Cystathionine Synthase Deficiency Research Articles

Poorly Controlled Homocystinuria: A Rare Cause of Ischemic Priapism?

We report on the 1st case of ischemic priapism secondary to poorly controlled homocystinuria. Homocystinuria is a rare, autosomal recessive, inherited disorder of metabolism that is caused by a deficiency of cystathionine synthase, leading to marked hyperhomocysteinemia. Arterial and/or venous thromboemboli are a major cause of mortality and morbidity in patients with homocystinuria. Untreated patients have a 50% chance of having a vascular event by 30 years of age. Increased homocysteine levels have been reported to upregulate prothrombotic factors and downregulate antithrombotic factors; in particular, increased homocystinuria has been found to downregulate nitric oxide (NO). Mice that are deficient in NO synthase in the cavernosal smooth muscles have a higher incidence of priapism. Decrease in NO synthase causes downregulation of cyclic guanosine monophosphate, phosphodiesterase type 5A, and Rho A/Rho-kinase. Because persistently increased homocysteine also downregulates NO, a similar mechanism could be proposed for priapism secondary to homocystinuria. In patients presenting with priapism, specific features of homocystinuria should be sought; in selected patients, screening with plasma total homocysteine might be appropriate. Ischemic priapism secondary to homocystinuria appears to respond well to the standard treatment options of aspiration, intracavernosal injection with phenylephrine, and, if required, a shunting procedure.Johnson M, Murphy E, Raheem A, Ralph D. Poorly Controlled Homocystinuria: A Rare Cause of Ischemic Priapism? Sex Med 2018;6:171–173.

Tall stature in children: differential diagnosis and management

Tall stature in children: differential diagnosis and management

Foreword to special issue on homocysteine disorders

Foreword to special issue on homocysteine disorders

Inborn Errors of Sulfur-Containing Amino Acid Metabolism

Two superimposed metabolic sequences, transsulfuration and the methionine/homocysteine cycle, form the pathway for methionine metabolism in mammalian liver. This combined pathway was formulated first to explain observations in subjects with homocystinuria caused by cystathionine synthase deficiency. Since that time additional inborn errors have been discovered, and currently we know of human subjects with isolated defects in all of the reactions of the combined pathway with only one exception: betaine homocysteine methyltransferase. Studies of these inborn errors have contributed significantly to our knowledge of human methionine metabolism and to the clinical consequences of impaired metabolism. Transsulfuration appears to function primarily for the metabolism of excess methionine, and each of the 5 defects in this pathway results in the accumulation of 1 or more of the normal metabolites. Thus, studies of these disorders may provide insight into both the potential pathological sequelae of nutritional methionine excess as well as whether laboratory testing allows the detection of excess.

Hyperhomocysteinemia and arteriosclerosis: historical perspectives

Early concepts of the origin of arteriosclerosis were introduced in the 19th century by Rokitansky and Virchow, who described mural thrombosis, inflammatory damage to arterial intima, increased intimal permeability to plasma, mucoid degeneration of arterial wall, deposition of plasma lipids in plaques, and fibrosis and calcification of plaques. Experimental production of arteriosclerosis by feeding animal foods to rabbits was attributed to protein intoxication by Ignatowsky in 1908 and to dietary cholesterol by Anitschkow in 1913. Newburgh confirmed the protein hypothesis in 1915-1925 but failed to identify which amino acid produced plaques because methionine (1922) and homocysteine (1932) had not yet been discovered. Cases of homocystinuria from inherited deficiency of cystathionine synthase were found to be associated with thrombosis and vascular disease in 1964. The index case of methionine synthase deficiency (cobalamin C disease) was found by McCully in 1969 to be associated with arteriosclerosis, leading to the homocysteine theory of arteriosclerosis. The theory explains experimental arteriosclerosis by deficiency of vitamin B6 in monkeys, choline deficiency in rats, thyroid deficiency in rats, and methionine deficiency in monkeys. The thrombogenic and atherogenic effects of homocysteine were demonstrated in rabbits, baboons and other species, reproducing the pathological findings found in homocystinuria. Clinical and epidemiological studies in the past two decades have demonstrated that elevated plasma homocysteine is a potent independent risk factor for arteriosclerosis in the general population, supporting the validity of the theory.

