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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
PubMed2004

The spectrum of mutations causing HPRT deficiency: an update.

Mutations in the gene encoding hypoxanthine-guanine phosphoribosyltransferase (HPRT) cause Lesch-Nyhan disease, which is characterized by hyperuricemia, severe motor disability, and self-injurious behavior. Mutations in the same gene also cause less severe clinical phenotypes with only some portions of the full syndrome. A large database of 271 mutations associated with both full and partial clinical phenotypes was recently compiled. Since the original database was assembled, 31 additional mutations have been identified, bringing the new total to 302. The results demonstrate a very heterogeneous collection of mutations for both LND and its partial syndromes. The differences between LND and the partial phenotypes cannot be explained by differences in the locations of mutations, but the partial phenotypes are more likely to have mutations predicted to allow some residual enzyme function. The reasons for some apparent exceptions to this proposal are addressed.

Databases as Topic↗
PubMed2002

Emergency management of inherited metabolic diseases.

Inherited metabolic diseases with acute severe manifestations can be divided into five categories: (1) disorders of the intoxication type, (2) disorders with reduced fasting tolerance, (3) disorders with disturbed energy metabolism, (4) disorders of neurotransmission and (5) disorders in which no specific emergency treatment is available. Diagnostic emergency laboratory evaluation should cover all differential diagnoses that are therapeutically relevant and should always include ammonia, glucose, lactate and acid-base status as well as testing the urine for ketones. These are indispensable for planning and conducting the first steps of metabolic emergency treatment and should be available within 30 min. According to the clinical situation and biochemical derangement, special metabolic investigations must be initiated in parallel. These include acylcarnitine profiling with tandem mass spectrometry (in plasma or dried blood spots) and analysis of amino acids in plasma and of organic acids in urine. The results of all laboratory investigations relevant to the diagnosis of metabolic disorders for which specific emergency therapy exists should be available within 24 h. There is general agreement with regard to some therapeutic strategies that are clearly explained by pathophysiology: in disorders with endogenous intoxication, anabolism must be promoted and specific detoxification measures initiated. In disorders with reduced fasting tolerance, administration of glucose at the rate of hepatic glucose production forms the basis of treatment. Correction of acidosis is a major goal in disorders with disturbed mitochondrial energy metabolism, while glucose supply may have to be limited. Many current therapeutic strategies are based on case reports and personal experiences at different metabolic centres. The aim of devising the 'best' management is often hampered by the lack of objective evidence of efficacy.

Emergency Medical Services↗
PubMed2001

Cloning of the human MCCA and MCCB genes and mutations therein reveal the molecular cause of 3-methylcrotonyl-CoA: carboxylase deficiency.

3-Methylcrotonyl-CoA: carboxylase (EC 6.4.1.4; MCC) deficiency is an inborn error of the leucine degradation pathway (MIM *210200) characterized by increased urinary excretion of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine. The clinical phenotypes are highly variable ranging from asymptomatic to profound metabolic acidosis and death in infancy. Sequence similarity with Glycine max and Arabidopsis thaliana genes encoding the two subunits of MCC permitted us to clone the cDNAs encoding the alpha- and beta-subunits of human MCC. The 2580 bp MCCA cDNA encodes the 725 amino acid biotin-containing alpha-subunit. The MCCA gene is located on chromosome 3q26-q28 and consists of 19 exons. The 2304 bp MCCB cDNA encodes the non-biotin-containing beta-subunit of 563 amino acids. The MCCB gene is located on chromosome 5q13 and consists of 17 exons. We have sequenced both genes in four patients with isolated biotin-unresponsive deficiency of MCC. In two of them we found mutations in the MCCA gene. Compound heterozygosity for a missense mutation (S535F) and a nonsense mutation (V694X) were identified in one patient. One heterozygous mutation (S535F) was found in another patient. The remaining two patients had mutations in the MCCB gene. One consanguineous patient was homozygous for a missense mutation (R268T). In the other we identified a missense mutation in one allele (E99Q) and allelic loss of the other. Mutations were correlated with an almost total lack of enzyme activity in fibroblasts. These data provide evidence that human MCC deficiency is caused by mutations in either the MCCA or MCCB gene.

