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Biomedical subjects

K Hyland

Publications and source records attributed to K Hyland.

At least 73 records · Page 4Linked to original sources
PubMed1993

Abnormalities of biogenic amine metabolism.

The term biogenic amine is an umbrella term that encompasses all amines with an origin in biological processes. This review will be restricted to the biogenic amine abnormalities that affect the metabolism of serotonin and the catecholamines. The synthesis and catabolism of these neurotransmitters are outlined, and a summary is given of the neurological details, biochemical features, and treatment of the inborn errors that primarily affect their metabolism. An idea is also developed that proposes that abnormalities of biogenic amine metabolism are far more common than is currently considered, and that the search for these problems may be appropriate in any neonate or infant who presents with neurological problems of unknown origin.

Biopterins↗
PubMed1993

Cerebrospinal fluid concentrations of pterins and metabolites of serotonin and dopamine in a pediatric reference population.

Accurate diagnosis and management of inborn errors of monoamine neurotransmitter and tetrahydrobiopterin metabolism depend on reliable reference ranges of key metabolites. Cerebrospinal fluid (CSF) was collected in a standardized way from 73 children and young adults with neurologic disease, with strict exclusions. In each specimen, concentrations of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (HIAA), total neopterin, 7,8-dihydrobiopterin, and tetrahydrobiopterin (BH4) were measured using HPLC. There was a continuous decrement in CSF HVA, HIAA, and BH4 during the first few years of life; this was independent of height (or length). Age-related reference ranges for each metabolite are given. Extensive correlations between HVA, HIAA, 7,8-dihydrobiopterin, and BH4 were further analyzed by multiple regression. Age and CSF BH4 were significant explanatory variables for CSF HIAA, but CSF HVA had only HIAA as a significant explanatory variable.

Adolescent↗
PubMed1992

Measurement of total plasma and cerebrospinal fluid homocysteine by fluorescence following high-performance liquid chromatography and precolumn derivatization with o-phthaldialdehyde.

Precolumn derivatization of amino acids with o-phthaldialdehyde followed by high-performance liquid chromatographic separation and fluorescence detection is used in many clinical and experimental laboratories for the measurement of primary amino acids. This technique was adapted for the measurement of homocysteine in plasma and cerebrospinal fluid (CSF) following alkylation of the free sulphydryl group with iodoacetate. The minimum detection limits are less than 1 microM in plasma and 80 nM in CSF. Within-day and between-day coefficients of variation for plasma and for CSF are less than 10%. Values for normal plasma homocysteine range from 6.04 to 16.2 microM and for CSF from 0.28 to 0.66 microM.

Chromatography, High Pressure Liquid↗
PubMed1992

Tryptophan and serotonin metabolism in familial erythrophagocytic lymphohistiocytosis.

Reduced concentrations of tryptophan and 5-hydroxyindoleacetic acid (the major CSF metabolite of serotonin) were found in the cerebrospinal fluid of two children with familial erythrophagocytic lymphohistiocytosis. This was associated with elevated cerebrospinal fluid neopterin concentrations indicating increased macrophage activity within the central nervous system. In one child, cytotoxic therapy induced a complete clinical remission and an increase of tryptophan and 5-hydroxyindoleacetic acid concentrations to normal; during a subsequent relapse, concentrations of these analytes again fell below normal. In the other child, in whom therapy produced only a transient improvement, tryptophan and 5-hydroxyindoleacetic acid concentrations remained low and the child died. It is likely that increased activity of indoleamine 2,3-dioxygenase induced by the activation of macrophages was responsible for the disturbance in serotonin and tryptophan homeostasis within the brain. Excessive tryptophan catabolism and the disturbance of serotonin turnover may play a role in the aetiology of the neurological symptoms seen in familial erythrophagocytic lymphohistiocytosis.

Aging↗
PubMed1992

Familial glucocorticoid deficiency with achalasia of the cardia associated with mixed neuropathy, long-tract degeneration and mild dementia.

