The natural history of vascular disease in homocystinuria and the effects of treatment

Among 40 patients with homocystinuria due to cystathionine beta-synthase deficiency diagnosed in the state of New South Wales, Australia (population 6 million) and followed long-term, there were 10 deaths at ages 2-30 years. Of these 8 were definite vascular deaths, one was a presumed vascular death, and the other was due to an accident and unrelated to homocystinuria. The vascular deaths were all early cases and only one patient, a pyridoxine-responsive 30-year-old woman, had been prescribed adequate treatment although it was uncertain that she was taking it. In 32 patients of mean age 30 years (range 9-66 years) there were 539 patient-years of treatment with pyridoxine, folic acid and hydroxocobalamin. There were 17 pyridoxine-responsive patients and all maintained plasma total free homocyst(e)ine levels <20 mu mol/L over an average treatment period of 16.6 years. The 15 nonresponsive patients received additionally 6-9 g of betaine daily. This resulted in a further 74% mean decline (+/- 14% SD) in plasma total free homocyst(e)ine, persisting during an average (post-betaine) treatment period of 11 years; current mean +/- SD levels are 33 +/- 17 mu mol/L (n = 15). There were two vascular events during treatment, one fatal pulmonary embolus (see above) and one myocardial infarction, whereas without treatment, 21 would have been expected, chi(2) = 14.22, p = 0.0001, relative risk 0.09 (95% CI 0.02 - 0.38). There were no events during 258 patient-years of treatment in the 15 pyridoxine-nonresponsive patients (p < 0.005 versus expected untreated). Nineteen patients had a total of 19 major and 15 minor operations requiring anaesthetic, and three had successful pregnancies, one whilst receiving betaine. There were no thromboembolic complications. We conclude that treatment which effectively lowers circulating homocyst(e)ine, even to suboptimal levels, markedly reduces cardiovascular risk in patients with cystathionine beta-synthase deficiency, and that betaine therapy contributes importantly to this in pyridoxine-nonresponsive patients. Betaine as additional therapy is safe and effective for at least 16 years. In 1985 Mudd and colleagues documented the natural history of homocystinuria based on an analysis of 629 patients with cystathionine beta-synthase (EC 4.2.1.22) deficiency. The data were provided by 113 physicians throughout the developed world and 14 authors contributed to this landmark study. The information was gathered in 1982 and early 1983 and defined outcomes in untreated patients. It was established that the usual cause of premature death was vascular disease and that thromboembolism was a major cause of morbidity. Thus the findings of that important study provide a basis upon which one can assess the effects of current treatment regimens on the occurrence of vascular events. This paper presents the vascular disease findings in homocystinuria due to cystathione beta-synthase deficiency seen while managing all patients identified with this disorder in the state of New South Wales, Australia. New South Wales has a population of 6 million.