Carbon-Carbon Ligases↗
PubMed2001

Medium-chain acyl coenzyme A dehydrogenase deficiency: occurrence in an infant and his father.

BACKGROUND: Autosomal recessive inborn errors of metabolism often present as life-threatening disease in infancy and have adverse effects on the nervous system. Parents are usually heterozygotes. This is true of most disorders of fatty acid oxidation, which are rare and present with hypoketotic hypoglycemia. However, the gene for medium-chain acyl coenzyme A dehydrogenase (MCAD) deficiency is common in white people, raising the possibility that a parent may be homozygous. OBJECTIVE: To document the occurrence of MCAD deficiency in a 12-month-old boy and his father, both of whom were homozygous for the A985G mutation. DESIGN: Clinical observations and definitive biochemical testing. SETTING: Children's hospital and university laboratory. PARTICIPANTS: One child and one adult. INTERVENTIONS: Diagnosis and treatment. MAIN OUTCOME MEASURES: Clinical outcome; analysis results of plasma and urine for carnitine and organic acids. RESULTS: An infant admitted with an acute illness requiring intensive care was found to have carnitine deficiency and dicarboxylic aciduria; MCAD deficiency was diagnosed by assay of his DNA for the common mutation. Test results of the father revealed him also to be homozygous. CONCLUSION: In MCAD deficiency, as opposed to the usual rare autosomal recessive metabolic disease, a parent may also be an affected homozygote.

Acyl-CoA Dehydrogenase↗
PubMed2001

Self-injurious behavior: gene-brain-behavior relationships.

This paper summarizes a conference held at the National Institute of Child Health and Human Development on December 6-7, 1999, on self-injurious behavior [SIB] in developmental disabilities. Twenty-six of the top researchers in the U.S. from this field representing 13 different disciplines discussed environmental mechanisms, epidemiology, behavioral and pharmacological intervention strategies, neurochemical substrates, genetic syndromes in which SIB is a prominent behavioral phenotype, neurobiological and neurodevelopmental factors affecting SIB in humans as well as a variety of animal models of SIB. Findings over the last decade, especially new discoveries since 1995, were emphasized. SIB is a rapidly growing area of scientific interest to both basic and applied researchers. In many respects it is a model for the study of gene-brain-behavior relationships in developmental disabilities.

Animals↗
PubMed2001

Nerve conduction changes in patients with mitochondrial diseases treated with dichloroacetate.

Serial measurements of nerve conduction velocities and amplitudes were performed in 27 patients with congenital lactic acidemia over 1 year of sodium dichloroacetate (DCA) administration. Patients were treated with oral thiamine (100 mg) and DCA (initial dose of 50 mg/kg) daily. Nerve conduction velocity and response amplitude were measured in the median, radial, tibial, and sural nerves at 0, 3, 6, and 12 months, and plasma DCA pharmacokinetics were measured at 3 and 12 months. Baseline electrophysiologic parameters in this population were generally below normal but as a group were within 2 standard deviations of normal means. Although symptoms of neuropathy were reported by only three patients or their families, nerve conduction declined in 12 patients with normal baseline studies, and worsening of nerve conduction occurred in the two who had abnormalities at baseline. Peripheral neuropathy appears to be a common side effect during chronic DCA treatment, even with coadministration of oral thiamine. Nerve conduction should be monitored during DCA treatment.

Action Potentials↗
PubMed2001

Creatine kinase and uric acid: early warning for metabolic imbalance resulting from disorders of fatty acid oxidation.