Homocysteine, B Vitamins, and Atherosclerosis

To the Editor: The conclusion by Folsom et al1 that raised homocysteine concentrations in the blood may be a consequence, not a cause, of coronary artery disease has serious clinical implications. As McCully2 pointed out in his recent editorial, arteriosclerosis in hyperhomocysteinemia may result from 3 different enzymatic abnormalities: deficiency of cystathionine synthase, which is a pyridoxal phosphate–dependent enzyme; deficiency of methyltetrahydrofolate homocysteine methyl transferase, which is a cobalamin-dependent enzyme; and deficiency of methylene tetrahydrofolate reductase, which is a folate-dependent enzyme. The last enzymatic abnormality explains the origin of arteriosclerosis observed in vitamin B6–deficient monkeys and choline-deficient rats, 2 important animal models in which hyperhomocysteinemia also leads to atherogenesis.2 Although I agree with Folsom et al1 that randomized trials are needed to better clarify the interrelationships of homocysteine, B vitamins, …

Homocysteine, Vitamin Deficiency and Prevention of Arteriosclerosis

The homocysteine theory of arteriosclerosis was discovered by study of children with homocystinuria caused by different enzymatic disorders of homocysteine metabolism. Deficiency of cystathionine synthase, a pyridoxal phosphate dependent enzyme, causes elevated levels of plasma homocysteine. Deficiency of methyl transferase, a folic acid and cobalamin dependent enzyme, causes elevated levels of plasma homocysteine and cystathionine. Arteriosclerosis was discovered to be associated with homocysteinemia in both of these inherited dirorders. Because of different metabolic consequences of these two diseases, it was possible to conclude that homocysteine causes arteriosclerosis by damaging the endothelial cells and producing hyperplasia of smooth muscle cells and other connective tissue changes. Deficiency of a third enzyme, methylenetetrahydrofolate reductase, also causes homocystinuria and arteriosclerotic plaques, providing independent evidence to support this conclusion. Further evidence to support this conclusion came from studies with animals showing that injection of homocysteine causes arteriosclerotic plaques and thrombosis that closely resemble the vascular changes in children with homocystinuria. The homocysteine theory of arteriosclerosis relates the pathogenesis of the disease in the general population to dietary deficiencies of vitamin B6, folic acid, and vitamin B12. Deficiencies of these vitamins are produced by losses incurred during processing and preservation of basic foodstuffs. Population surveys have concluded that elevated levels of plasma homocysteine are an independent risk factor for arteriosclerosis, heart disease, and stroke. Elevated homocysteine levels have in turn been related to widespread deficiencies of folic acid and vitamin B6 within susceptible populations. The decline in mortality from coronary heart disease in the U.S. during the past three decades is attributed to increased vitamin B6 and folic acid that were introduced into the food supply through voluntary fortification and supplementation. A properly designed intervention trial is needed to show a major reduction in cardiovascular disease risk and complications by a diet and supplementary nutrients that reduce levels of homocysteine in the plasma.

Homocysteine, Folate, Vitamin B<SUB>6</SUB>, and Cardiovascular Disease

The importance of hyperhomocysteinemia in the pathogenesis of arteriosclerosis was first recognized by study of vascular pathology in children with homocystinuria caused by 2 different enzymatic abnormalities of homocysteine metabolism. 1 Homocystinuria caused by deficiency of cystathionine synthase, a pyridoxal phosphate-dependent enzyme, is characterized by vascular abnormalities and frequent arterial and venous thromboses. 2 In 1968 a 2-month-old boy with a rare form of homocystinuria caused by deficiency of methyltetrahydrofolate homocysteine methyl transferase, a cobalamindependent enzyme, was discovered to have rapidly progressive arteriosclerosis. 1 Because of the different metabolic patterns caused by these 2 enzymatic abnormalities, it was suggested that homocysteine causes arteriosclerotic plaques by a direct effect on the cells and tissues of the arteries. A third enzyme abnormality leading to homocystinuria, deficiency of methylenetetrahydrofolate reductase, a folate-dependent enzyme, was found to cause arteriosclerotic plaques, 3 also supporting the conclusion that homocysteine is atherogenic. This interpretation explains the origin of arteriosclerosis observed in vitamin B6‐deficient monkeys and choline-deficient rats, 2 important animal models in which hyperhomocysteinemia also leads to atherogenesis. The atherogenic effect of homocysteine was subsequently demonstrated experimentally by parenteral and alimentary administration of the amino acid to rabbits 4,5 and baboons. 6

