A survey of natural protein intake in Dutch phenylketonuria patients: insight into estimation or measurement of dietary intake.

This study investigated which methods patients and parents used to determine phenylalanine (Phe) intake and the relationship between the methods applied, age, and blood Phe concentration, as this practice had not been studied before in relation to metabolic control. A questionnaire was sent to 327 Dutch phenylketonuria patients (age 0-29 years) to investigate the method used to determine Phe intake (either by estimation, exact measurement, or a combination of both). Mean blood Phe concentration of each individual patient was related to the method reported to be used. Three different age groups (<10 years, > or =10-15 years, and > or =16 years) were distinguished. The response rate for the questionnaires was 73%. In these 188 patients, data for both Phe concentrations and questionnaires could be used. Of these, 75 used exact measurement, 75 used estimation, and 38 used both methods. The number of patients that estimated Phe intake clearly increased with age. Whatever method was used, an increase in Phe concentrations was seen with age. During childhood, exact measurement was used more frequently, and from adolescence on estimation was used more frequently. The method (exact measurement and/or estimation) did not result in statistically different Phe concentrations in any of the three age groups, although blood Phe concentration tended to be lower in adolescence using exact measurement. Data suggest that estimation and exact measurement of Phe intake are both reliable methods. Therefore, in addition to exact measurement, patients should be instructed in both methods at an early age, so that both methods can be used adequately.

Unique efficiency of methionine metabolism in premenopausal women may protect against vascular disease in the reproductive years.

Premenopausal women develop occlusive artery disease less frequently than postmenopausal women. In coronary heart disease, higher blood levels of homocysteine-cysteine mixed disulphide have been reported. Therefore, in healthy subjects, we studied the role of menopausal status in the transsulphuration of methionine in 10 premenopausal and 10 postmenopausal women. To exclude the role of aging, we compared these results with those in 10 younger and 10 older men of comparable age groups. An oral methionine load (0.1 g/kg of body weight) was administered after overnight fasting. Before and during 8 h, thereafter, serum levels of methionine, homocystine, and homocysteine-cysteine mixed disulphide were measured. In the fasting state, serum methionine levels were similar in the premenopausal women and both groups of men. Postmenopausal women had significantly lower fasting levels. Peak levels and clearances of methionine after loading did not differ between the groups. In the fasting state, homocystine was never detectable; yet, after methionine loading, slight homocystinemia was present in 12 out of 20 men, and was more pronounced in all postmenopausal women. However, homocystinemia did not occur in any of the premenopausal women after loading. Fasting serum homocysteine-cysteine mixed disulphide levels did not differ between both groups of men and postmenopausal women. In premenopausal women, both fasting and postloading disulphide levels were significantly lower than in any other group. We conclude that premenopausal women have a unique efficiency of methionine handling, and thereby are preserved against the accumulation of homocysteine after methionine loading. We speculate that this phenomenon might account for the lower incidence of vascular disease in women in the reproductive life cycle.

Defective cystathionine beta-synthase regulation by S-adenosylmethionine in a partially pyridoxine responsive homocystinuria patient.

We determined the molecular basis of cystathionine beta-synthase (CBS) deficiency in a partially pyridoxine-responsive homocystinuria patient. Direct sequencing of the entire CBS cDNA revealed the presence of a homozygous G1330A transition. This mutation causes an amino acid change from aspartic acid to asparagine (D444N) in the regulatory domain of the protein and abolishes a TaqI restriction site at DNA level. Despite the homozygous mutation, CBS activities in extracts of cultured fibroblasts of this patient were not in the homozygous but in the heterozygous range. Furthermore, we observed no stimulation of CBS activity by S-adenosylmethionine, contrary to a threefold stimulation in control fibroblast extract. The mutation was introduced in an E. coli expression system and CBS activities were measured after addition of different S-adenosylmethionine concentrations (0-200 microM). Again, we observed a defective stimulation of CBS activity by S-adenosylmethionine in the mutated construct, whereas the normal construct showed a threefold stimulation in activity. These data suggest that this D444N mutation interferes in S-adenosylmethionine regulation of CBS. Furthermore, it indicates the importance of S-adenosylmethionine regulation of the transsulfuration pathway in homocysteine homeostasis in humans.

Thiamine (vitamin B1) supplementation does not reduce 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 B12, 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.

Growth promotion by homocysteine but not by homocysteic acid: a role for excessive growth in homocystinuria or proliferation in hyperhomocysteinemia?

