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Biomedical subjects

G H Boers

Publications and source records attributed to G H Boers.

At least 19 recordsLinked to original sources
PubMed2003

[Hemopyrrollactamuria (HPU); from spots to pseudo-disease].

In recent years, patients in the Netherlands confront their doctors with the diagnosis 'haemopyrollactamuria' (HPU), based on the presence of the haemopyrrollactam complex in their urine. The diagnosis is made by a commercial laboratory in the Netherlands (www.keac.nl). We have not been able to find peer-reviewed scientific literature on this metabolic disease. The haemopyrrollactam complex represents the so-called mauve spot, which was the subject of much controversy in schizophrenia research in the previous century. Reviewing all of the available data, we feel that HPU should be classified as a pseudo-disease.

Humans↗
PubMed2001

[From gene to disease; from homocysteine to hyperhomocysteinemia].

Homocysteine is a sulfhydryl containing amino acid which is produced as an intermediate product in the metabolism of the essential amino acid methionine. Apart from environmental factors such as the intake of folate and other B vitamins, the level of homocysteine in the blood is determined by the genetically based activities of several enzymes involved in the methionine or folate cycle. The well-known congenital defect homocystinuria is due to homozygosity for mutated cystathionine beta synthase. It is characterized by severe hyperhomocysteinemia, which leads to arterial and venous disease at a very young age. Mild to moderate hyperhomocysteinemia, due to either heterozygosity for severe mutations in the genes of enzymes involved or based upon homozygosity for more mild mutations, has also been recognized as a risk factor for vascular disease in the last decade. However, ongoing clinical intervention studies still need to demonstrate a casual role of mildly increased homocysteine levels in vascular disease.

Cystathionine beta-Synthase↗
PubMed2001

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.

Adult↗
PubMed2001

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.

Alleles↗
PubMed2001

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.

Adolescent↗
PubMed2000

Betaine-homocysteine methyltransferase (BHMT): genomic sequencing and relevance to hyperhomocysteinemia and vascular disease in humans.

Elevated homocysteine levels have been associated with arteriosclerosis and thrombosis. Hyperhomocysteinemia is caused by altered functioning of enzymes of its metabolism due to either inherited or acquired factors. Betaine-homocysteine methyltransferase (BHMT) serves, next to methionine synthase, as a facilitator of methyl group donation for remethylation of homocysteine into methionine, and reduced functioning of BHMT could theoretically result in elevated homocysteine levels. Recently, the genomic sequence of the BHMT gene was published. Mutation analysis may reveal mutations of the BHMT gene that could lead to hyperhomocysteinemia. In the present study we performed genomic sequencing of the BHMT gene of 16 vascular patients with hyperhomocysteinemia and detected three mutations in the coding region of this gene. The first was an amino acid substitution of glycine to serine (G199S), which was found only in the heterozygous state. The second mutation was a substitution of glutamine to arginine (Q239R), and the last mutation was an amino acid substitution of glutamine to histidine (Q406H). The latter was also found only in the heterozygous state. The relevance of these mutations was tested in a study group, which consists of 190 cases with vascular disease and 601 controls. The influence of these three mutations on homocysteine levels was investigated. None of the three mutations led to significantly changed homocysteine levels. In addition, no differences in genotype distribution between cases and controls were found. So far, our results provide no evidence for a role of defective BHMT functioning in hyperhomocysteinemia or subsequently in vascular disease.

Amino Acid Substitution↗
PubMed2000

Hyperhomocysteinemia as a cause of superior vena cava syndrome.

A case is presented in which superior vena cava (SVC) syndrome was caused by a stenosis of the SVC due to thrombosis. Hyperhomocysteinemia was diagnosed as a possible underlying mechanism. The role of hyperhomocysteinemia as a risk factor for the development of recurrent venous thrombosis, its diagnosis, and treatment are discussed.

Adult↗
PubMed2000

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.

Adolescent↗
PubMed2000

Mild hyperhomocysteinemia is an independent risk factor of arterial vascular disease.

