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Biomedical subjects

Ron A Wevers

Publications and source records attributed to Ron A Wevers.

At least 37 records · Page 2Linked to original sources
PubMed2004

A combined defect in the biosynthesis of N- and O-glycans in patients with cutis laxa and neurological involvement: the biochemical characteristics.

Based on our preliminary observation of abnormal glycosylation in a cutis laxa patient, nine cutis laxa patients were analyzed for congenital defects of glycosylation (CDG). Isoelectric focusing of plasma transferrin and apolipoproteinC-III showed that three out of nine patients had a defect in the biosynthesis of N-glycans and core 1 mucin type O-glycans, respectively. Mass spectrometric N-glycan analyses revealed a relative increase of glycans lacking sialic acid and glycans lacking sialic acid and galactose residues. Mutation analysis of the fibulin-5 gene (FBLN5), which has been reported in cases of autosomal recessive cutis laxa, revealed no mutations in the patients' DNA. Evidence is presented that extracellular matrix (ECM) proteins of skin are likely to be highly glycosylated with N- and/or mucin type O-glycans by using algorithms for predicting glycosylation. The conclusions in this study were that the clinical phenotype of autosomal recessive cutis laxa seen in three patients is not caused by mutations in the FBLN5 gene. Our findings define a novel form of CDG with cutis laxa and neurological involvement due to a defect in the sialylation and/or galactosylation of N- and O-glycans. Improper glycosylation of ECM proteins of skin may form the pathophysiological basis for the cutis laxa phenotype.

Apolipoproteins C↗
PubMed2004

beta-Ureidopropionase deficiency: an inborn error of pyrimidine degradation associated with neurological abnormalities.

beta-Ureidopropionase deficiency is an inborn error of the pyrimidine degradation pathway, affecting the cleavage of N-carbamyl-beta-alanine and N-carbamyl-beta-aminoisobutyric acid. In this study, we report the elucidation of the genetic basis underlying a beta-ureidopropionase deficiency in four patients presenting with neurological abnormalities and strongly elevated levels of N-carbamyl-beta-alanine and N-carbamyl-beta-aminoisobutyric acid in plasma, cerebrospinal fluid and urine. No beta-ureidopropionase activity could be detected in a liver biopsy obtained from one of the patients, which reflected the complete absence of the beta-ureidopropionase protein. Analysis of the beta-ureidopropionase gene (UPB1) of these patients revealed the presence of two splice-site mutations (IVS1-2A>G and IVS8-1G>A) and one missense mutation (A85E). Heterologous expression of the mutant enzyme in Escherichia coli showed that the A85E mutation resulted in a mutant beta-ureidopropionase enzyme without residual activity. Our results demonstrate that the N-carbamyl-beta-amino aciduria in these patients is due to a deficiency of beta-ureidopropionase, which is caused by mutations in the UPB1 gene. Furthermore, an altered homeostasis of beta-aminoisobutyric acid and/or increased oxidative stress might contribute to some of the clinical abnormalities encountered in patients with a beta-ureidopropionase deficiency. An analysis of the presence of the two splice site mutations and the missense mutation in 95 controls identified one individual who proved to be heterozygous for the IVS8-1G>A mutation. Thus, a beta-ureidopropionase deficiency might not be as rare as is generally considered.

Amidohydrolases↗
PubMed2004

High-resolution 1H NMR spectroscopy of amniotic fluids from spina bifida fetuses and controls.

OBJECTIVE: To quantify proton containing metabolites by in vitro 1H NMR spectroscopy of amniotic fluids from fetuses with spina bifida and controls. STUDY DESIGN: Fourteen amniotic fluids from spina bifida fetuses and 18 controls were obtained. Concentrations of carbohydrates, organic acids and amino acids were determined. Multiple linear regression analysis was used to evaluate the data. RESULTS: At 15 and 39 weeks amenorrhea, the estimated median amniotic fluid concentrations of succinic acid and glutamine were significantly higher in the spina bifida group compared to controls, 37 and 64%, respectively. Whereas creatine and creatinine were significantly lower, 27 and 36%, respectively. Amenorrhea influenced the concentrations of most compounds with the exception of lactic acid. CONCLUSION: 1H NMR spectroscopy shows significantly higher succinic acid and glutamine concentrations in amniotic fluids derived from spina bifida fetuses compared with controls. A derangement in amino acid metabolism is suggested.

