Josef Hyánek

Essential hypertension in adolescents: Association with insulin resistance and with metabolism of homocysteine and vitamins

BACKGROUND Although insulin resistance and elevated plasma homocysteine are associated with hypertension in adults, the role of these conditions in the initial phase of hypertension is largely unknown. We examined whether insulin resistance and disturbed homocysteine metabolism are present in young adults at the early stages of essential hypertension. METHODS We measured physical characteristics, plasma levels of insulin, lipids, total homocysteine, and vitamins in 164 patients with essential juvenile hypertension (median age, 19 years; 92% males) and in 173 controls (median age, 18 years; 66% males). Furthermore, we analyzed the prevalence of six polymorphisms in four genes of the methionine cycle. RESULTS Patients with hypertension and controls differed significantly (P <.05) in body mass index, levels of insulin, high-density lipoprotein-cholesterol, fasting and post-load plasma homocysteine, and folates. Systolic blood pressure was correlated with homocysteine levels and inversely correlated with plasma folates. Logistic regression showed that fasting homocysteine, vitamin B(12), and low-density lipoprotein-cholesterol were associated with a significantly increased risk of juvenile hypertension. In contrast, the birth length, polymorphism c.2756 A-->G in the MTR gene and plasma folate were associated with a significantly decreased risk of juvenile hypertension. CONCLUSIONS Our study showed that essential hypertension in adolescents is associated with lower folate and higher homocysteine levels, and with signs of insulin resistance. These data suggest that hypertension in young individuals may be a part of early manifestation of insulin resistance syndrome, and that disturbed folate and homocysteine metabolism may play a role in the early stages of hypertension.

Genetic variants of homocysteine metabolizing enzymes and the risk of coronary artery disease.

It is unresolved whether elevated homocysteine in coronary artery disease (CAD) is the cause of arteriosclerosis or its consequence. In contrast, genetic variants of enzymes that metabolize homocysteine cannot be altered by arteriosclerosis. Consequently, their association with CAD would permit to imply causality. We modeled by regression analysis the effect of 11 variants in the methionine cycle upon CAD manifestation in 591 controls and 278 CAD patients. Among the examined variants only the carriership for the c.844ins68 in the cystathionine beta-synthase (CBS) gene was associated with a significantly lowered risk of CAD (OR=0.56; 95% CI=0.35-0.90 in the univariable, and OR=0.41, 95% CI=0.19-0.89 for obese people in the multivariable analysis, respectively). Healthy carriers of the c.844ins68 variant exhibited, compared to the wild type controls, significantly higher postload ratios of blood S-adenosylmethionine to S-adenosylhomocysteine (61.4 vs. 54.9, p=0.001) and of plasma total cysteine to homocysteine (8.6 vs. 7.3, p=0.004). The changes in these metabolites are compatible with an improved methylation status and with enhanced activity of homocysteine transsulfuration. In conclusion, the coincidence of clinical and biochemical effects of a common c.844ins68 CBS variant supports the hypothesis that compounds relating to homocysteine metabolism may play role in the development and/or progression of CAD.

Facts and artefacts in mevalonic aciduria: development of a stable isotope dilution GCMS assay for mevalonic acid and its application to physiological fluids, tissue samples, prenatal diagnosis and carrier detection☆

A stable isotope dilution assay using D3-mevalonic acid was developed and applied to the study of mevalonic aciduria. The method also appears to be suitable for the evaluation of different therapeutic regimens in patients with hypercholesterolemia. Mevalonic acid was isolated by liquid partition chromatography and quantified as the underivatized lactone by means of ammonia chemical ionization selected ion monitoring capillary gas chromatography-mass spectrometry. In heterozygotes there was significantly greater urinary excretion of mevalonic acid, while the range of enzymatic activity of mevalonate kinase showed an overlap with that of controls. The analysis of amniotic fluids of two pregnancies at risk for mevalonic aciduria showed a 3277-fold elevation as compared to controls in the first case, diagnostic of an affected fetus, and a normal value in the second one. Mevalonic acid concentration was much increased in tissues of the affected and aborted fetus. Concentrations ranged from 840 to 1120 mumol/kg in various tissues and were as high as 1810 mumol/kg in brain. Concentrations in control fetal tissues were approximately 1 mumol/kg.

Results of screening for phenylalanine and other amino acid disturbances among pregnant women

Blood specimens were collected from 15000 pregnant women during the first 3 months of their pregnancy and screened for amino acid disturbances by means of paper chromatography. A high incidence of disturbances in the phenylalanine metabolism was discovered: three cases of mild hyperphenylalaninaemia without phenylpyruvicaciduria (incidence 1:5000); two cases of mild hyperphenylalaninaemia with phenylpyruvicaciduria (incidence 1:7550); four cases of mild phenylketonuria (incidence 1:3750). Disturbances in the metabolism of other amino acids were found to be rare. Metabolic and genealogical findings in some detected families are briefly described.