UNLABELLED: In eight patients with disorders of fatty acid oxidation, analysis of uric acid and creatine kinase served as indicators of the underlying disorder in episodes of acute metabolic imbalance. Six patients had deficiency of medium-chain acyl-CoA dehydrogenase, one had long-chain hydroxyacyl-CoA dehydrogenase deficiency, and one very long-chain acyl-CoA dehydrogenase deficiency. The most common presentation was with symptomatic hypoglycemia; there was one Reye-like presentation and one of rhabdomyolysis. The mechanism of the elevation of uric acid and creatine kinase appears to be the breakdown of tissue. CONCLUSION: it is concluded that uric acid and creatine kinase provide a useful alerting signal to the presence of a disorder of fatty acid oxidation. Maximal levels of uric acid in this series were 6.2-21.5 mg/dl and of creatine kinase 879-27,557 U/l.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed2000

Kearns-Sayre syndrome presenting as 2-oxoadipic aciduria.

A patient with 2-oxoadipic aciduria and 2-aminoadipic aciduria presented at 2 years of age with manifestations typical of organic acidemia, episodes of ketosis and acidosis, progressive to coma. This resolved and the key metabolites disappeared from the urine and blood. At 9 years of age she developed typical Kearns-Sayre syndrome with complete heart block, retinopathy, and ophthalmoplegia. Southern blot revealed a deletion in the mitochondrial genome.

2-Aminoadipic Acid↗
PubMed2000

An unexpected affected female patient in a classical Lesch-Nyhan family.

Lesch-Nyhan disease is a genetic disorder of purine metabolism caused by defective activity of the enzyme hypoxanthine-guanine phosphoribosyl transferase (HPRT), resulting from mutation in the corresponding gene on the long arm of the X chromosome (Xq26). The classical phenotype, which includes spasticity, involuntary movements, developmental disability, and self-injurious behavior, occurs exclusively in males, while heterozygous, carrier females are clinically normal. We analyzed an Argentine family in which there were male and female siblings with clinically identical classic features of Lesch-Nyhan disease. The mother and an older daughter were carriers and had normal phenotypes. We identified the HPRT mutation in the family. It is a C --> T transition at position 508 of the cDNA (c.508 C --> T) that changes the CGA codon for Arg(169) to the TGA stop codon (R169X). The female patient was karyotypically normal and heterozygous for the mutation. She inherited the HPRT mutation from her mother, but she also had unexpected nonrandom inactivation of the paternal X chromosome carrying the normal HPRT gene. This additional genetic alteration is the cause of the clinical expression of disease in this female patient.

Adult↗
PubMed2000

The spectrum of inherited mutations causing HPRT deficiency: 75 new cases and a review of 196 previously reported cases.

In humans, mutations in the gene encoding the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) are associated with a spectrum of disease that ranges from hyperuricemia alone to hyperuricemia with profound neurological and behavioral dysfunction. Previous attempts to correlate different types or locations of mutations with different elements of the disease phenotype have been limited by the relatively small numbers of available cases. The current article describes the molecular genetic basis for 75 new cases of HPRT deficiency, reviews 196 previously reported cases, and summarizes four main conclusions that may be derived from the entire database of 271 mutations. First, the mutations associated with human disease appear dispersed throughout the hprt gene, with some sites appearing to represent relative mutational hot spots. Second, genotype-phenotype correlations provide no indication that specific disease features associate with specific mutation locations. Third, cases with less severe clinical manifestations typically have mutations that are predicted to permit some degree of residual enzyme function. Fourth, the nature of the mutation provides only a rough guide for predicting phenotypic severity. Though mutation analysis does not provide precise information for predicting disease severity, it continues to provide a valuable tool for genetic counseling in terms of confirmation of diagnoses, for identifying potential carriers, and for prenatal diagnosis.

Amino Acid Substitution↗
PubMed2000

Dopamine function in Lesch-Nyhan disease.

Lesch-Nyhan disease is a disorder of purine metabolism resulting from mutations in the gene for hypoxanthine guanine phosphoribosyl transferase on the X chromosome. It is characterized by hyperuricemia and all of its consequences, as in gout; but in addition, patients have impressive disease of the central nervous system. This includes spasticity, involuntary movements, and retardation of motor development. The behavioral phenotype is best remembered by self-injurious biting behavior with attendant destruction of tissue. The connection between aberrant metabolism of purines and these neurologic and behavioral features of the disease is not clear. Increasing evidence points to imbalance of neurotransmitters. There is increased excretion of the serotonin metabolite 5-hydroxyindoleacetic acid in the urine. There are decreased quantities and activities of a number of dopaminergic functions. Positron emission tomography scanning has indicated deficiency in the dopamine transporter.