Adult↗
PubMed2004

Myo-inositol, glucose and zinc status as risk factors for non-syndromic cleft lip with or without cleft palate in offspring: a case-control study.

OBJECTIVE: To investigate myo-inositol, glucose and zinc status in mothers and their infants on cleft lip with or without cleft palate risk (CLP). DESIGN: Case-control study. SETTING: University Medical Centre Nijmegen, the Netherlands. POPULATION: Eighty-four mothers and their CLP child and 102 mothers and their healthy child. METHODS: Venous blood samples were obtained to determine serum myo-inositol and glucose and red blood cell zinc concentrations in mothers and children. Geometric means were calculated and compared between the groups. The blood parameters were dichotomised with cutoff points based on control values, P90 for glucose concentrations. MAIN OUTCOME MEASURES: Geometric means (P5-P95) and odds ratios (95% confidence intervals). RESULTS: The CLP children (P= 0.003) and their mothers (P= 0.02) had significantly lower red blood cell zinc concentrations than controls. A low maternal serum myo-inositol concentration (<13.5 micromol/L) and a low red blood cell zinc concentration (<189 micromol/L) increased CLP risk [odds ratio 3.0 (95% CI 1.2-7.4) and 2.0 (95% CI 0.8-4.8), respectively]. Children with low myo-inositol (<21.5 micromol/L ) or low red blood cell zinc concentrations (<118 micromol/L) were more likely to have CLP [odds ratio 3.4 (95% CI 1.3-8.6) and 3.3 (95% CI 1.3-8.0), respectively]. Glucose was not a risk factor for CLP in mothers and children. Maternal and child myo-inositol as well as zinc concentrations were slightly, albeit significantly correlated, r(Pearson)= 0.33 (P= 0.0006) and r(Pearson)= 0.23 (P= 0.01), respectively. CONCLUSION: This study demonstrates for the first time that zinc and myo-inositol are important in the aetiology of CLP.

Adult↗
PubMed2003

N-acetylated metabolites in urine: proton nuclear magnetic resonance spectroscopic study on patients with inborn errors of metabolism.

BACKGROUND: There is no comprehensive analytical technique to analyze N-acetylated metabolites in urine. Many of these compounds are involved in inborn errors of metabolism. In the present study, we examined the potential of proton nuclear magnetic resonance ((1)H-NMR) spectroscopy as a tool to identify and quantify N-acetylated metabolites in urine of patients with various inborn errors of metabolism. METHODS: We performed (1)H-NMR spectroscopy on a 500 MHz spectrometer. Using a combination of one- and two-dimensional correlation spectroscopy (COSY) (1)H-NMR spectra, we were able to assign and quantify resonances of characteristic N-acetylated compounds products in urine of patients with 13 inborn errors of metabolism. RESULTS: The disease-specific N-acetylated metabolites were excreted at concentrations >100 micromol/mmol of creatinine in the patients' urine. In control urine samples, the concentration of individual N-acetyl-containing compounds was <40 micromol/mmol of creatinine. The combination of one- and two-dimensional COSY NMR spectroscopy led to the correct diagnosis of nine different inborn errors of metabolism. No abnormalities were observed in the spectra of urine from patients with G(M1)- or G(M2)-gangliosidosis. We also determined the (1)H-NMR characteristics of N-acetylated metabolites that may be relevant to human metabolism. CONCLUSION: (1)H-NMR spectroscopy may be used to identify and quantify N-acetylated metabolites of diagnostic importance for the field of inborn errors of metabolism.

Acetates↗
PubMed2003

Late-Onset visceral presentation with cardiomyopathy and without neurological symptoms of adult Sanfilippo A syndrome.