Hyperhomocysteinemia as a Risk Factor for Arterial and Venous Disease. A Review of Evidence and Relevance

In homozygous homocystinuria due to cystathionine synthase deficiency, characterized by severe hyperhomocysteinemia, there is a high incidence of vascular complications. These observations focus on homocysteine as an atherogenic and thrombophilic agent. At the present time, there is also convincing evidence that even mild hyperhomocysteinemia is a risk factor for cardiovascular disease due to occlusive arterial complications. Furthermore, a positive association between mild hyperhomocysteinemia and the occurrence of venous thrombosis has been shown but needs further study. Mildly elevated homocysteine levels affect the arterial system independently from conventional risk factors. This newly- recognized factor seems equally strong in risk to hypercholesterolemia and smoking, while hypertension leads to a larger excess risk. It interacts synergistically with hypertension and smoking in a joint arteriosclerotic effect in patients with the concomitant presence of these risk factors. The homocysteine-lowering efficacy of a simple and safe vitamin regimen has been proven but data on the clinical outcome of such intervention are lacking thus far.

Thiamine (vitamin B1) supplementation does not reduces fasting blood homocysteine concentration in most homozygotes for homocystinuria

Homozygotes for homocystinuria due to cystathionine synthase (CS) deficiency accumulate homocysteine and methionine in their blood and tissues. High-dose pyridoxin, folic acid, vitamin B 12, or betaine are therapeutical options to lower the elevated homocysteine concentration. These compounds stimulate the transsulfuration or remethylation of homocysteine. Despite such treatment, elevated blood homocysteine concentrations may persist in many homocystinurics. Therefore, it is warranted to study alternative regimen to reduce the blood homocysteine concentration in homocystinurics. Apart from entering the transsulfuration pathway, methionine can be catabolized via the transamination pathway, by conversion into 4-methylthio-2-oxobutyrate (MTOB), followed by oxidative decarboxylation of MTOB to 3-methylthiopropionate. Thiamine pyrophosphate, the active form of thiamine, is a cofactor of the supposed rate-limiting oxidative decarboxylation in the transamination of methionine. The effect of thiamine administered in 2 or 3 daily doses of 25 mg orally, was studied in nine homozygote CS deficient patients. Methionine levels decreased in 6 out of 9 patients. In 8 out of 9 patients, however, the levels of plasma homocysteine remained virtually unchanged, as did the serum transamination metabolites in all patients. We conclude that vitamin B1 cannot be used as an additional homocysteine-lowering treatment in most homozygotes for homocystinuria.

Delay in diagnosis of homocystinuria: retrospective study of consecutive patients.

To assess the causes for delay in the diagnosis of homocystinuria. Clinical and laboratory data were collected from patients diagnosed as having homocystinuria due to cystathionine synthase deficiency, with special reference to the ages at which the patients had their first major signs of the disease, ectopia lentis was established, and homocystinuria was diagnosed. University hospital in the Netherlands. 34 patients (18 males) in whom homocystinuria due to cystathionine synthase deficiency was diagnosed in the period 1970-94. Among 34 consecutively detected homocystinuria patients the mean age at diagnosis of homocystinuria was 24 (range 1-61) years. Despite frequent ocular manifestations, serious complications in the vascular, skeletal, and central nervous systems, and repeated examinations performed in these patients by clinicians of various disciplines, there was a mean delay of 11 (0-43) years between the first major signs of the disease (at mean age 13 (1-40) years) and the ultimate diagnosis of homocystinuria. Even when ectopia lentis was diagnosed (in 26 (76%) patients, mean age 18 (1-50) years), this did not lead to adequate biochemical analysis for homocystinuria at the time of detection, causing a mean diagnostic delay of 8 (0-24) years in these patients. Three factors should have precipitated the diagnosis of homocystinuria: early recognition that unusual myopia (high, very high, abnormal progressive, or at young age) was caused by subluxation of the ocular lenses; awareness that the occurrence of myopia combined with systemic complications ("myopia plus") might be due to homocystinuria; and appropriate biochemical investigations carried out in patients with ectopia lentis and in their siblings.

