU results in marked repression of BHMT expression. 7 HCU, if untreated, is typically accompanied by marfanoid skeletal abnormalities, osteoporosis, ectopia lentis and/or severe myopia, cognitive impairment, and a dramatically increased incidence of atherosclerosis and thromboembolic disease. 6 In terms of the correlation between genotype and phenotype, there is a functional trichotomy in CBS mutations.…”

“…For example, Western blotting analysis has revealed that BHMT protein levels are significantly repressed in untreated HCU HO mice, but are significantly induced in the presence of betaine treatment. 7 The aforementioned reduction in the ability of betaine to lower plasma tHcy levels during long-term therapy with betaine poses the question as to how this metabolic adaption arises? Despite serving a fundamental metabolic role in cysteine synthesis, CBS is not ubiquitously expressed in all tissues and in the absence of transsulfuration, the methionine cycle is essentially regarded as a closed loop.…”

Vitamin B6 Deficiency, Genome Instability and Cancer

“…Nowadays, it is established that breast, pancreas, and gastrointestinal cancers are associated with a higher incidence of thrombosis (Nadja et al, 2012). With more advanced stages of cancer there is lower overall survival rate (Renga, 2011), but, also a greater risk of venous thromboembolism, what can additionally influences on the survival of patients (Maclean et al, 2012).…”