Evidence of a positive association between mild hyperhomocysteinemia and arterial vascular disease has been accumulating in the last decade. Mild hyperhomocysteinemia acts as an independent vascular risk factor with equal strength as hypercholesterolemia and smoking. If jointly present with hypertension and smoking, its effect seems synergistic. This could make the outcome of homocysteine-lowering intervention beneficial, particularly in cases with concomitance of conventional vascular risk factors. So far, however, data on the clinical outcome of homocysteine-lowering treatment with a simple, safe, and cheap vitamin regimen are lacking. Trials investigating a beneficial clinical effect of homocysteine-lowering treatment using folic acid in a dose ranging from 0.2 to 5 mg daily, alone or in combination with vitamin B12 with or without vitamin B6 versus placebo, are ongoing. Furthermore, exploration of the unifying mechanism by which increased homocysteine levels may lead to both arterial and venous occlusions is warranted. These lines of investigations have to provide the ultimate proof of causality of hyperhomocysteinemia in vascular disease in the near future.

Arteriosclerosis↗
PubMed2000

Vascular complications of severe hyperhomocysteinemia in patients with homocystinuria due to cystathionine beta-synthase deficiency: effects of homocysteine-lowering therapy.

Homocystinuria (HCU) due to cystathionine beta-synthase (CBS) deficiency leads to severe hyperhomocysteinemia (HHcy). Vascular events (VE) remain the major cause of morbidity and mortality in the untreated patients with HCU. The study on the natural history of untreated HCU disclosed that, at the time of maximal risk, in other words beyond 10 years old, there was one event per 25 years. Recent studies from Australia (n = 32), The Netherlands (n = 28), and Ireland (n = 24) have documented the effects of long-term treatment on the vascular outcome of a total of 84 patients with 1314 patient-years of treatment for HCU. The mean (range) age was 27.8 (2.5 to 70) years. Five VE were recorded during treatment; one pulmonary embolism, two myocardial infarctions, and two abdominal aneurysms. All five VE occurred in B6-responsive patients at a mean (range) age of 48.8 (30 to 60) years. In 1314 patient-years of treatment, 53 VE would have been expected if they remained untreated; instead only 5 were documented, relative risk = 0.091 (95% confidence interval [CI] 0.043 to 0.190; p < 0.001). Appropriate homocysteine-lowering therapy for severe HHcy significantly reduced the vascular risk in patients with HCU. VE were rare with treatment despite the fact that the post-treatment homocysteine levels were several times higher than the cutoff point for homocysteine in the normal population. The present findings may have relevance to the current concept of "mild HHcy" as a risk factor for vascular disease, with elevated plasma homocysteine levels considerably lower than that of the post-treatment levels in this group of reported patients.

Adolescent↗
PubMed2000

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.

Adult↗
PubMed1999

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.

Adolescent↗
PubMed1999

Cystathionine beta-synthase mutations in homocystinuria.

The major cause of homocystinuria is mutation of the gene encoding the enzyme cystathionine beta-synthase (CBS). Deficiency of CBS activity results in elevated levels of homocysteine as well as methionine in plasma and urine and decreased levels of cystathionine and cysteine. Ninety-two different disease-associated mutations have been identified in the CBS gene in 310 examined homocystinuric alleles in more than a dozen laboratories around the world. Most of these mutations are missense, and the vast majority of these are private mutations. The two most frequently encountered of these mutations are the pyridoxine-responsive I278T and the pyridoxine-nonresponsive G307S. Mutations due to deaminations of methylcytosines represent 53% of all point substitutions in the coding region of the CBS gene.

CpG Islands↗
PubMed1999

Variability of fasting and post-methionine plasma homocysteine levels in normo- and hyperhomocysteinaemic individuals.

To assess the variability of plasma homocysteine levels, fasting and post-methionine homocysteine levels were measured twice, at baseline and after follow-up of 1-4 months, in 16 individuals with normal and 26 with elevated homocysteine levels after methionine loading. The intra-individual coefficients of variation varied from 15 to 23% for fasting and post-methionine homocysteine levels, whether these levels were within the normal range or not. As a result, test-retest agreement was poor when subjects were dichotomized as having 'normal' or 'abnormal' homocysteine levels (itself a questionable concept). There was a relation between the average post-methionine homocysteine levels (at the first and second measurement) and the difference between both measurements (r = 0.37, P = 0.016). In normohomocysteinaemic individuals, delta (i.e., the difference between baseline and follow-up) fasting homocysteine and delta post-methionine homocysteine were correlated negatively with delta folate serum levels: r = -0.64, P = 0.007 and r = -0.50, P = 0.05, respectively. Individuals homozygous for the 677 C-->T mutation in the 5,10-methylenetetrahydrofolate reductase gene showed a greater variation of fasting homocysteine levels than those homozygous for the wild type (P = 0.017). In summary, we suggest that there is a substantial intra-individual variability in plasma homocysteine levels over time and that this variability is significantly related to the variability in serum folate levels, especially in normohomocysteinaemic individuals.