Treatment of Hyperhomocyst(e)inemia: Physiological Basis

Hyperhomocyst(e)inemia (HCY) is caused either by genetic or nongenetic defect(s), and the clinical severity of HCY is correlated with the biochemical abnormality. Treatment of HCY is approached on the basis of its eitology and severity of defect. The preferred method of treatment for genetic HCY is activation of mutant enzyme activity with the cofactor or the precursor of cofactor. If HCY does not respond to this treatment, pharmacological doses of betaine or folic acid should be used to enhance the alternative pathway of homocysteine turnover. Phenotypic expression of minor genetic defects, such as heterozygous cystathionine synthase deficiency and thermolabile methylenetetrahydrofolate reductase (MTHFR) can be amplified or masked by nongenetic (nutritional) factor(s). Hence, supplementation of folic acid, vitamin B-12, pyridoxine and choline to maintain their serum concentrations above low normal range may satisfactorily prevent the development of moderate HCY due to a minor genetic defect.

Genetic and nongenetic factors for moderate hyperhomocyst(e)inemia

To assess the risk for homocyst(e)ine-associated vascular disease, overt hyperhomocyst(e)inemia should be demonstrated. In nonhomocystinuric subjects, clinical vascular disease must have developed after 40 or more years of persistent hyperhomocyst(e)inemia which may not be present without a genetic defect(s). Nongenetic factors, however, may amplify or mask phenotypic expression of a genetic defect, causing difficulties for the evaluation of hyperhomocyst(e)inemia based on plasma homocyst(e)ine concentration alone. Therefore, the search for genetic defects seems as important as the determination of plasma homocyst(e)ine concentration in evaluating the relationship between hyperhomocyst(e)inemia and the development of vascular disease. If genetic defect, such as heterozygous cystathionine synthase deficiency or thermolabile methylenetetrahydrofolate reductase is not detected, post-methionine homocyst(e)ine determination is a suitable means to identify genetic susceptibility to hyperhomocyst(e)inemia when the environmental factors are similar in the control and study groups.

Homocysteine and coronary artery disease.

Homocystinuria is a rare autosomal recessive disease complicated by early and aggressive occlusive arterial disease. This may be related to the grossly increased homocysteine concentrations seen in this disease. More recently, milder hyperhomocysteinemia has been proposed as an independent risk factor for coronary artery disease. Many patients with homozygous homocystinuria develop severe premature atherosclerosis and thromboembolism, probably caused by abnormally high concentrations of homocysteine. Homocysteine undergoes metabolism either by remethylation or transsulfuration, and deficiency or dysfunction of any of the substances that regulate these reactions may lead to hyperhomocysteinemia. Homocysteine may have adverse effects on platelets, clotting factors, and endothelial cells. Studies have demonstrated significantly higher plasma homocysteine levels in patients with occlusive arterial disease than in controls. The causes are not clearly understood but may include deficiency of vitamin B6, vitamin B12, and folic acid and heterozygosity for cystathionine synthase deficiency. Vitamin supplementation can lower plasma homocysteine levels. Whether measuring plasma homocysteine levels in patients with coronary artery disease should be routine and whether treating hyperhomocysteinemia in these patients may reduce the risk of coronary events remains to be determined.

No sensory neuropathy during pyridoxine treatment in homocystinuria.

