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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:2080.)
© 2001 American Heart Association, Inc.

Thrombosis

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

A Multicenter Observational Study

Sufin Yap; Godfried H.J. Boers; Bridget Wilcken; David E.L. Wilcken; David P. Brenton; Philip J. Lee; John H. Walter; Pamela M. Howard; Eileen R. Naughten

From the National Center for Inherited Metabolic Disorders (S.Y., P.M.H., E.R.N.), The Children’s Hospital, Dublin, Ireland; Department of General Internal Medicine (G.H.J.B.), University Hospital Nijmegen, The Netherlands; The Children’s Hospital at Westmead (B.W.), Sydney, Australia; University of New South Wales (D.E.L.W.), Department of Cardiovascular Medicine, Prince of Wales Hospital, Randwick, Sydney, Australia; Postgraduate Center (D.P.B.), Middlesex Hospital, London, UK; The National Hospital for Neurology and Neurosurgery (P.J.L.), London, UK; and Willink Biochemical Genetics Unit (J.H.W.), Royal Manchester Children’s Hospital, Manchester, UK.

Correspondence to Eileen R. Naughten. National Center for Inherited Metabolic Disorders, The Children’s Hospital, Temple Street, Dublin 1, Ireland. E-mail tchmeta{at}indigo.ie

	Abstract

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An inborn error of metabolism, homocystinuria due to cystathionine ß-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 ß-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 (n=3), myocardial infarction (n=2), deep venous thrombosis (n=5), cerebrovascular accident (n=3), transient ischemic attack (n=1), sagittal sinus thrombosis (n=1), and abdominal aortic aneurysm (n=2). Without treatment, 112 vascular events would have been expected, for a relative risk of 0.09 (95% CI 0.036 to 0.228; P<0.0001). Treatment regimens designed to lower plasma homocysteine significantly reduce cardiovascular risk in cystathionine ß-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.

Key Words: homocysteine • cardiovascular disease • cystathionine beta-synthase deficiency • risk factors

	Introduction

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The association between modest elevations of circulating homocysteine and coronary artery disease, first shown in 1976¹ and subsequently confirmed for vascular disease generally in many studies,² arose from observations in patients with the inborn error of homocystinuria due to cystathionine ß-synthase deficiency (CßS). This is a recessively inherited disorder of the transsulfuration pathway of methionine metabolism. Homocystinuria was first recognized in 1962^3,4 and the enzyme defect identified 2 years later.⁵ The worldwide birth prevalence based on newborn screening has been reported at 1 in 344 000, a minimal incidence because cases are known to be missed by such screening.⁶ There is a much higher birth prevalence in Ireland, estimated at 1 in 65 000, derived from both newborn screening and clinically detected cases,⁷ and in New South Wales, Australia.⁸ CßS deficiency is characterized biochemically by severe hyperhomocysteinemia, hypermethioninemia, and hypocysteinemia. The pathological sequelae include ectopia lentis, osteoporosis, mental retardation, and most importantly, a greatly increased risk of vascular events.

Approximately 50% of patients worldwide are biochemically responsive to pharmacological doses of pyridoxine.⁹ Since 1967, many patients have been treated by dietary methionine restriction, pyridoxine (vitamin B₆) in combination with folate, and sometimes vitamin B₁₂. Since the 1980s, betaine has been used to remethylate homocysteine back to methionine.¹⁰ Early anecdotal reports showed that these regimens result in some biochemical control and might prevent or delay clinical complications.^11–13

In 1985, an international study by Mudd and colleagues⁹ documented the natural history of CßS deficiency in 629 patients by time-to-event analyses for patients before treatment. It showed that by age 10 years, 70% had dislocated lenses; by age 15 years, 50% had radiographically detected spinal osteoporosis; and by age 30 years, there was a mortality rate of 23% in B₆-nonresponsive patients and 4% in B₆-responsive patients. There was a 30% chance of a vascular event before the age of 20 years, which increased to 50% by the age of 30 years. Beyond 10 years of age, there was 1 vascular event per 25 years, and the event incident rate was constant. This study thus established baselines for the evaluation of the effect of treatment and provided suggestive evidence for benefit.⁹

There is now evidence that early treatment delays or prevents ectopia lentis.^9,14,15 The effects of long-term treatment on vascular outcome have been reported in a single-center study that identified a significant benefit from homocysteine-lowering therapy.¹⁶ The findings were similar when patients from 2 additional centers were studied.¹⁷ However, the total number of patients assessed was still comparatively small, and premature vascular events remain the most life-threatening complication in untreated patients. The aims of the present international multicenter study were to definitively document vascular outcomes in relation to biochemical control in a large group of patients and to explore the effect of homocysteine-lowering treatment on cardiovascular risk. The findings could also shed light on the significance of the modest homocysteine elevation commonly found in the general vascular disease population.

