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Biomedical subjects

W L Nyhan

Publications and source records attributed to W L Nyhan.

At least 19 recordsLinked to original sources
PubMed1992

A new quantitative assay for glycosaminoglycans.

A direct dye-binding technique has been developed to measure total glycosaminoglycans in urine. Fifty or 100 microliters of urine was mixed with a solution of Azure A (10 mg/l) and Azure B (10 mg/l) and the resulting decrease in absorbance at 610 nm was measured. The standard curve with chondroitin sulfate C was linear from 1 to 20 micrograms/assay. The normal value for total urinary glycosaminoglycans in adults was 1.8 +/- 0.6 g/mol creatinine. Other normal values were age-dependent. The assay is inexpensive, simple, precise, sensitive and suitable for screening for the mucopolysaccharidoses in pediatric patients.

Adolescent↗
PubMed1992

Histidinuria: defective transport of histidine.

A-7-year-old boy was found to have histidinuria without histidinemia. Low concentrations of histidine in plasma were consistent with impaired intestinal and renal tubular absorption of histidine. The patient was developmentally delayed and had some minor anomalies. Only 4 other patients in 3 families have been reported. Each had abnormality of the central nervous system. All were male.

Child↗
PubMed1992

Hawkinsinuria in two families.

Hawkinsinuria, a disorder of tyrosine metabolism has been documented in two families in the United States, in one of which there was clear evidence of autosomal dominant inheritance. Metabolic acidosis and failure to thrive appear to be confined to infancy. Tyrosyl metabolites and 5-oxoproline are also found only in infancy, while 4-hydroxycyclohexylacetic acid was present only with time. The disease may be detected by organic acid analysis or by staining an electropherogram for sulfur containing compounds.

Acidosis↗
PubMed1992

An unusual presentation of medium-chain acyl coenzyme A dehydrogenase deficiency.

OBJECTIVE: To report an atypical presentation of medium-chain acyl Coenzyme A dehydrogenase deficiency in a 13-year-old girl with hyperammonemic encephalopathy and orotic aciduria meeting the accepted criteria for diagnosis of a female heterozygous for ornithine transcarbamylase deficiency. DESIGN: Case report and definitive biochemical testing. SETTING: Children's hospital and university laboratory. PARTICIPANT: One teenager. INTERVENTIONS: Diagnosis and treatment with carnitine. MEASUREMENTS/MAIN RESULTS: Assay ornithine transcarbamylase deficiency had normal results. The diagnosis was confirmed by DNA analysis, which revealed homozygosity for prevalent mutation (the adenine to guanine transition at position 985). CONCLUSIONS: Patients with a clinical diagnosis of Reye's syndrome have, in general, an inborn error of metabolism. Medium-chain acyl Coenzyme A dehydrogenase deficiency and other disorders of fatty acid oxidation may present long after infancy. They may mimic the presentation of defects in the urea cycle.

Adolescent↗
PubMed1992

Characterization of mutations in phenotypic variants of hypoxanthine phosphoribosyltransferase deficiency.

The Lesch-Nyhan disease is caused by an almost complete lack of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). Partial HPRT-deficiency, associated with less severe phenotype, has also been identified. We have characterized mutations occurring in HPRT cDNA isolated from patients with HPRT-deficiency with an emphasis on examining the more unusual partial variants of HPRT-deficiency. HPRT cDNA was amplified by PCR, cloned and analyzed by automated DNA sequence analysis. Twenty-two, unrelated individuals with HPRT deficiency were studied including eight classic Lesch-Nyhan patients and fourteen patients representing the different groups of partial HPRT deficiency. We found a diverse pattern of mutations with point mutations accounting for the majority of abnormal HPRT genes. Nonsense mutations and exon deletions were only found in HPRT cDNA isolated from classic Lesch-Nyhan patients. Mutations associated with partial HPRT-deficiency were frequently located in the amino terminal part of the molecule. A CpG mutational hot spot was identified at the position for Arg-51 in the HPRT protein. Two hyperuricemic patients exhibited unusual splice site mutations: in one this led to the creation of an additional exon in the HPRT gene and in the other part of exon 6 was missing in a subpopulation of the transcripts, producing the effect of a dominant, negative mutation.