Excessive growth of long bones in patients with homocystinuria is still unexplained and previous work incriminating homocysteic acid could not be confirmed by others. In vitro studies from our laboratory showed that homocysteine stimulated growth in a clonogenic assay. This observation made us study plasma cyclin dependent kinase (CDK), homocyst(e)ine and homocysteic acid in 10 patients with homocystinuria and 20 controls. In addition, homocysteine and homocysteic acid were tested in a clonogenic assay to correlate the growth promoting activity with CDK. Plasma CDK (protein) correlated strongly with homocysteine (r=0.84) but not with homocysteic acid. Supernatants of the clonogenic assay samples showed up to three times higher CDK levels in the presence of homocyst(e)ine but not homocysteic acid. In vitro data and the strong correlation between homocysteine and CDK suggest a role for homocysteine stimulating CDK, the starter of mitosis, with subsequent stimulation of growth.

Evidence for McKusick's hypothesis of deficient collagen cross-linking in patients with homocystinuria.

Osteoporosis occurs commonly in homocystinuria. The underlying pathobiochemical mechanism remains unclear; disturbed cross-linking of collagen has been suggested but this hypothesis has not been fully tested, nor have studies on collagen synthesis been performed. We therefore used recently available noninvasive tests for collagen synthesis and cross-linking to examine 10 patients with homocystinuria. Synthesis of collagen type I and type III was not different from age-matched healthy controls as reflected by comparable plasma levels of carboxyterminal propeptide of type I procollagen (PICP) and of plasma levels of N-terminal propeptide of procollagen type III (PIIINP). Collagen type I cross-links expressed by serum carboxyterminal telopeptide of collagen type I (ICTP) were 1.14 +/- 0.24 micrograms/l in the patient group versus 3.29 +/- 0.32 micrograms/l in the control group. This significant reduction of cross-links in the group with homocystinuria did not correlate with serum homocysteine or homocysteic acid concentrations. Our data clearly indicate that the disturbed cross-linking hypothesis still holds and that the bone manifestations of homocystinuria are not due to deficient collagen synthesis.

beta-Trace protein in human cerebrospinal fluid: a diagnostic marker for N-glycosylation defects in brain.

As carbohydrate-deficient glycoprotein syndromes (CDGS) are multisystemic disorders with impaired central nervous function in nearly all cases, we tested isoforms of beta-trace protein (beta TP), a 'brain-type' glycosylated protein in cerebrospinal fluid (CSF) of nine patients with the characteristic CDGS type I pattern of serum transferrin. Whereas the serum transferrin pattern did not discriminate between the various subtypes of CDGS type I (CDGS type Ia, type Ic, and patients with unknown defect), beta TP isoforms of CDGS type Ia patients differed from that of the other CDGS type I patients. The percentage of abnormal beta TP isoforms correlated with the severity of the neurological symptoms. Furthermore, two patients are described, who illustrate that abnormal protein N-glycosylation can occur restricted to either the 'peripheral' serum or the central nervous system compartment. This is the first report presenting evidence for an N-glycosylation defect restricted to the brain. Testing beta TP isoforms is a useful tool to detect protein N-glycosylation disorders in the central nervous system.

Vascular outcome in patients with homocystinuria due to cystathionine beta-synthase deficiency treated chronically: a multicenter observational study.

An inborn error of metabolism, homocystinuria due to cystathionine beta-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 beta-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 beta-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.

A second common variant in the methylenetetrahydrofolate reductase (MTHFR) gene and its relationship to MTHFR enzyme activity, homocysteine, and cardiovascular disease risk.

Molecular defects in genes encoding enzymes involved in homocysteine metabolism may account for mild hyperhomocysteinemia, an independent and graded risk factor for cardiovascular disease (CVD). We examined the relationship of two polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, the 677C-->T and 1298A-->C variants, to MTHFR activity, homocysteine concentrations, and risk of CVD in a population of 190 vascular disease patients and 601 apparently healthy controls. The mean specific and residual MTHFR activities were significantly lower in 677CT and 677TT individuals (both P<0.001). The 1298A-->C mutation alone showed no effect on MTHFR activities. However, when the 677C-->T genotype was taken into account, the 1298A-->C mutation also caused a significant decrease in MTHFR activities, which was observed in both the homozygous 1298CC (P<0.001) and the heterozygous 1298AC states (P=0.005). Both the 677TT as the 677CT genotypes were associated with significantly higher fasting and postload homocysteine levels than 677CC (P<0.001 and P=0.003, respectively). The 1298A-->C mutation had no effect on fasting or postload homocysteine levels. Since homocysteine itself is considered to be positively associated with the risk of CVD, these findings indicate that the 1298A-->C mutation cannot be considered a major risk factor for CVD.