Dopamine↗
PubMed1999

Prenatal diagnosis of holocarboxylase synthetase deficiency by assay of the enzyme in chorionic villus material followed by prenatal treatment.

Deficiency of holocarboxylase synthetase leads to multiple carboxylase deficiency, which is fatal in the absence of prompt diagnosis and treatment with biotin. In a pregnancy at risk for deficiency of holocarboxylase synthetase, prenatal diagnosis was performed by assay of the enzyme in chorionic villus material. The Km for biotin was 220.8 nmol/l, which was 33 times the control value of 6.6 nmol/l. Biotinyl AMP synthesis was undetectable in cultured chorionic villus material. Prenatal treatment of the mother was begun with 10 mg a day of biotin and continued through pregnancy. There was no accumulation of the characteristic metabolites in the urine at birth and prior to oral treatment of the newborn. Holocarboxylase synthetase activity was undetectable in lymphocytes and in fibroblasts of the newborn. Furthermore, the activities of all three carboxylases in fibroblasts of the infant were deficient. The newborn was clinically well and maintained on biotin treatment after birth at 20 mg per day. Carboxylase activities in lymphocytes were normal or slightly lower than the normal range.

Biotin↗
PubMed1999

Neurologic nonmetabolic presentation of propionic acidemia.

BACKGROUND: Patients with propionic acidemia usually present in the neonatal period with life-threatening ketoacidosis, often complicated by hyperammonemia. It was thought that the neurologic abnormalities seen in this disease were exclusively the consequences of these acute crises. Experience with 2 patients with propionic acidemia indicates that this disease may present first with prominent neurologic disease without the life-threatening episodes of ketoacidosis that usually serve as the alerting signals for a diagnosis of an organic acidemia. OBJECTIVE: To examine the clinical and metabolic aspects of 2 patients with a phenotype that suggested disease of the basal ganglia. DESIGN: Examination of patterns of organic acids of the urine and enzyme assay for propionyl-CoA carboxylase in fibroblasts and lymphocytes. SETTING: Referral population to a biochemical genetics laboratory. PATIENTS: Two patients whose prominent features were hypotonia followed by spastic quadriparesis and choreoathetosis. Both had seizures. One patient was mildly mentally retarded but grew normally physically. The other had profound mental retardation and failure to thrive; he also self-mutilated his lower lip. Self-injurious behavior has not been reported in this disease. MAIN OUTCOME MEASURES: Clinical description, blood ammonia levels, organic acid levels in the urine, and enzyme activity. RESULTS: Excretion of metabolites, including methylcitrate, was typical. Residual activity of propionyl-CoA carboxylase approximated 5% of the control in each patient. CONCLUSIONS: Propionic acidemia can present as a pure neurologic disease without acute episodes of massive ketoacidosis. Hyperammonemia may occur after infancy in some patients, presenting as Reye syndrome.

Adult↗
PubMed1999

Prenatal diagnosis and treatment of holocarboxylase synthetase deficiency.

Holocarboxylase synthetase is one of two enzymes known to be involved in the metabolism of biotin. It catalyses the fixation of biotin to inactive apocarboxylases yielding active carboxylases. Deficiency of this enzyme leads to multiple carboxylase deficiency which is fatal in the absence of prompt diagnosis and treatment with biotin. In a pregnancy at risk for deficiency of holocarboxylase synthetase prenatal diagnosis was performed by assay of the enzyme in amniocytes. The Km for biotin was 62.8 nM which was 12 times the control value of 5.0 nM. The Vmax was 2 per cent of the control value. This was confirmed by assay of the activity of propionyl CoA carboxylase (20-26 per cent control), 3-methylcrotonyl CoA carboxylase (14-19 per cent control) and pyruvate carboxylase (12-30 per cent control) and demonstration of biotin responsiveness in vitro. All carboxylase activities were restored to 51-58 per cent of control when amniocytes were cultured in medium containing 1 microM biotin. Diagnosis was ultimately confirmed by assay of holocarboxylase synthetase in lymphocytes from the infant after birth. The Km for biotin of the holocarboxylase synthetase of the infant was 60.3 nM while that of a parallel control was 6.9 nM. Prenatal treatment of the mother with biotin led to a concentration of biotin of 240 nM in the serum of the infant at birth that was four times the Km of the enzyme for biotin. The infant was clinically well at birth, and organic acid analysis of the blood and urine revealed no accumulation of the characteristic metabolites.