This paper describes the progress of two previously reported brothers with familial glucocorticoid deficiency, achalasia of the cardia, and alacrima. In their early 'teens both boys developed polyneuropathy with sensory, motor and autonomic components, Parkinsonism, and signs of both dorsal column and pyramidal tract damage. The older boy also showed signs of dementia. Red cell folate levels were markedly reduced but plasma and CSF folate were normal. Serum B12 and erythrocyte concentrations were at or below the lower limit of normal CSF levels of homovanillic acid and 5-hydroxyindole acetic acid (the major metabolites of dopamine and serotonin in brain) were low, indicating impaired turnover of the two amines within the nervous system. Positron emission photometry scans in the older boy showed low binding of c-methyl-spiperone and reduced uptake of 18-F-L-fluorodopa in the striatum, confirming the impairment in dopamine metabolism and suggesting both reduced synthesis and reduced receptor density. Treatment with L-dopa up to 800 mg/day (along with carbidopa 200 mg/day) corrected the low CSF homovanillic acid levels and produced some improvement in the Parkinsonism but no other obvious clinical benefit. Empirical treatment with hydroxycobalamin (1000 micrograms three times a week) and folinic acid (15 mg/day) was without clinical effect. The cause of the neurological disorder, low red-cell folate concentrations, and amine disturbance remains unknown, as does the pathogenesis of the adrenocortical failure.

Adolescent↗
PubMed1992

Folate deficiency, biopterin and monoamine metabolism in depression.

Seven (21%) of 34 patients with a severe DSM-III diagnosis of major depression had red-cell folate levels below 150 ng/ml. This subgroup with folate deficiency had significantly lower CSF 5-hydroxyindoleacetic acid (5HIAA) compared to neurological controls. For all depressed patients red-cell folate was significantly correlated with CSF 5HIAA and homovanillic acid (HVA). CSF tetrahydrobiopterin (BH4) was significantly correlated with CSF 5HIAA and HVA and red-cell folate. Our observations provide further evidence of the links between folate, biopterin and monoamine metabolism in depression.

Adult↗
PubMed1992

Aromatic L-amino acid decarboxylase deficiency: clinical features, diagnosis, and treatment of a new inborn error of neurotransmitter amine synthesis.

We report the clinical features, biochemical details, and treatment of the first detected cases of an inborn error of aromatic L-amino acid decarboxylase. Male monozygotic twins presented with extreme hypotonia and oculogyric crises. Concentrations of biogenic amines and their metabolites were reduced considerably both centrally and peripherally. Pterin and phenylalanine metabolism were normal. Activity of aromatic L-amino acid decarboxylase was virtually absent in a liver biopsy sample and greatly reduced in plasma. Concentrations of L-dopa, 3-methoxytyrosine, and 5-hydroxytryptophan were elevated in CSF, plasma, and urine. CSF S-adenosylmethionine concentrations were reduced. Pyridoxine treatment had no clinical effect but led to a fall in CSF L-dopa and 3-methoxytyrosine and a rise in S-adenosylmethionine. Treatment with either bromocriptine or tranylcypromine stopped the abnormal eye movements; tranylcypromine treatment also improved muscle tone and led to a rise in plasma norepinephrine and whole blood serotonin. Combined treatment with pyridoxine, bromocriptine, and tranylcypromine produced sustained improvement in tone and voluntary movements. The twins' parents were asymptomatic but had reduced plasma aromatic L-amino acid decarboxylase activity, consistent with heterozygosity. We monitored a subsequent pregnancy through biochemical analyses of a fetal liver biopsy sample and of amniotic fluid. We predicted an unaffected fetus, which was confirmed clinically and biochemically after birth.

Amniotic Fluid↗
PubMed1992

Aromatic L-amino acid decarboxylase deficiency: diagnostic methodology.

Aromatic L-amino acid decarboxylase (EC. 4.1.1.28) deficiency is a newly described inborn error of metabolism that affects serotonin and dopamine biosynthesis. The major biochemical markers for this disease are increases of L-dopa, 3-methoxytyrosine, and 5-hydroxytryptophan in urine, plasma, and cerebrospinal fluid together with decreased cerebrospinal fluid concentrations of homovanillic acid and 5-hydroxyindoleacetic acid. In addition, concentrations of vanillactic acid are increased in the urine. Specific HPLC and gas chromatography-mass spectrometry methods are described that permit the identification and measurement of these metabolites in the above body fluids. Simplified assays for human plasma L-dopa decarboxylase and liver L-dopa and 5-hydroxytryptophan decarboxylase, used to demonstrate the enzyme deficiency, are also reported.