Tamoxifen suppresses gonadotropin-induced 17 alpha-hydroxyprogesterone accumulation in normal men.

Intramuscular administration of 1500 IU hCG daily for 3 days induced a transient accumulation of 17 alpha-hydroxyprogesterone (17 OHP) relative to testosterone (T) in normal men, reaching its maximum 24 h after the first injection (17 OHP to T ratio, 1.7 +/- 0.3 times baseline; P < 0.01). Simultaneous administration of hCG and the estrogen antagonist tamoxifen (20 mg twice daily) almost completely abolished the hCG-induced steroidogenic block localized between 17 OHP and T (17 OHP to T ratio at 24 h, 1.1 +/- 0.1 times baseline; P < 0.01 vs. hCG alone). These data indirectly suggest that, in man, the hCG-induced steroidogenic lesion might be mediated through its estrogen-stimulating effect.

Differential effect of single high dose and divided small dose administration of human chorionic gonadotropin on Leydig cell steroidogenic desensitization.

This study compared the effect of a single high dose of hCG (1500 IU) with that of the same dose administered in multiple small doses (300 IU, once daily for 5 days) on Leydig cell steroidogenesis. Administration of a single high dose of hCG to seven healthy men raised the mean plasma testosterone (T) level to peak levels 2.1 +/- 0.2 (SEM) X the baseline value at 48 h. Thereafter plasma T decreased to below normal (0.7 +/- 0.1 X baseline) 7 days after the injection. The mean 17-hydroxyprogesterone (17-OHP) level peaked at 24 h (2.5 +/- 0.2 X baseline) and then also fell to a nadir value of 0.6 +/- 0.2 X baseline on day 7. Reflecting the early accumulation of 17-OHP over T, the 17 OHP/T ratio reached its maximum (1.6 +/- 0.1 X baseline) at 24 h at the same time when plasma estradiol [(E2) 4.4 +/- 0.6 X baseline] and the ratio E2/T (2.7 +/- 0.3 X baseline) achieved their maximal values. Administration of 1500 IU hCG in five divided doses of 300 IU daily increased the mean plasma T levels to peak value of 2.1 +/- 0.2 X baseline at 5 days and the levels remained elevated thereafter. The response of T as reflected by the area under the curve was almost twice as great as in the single dose study (2844 +/- 360 vs. 1647 +/- 214). In contrast to the single high dose experiment, mean plasma 17-OHP levels in the divided dose protocol did not peak at 24 h but only gradually increased. As the increase of T exceeded the 17-OHP increase at almost all time intervals, no accumulation of 17-OHP over T occurred as in the single dose experiment. Instead the 17-OHP/T ratio fell to a nadir value of 0.6 +/- 0.1 X baseline on day 7. The initial E2 peak was absent in the divided dose protocol and the E2/T ratio only marginally increased. Considering both experiments together a close relation was found between the hCG-induced increases in E2 and 17-OHP (r = +0.88, P less than 0.001), as well as the ratio 17 OHP/T (r = +0.64, P less than 0.02).(ABSTRACT TRUNCATED AT 400 WORDS)

Predictive value of luteinizing hormone releasing hormone (LHRH) bolus testing before and after 36-hour pulsatile LHRH administration in the differential diagnosis of constitutional delay of puberty and male hypogonadotropic hypogonadism.