	Methods

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Study Population
Five centers, in Ireland, Australia, The Netherlands, and the United Kingdom, had a total of 158 patients with CßS deficiency who had been treated chronically (Table 1). The diagnostic criteria for CßS deficiency in these patients have been published previously.^14–19 Pyridoxine-responsive patients were those whose total free plasma homocysteine level was reduced to <20 µmol/L with pyridoxine treatment (see below).¹⁶

View this table: [in this window] [in a new window]   Table 1. Demographics of Patients With CßS Deficiency Treated in Sydney, Nijmegen, Dublin, Manchester, and London

Treatment Regimens
Three main treatment regimens were used by all centers with minor modifications (Table 2). First, therapeutic doses of pyridoxine were given in combination with folate. Worldwide, 50% of CßS patients are B₆ responsive; however, the Irish population is predominately B₆ nonresponsive because of the "Celtic mutation," G307S.²⁰ Adequate response to B₆ may be masked in the presence of inadequate folate and B_12.²¹ If response to B₆ was inadequate, dietary methionine restriction was attempted. Although B₆ nonresponsive, pyridoxine was continued to be given to many of these patients because of reports of its beneficial effects in such cases.^10,22–24 The third therapeutic option was the use of betaine, a methyl donor, to remethylate homocysteine back to methionine, mainly in patients who were B₆ nonresponsive.^10,15,16 Specific treatment regimens for each center have been published previously.^14–19

View this table: [in this window] [in a new window]   Table 2. Treatment Regimens, Biochemical Criteria for B6 Responsiveness, Biochemical Markers Used in Monitoring, and the Frequency of Monitoring in Each Respective Center Treating Patients With CßS Deficiency

Biochemical Markers
Methods for the measurement of plasma amino acids in each center have been reported.^14–19 Homocysteine exists in several forms in plasma, with a protein-bound and a non–protein-bound (free) fraction. Total homocysteine (tHcy) includes all homocysteine species, both protein bound and free. Total free homocysteine (tfHcy) is the non–protein-bound fraction, which is calculated as twice the concentration of free homocystine (the homocysteine-homocysteine disulfide) plus the concentration of homocysteine-cysteine mixed disulfide. Homocystine (Hcy-Hcy) is the non–protein-bound (free) homocystine, the disulfide. To monitor biochemical control, the centers in Sydney and Nijmegen have used tfHcy.^16,18 Dublin, Manchester, and London have used homocystine.^14,15,19 Recently, some centers have started to use tHcy (Table 3). Plasma homocystine (Hcy-Hcy) is not detectable in the normal population. The mean±SD value for tfHcy in the normal Australian population is 3.7±1 µmol/L.²⁵ The mean±SD value for tfHcy in the normal Dutch population is 3.3±1.3 µmol/L,²⁶ whereas the upper limit of normal for tHcy is 19 µmol/L.²⁷ The upper limit of tHcy for the normal Irish and New South Wales populations is 15 µmol/L.

View this table: [in this window] [in a new window]   Table 3. Patient-Years of Treatment, Predicted and Actual Number of Vascular Events, and the Biochemical Control of CßS-Deficient Patients Treated in the Respective Centers

Study Procedure
Patient records were analyzed for age at diagnosis, mode of diagnosis, B₆ responsiveness, treatment regimens, period of treatment for each regimen, and frequency of biochemical monitoring. For vascular events, the frequency, age of occurrence, and type were identified. All vascular events were diagnosed by appropriate contemporary diagnostic methods used by the respective teaching hospitals at the time of the events. The study period was until the end of 1998, and the current age of each patient was taken as of December 31, 1998. The period of treatment was calculated and expressed as patient-years of treatment. For biochemical control, the homocyst(e)ine level was expressed as mean±SD for patient groups attending each of the centers and was compared with the mean±SD for the respective normal population. The total number of expected vascular events if the study population had remained untreated was derived from the data of Mudd and colleagues.⁹ Data were analyzed for each individual center with a final calculation from the pooled data.

Statistical Analysis
All statistical analyses were performed in collaboration with a medical statistician using SAS version 6.12 data analysis software. Two-tailed significance tests and the conventional level of significance (P<0.05) were used. The number of actual events related to the number of patient-years of treatment was compared with the expected number of events from Mudd and colleagues⁹ based on the same number of patient-years. The odds ratios from each of the 2x2 contingency tables for the different countries were combined by the Mantel-Haenszel procedure to give an estimate of the common ratio. The probability values quoted are based on ² values from analysis of the individual contingency tables. The Breslow-Day test for homogeneity of the odds ratios was also performed. This statistical approach tests the hypothesis that odds ratios for the various centers are not different.