Amino Acid Sequence↗
PubMed1992

Neurological diseases in disorders of organic acids.

Organic acidemias remain a significant cause of mortality and morbidity, particularly resulting in neurological sequelae. The rapid recent expansion of technology has resulted in significant advances in the diagnosis of the disorders, but it can still be quite difficult. Recognition of specific features on neuroimaging can complement the biochemical and clinical assessment. Disorders of fatty acid oxidation have recently been recognized. It has become apparent that they occur more frequently and with a much wider clinical and biochemical spectrum than previously thought.

Acidosis↗
PubMed1991

A new immunochemical assay for biotin.

A double antibody technique has been developed to separate free biotin from bound biotin after competitive binding of [3H]biotin and unlabelled biotin to avidin. Antiavidin goat antibody was added followed by the addition of antigoat IgG antibody linked to agarose. Centrifugation separated the free biotin from the biotin bound to the avidin complex. The method was suitable for the detection of the amounts of biotin contained in 100-200 microliters of plasma or 5-10 microliters of urine. Normal values for the concentration of biotin in plasma and urine determined by this assay were 1.27 +/- 0.67 nmol/l and 49.1 +/- 35.7 mumol/mol creatinine, respectively.

Animals↗
PubMed1991

Osteodysplastic variant of primordial dwarfism.

A patient with intrauterine growth retardation and marked postnatal retardation of growth had microcephaly and the orofacial and dental characteristics of the Seckel phenotype. In addition she had short forearms, metaphyseal flare, especially of the distal femora, triangular distal femoral epiphyses, and pseudoepiphyses of the hands, all characteristics of an osteodysplastic variant. Parental consanguinity suggests autosomal recessive inheritance.

Abnormalities, Multiple↗
PubMed1991

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.

Adult↗
PubMed1991

Urinary excretion of 2-methylacetoacetate, 2-methyl-3-hydroxybutyrate and tiglylglycine after isoleucine loading in the diagnosis of 2-methylacetoacetyl-CoA thiolase deficiency.

The concentrations of 2-methylacetoacetate, 2-methyl-3-hydroxybutyrate and tiglylglycine were determined by gas chromatography-mass spectrometry in urine collected before and for 8 h after loading with 100 mg of isoleucine per kg of body weight. The sum of 2-methylacetoacetate and 2-butanone, a decarboxylation product, was determined as the 2-butanone dinitrophenylhydrazone derivative. Substantial increases in each compound were encountered in a patient with a documented defect of 2-methylacetoacetyl-CoA thiolase. Increased quantities of 2-methyl-3-hydroxybutyrate and tiglylglycine were also found in four children with clinical symptoms similar to those associated with 2-methylacetoacetyl-CoA thiolase deficiency but in whom the activity of the enzyme was found to be normal. The concentration of 2-methylacetoacetate plus 2-butanone in the urine increased after an isoleucine load only in the patient with 2-methylacetoacetyl-CoA thiolase deficiency.

Acetoacetates↗
PubMed1991

Metabolism of 1-13C-propionate in vivo in patients with disorders of propionate metabolism.

Metabolism of propionate in human subjects was studied using bolus administration of 1-13C-propionate i.v. or orally. The study population consisted of five patients with propionic acidemia (PA), eight with methylmalonic acidemia (MMA; four responsive to vitamin B12), one each with multiple carboxylase deficiency and transcobalamin-II deficiency, and five healthy volunteers. Concentrations of 1-13C-propionate were measured in blood in three patients with PA, two with MMA, and two controls. Breath samples were obtained at intervals during 3 h after the dose, isotopic enrichment of 13CO2 was measured, and the cumulative percentage of recovery of 13C was calculated from the individual's predicted resting energy expenditure. Recovery of 13CO2 and half-time of 1-13C-propionate in PA were significantly less than normal. The same parameters in MMA were below normal, but significantly greater than in PA. Recovery of 13CO2 was well correlated with clinical severity in PA, but did not correlate in MMA. Differences between MMA and PA may indicate different distribution of propionate pools, differences in inducibility of residual enzyme activities, or an alternate pathway for decarboxylation of propionate available in MMA but not PA. Only one patient with PA demonstrated increased 13CO2 production during biotin treatment. In a B12-responsive MMA patient, no differences were noted within 2 d of initiating treatment with B12, but there was an increase in 13CO2 production after 4 mo. Recovery of 13CO2 was normal in the patient with transcobalamin-II deficiency before and after treatment with vitamin B12.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

3-Hydroxyisobutyric aciduria: an inborn error of valine metabolism.