Intravenous LHRH bolus testing (100 micrograms) after 36 h of pulsatile LHRH administration (5 micrograms/90 min) preliminary has been reported to allow complete differentiation between constitutional delay of puberty (DP) and hypogonadotropic hypogonadism (HH) in a small group of sexually immature patients. So far, these data have never been confirmed. To assess the discriminatory power of the test, 33 patients with a presumptive diagnosis of either DP (n = 17) or HH (n = 16), confirmed by clinical follow-up, were studied accordingly. Both groups of patients had similar mean basal LH and FSH levels (P > 0.10). The mean basal plasma testosterone level was three times higher in DP than in HH (4.2 +/- 1.0 vs. 1.4 +/- 0.2 nmol/L, P* < 0.001), but there was a wide overlap. In response to the first LHRH bolus test, the mean LH increment was significantly lower in HH than in DP patients (P < 0.001), but, in 44% of the patients, the values overlapped. The FSH increments were similar in HH and DP. Pulsatile LHRH administration for 36 h similarly increased LH levels in HH and DP to values (2.7 +/- 0.4 and 3.8 +/- 0.5, respectively) slightly higher than before (P < 0.01), but again, not statistically significantly different from each other. The mean testosterone levels increased 2-fold in both groups and remained significantly higher in DP than in HH (7.6 +/- 2.1 vs. 2.8 +/- 0.5 nmol/L P* < 0.05). The mean FSH levels after priming also rose, however, to levels significantly higher in HH than in DP (5.2 +/- 0.8 vs. 3.5 +/- 0.4, P* < 0.05). In HH the ratio of FSH to LH almost doubled, whereas it virtually remained unchanged in DP. LHRH bolus testing after LHRH priming evoked a significantly lower LH response in both HH and DP than before priming despite only slightly higher baseline LH values. The LH increment in HH was five times lower in HH than in DP. In any of the 16 HH patients, the LH increment was < or = 3 IU/L, whereas in 15 out of 17 DP patients the increase was higher (sensitivity of the test 100%, specificity 88%, and diagnostic efficiency 94% after LHRH priming against 56%, 94%, and 75% respectively, before LHRH priming.(ABSTRACT TRUNCATED AT 400 WORDS)

Aromatase inhibition by delta 1-testolactone does not relieve the gonadotropin-induced late steroidogenic block in normal men.

Aromatase inhibition by delta 1-testolactone [(17 oxa-D-homo 1,4 androstanediene-3,17 dione) 500 mg twice daily for 10 days] in nine normal men lowered circulating estradiol (E2) levels by about 25%, enhanced the secretion of FSH, 17-hydroxyprogesterone (17-OHP), and to a lesser degree testosterone (T), but did not affect serum LH levels. Despite E2 lowering there was greater accumulation of 17-OHP than of T after 7 days of treatment, suggesting 17,20-lyase inhibition. Unexpectedly, administration of delta 1-testolactone almost halved the T response to hCG (Pregnyl, 1500 IU), but did not affect the 17-OHP response. Thus, E2 lowering by testolactone aggravated the hCG-induced 17,20-lyase block present before testolactone administration. Although the present data might suggest that estrogens do not play a role in the genesis of the hCG-induced late steroidogenic block, the results suggest that testolactone per se, in addition to its reported antiestrogenic action, inhibits 17,20 lyase.

A 31 bp VNTR in the cystathionine beta-synthase (CBS) gene is associated with reduced CBS activity and elevated post-load homocysteine levels.

Molecular defects in genes encoding enzymes involved in homocysteine metabolism may account for mild hyperhomocysteinaemia, an independent and graded risk factor for cardiovascular disease (CVD). Although heterozygosity for cystathionine beta-synthase (CBS) deficiency has been excluded as a major genetic cause of mild hyperhomocysteinaemia in vascular disease, mutations in (non-)coding DNA sequences may lead to a mildly decreased CBS expression and, consequently, to elevated plasma homocysteine levels. We assessed the association between a 31 bp VNTR, that spans the exon 13-intron 13 boundary of the CBS gene, and fasting, post-methionine load and increase upon methionine load plasma homocysteine levels in 190 patients with arterial occlusive disease, and in 381 controls. The 31 bp VNTR consists of 16, 17, 18, 19 or 21 repeat units and shows a significant increase in plasma homocysteine concentrations with an increasing number of repeat elements, in particular after methionine loading. In 26 vascular disease patients the relationship between this 31 bp VNTR and CBS enzyme activity in cultured fibroblasts was studied. The CBS enzyme activity decreased with increasing number of repeat units of the 31 bp VNTR. RT-PCR experiments showed evidence of alternative splicing at the exon 13-intron 13 splice junction site. The 31 bp VNTR in the CBS gene is associated with post-methionine load hyperhomocysteinaemia that may predispose individuals to an increased risk of cardiovascular diseases.

Unfiltered coffee increases plasma homocysteine concentrations in healthy volunteers: a randomized trial.