	Results

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Demographics of the Study Population
Until the end of 1998, a total of 158 patients with CßS deficiency (45% B₆ responsive) at the 5 centers had been treated and followed up for a mean of 17.9 years. The mean age was 29.4 years, with a range of 4.5 to 70 years. Only 3% were younger than 10 years of age, with 36% older than 30 years and 6.3% older than 50 years. The Irish group was younger, with a comparable mean period of treatment, because of Ireland’s national newborn screening program for homocystinuria (n=21). Approximately one third of the patients (n=11) attending Manchester were also detected through newborn screening. (See Table 1.)

Treatment Regimens and Biochemical Monitoring
All 5 centers used recognized treatment regimens with minor modifications, as outlined in Table 2. Biochemical markers used for monitoring differed slightly among centers (Table 2). The frequencies of monitoring were similar except that the Irish group was monitored more often to avoid nutritional deficiency while trying to achieve good biochemical control in a group of patients who were predominantly in a growth period. Pretreatment plasma free homocystine levels were between 11 and 187 µmol/L (Dublin, London, and Manchester), and plasma tfHcy levels were between 42 and 266 µmol/L (Sydney and Nijmegen), which equates to tHcy levels well in excess of 150 µmol/L. tHcy measurements were not available at the time.

Patient-Years of Treatment, Vascular Risk, and Biochemical Control
The 158 patients studied had a total of 2821.6 patient-years of treatment (Table 3). There were 1243.8 patient-years of treatment in the B₆ responders and a further 1577.8 patient-years of treatment in the B₆ nonresponders. As 1 vascular event per 25 years was expected, in 2821.6 patient-years at least 112 vascular events would have occurred if these patients had remained untreated.⁹ Instead, only 17 vascular events occurred in 12 patients who were undergoing treatment. This difference is highly significant (relative risk 0.09, 95% CI 0.036 to 0.228; P<0.0001). Statistical analyses were repeated that used only the first vascular event in each patient, and the results were not different from that including all vascular events (relative risk 0.09, 95% CI 0.036 to 0.228; P<0.0001); indeed, it was more significant for the London center (relative risk 0.1243, 95% CI 0.043 to 0.353; P<0.0001). These events occurred at a mean (range) age of 42.5 (18 to 67) years. There was also no evidence of nonhomogeneity in the vascular outcomes of each center (P=0.156) despite the slightly different combinations of treatment regimens used by the 5 centers.

The documented vascular events were pulmonary embolism (n=3), myocardial infarction (n=2), abdominal aortic aneurysm (n=2), transient ischemic attack (n=1), sagittal sinus thrombosis (n=1), deep venous thrombosis (n=5), and cerebrovascular accident (n=3). One B₆-nonresponsive patient had 2 episodes of deep vein thrombosis at 21 and 24 years, respectively. Another patient, who was B₆ responsive, had 3 cerebrovascular accidents and 2 episodes of deep vein thrombosis in her 60s. Of the 17 vascular events, 12 occurred in 8 B₆ responders at a mean (range) age of 51.6 (25 to 67) years and another 5 in 4 B₆ nonresponders at a younger mean (range) age of 20.6 (18 to 24) years. There were 5 vascular deaths resulting from the above events, 2 in B₆ responders at ages 30 (pulmonary embolism, Sydney) and 43 (myocardial infarction, Nijmegen) years. The remaining 3 were among B₆ nonresponders at ages 18 and 21 (pulmonary embolisms, Manchester) and 19 years (sagittal sinus thrombosis, Manchester). Postmortem examinations were performed on these deaths where the diagnoses were not defined clinically before death.

Biochemical control was expressed as the mean (±SD) level of plasma homocysteine measured during long-term treatment. These levels were several times higher than the mean for the respective normal population of each center, despite the aim of achieving normal levels.

The patient-years of treatment were calculated separately for B₆ responders and nonresponders. In the total of 825 patient-years of betaine treatment, there were no reports of significant side effects. The longest period of betaine treatment was 17 years.