5,10-Methylenetetrahydrofolate Reductase (FADH2)↗
PubMed1999

Homocysteine, vitamin status and risk of vascular disease; effects of gender and menopausal status. European COMAC Group.

BACKGROUND: Elevated plasma total homocysteine (tHcy) is a known risk factor for vascular disease. Gender, age, and circulating levels of folate, vitamins B(6)and B(12)affect tHcy levels. Objectives To study associations of gender and age with levels of plasma tHcy, and to examine the relationships of tHcy and circulating levels of folate, vitamins B(6)and B(12)with risk of vascular disease in men and women (pre- and post-menopausal). MATERIAL AND METHODS: In a multicentre case-control study in Europe, 750 patients (544 men, 206 women) with documented vascular disease of the coronary, cerebral, or peripheral vessels and 800 control subjects (570 men, 230 women) were enrolled. Plasma tHcy levels (fasting and after methionine loading) and circulating levels of the vitamins were measured. Adjustment for age and centre was carried out for all statistical analyses, with additional adjustment for serum creatinine and vitamins for the tHcy comparisons between the sexes and between cases and controls. Risk analyses included adjustment for creatinine and traditional risk factors. Relationships between age, gender and tHcy were studied among control subjects only. RESULTS: Fasting tHcy levels were lower in women than in men. Levels of tHcy showed a positive association with age, for both sexes. In the post-menopausal age category, female post-methionine load tHcy levels surpassed levels of men. Elevation of tHcy (defined as >80th percentile of controls) appeared to be at least as strong a risk factor for vascular disease in women as in men, even before the menopause. For post-methionine load tHcy, there was a 40% stronger association with vascular disease in women than in men. In both sexes, but especially in pre-menopausal women, low circulating levels of vitamin B(6)conferred a two- to threefold increased risk of vascular disease, independent of tHcy. In men, but not in women, low (defined as <20th percentile of controls) circulating folate levels were associated with a 50% increased risk of vascular disease. CONCLUSIONS: Elevation of tHcy appears to be at least as strong a risk for vascular disease in women as men, even before the menopause. Our data indicate that associations of the various tHcy measurements (and the vitamins that determine them), with risks of vascular disease may differ between the sexes. The tHcy-independent relationship of vitamin B(6)with vascular disease indicates that it will be advisable to test the effects of vitamin B(6)in clinical trials.

Case-Control Studies↗
PubMed1999

The molecular basis of cystathionine beta-synthase deficiency in Dutch patients with homocystinuria: effect of CBS genotype on biochemical and clinical phenotype and on response to treatment.

Homocystinuria due to cystathionine beta-synthase (CBS) deficiency, inherited as an autosomal recessive trait, is the most prevalent inborn error of methionine metabolism. Its diverse clinical expression may include ectopia lentis, skeletal abnormalities, mental retardation, and premature arteriosclerosis and thrombosis. This variability is likely caused by considerable genetic heterogeneity. We investigated the molecular basis of CBS deficiency in 29 Dutch patients from 21 unrelated pedigrees and studied the possibility of a genotype-phenotype relationship with regard to biochemical and clinical expression and response to homocysteine-lowering treatment. Clinical symptoms and biochemical parameters were recorded at diagnosis and during long-term follow-up. Of 10 different mutations detected in the CBS gene, 833T-->C (I278T) was predominant, present in 23 (55%) of 42 independent alleles. At diagnosis, homozygotes for this mutation (n=12) tended to have higher homocysteine levels than those seen in patients with other genotypes (n=17), but similar clinical manifestations. During follow-up, I278T homozygotes responded more efficiently to homocysteine-lowering treatment. After 378 patient-years of treatment, only 2 vascular events were recorded; without treatment, at least 30 would have been expected (P<.01). This intervention in Dutch patients significantly reduces the risk of cardiovascular disease and other sequelae of classical homocystinuria syndrome.

Adolescent↗
PubMed1998

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.

Adolescent↗