Sanfilippo A syndrome, mucopolysaccharidosis type IIIA, is caused by a deficiency of heparan sulphamidase activity, and usually presents in childhood with neurodegeneration leading to death in teenage years. Visceral symptoms are limited to coarsening and diarrhea. We now describe an adult patient who presented with cardiomyopathy. At age 45 years she had hypertension, and the next year she developed a progressively worsening cardiomyopathy with prominent apical hypertrophy and atrial fibrillation. At age 53, she had severe concentric hypertrophic nonobstructive cardiomyopathy in both ventricles. There was no coarsening of features. Neurologic function, skeleton, cornea, liver, and spleen were normal. Percutaneous endomyocardial biopsy showed ballooned cardiomyocytes with storage vacuoles, containing acid mucopolysaccharides. Leucocytes, uterus, and brain biopsy did not show this storage material. There was a slight increase in total urine mucopolysaccharides, with an increased proportion of heparan sulfates. Heparan sulphamidase activity was deficient in leukocytes and heparan sulphamidase protein and activity were reduced in cultured fibroblasts. No mutations were identified after sequencing of the heparan sulphamidase gene at the cDNA and the genomic level. This new clinical presentation expands the clinical spectrum of Sanfilippo A syndrome to include a primary visceral presentation of cardiomyopathy without neurologic symptoms in the adult. The late onset may be related to the residual heparan sulphamidase activity. The genetic basis of this new variant is still unclear. Physicians evaluating adults must remain aware of possible new adult presentations of storage conditions.

Cardiomyopathies↗
PubMed2003

Tyrosine hydroxylase deficiency causes progressive encephalopathy and dopa-nonresponsive dystonia.

Tyrosine hydroxylase (TH) is the key enzyme in the biosynthesis of the catecholamines dopamine, epinephrine, and norepinephrine. Recessively inherited deficiency of TH was recently identified and incorporated into recent concepts of genetic dystonias as the cause of recessive Dopa-responsive dystonia or Segawa's syndrome in analogy to dominantly inherited GTP cyclohydrolase I deficiency. We report four patients with TH deficiency and two with GTP cyclohydrolase I deficiency. Patients with TH deficiency suffer from progressive infantile encephalopathy dominated by motor retardation similar to a primary neuromuscular disorder, fluctuating extrapyramidal, and ocular and vegetative symptoms. Intellectual functions are mostly compromised. Prenatally disturbed brain development and postnatal growth failure were observed. Treatment with levodopa ameliorates but usually does not normalize symptoms. Compared with patients with dominantly inherited GTP cyclohydrolase I deficiency, catecholaminergic neurotransmission is severely and constantly impaired in TH deficiency. In most patients, this results not in predominating dystonia, a largely nondegenerative condition, but in a progressive often lethal neurometabolic disorder, which can be improved but not cured by L-dopa. Investigations of neurotransmitter defects by specific cerebrospinal fluid determinations should be included in the diagnostic evaluation of children with progressive infantile encephalopathy.

Amino Acid Metabolism, Inborn Errors↗
PubMed2003

Maternal myo-inositol, glucose, and zinc status is associated with the risk of offspring with spina bifida.

OBJECTIVE: The purpose of this study was to investigate the maternal and children's myo-inositol, glucose, and zinc status in association with spina bifida risk. STUDY DESIGN: Sixty-three mothers and 70 children with spina bifida and 102 control mothers and 85 control children were investigated. The maternal and child serum myo-inositol, serum glucose, and red blood cell zinc concentrations were measured when the child was between 1 and 3 years old. These data were compared between cases and control subjects. The association with spina bifida was expressed by the ratio of geometric means and by odds ratios and 95% CI for a cutoff value at the extreme 10th percentile of the control group. RESULTS: The geometric mean of the maternal myo-inositol concentration tended to be 5% (95% CI, -1% to 11%) lower in cases. Interestingly, the odds ratio for the extreme low maternal myo-inositol concentration was 2.6 (95% CI, 1.1-6.0). The glucose and zinc concentrations were significantly higher at 7% (95% CI, 4%-10%) and significantly lower at 5% (95% CI, 0%-9%), in case mothers compared with control mothers. The odds ratios (95% CI) for maternal high glucose and low zinc concentrations were 4.6 (2.0-10.5) and 2.9 (1.2-7.0), respectively. The geometric mean of the myo-inositol concentration tended to be 7% (95% CI, 0%-14%) lower in children with spina bifida; the glucose and zinc concentrations were comparable. CONCLUSION: Maternal myo-inositol, glucose, and zinc status are associated with the risk of spina bifida in offspring. Furthermore, the myo-inositol status of the child seems to contribute to this risk as well.