Seventeen patients with cystathionine synthase deficiency homocystinuria were examined clinically and neurophysiologically for evidence of sensory neuropathy. All had received high dose pyridoxine (vitamin B-6) for many years. Absence of neurological disturbance in all cases suggests long term treatment with pyridoxine in the dosages used in homocystinuric patients is not harmful.

Alternative methionine degradation via the transamination pathway: an option for therapy for homocystinuria due to cystathionine synthase deficiency

Alternative methionine degradation via the transamination pathway: an option for therapy for homocystinuria due to cystathionine synthase deficiency

Plasma Homocysteine in Venous Thromboembolism

Severe hyperhomocysteinemia due to inborn errors of methionine metabolism results in precocious development of arteriosclerosis and predisposition to venous and arterial thromboembolism. Although the findings of several studies have indicated that mild hyperhomocysteinemia is common in occlusive arterial disease, no similar studies have been made on venous thromboembolism. In this study of subjects under 50 years of age, we found no significant differences in the plasma homocysteine concentrations, either in the fasting state or after methionine loading, between 42 patients with venous thromboembolism and 42 healthy controls. Nonetheless, male patients manifested a tendency toward higher homocysteine concentrations than male controls; 6 patients (14%) versus 2 controls (5%) responded abnormally to methionine loading which might indicate heterozygosity for cystathionine synthase deficiency. Thus, further studies on plasma homocysteine in venous thromboembolism are warranted.

Cystathionine-synthase-deficient patients do not use the transamination pathway of methionine to reduce hypermethioninemia and homocystinemia

Methionine is supposed to be degraded via two known routes, the transsulfuration and the transamination pathways. In particular, patients with hypermethioninemia, due to a defect in the transsulfuration pathway, may catabolize significant amounts of methionine via the transamination pathway. In this study the relative amount of methionine degraded via the transamination pathway in 17 patients with homozygous homocystinuria, due to cystathionine synthase deficiency, was compared with 23 normal subjects, and with a patient with hypermethioninemia due to a deficiency in methionine adenosyltransferase. The homocystinuric patients and the normal subjects were studied in the fasting state as well as after methionine loading (0.1 g/kg body weight). It is concluded that in cystathionine synthase deficient patients, the transamination pathway is not quantitatively important in methionine degradation despite elevated methionine levels. This is in contrast to the patient with methionine adenosyltransferase deficiency, who catabolizes at least 20% of his dietary methionine via the transamination pathway.

Carriership for homocystinuria in juvenile vascular disease.

The frequency of pathological homocysteine accumulation after standardized methionine loading was investigated in 75 patients with clinical signs of ischemic disease before age 50: 25 with occlusive peripheral arterial disease, 25 with occlusive cerebrovascular disease, and 25 with myocardial infarction. On the basis of abnormally high homocysteinemia after methionine loading and cystathionine synthase deficiency in fibroblast cultures, carriership for homocystinuria could be established in 7 patients in each of the first two groups, however in none of the patients in the third group. This high frequency of heterozygosity compared with the frequency of 1 in 70 at the most in the normal population leads to the conclusion that such carriership predisposes to the development of premature occlusive arterial disease.

Heterozygosity for Homocystinuria in Premature Peripheral and Cerebral Occlusive Arterial Disease

Premature arteriosclerosis and thromboembolic events are well-known complications of homozygous homocystinuria due to cystathionine synthase deficiency. It is unknown whether heterozygosity for homocystinuria predisposes to premature vascular disease. We explored the frequency of excessive homocysteine accumulation after standardized methionine loading in 75 patients presenting with clinical signs of ischemic disease before the age of 50:25 with occlusive peripheral arterial disease, 25 with occlusive cerebrovascular disease, and 25 with myocardial infarction. In seven patients in each of the first two groups but in none of the patients in the third group, heterozygosity for homocystinuria was established on the basis of pathological homocysteinemia after methionine loading and cystathionine synthase deficiency in skin fibroblast cultures. Because the frequency of heterozygosity for homocystinuria in the normal population is 1 in 70 at the most, we conclude that this condition predisposes to the development of premature occlusive arterial disease, causing intermittent claudication, renovascular hypertension, and ischemic cerebrovascular disease.