3-Hydroxyisobutyric aciduria, a disorder of valine metabolism, has been found in a boy in whom the clinical picture was that of a typical organic acidemia with repeated episodes of ketoacidosis requiring admission to hospital and parenteral fluid therapy, along with impressive failure to thrive and chronic lactic acidemia. The excretion of 3-hydroxyisobutyric acid ranged from 170 to 390 mmol/mol of creatinine. The administration of valine increased this to 18,700 mmol/mol of creatinine and reproduced the clinical picture of ketoacidosis. Concentrations of free carnitine were low, and esterified carnitine was elevated. Treatment with carnitine and a diet restricted in protein appeared to be beneficial.

Amino Acid Metabolism, Inborn Errors↗
PubMed1990

Transcobalamin II deficiency presenting with methylmalonic aciduria and homocystinuria and abnormal absorption of cobalamin.

An infant with deficiency of transcobalamin II (TCII) presented with virtually complete failure to thrive and life-threatening pancytopenia. Methylmalonic acid and homocystine were found in the urine. The concentration of B12 in the serum was 26 pg/ml. Fibroblasts derived from the patient failed to take up labeled cobalamin in the absence of a source of TCII. Uptake was normal in the presence of TCII. Treatment with parenteral cobalamin reversed the clinical and hematological manifestations of the disease but she developed glossitis when the interval between injections was lengthened. Intestinal absorption of 57Co-cobalamin was less than 1% and remained abnormal when highly purified human intrinsic factor was given along with the labeled B12. Absorption improved when the labeled B12 was given together with rabbit TCII. The data suggest that TCII as well as intrinsic factor is required for transport of cobalamin from the intestine to the blood.

Failure to Thrive↗
PubMed1990

Stable isotope dilution analysis of 4-hydroxybutyric acid: an accurate method for quantification in physiological fluids and the prenatal diagnosis of 4-hydroxybutyric aciduria.

A quantitative assay for 4-hydroxybutyric acid was developed using D6-4-hydroxybutyric acid as an internal standard. 4-Hydroxybutyric acid was isolated by liquid chromatography and the amount quantified by selected ion monitoring, ammonia chemical ionization gas chromatography/mass spectrometry of the trimethylsilyl derivatives. The concentrations of 4-hydroxybutyric in control physiological fluids were: 2.64 +/- 3.46 mmol mol-1 creatinine in urine, 1.09 +/- 2.87 mumol l-1 in plasma, 0.98 +/- 1.17 mumol l-1 in cerebrospinal fluid and 1.28 +/- 0.47 mumol l-1 in amniotic fluid. The concentration of 4-hydroxybutyric acid in the amniotic fluid from a pregnancy at risk for 4-hydroxybutyric aciduria was 2.30 mumol l-1, indicating an unaffected fetus. The stable isotope dilution assay of 4-hydroxybutyric acid in physiological fluid samples is a rapid, sensitive and accurate method for quantification, as well as a valuable technique for the prenatal diagnosis of 4-hydroxybutyric aciduria.

Acidosis↗
PubMed1990

Cytochrome c oxidase deficiency in muscle with dicarboxylic aciduria and renal tubular acidosis.

A patient with deficient activity of cytochrome c oxidase in muscle presented at 1 year of age with extreme failure to thrive. He was found to have dicarboxylic aciduria, renal tubular acidosis, and deficiency of carnitine. Treatment with sodium bicarbonate, riboflavin, and carnitine led to considerable improvement in growth and a significant reduction in the dicarboxylic aciduria.

Acidosis, Renal Tubular↗