Adult↗
PubMed1999

D-2-Hydroxyglutaric aciduria: biochemical marker or clinical disease entity?

D-2-Hydroxyglutaric aciduria has been observed in patients with extremely variable clinical symptoms, creating doubt about the existence of a disease entity related to the biochemical finding. An international survey of patients with D-2-hydroxyglutaric aciduria was initiated to solve this issue. The clinical history, neuroimaging, and biochemical findings of 17 patients were studied. Ten of the patients had a severe early-infantile-onset encephalopathy characterized by epilepsy, hypotonia, cerebral visual failure, and little development. Five of these patients had a cardiomyopathy. In neuroimaging, all patients had a mild ventriculomegaly, often enlarged frontal subarachnoid spaces and subdural effusions, and always signs of delayed cerebral maturation. In all patients who underwent neuroimaging before 6 months, subependymal cysts over the head or corpus of the caudate nucleus were noted. Seven patients had a much milder and variable clinical picture, most often characterized by mental retardation, hypotonia, and macrocephaly, but sometimes no related clinical problems. Neuroimaging findings in 3 patients variably showed delayed cerebral maturation, ventriculomegaly, or subependymal cysts. Biochemical findings included elevations of D-2-hydroxyglutaric acid in urine, plasma, and cerebrospinal fluid in both groups. Cerebrospinal fluid gamma-aminobutyric acid was elevated in almost all patients investigated. Urinary citric acid cycle intermediates were variably elevated. The conclusion of the study is that D-2-hydroxyglutaric aciduria is a distinct neurometabolic disorder with at least two phenotypes.

Biomarkers↗
PubMed1999

Mitochondrial DNA polymerase gamma deficiency and mtDNA depletion in a child with Alpers' syndrome.

Deficiency of mitochondrial DNA polymerase gamma activity was found in a patient with mtDNA depletion and Alpers' syndrome. Metabolic evaluation revealed fasting hypoglycemia, dicarboxylic aciduria, and reduced activity of the electron transport chain in skeletal muscle. The patient died in early childhood of fulminant hepatic failure, refractory epilepsy, lactic acidemia, and coma. mtDNA content was 30% of normal in skeletal muscle and 25% in the liver. The activity of mtDNA polymerase gamma was undetectable.

Ataxia↗
PubMed1999

Glutaryl-CoA dehydrogenase deficiency presenting as 3-hydroxyglutaric aciduria.

Two siblings who were found to have deficiency of glutaryl-CoA dehydrogenase were identified by the presence of large amounts of 3-hydroxyglutaric acid in the urine. Patients with this disease, termed glutaric acidemia or glutaric acidemia Type I, usually present with large amounts of glutaric acid in the urine, and amounts of 3-hydroxyglutaric acid found are less. Patients were ataxic and dystonic. Intelligence was normal. 3-Hydroxyglutaric acid in the urine was quantified by organic acid analysis via gas chromatography mass spectrometry (GCMS) and by stable isotope-dilution (internal standard) GCMS. Glutaryl-CoA dehydrogenase activity in cultured fibroblasts was found to be 2% of the control level. The nature of the mutations was identified, and both patients were found to be compound heterozygotes for R227P, which changed an arginine to a proline, and E365K, which changed a glutamate to a lysine.

Amino Acid Metabolism, Inborn Errors↗