5-Hydroxytryptophan↗
PubMed1991

Mitochondrial phosphoenolpyruvate carboxykinase deficiency.

The sibling of a patient in whom a diagnosis of phosphoenolpyruvate carboxykinase had been made developed a similar clinical illness with liver failure. However the activity of phosphoenolpyruvate carboxykinase in leucocytes and fibroblasts was normal. Phosphoenolpyruvate carboxykinase is not the primary defect in this family.

Humans↗
PubMed1990

Central-nervous-system methyl-group metabolism in children with neurological complications of HIV infection.

To assess methyl-group metabolism in the central nervous system in infection with human immunodeficiency virus (HIV), levels of 5-methyltetrahydrofolate, methionine, and S-adenosylmethionine were measured by high-performance liquid chromatography in cerebrospinal fluid (CSF) from six children with congenital HIV infection and neurological complications. Total neopterins were also measured, as a marker of macrophage activation. In all six children concentrations of one or more methyl-group carriers were lower than those in a reference population of children, and all of the five in whom CSF neopterins were measured had higher than normal levels. Defective methylation may play a part in the neurological damage caused by HIV infection.

Biopterins↗
PubMed1990

Neuroblastoma in a patient with dihydropteridine reductase deficiency.

Tetrahydrobiopterin (BH4) deficiency is a rare cause of hyperphenylalaninaemia (HPA) and usually leads to progressive neurological deterioration despite early dietary control of plasma phenylalanine concentrations. Dihydropteridine reductase (DHPR) deficiency is the most severe cause with respect to a fatal outcome. We report a 7-year-old girl with HPA diagnosed on neonatal Guthrie screening who at the age of 6 months had cytotoxic therapy for an adrenal neuroblastoma which secreted catecholamines. When 4 years old she was found to have DHPR deficiency. Although developmentally retarded and microcephalic she has failed to develop the florid neurological features often associated with the condition.

Adrenal Gland Neoplasms↗
PubMed1990

Cerebrospinal fluid concentrations of S-adenosylmethionine, methionine, and 5-methyltetrahydrofolate in a reference population: cerebrospinal fluid S-adenosylmethionine declines with age in humans.

Cerebrospinal fluid concentrations of S-adenosylmethionine, methionine, and 5-methyltetrahydrofolate were measured in 80 children and young adults in whom there was no disturbance of the methyl transfer pathway. Cerebrospinal fluid was collected under standardized conditions and analyzed by high-performance liquid chromatography. S-Adenosylmethionine, but not methionine nor 5-methyltetrahydrofolate, concentrations declined sharply during the first year of life. There was no correlation between concentrations of S-adenosylmethionine and methionine or 5-methyltetrahydrofolate. Reference ranges for the three metabolites are given.

Adolescent↗
PubMed1990

L-3,4-dihydroxyphenylalanine (levodopa) lowers central nervous system S-adenosylmethionine concentrations in humans.

To determine whether levodopa reduces the levels of S-adenosylmethionine in the human central nervous system, cerebrospinal fluid (CSF) concentrations of S-adenosylmethionine, methionine, 3-methoxytyrosine, levodopa and 5-methyltetrahydrofolate were measured in six children with dopamine deficiency before and after treatment. In four, the lack of dopamine was secondary to a reduction in concentration of levodopa and these were treated with levodopa together with a peripheral dopa-decarboxylase inhibitor. In the other two, levodopa in the central nervous system naturally accumulated due to a congenital deficiency of aromatic-L-amino acid decarboxylase and these were treated with pyridoxine (which in this condition lowers central levodopa concentrations). Raising levodopa concentrations in the central nervous system caused a fall in CSF S-adenosyl-methionine concentration and a rise in CSF 3-methoxytyrosine concentration. No change was observed in CSF methionine concentration and in all patients CSF 5-methyltetrahydrofolate concentration was normal. With one exclusion there was a linear relationship between CSF S-adenosylmethionine and 3-methoxytyrosine concentrations. This is the first demonstration of such effects in humans and the implications upon levodopa therapy are discussed.

Adolescent↗
PubMed1990

Central nervous system involvement in the erythrophagocytic disorders of infancy: the role of cerebrospinal fluid neopterins in their differential diagnosis and clinical management.