Accumulation and impaired in vivo metabolism of di- and trihydroxycholestanoic acid in two patients

Two patients with a suspected peroxisomal disorder on the basis of neurological, craniofacial, hepatological and other abnormalities were studied. The phenotype of both girls was remarkably similar from birth until age 1.5 yr. Detailed studies in plasma revealed normal plasma very-long-chain fatty acids but the presence of di- and trihydroxycholestanoic acids and the C29-dicarboxylic bile acid, all known to occur in plasma from Zellweger patients. These results suggest an isolated defect in the peroxisomal beta-oxidation of the side chains of the cholestanoic acids. Activation of trihydroxycholestanoic acid and beta-oxidation of trihydroxycholestanoyl-CoA, measured in a liver biopsy, were normal, however, as was the peroxisomal beta-oxidation of palmitate. Although the molecular defect remains unknown, the results stress the importance of performing multiple analyses in any patient suspected to suffer from a peroxisomal disorder and indicate that screening for peroxisomal disorders based upon analysis of only plasma very long chain fatty acids with or without analysis of erythrocyte plasmalogen levels, may be inadequate.

Unusual clinical presentation in two boys with cytochrome c oxidase deficiency.

Cytochrome c oxidase deficiency has been described in patients with myopathies (fatal and benign infantile myopathies) and encephalomyopathies (e.g. subacute necrotizing encephalomyopathy or Leigh syndrome, progressive infantile poliodys trophy or Alpers syndrome and MERRF syndrome) (Lombes et al 1989). The clinical symptoms of mitochondrial encephalomyopathies are extremely variable and many patients present with overlapping phenotypes or atypical symptoms. We present two unrelated patients with cytochrome c oxidase deficiency, established in cultured skin fibroblasts, with unusual symptoms

Di- and trihydroxycholestanaemia in twin sisters

Diand trihydroxycholestanoic acids are normal intermediates in the synthesis of chenodeoxycholic acid and cholic acid, respectively. The two cholestanoic acids are produced from cholesterol via a complex series of enzymic reactions taking place in different compartments of the cell. Following their production from cholesterol, diand trihydroxycholestanoic acid are activated to their corresponding CoA-esters followed by fl-oxidative chain shortening in peroxisomes (Wanders et al., 1990). In patients lacking peroxisomes, diand trihydroxycholestanoic acids accumulate in the body fluids due to their deficient fl-oxidation in peroxisomes (Kase et al., 1985). Furthermore, accumulation of diand trihydroxycholestanoic acid has been reported in patients with a defect in peroxisomal fl-oxidation at the level of bifunctional protein and peroxisomal thiolase (see Wanders et al., 1990 for review). In this paper we describe twin sisters with a variety of clinical abnormalities suggestive of a peroxisomal disorder. Detailed studies revealed normal values for all peroxisomal parameters studied except for the accumulation of diand trihydroxycholestanoic acids. The results of this study are described here.

Phenylalanine loading tests in genetic counselling: 5 Years experience with its premarital use

Genetic counselling has been given to 71 engaged couples at risk of producing a phenylketonuric child. Five marriages were not recommended. None of the 51 children born to the recommended marriages has phenylketonuria.

Lathosterol and Noncholesterol Sterols in Routine Use for the Differentiation and Monitoring of Dietary and Drug Induced Treatment of Hypercholesterolemias in Children and Adolescents

Aims : The authors discuss their 15 years of experience with use of noncholesterol sterols (NCS) when diagnosing heterozygous familial hypercholesterolemia (HFH) and the dietary and drug treatment of children and adolescents when lathosterol (Lat) and desmosterol (Des) as cholesterol synthesis precursors, and campesterol (Cam) and sitosterol (Sit) as cholesterol absorption precursors are included. Patients and Methods : 38 children and adolescents (6-18 yrs) with HFH proven by molecular genetic testing of LDL-cholesterol deficit; 107 children patients with clinical and laboratory symptoms of other hypercholesterolemias; 84 healthy school-age children as a control group. Routine lipid spectrum scan—total cholesterol (TCh), LDL-Ch, HDL-Ch, TAG, with additional apo A1, apo B, Lp (a), LDL-receptors, apo E polymorphism; Lat, Des, Cam and Sit in the plasma—was established by means of GC/MS. Results : The HFH patients on a low cholesterol diet (LCHD) who come to our lipid outpatient clinic have elevated levels of Lat and Des, unlike patients with alimentary hypercholesterolemia (p<0, 001). Lat and Des levels are high following interruption of medical treatment during long vacations or when drug treatment is neglected. Administration of statins only in sufficiently high therapeutic doses reduces Lat and Des (p<0, 001). Compensatory elevation of Cam and Sit occurs only in few pediatric patients. Ezetimibe decreases Cam and Sit more efficiently than Lat or Des. Combination of statin with ezetimibe is most efficient in decrease of not only TCh but also Lat and Des, as well as Cam and Sit. Conclusions : Extending the laboratory spectrum by precursors of cholesterol synthesis and absorption improves the differential diagnosis of HFH and makes monitoring and/or treatment of children and adolescents more precise.

Urinary pterins in Lesch-Nyhan syndrome.

The Lesch-Nyhan syndrome results from a complete deficiency of the purine salvage enzyme hypoxanthine guanine phosphoribosyltransferase (HPRT E.C.2.4.2.8). Clinical manifestations include muscle hypotonia, torsion dystonia, delayed motor development, compulsive self-mutilative behaviour, and mental handicap, as well as increased quantities of uric acid in body fluids, which may lead to nephropathy, renal calculi, tophi and gouty arthritis. The latter manifestations are effectively controlled using allopurinol and the pathophysiological mechanism of overproduction of uric acid is known. However, there is no effective treatment for the neurologic and behavioural features and the processes by which a lack of HPRT brings about the neurological dysfunction remain unclear (1).