	Discussion

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The immediate aim of treatment in CßS deficiency is to control biochemically and, if possible, normalize the severe hyperhomocysteinemia characteristically associated with the condition, with the hope that the development of recognized complications of untreated homocystinuria, in particular life-threatening vascular events, can be prevented. The purpose of this study was to determine the effects of long-term treatment on the vascular risk of patients with CßS deficiency. A randomized controlled trial never seemed feasible because of a widespread belief, based on early reports, that lowering homocysteine levels had a beneficial effect.^11–13 Additionally, the time course of the disease is long and the disease itself is uncommon, so that numbers in any study would be necessarily small. To gather sufficient data, we studied patients from 5 centers treating CßS deficiency, comparing the findings with those in the study on the natural history by Mudd and colleagues.⁹

Our study provides the first overview of vascular outcome in a large number of patients treated chronically. It confirms and amplifies the findings of an earlier, smaller study.¹⁶ The risk reduction we observed is highly significant (P<0.0001) compared with the expected vascular events in untreated patients for a similar period. Despite all 5 centers having slightly different combinations of treatment regimens, there was no evidence of nonhomogeneity in the vascular outcomes of each center. Of the 17 vascular events that occurred, 9 were venous, 5 were arterial (including 2 myocardial infarctions), and cerebrovascular accidents accounted for another 3. This distribution is not dissimilar from that of untreated patients.⁹ There were only 5 vascular deaths during the treatment period, consistent with a lower mortality rate than that of untreated patients.⁹ The B₆-nonresponsive patients were younger at the time of their vascular event than were the B₆-responsive patients, and this may have been because their mean posttreatment homocyst(e)ine levels were higher (Table 3), and consistent compliance with the required regimen was more difficult.

Although our study shows that patients with CßS deficiency treated with various combinations of low-methionine diet, pyridoxine, folic acid, vitamin B₁₂, and betaine have much improved vascular outcome, it is not clear whether this results entirely from lowering the extremely high pretreatment levels of homocysteine or from some other aspect of the treatment. The biochemical control achieved by treatment did not result in normal levels of circulating homocysteine in most patients; levels usually remained moderately elevated. In B₆-nonresponsive patients, this was some 3 to 5 times the upper limit of normal for the populations. It is possible that some of the treatment modalities that lowered homocysteine levels may have had other as-yet-unidentified protective effects related to vascular events. In addition, some patients in the study were taking other treatment than that specifically designed to lower homocysteine. Some older patients (n=23) were taking aspirin therapy, and 1 was undergoing lipid-lowering therapy. This may have been different from the experience of the control group collected in 1985. However, before the diagnosis of CßS deficiency, 9 of the older Dutch patients (>30 years) had had recurrent thromboembolic events despite anticoagulation with warfarin. All but 1 had no further episodes of thrombosis after the commencement of homocysteine-lowering therapy. This experience supports the earlier report by Schulman and colleagues²⁸ that some CßS-deficient patients with persistent severe hyperhomocysteinemia may continue to have serious vascular complications despite treatment with dipyridamole and aspirin.

The use of historical controls was unavoidable, as already discussed, but could introduce biases because of changes in the background rate of vascular disease. However, it is unlikely that lifestyle changes could account for the uniformly good results obtained in the widely separated centers of the study. Indeed, reductions in the incidence of cardiovascular disease in the general population, presumably due to lifestyle changes, have only occurred in the United Kingdom and Ireland very recently.

Based on the prevalence of a CßS mutation among newborns in the Danish population, Gaustadnes and colleagues²⁹ estimated the incidence of homocystinuria to be 1 in 20 500, albeit with a wide confidence interval. This incidence is much higher than any reported frequency based on newborn screening,⁶ but newborn screening for homocystinuria is recognized to have false-negative results.³⁰ Despite the presence of characteristic clinical signs and complications, the diagnosis of CßS deficiency is often missed. Cruysberg et al³¹ reported a mean delay of 11 (0 to 43) years between the first major sign of the condition at mean age 13 (1 to 40) years and the ultimate diagnosis of CßS deficiency in 34 patients. Early diagnosis and prompt treatment of CßS deficiency appears crucial in the prevention of complications.^9,14

Mild hyperhomocysteinemia is regarded as a risk factor for vascular disease. An increase in plasma homocysteine to 1 SD above the mean in the normal population has been shown to be associated with a 60% increase in relative risk for coronary disease.³² Despite that, vascular events in our study population were uncommon, although the posttreatment mean homocysteine levels were still several times higher than those in the respective normal populations. This finding could have relevance to the current concept of mild hyperhomocysteinemia and its association with cardiovascular disease, in which the causal role of a mildly elevated homocysteine level is not yet definitively proven.^33–35 The results of the several large ongoing trials of the effect of folic acid on vascular outcome and plasma homocysteine levels are awaited with interest.²

We conclude that long-term treatment to lower the markedly elevated plasma levels of homocysteine seen in homocystinuria due to CßS deficiency is effective in reducing the potentially life-threatening vascular risk, despite giving imperfect biochemical control. It is as yet uncertain whether lowering plasma homocysteine levels in the general population of patients with vascular disease will reduce cardiovascular risk.

Received May 2, 2001; accepted September 11, 2001.

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