Search

Aims : To demonstrate the origin and the diagnostic significance of non-cholesterol sterols (NCSs) in healthy pregnant women with gestational hypercholesterolemia. Patients and Methods: Based on a total of 21,000 clinical biochemistry tests of healthy pregnant women with hypercholesterolemia observed during pregnancy, a group of 84 women with TC (total cholesterol) >7.0 mmol/L was recruited to analyze their NCSs using Gas Chromatography–Mass Spectrometry. The NCSs under examination comprised lathosterol (Lat) and desmosterol (Des) as markers of endogenous cholesterol synthesis, and campesterol (Cam) and sitosterol (Sit) as markers for intestinal absorption. Results : In the total of 21,000 pregnant women, the median values were: TC 6.8 mol/l, LDL-C 4.6 mmol/L, and HDL-C 2.2 mmol/L. In the testing group of 84 women, the average values were: Lat 7.8+/-1.7 I¼mol/L, Des 4.7+/-0.9 I¼mol/L, Cam 9.8+/-2.6 I¼mol/L, and Sit 9.6 +/-3.8 I¼mol/L. Lat was found to correlate with TC (r = 0.53), LDL-C (r = 0.36), and non-HDL-C (r = 0.35). No such correlations were observed for Sit (r = 0.162) or Cam (r = 0.153). Conclusion : Our findings show that the high incidence of hypercholesterolemia during pregnancy is caused by increased endogenous cholesterol synthesis via lathosterol. The enormous rise of TC levels during pregnancy can be effectively used to detect familial hypercholesterolemia in women.

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

Several recent studies describing a solely vascular presentation of cystathionine beta-synthase (CBS) deficiency in adulthood prompted us to analyze the frequency of patients manifesting with vascular complications in the Czech Republic. Between 1980 and 2009, a total of 20 Czech patients with CBS deficiency have been diagnosed yielding an incidence of 1:311,000. These patients were divided into three groups based on symptoms leading to diagnosis: those with vascular complications, with connective tissue manifestation and with neurological presentation. A vascular event such as a clinical feature leading to diagnosis of homocystinuria was present in five patients, while two of them had no other symptoms typical for CBS deficiency at the time of diagnosis. All patients with the vascular manifestation were diagnosed only during the past decade. The median age of diagnosis was 29 years in the vascular, 11.5 years in the connective tissue and 4.5 years in the neurological group. The ratio of pyridoxine responsive to nonresponsive patients was higher in the vascular (4 of 5 patients) and connective tissue groups (6 of 7 patients) than in the neurological group (2 of 8 patients). Mutation c.833T>C (p.I278T) was frequent in patients with vascular (6/10 alleles) and connective tissue presentation (8/14 alleles), while it was not present in patients with neurological involvement (0/16 alleles). During the last decade, we have observed patients with homocystinuria diagnosed solely due to vascular events; this milder form of homocystinuria usually manifests at greater ages, has a high ratio of pyridoxine responsiveness/nonresponsiveness, and the mutation c.833T>C (p.I278T) is often present.

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.

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.

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

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 C 29 -dicarboxylic bile acid, all known to occur in plasma from Zellweger patients. These results suggest an isolated defect in the peroxisomal β-oxidation of the side chains of the cholestanoic acids. Activation of trihydroxycholestanoic acid and β-oxidation of trihydroxycholestanoyl-CoA, measured in a liver biopsy, were normal, however, as was the peroxisomal β-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.

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.

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.

Disturbances of phenyalanine metabolism have a relatively high incidence in Slavonic populations in comparison with other populations (Thalhammer et al., 1975). The aim of this study is to find out whether the incidence of cystinuria (McKusick 22010) among newborns, normals or mentally retarded populations also differs from the findings of Levy (1973), Smith and Procopis (1975) and Moore et al. (1972).

The FEL-EXPERT shell and its versions are briefly described in the first part of the chapter. The main focus is clinical applications developed under the FEL-EXPERT project which are oriented towards genetic counselling.

LOWE ET AL 1 have described a disease characterized by organic aciduria, decreased renal ammonia production, hydrophthalmos, and mental retardation. Since their original report, approximately 50 cases have been published. 2 The disease is called the oculocerebrorenal syndrome or Lowe's syndrome. It is a congenital condition, manifested by ocular defects (cataracts, glaucoma, nystagmus), central nervous system defects (mental retardation, generalized hypotonia, tendon hyporeflexia), and kidney damage (permanent proteinuria). Biochemical abnormalities include metabolic acidosis, proteinuria, hyperamino-aciduria, and organic aciduria. All patients with this syndrome described to date have been of the male sex with the exception of the cases of Scholten. 3 The purpose of this paper is to report an example of Lowe's syndrome occurring in a female child. Report of a Case History. —This female child was the product of the mother's second pregnancy. The mother and father are living and well. An 8-year-old sister and a younger brother

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).

The intellectual development and school performance of 81 adolescents with hyperphenylalaninaemia type I between the ages 15 and 19 years were evaluated in a retrospective study. All adolescents were born between 1975-1979. In spite of the continuous changes and improvement of dietary treatment, there were no differences in the dietary approach in all phenylketonuria centres involved. A significant negative correlation between IQ of adolescents with phenylketonuria and the onset of dietary treatment was observed (r = -0.37, P0.01). The best school performance was found in the group of adolescents with dietary therapy which was introduced in the first weeks of life. There was no correlation between IQ of the adolescents and their phenylalanine level in the neonatal period. There was a significant negative correlation between IQ of adolescents and the average level of blood phenylalanine in the first 5 years of life (r = -0.42, P0.01), but this correlation was less significant later on and was not present after the age of 14 years. Dietary compliance was much more difficult to achieve in adolescence than in childhood.

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.

The first described “cases” of histidinaemia were accompanied with typical clinical symptoms—speech disturbances. The purpose of this paper is to establish the blood and urine levels of histidine and its metabolites found in patients presenting with speech neuroses.