Adult↗
PubMed2003

Are myo-inositol, glucose and zinc concentrations in amniotic fluid of fetuses with spina bifida different from controls?

OBJECTIVE: Associations are reported between myo-inositol, glucose, zinc and the occurrence of spina bifida. To gain more insight into the pathogenesis of spina bifida, the concentrations of myo-inositol, glucose and zinc were determined in amniotic fluids from pregnancies with a spina bifida or unaffected control fetus. METHODS: Amniotic fluids of 27 pregnancies complicated by spina bifida and 49 controls were collected at the Department of Obstetrics and Gynecology of the University Medical Center Nijmegen in the Netherlands. Myo-inositol, glucose and zinc concentrations were determined. By indication, the samples were taken at different gestational ages. Therefore, the data were evaluated using multiple linear regression analysis to adjust for gestational age. RESULTS: Amniocentesis was performed at a more advanced gestational age in the spina bifida group than in controls. In the spina bifida group, amniotic fluid myo-inositol, glucose and zinc concentrations gradually declined throughout pregnancy. At a gestational age of 15 weeks, the estimated mean amniotic fluid glucose and zinc concentrations in the spina bifida group were, respectively, significantly lower (p< or =0.5) and higher (p< or =0.5) compared with the control group. At the same gestational age, the estimated mean myo-inositol concentrations were comparable in both groups. At a gestational age of 38 weeks, the estimated mean myo-inositol, glucose and zinc concentrations were not significantly different in the spina bifida compared with the control group. CONCLUSION: This study may suggest that a derangement in zinc and glucose transfer or metabolism is associated with spina bifida. Since compounds in amniotic fluid are only a very crude marker of the actual fetal condition, studies that focus on the metabolism of these compounds on tissue or even cellular level should be performed to clarify their role in the pathogenesis and future prevention of spina bifida.

Adult↗
PubMed2003

Cobalamin-binding proteins in normal and cobalamin-deficient older subjects.

BACKGROUND: The causes of cobalamin (vitamin B(12)) deficiency in older people are only partly understood. We investigated the role of the cobalamin-binding proteins and tested the hypothesis that low saturated transcobalamin concentration is an early marker of cobalamin deficiency. METHODS: We measured saturated (holo) and unsaturated (apo) transcobalamin and haptocorrin concentrations in healthy middle-aged volunteers, healthy older volunteers, cobalamin-deficient older volunteers and cobalamin-deficient older patients. RESULTS: Holo and apo concentrations of transcobalamin and haptocorrin were similar in healthy middle-aged and older subjects. Holotranscobalamin concentrations were significantly decreased in cobalamin-deficient subjects but did not differ between healthy volunteers and patients. Furthermore, the relative amount of cobalamin on transcobalamin (i.e. holotranscobalamin/holotranscobalamin + holohaptocorrin) was similar in all four groups. CONCLUSIONS: Abnormalities of the cobalamin-binding proteins are not a cause of cobalamin deficiency in the aged. Plasma holotranscobalamin concentration did not differ between stages of cobalamin deficiency in older persons. Therefore, plasma holotranscobalamin is not an early marker of cobalamin deficiency in older people and has no additional value in the diagnostic work-up of reduced plasma cobalamin concentrations in older people.

Adult↗
PubMed2003

Kinetics of myo-inositol loading in women of reproductive age.

BACKGROUND: Myo-inositol plays a key role in an important intracellular signalling pathway. A deranged myo-inositol metabolism has been associated with neural tube defects. A myo-inositol loading test was performed to investigate the kinetics in healthy women of reproductive age. METHODS: Five healthy non-obese females [mean age (standard deviation: SD) 22.8 (2.2) years] were recruited at the University Medical Center Nijmegen. Blood samples were drawn fasting and at 20, 40, 60, 90, 180 and 270 min after ingestion of 100 mg/kg body weight of myo-inositol. Urine samples were collected before myo-inositol loading and at 180 and 270 min post-loading. Samples were analysed for serum myo-, epi- and scyllo-inositol and glucose concentrations by gas chromatography. Plasma insulin concentrations were determined by radio-immunoassay. Random intercept models were fitted to evaluate the data. RESULTS: The estimated myo-inositol and scyllo-inositol concentrations both reached maximum values at 180 min post-loading, respectively: mean (SD) 101.5 (9.2) micro mol/L and 1.09 (0.11) micro mol/L. The estimated plasma insulin and serum glucose concentrations decreased slightly but significantly during the experiment: P < 0.0001 and P < 0.05, respectively. At 180 and 270 min post-loading, urinary myo-inositol concentrations were increased and urinary glucose concentrations were unchanged. CONCLUSIONS: Myo-inositol enters the bloodstream quickly after oral ingestion and a small amount of myo-inositol is converted to scyllo-inositol. The synthesis of glucose from myo-inositol could not be detected by serum measurements. These data can be used in further research into the association between myo-inositol and neural tube defects.

