Vascular Outcome in Patients With Homocystinuria due to Cystathionine β-Synthase Deficiency Treated Chronically

Abstract

Abstract-An inborn error of metabolism, homocystinuria due to cystathionine ␤-synthase deficiency, results in markedly elevated levels of circulating homocysteine. Premature vascular events are the main life-threatening complication. Half of all untreated patients have a vascular event by 30 years of age. We performed a multicenter observational study to assess the effectiveness of long-term homocysteine-lowering treatment in reducing vascular risk in 158 patients. Vascular outcomes were analyzed and effectiveness of treatment in reducing vascular risk was evaluated by comparison of actual to predicted number of vascular events, with the use of historical controls from a landmark study of 629 untreated patients with cystathionine ␤-synthase deficiency. The 158 patients had a mean (range) age of 29.4 (4.5 to 70) years; 57 (36%) were more than 30 years old, and 10 (6%) were older than 50 years. There were 2822 patient-years of treatment, with an average of 17.9 years per patient. Plasma homocysteine levels were markedly reduced from pretreatment levels but usually remained moderately elevated. There were 17 vascular events in 12 patients at a mean (range) age of 42.5 (18 to 67) years: pulmonary embolism (nϭ3), myocardial infarction (nϭ2), deep venous thrombosis (nϭ5), cerebrovascular accident (nϭ3), transient ischemic attack (nϭ1), sagittal sinus thrombosis (nϭ1), and abdominal aortic aneurysm (nϭ2). Without treatment, 112 vascular events would have been expected, for a relative risk of 0.09 (95% CI 0.036 to 0.228; PϽ0.0001). Treatment regimens designed to lower plasma homocysteine significantly reduce cardiovascular risk in cystathionine ␤-synthase deficiency despite imperfect biochemical control. These findings may be relevant to the significance of mild hyperhomocysteinemia that is commonly found in patients with vascular disease.

Recombinant adeno-associated virus mediated gene transfer in a mouse model for homocystinuria

“…Most treated patients (even pyridoxine-responsive cases) have total homocysteine levels well above normal. These levels were several times higher in patients with CBS deficiency compared with the means for the respective normal population of each center (Yap et al, 2001). Therefore, effective and long-term treatments to reduce homocysteine levels in severe types of homocystinuria are needed, and gene therapy, which has not yet been studied, could provide a novel approach to treating the disease.…”

“…However, approximately 50% of patients are biochemically responsive to pharmacological doses of pyridoxine and the treatment must be continued throughout the individual's life (Mudd et al, 1985). A multi-center study that conducted long-term treatment to lower the markedly elevated plasma levels of homocysteine in patients showed unsatisfactory results (Yap et al, 2001). Most treated patients (even pyridoxine-responsive cases) have total homocysteine levels well above normal.…”

Micronutrient Vitamin Deficiencies and Cardiovascular Disease Risk: Advancing Current Understanding

“…C: B-vitamin deficiency can induce autoimmune dysfunction leading to deposition of immune complexes, dyslipidemia, atherosclerosis, and cardiovascular disease. Decreasing the plasma total homocysteine level by providing the cofactors for its metabolism (folic acid, vitamins B 6, and B 12 ) has been shown to reduce CVD risk [77,78]. In fact, it is proposed that for every 3 µmol/L decrease in serum homocysteine, there is a mean 16% reduction in CVD risk [79].…”

Associations of Thrombotic-Hemostatic Factors with Cardiovascular Disease~!2009-10-29~!2009-12-22~!2010-04-08~!

“…In addition, a population based cohort study in Canada and the United States demonstrated that folic acid fortification of food results in an improvement in stroke mortality [110]. Furthermore, Hcy lowering regimens significantly reduce CV risk in patients with cystathionine beta synthase deficiency despite imperfect biochemical control [111].…”