BACKGROUND: An elevated plasma homocysteine concentration is a putative risk factor for cardiovascular disease. Observational studies have reported an association between coffee consumption and plasma homocysteine concentrations. OBJECTIVE: We studied the effect of coffee consumption on plasma homocysteine in a crossover trial. We used unfiltered coffee so as to include the possible effects of coffee diterpenes, which are removed by filtering. DESIGN: Sixty-four healthy volunteers (31 men and 33 women) with a mean (+/-SD) age of 43 +/- 11 y were randomly assigned to 2 groups. One group (n = 30) drank 1 L unfiltered cafetière (French press) coffee daily for 2 wk. Such coffee is rich in the cholesterol-raising diterpenes kahweol and cafestol. The other group (n = 34) received water, milk, broth, tea, and chocolate drinks instead of coffee. After a washout period of 8 wk, both groups received the alternate intervention for another 2 wk. RESULTS: Consumption of 1 L unfiltered coffee/d for 2 wk significantly raised fasting plasma homocysteine concentrations by 10%, from 12.8 to 14.0 micromol/L. CONCLUSIONS: Unfiltered coffee increases plasma homocysteine concentrations in volunteers with normal initial concentrations. It is unclear whether the effect is caused by the cholesterol-raising diterpenes present exclusively in unfiltered coffee or by factors that are also present in filtered coffee.

Prevalence of familial mild hyperhomocysteinemia.

Previous studies have shown that elevated basal homocysteine levels are correlated among family members of patients with coronary vascular disease and juvenile venous thrombosis. This suggests the possibility of the presence of inherited basal mild hyperhomocysteinemia (mHH). We studied homocysteine levels, fasting as well as after methionine load, among 96 family members of 21 post-load hyperhomocysteinemic vascular index patients, i.e. 6 parents, 27 offspring, 38 siblings, 19 uncles and aunts and 6 cousins. In 15 out of 21 screened families post-load mHH was established in at least one family member. Fasting and post-load mHH was observed in 19 out of 89 (21%) screened family members (fasting homocysteine levels not measured in seven family members), and 31 out of 96 screened family members (32%), respectively. In 40% of all family members, post-load mHH was not accompanied by fasting mHH. We conclude that both fasting and post-load mHH seems to be inherited in the majority of hyperhomocysteinemic vascular patients.

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.

Homocysteine metabolism in endothelial cells of a patient homozygous for cystathionine beta-synthase (CS) deficiency.

Homocystinuria due to cystathionine beta-synthase (CS) deficiency is the most common inborn error of methionine metabolism. Patients with CS-deficiency have an extremely high risk of vascular disease. The underlying mechanism is still unsolved. Dysfunction of endothelial cells could be the trigger in the formation of atherosclerosis and thrombosis. Therefore, differences in cell function were studied between normal and CS-deficient human umbilical endothelial cells (HUVECs). Total homocysteine (tHcy) concentrations in culture media as a measure of homocysteine export increased in all cell lines, including the cell line with CS-deficiency, with constant amounts of approximately 2.5 microM every 24 h. von Willebrand factor (vWF), tissue plasminogen activator (tPA) and plasminogen activator inhibitor (PAI-1) in culture media were used as markers of endothelial function and increased also with progression of culture time. The effects of additions of folate, vitamin B6 and methionine to the culture medium were studied. The homocysteine export and the markers of endothelial function did not differ between the control and the CS-deficient HUVECs under various test conditions. These data show that CS-deficient endothelial cells have normal homocysteine export and normal endothelial cell function. In CS-deficient patients the very high blood levels of homocysteine, probably due to deficient CS function in liver and kidney, seems to be the hazardous factor to endothelial cells, thus promoting atherosclerosis and thrombosis in CS-deficient patients.

Methionine transamination in patients with homocystinuria due to cystathionine beta-synthase deficiency.

To assess the ability of patients with homocystinuria due to cystathionine beta-synthase (CBS) deficiency to perform the reactions of the methionine transamination pathway, the concentrations of the products of this pathway were measured in plasma and urine. The results clearly demonstrate that CBS-deficient patients develop elevations of these metabolites once a threshold near 350 micromol/L for the concurrent plasma methionine concentration is exceeded. The absence of elevated methionine transamination products previously reported among 16 CBS-deficient B6-responsive patients may now be attributed to the fact that in those patients the plasma methionine concentrations were below this threshold. The observed elevations of transamination products were similar to those observed among patients with isolated hypermethioninemia. Plasma homocyst(e)ine did not exert a consistent effect on transamination metabolites, and betaine appeared to effect transamination chiefly by its tendency to elevate methionine. Even during betaine administration, the transamination pathway does not appear to be a quantitatively major route for the disposal of methionine.

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.