Adult↗
PubMed2003

Moderate citrullinaemia without hyperammonaemia in a child with mutated and deficient argininosuccinate synthetase.

In a patient with microcephaly, feeding problems and restlessness, moderately increased serum and urine citrulline concentrations were observed. Protein and allopurinol loading did not result in additional indications for a urea cycle defect. The diagnosis of citrullinaemia was made at both the enzyme and DNA level, resulting from a novel mutation in the argininosuccinate synthetase gene. The fact that the patient has not suffered from severe deterioration, and that there were only minor abnormalities in metabolite concentrations, suggests that the argininosuccinate synthetase capacity was less affected in vivo than in vitro. In vitro nuclear magnetic resonance investigation suggested an active acetylation mechanism for citrulline. This case illustrates the importance of performing extensive biochemical and molecular investigations in order to reach a definitive diagnosis, particularly in instances of moderate citrullinaemia.

Amino Acids↗
PubMed2003

Reversal of clinical symptoms and radiographic abnormalities with protein restriction and ascorbic acid in alkaptonuria.

There is no definitive treatment protocol for alkaptonuria. A patient with alkaptonuria was treated with ascorbic acid (0.5 g/day) from the age of 4 years. He developed episodes of severe recurrent joint pain at 9.5 years of age after which a protein-restricted diet (1.3 g/kg/day) was started. Protein restriction in combination with ascorbic acid therapy (1 g/day in two divided doses) resulted in a significant decrease but not a normalization of the urinary homogentisic acid excretion. Joint pain resolved and the radiological evidence of 'moth-eaten' irregularities on the articular surface in both knees disappeared. He is currently well, growing normally and in nitrogen balance. Our findings document a reversal of bone abnormalities and clinical symptoms in a case of alkaptonuria. The results should be confirmed in a larger study. We suggest that protein restriction should be applied in combination with ascorbic acid in affected patients as soon as joint pain occurs.

Alkaptonuria↗
PubMed2003

Apolipoprotein C-III isofocusing in the diagnosis of genetic defects in O-glycan biosynthesis.

BACKGROUND: Defects in the biosynthesis of N-glycans may be found by isoelectric focusing (IEF) of plasma transferrin. No test is available to demonstrate O-glycan biosynthesis defects. METHODS: We used isoforms of apolipoprotein C-III (apoC-III) as a marker for the biosynthesis of core 1 mucin type O-glycans. Plasma samples from patients with primary defects and secondary alterations in N-glycan biosynthesis were studied by apoC-III isofocusing. RESULTS: Age-related reference values for apoC-III were determined. Plasma samples from patients with the primary congenital disorders of glycosylation (CDG) types Ia-Ic, Ie, If, IIa, and IId all showed a normal apoC-III isofocusing profile. Plasma from two patients with CDG type IIx were tested: one showed a normal apoC-III distribution, whereas the other showed a hypoglycosylation profile. In plasma from patients with hemolytic uremic syndrome (HUS), a hypoglycosylation profile was obtained. CONCLUSIONS: IEF of apoC-III is a rapid and simple technique that may be used as a screening assay for abnormalities in core 1 mucin type O-glycans. Evidence that a patient in this study has a primary genetic defect affecting both N- and O-glycosylation provides the first example of an inborn error of metabolism affecting the biosynthesis of core 1 mucin type O-glycans. Our data narrow the options for the position of the primary defect in this patient down to a step in the biosynthesis, activation, or transfer of galactose or N-acetylneuraminic acid to both N- and O-glycans. Circulating neuraminidase excreted by Streptococcus pneumoniae caused the high percentage of asialo apoC-III in two HUS patients.