In two children with familial erythrophagocytic lymphohistiocytosis accompanied by neurologic symptoms, total neopterin concentrations in cerebrospinal fluid were 200 times higher than in controls and 10 to 20 times higher than in five children with presumed neurologic disease due to primary viral infections (human immunodeficiency virus, herpes simplex, measles) of the CNS. In one child with familial erythrophagocytic lymphohistiocytosis, clinical remission was accompanied by a fall in neopterin concentrations to normal; in a second child, who died, total neopterin concentrations remained high. In two other children with a diagnosis of infection-associated hemophagocytic syndrome without any neurologic disturbance, neopterin concentrations were also elevated but only to 10 times the concentrations in controls. Total neopterin concentrations in cerebrospinal fluid provide a measure of the severity of macrophage infiltration and activation within the CNS, and are useful in assessing the need for intensive chemotherapy and monitoring the response to treatment.

Biopterins↗
PubMed1989

Determination of quinonoid dihydrobiopterin by high-performance liquid chromatography and electrochemical detection.

Sodium bisulphite is shown to react with quinonoid dihydrobiopterin to form a stable adduct. Sodium bisulphite does not react with tetrahydrobiopterin. Quinonoid dihydrobiopterin reacts with dithioerythritol to form tetrahydrobiopterin, whereas the quinonoid dihydrobiopterin bisulphite adduct does not. Using these properties we have developed an indirect method for the quantitative measurement of quinonoid dihydrobiopterin. The method requires division of a sample into two. Dithioerythritol is added to one half (a). This converts quinonoid dihydrobiopterin to tetrahydrobiopterin and prevents the oxidation of tetrahydrobiopterin. Measurement of the tetrahydrobiopterin content of this sample by electrochemistry following high-performance liquid chromatographic separation (with dithioerythritol present in the mobile phase to prevent autoxidation of the tetrahydrobiopterin on column), therefore provides a total value of the tetrahydrobiopterin plus quinonoid dihydrobiopterin present within the original sample. Sodium bisulphite is added to the other portion of the sample (b), followed immediately by dithioerythritol which prevents autoxidation of the remaining tetrahydrobiopterin. The bisulphite reacts with the quinonoid dihydrobiopterin present and the quinonoid dihydrobiopterin-bisulphite adduct is no longer detected by electrochemistry at the retention time of tetrahydrobiopterin. Using reversed-phase high-performance liquid chromatography and redox electrochemical detection, measurement of tetrahydrobiopterin in the absence (a) and presence (b) of bisulphite enables the concentration of quinonoid dihydrobiopterin to be calculated by subtraction (a - b). This method is shown to be quantitative and preliminary experiments demonstrate that it can be adapted for biological samples.

Biopterins↗
PubMed1989

Neurodevelopmental delay and focal seizures as presenting symptoms of human immunodeficiency virus I infection.

Three children presenting with neurological symptoms were subsequently diagnosed as being infected with the human immunodeficiency virus I (HIV). All children showed normal development for about 12-18 months of age but later developed psychomotor and developmental regression. One child presented with generalised hypotonia, another with focal seizures, and the third with spastic quadriplegia. Two of the children showed areas of abnormal brain density on computed tomography and in one case there was calcification of the basal ganglia. In two of the children cerebrospinal fluid contained reduced amounts of total folate and elevated concentrations of neopterin. The possibility of a link between the deranged folate metabolism and the neurological symptoms in HIV infection is discussed.

Acquired Immunodeficiency Syndrome↗
PubMed1989

A method for the measurement of S-adenosylmethionine in small volume samples of cerebrospinal fluid or brain using high-performance liquid chromatography-electrochemistry.

A method for the measurement of S-adenosylmethionine in cerebrospinal fluid and brain using high-performance liquid chromatography with electrochemical detection is described. The method is based upon the catechol O-methyltransferase-catalyzed methylation of dihydroxybenzylamine to its 3- and 4-methoxy derivatives and measurement of the latter. Detection limits are 0.1 pmol for 3- and 4-methoxyhydroxybenzylamine, recovery is 100%, and variability is less than 8%. HPLC measurement of 3- and 4-methoxyhydroxybenzylamine is linear up to at least 100 pmol injected. The use of a nonbiological catechol in the assay minimizes interference from endogenous and exogenous catechols and the wide limits of linearity allows the assay of small volumes of cerebrospinal fluid or brain extract without further concentration or dilution.

Animals↗