Adolescent↗
PubMed2002

Tyrosine hydroxylase deficiency: clinical manifestations of catecholamine insufficiency in infancy.

Inborn errors of catecholamine biosynthesis are rare but of great interest as they are genetic disorders, and in some, treatment may completely reverse severe neurological abnormalities. They also provide insights into the action of the biogenic amines in the developing brain. We describe the clinical course of an infant with tyrosine hydroxylase (TOH) deficiency over a 30-month period. The parents are consanguineous, and genetic analysis revealed the infant to be homozygous for the common G698A mutation in the TOH gene. TOH deficiency can be seen as a model of pure catecholamine deficiency. Experimental evidence, reports of other disorders of biogenic amines, and our experience with this infant suggest that the symptoms of catecholamine deficiency in infancy can be broadly subdivided. Signs of dopamine deficiency include tremor, hypersensitivity to levadopa (L-dopa) therapy, oculogyric crises, akinesia, rigidity, and dystonia. Manifestations of norepinephrine deficiency include ptosis, miosis, profuse oropharyngeal secretions, and postural hypotension. Hypersensitivity to L-dopa was a particular management problem in this infant.

Consanguinity↗
PubMed2002

In vivo quantitative near-infrared spectroscopy in skeletal muscle during incremental isometric handgrip exercise.

The aim of this study was to investigate the performance of in vivo quantitative near-infrared spectroscopy (NIRS) in skeletal muscle at various workloads. NIRS was used for the quantitative measurement of O2 consumption (mVO2) in the human flexor digitorum superficialis muscle at rest and during rhythmic isometric handgrip exercise in a broad range of work intensities (10-90% MVC=maximum voluntary contraction force). Six subjects were tested on three separate days. No significant differences were found in mVO2 measured over different days with the exception of the highest workload. The within-subject variability for each workload measured over the three measurements days ranged from 15.7 to 25.6% and did not increase at the high workloads. The mVO2 was 0.14 +/- 0.01 mlO2 min-1 100 g-1 at rest and increased roughly 19 times to 2.68 +/- 0.58 mlO2 min-1 100 g-1 at 72% MVC. These results show that local muscle oxygen consumption at rest as well as during exercise at a broad range of work intensities can be measured reliably by NIRS, applied to a uniform selected subject population. This is of great importance as direct local measurement of mVO2 during exercise is not possible with the conventional techniques. The method is robust enough to measure over separate days and at various workloads and can therefore contribute to a better understanding of human physiology in both the normal and pathological state of the muscle.

Adult↗
PubMed2002

1H-NMR spectroscopy of cerebrospinal fluid of fetal sheep during hypoxia-induced acidemia and recovery.

The purpose of the study was to investigate the sequence of processes occurring during and after hypoxia-induced acidemia. We used proton nuclear magnetic resonance spectroscopy, which provides an overview of metabolites in cerebrospinal fluid (CSF), reflecting neuronal metabolism and damage. The pathophysiological condition of acute fetal asphyxia was mimicked by reducing maternal uterine blood flow in 14 unanesthetized pregnant ewes. CSF metabolites were measured during hypoxia-induced acidemia, and during the following recovery period, including the periods at 24 and 48 h after the hypoxic insult. Maximum values of the following CSF metabolites were reached during severe hypoxia (pH <or= 7.00): glucose, lactate, pyruvate, hypoxanthine, alanine, beta-hydroxybutyrate, choline, creatine, myo-inositol, citrate, succinate, valine, and an unknown metabolite characterized by a resonance at 1.56 ppm in the proton nuclear magnetic resonance spectrum. Twenty-four hours after the hypoxic insult, myo-inositol was increased, and alanine was decreased 48 h after the hypoxic insult, both compared with control values. Choline levels in CSF had a linear relationship with arterial pH (r = 0.26, p < 0.005). During severe hypoxia, CSF levels of succinate and choline are increased. Increased CSF levels of succinate may indicate dysfunction of the mitochondrial respiratory chain, whereas elevated CSF choline levels may indicate disrupted cell membranes. The increase of the CSF myo-inositol level after 24 and 48 h may indicate osmolytic cell changes causing cell edema. Decreased alanine level may represent changes in the source of excitatory amino acid synthesis.

3-Hydroxybutyric Acid↗