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M. A. Kurian - One of the best experts on this subject based on the ideXlab platform.
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Monoamine Neurotransmitter disorders clinical advances and future perspectives
Nature Reviews Neurology, 2015Co-Authors: J Ng, Simon J. R. Heales, Apostolos Papandreou, M. A. KurianAbstract:The Monoamine Neurotransmitter disorders are important genetic syndromes that cause disturbances in catecholamine (dopamine, noradrenaline and adrenaline) and serotonin homeostasis. These disorders result in aberrant Monoamine synthesis, metabolism and transport. The clinical phenotypes are predominantly neurological, and symptoms resemble other childhood neurological disorders, such as dystonic or dyskinetic cerebral palsy, hypoxic ischaemic encephalopathy and movement disorders. As a consequence, Monoamine Neurotransmitter disorders are under-recognized and often misdiagnosed. The diagnosis of Monoamine Neurotransmitter disorders requires detailed clinical assessment, cerebrospinal fluid Neurotransmitter analysis and further supportive diagnostic investigations. Prompt and accurate diagnosis of Neurotransmitter disorders is paramount, as many are responsive to treatment. The treatment is usually mechanism-based, with the aim to reverse disturbances of Monoamine synthesis and/or metabolism. Therapeutic intervention can lead to complete resolution of motor symptoms in some conditions, and considerably improve quality of life in others. In this Review, we discuss the clinical features, diagnosis and management of Monoamine Neurotransmitter disorders, and consider novel concepts, the latest advances in research and future prospects for therapy.
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Clinical Features and Pharmacotherapy of Childhood Monoamine Neurotransmitter Disorders
Pediatric Drugs, 2014Co-Authors: J Ng, Simon J. R. Heales, M. A. KurianAbstract:Childhood Neurotransmitter disorders are increasingly recognised as an expanding group of inherited neurometabolic syndromes. They are caused by disturbance in synthesis, metabolism, and homeostasis of the Monoamine Neurotransmitters, including the catecholamines (dopamine, norepinephrine, and epinephrine) and serotonin. Disturbances in Monoamine neurotransmission will lead to neurological symptoms that often overlap with clinical features of other childhood neurological disorders (such as hypoxic ischaemic encephalopathy, cerebral palsy, other movement disorders, and paroxysmal conditions); consequently, Neurotransmitter disorders are frequently misdiagnosed. The diagnosis of Neurotransmitter disorders is made through detailed clinical assessment, analysis of cerebrospinal fluid Neurotransmitters, and further supportive diagnostic investigations. Early and accurate diagnosis of Neurotransmitter disorders is important, as many are amenable to therapeutic intervention. The principles of treatment for Monoamine Neurotransmitter disorders are mainly directly derived from understanding these metabolic pathways. In disorders characterized by enzyme deficiency, we aim to increase Monoamine substrate availability, boost enzyme co-factor levels, reduce Monoamine breakdown, and replace depleted levels of Monoamines with pharmacological analogs as clinically indicated. Most Monoamine Neurotransmitter disorders lead to reduced levels of central dopamine and/or serotonin. Complete amelioration of motor symptoms is achievable in some disorders, such as Segawa’s syndrome, and, in other conditions, significant improvement in quality of life can be attained with pharmacotherapy. In this review, we provide an overview of the clinical features and current treatment strategies for childhood Monoamine Neurotransmitter disorders.
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What is new for Monoamine Neurotransmitter disorders?
Journal of Inherited Metabolic Disease, 2014Co-Authors: Clara Marecos, M. A. KurianAbstract:The Monoamine Neurotransmitter disorders are increasingly recognized as an expanding group of inherited neurometabolic syndromes caused by disturbances in the synthesis, transport and metabolism of the biogenic amines, including the catecholamines (dopamine, norepinephrine, and epinephrine) and serotonin. Disturbances in Monoamine metabolism lead to neurological syndromes that frequently mimic other conditions, such as hypoxic ischemic encephalopathy, cerebral palsy, parkinsonism-dystonia syndromes, primary genetic dystonia and paroxysmal disorders. As a consequence, Neurotransmitter disorders are frequently misdiagnosed. Early and accurate diagnosis of these Neurotransmitter disorders is important, as many are highly amenable to, and some even cured by, therapeutic intervention. In this review, we highlight recent advances in the field, particularly the recent extensive characterization of known Neurotransmitter disorders and identification of novel Neurotransmitter disorders. We also provide an overview of current and future research in the field focused on developing novel treatment strategies.
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the Monoamine Neurotransmitter disorders an expanding range of neurological syndromes
Lancet Neurology, 2011Co-Authors: M. A. Kurian, Paul Gissen, Peter E Clayton, Simon J. R. Heales, Martin SmithAbstract:Summary The Monoamine Neurotransmitter disorders consist of a rapidly expanding heterogeneous group of neurological syndromes characterised by primary and secondary defects in the biosynthesis degradation, or transport of dopamine, norepinephrine, epinephrine, and serotonin. Disease onset can occur any time from infancy onwards. Clinical presentation depends on the pattern and severity of Neurotransmitter abnormalities, and is predominated by neurological features (encephalopathy, epilepsy, and pyramidal and extrapyramidal motor disorders) that are primarily attributed to deficiency of cerebral dopamine, serotonin, or both. Many Neurotransmitter disorders mimic the phenotype of other neurological disorders (eg, cerebral palsy, hypoxic ischaemic encephalopathy, paroxysmal disorders, inherited metabolic diseases, and genetic dystonic or parkinsonian syndromes) and are, therefore, frequently misdiagnosed. Early clinical suspicion and appropriate investigations, including analysis of Neurotransmitters in CSF, are essential for accurate clinical diagnosis. Treatment strategies focus on the correction of Monoamine deficiency by replacement of Monoamine precursors, the use of Monoamine analogues, inhibition of Monoamine degradation, and addition of enzyme cofactors to promote Monoamine production.
Keith Hyland - One of the best experts on this subject based on the ideXlab platform.
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clinical utility of Monoamine Neurotransmitter metabolite analysis in cerebrospinal fluid
Clinical Chemistry, 2008Co-Authors: Keith HylandAbstract:BACKGROUND: Measurements of Monoamine Neurotransmitters and their metabolites in plasma and urine are commonly used to aid in the detection and monitoring of neuroblastoma and pheochromocytoma and the evaluation of hypotension or hypertension. Measurements of these Neurotransmitters and metabolites can also be helpful in the investigation of disorders that primarily affect the central nervous system, but only when the measurements are made in cerebrospinal fluid (CSF). CONTENT: I describe CSF profiles of Monoamine metabolites in the primary and secondary defects affecting serotonin and catecholamine metabolism. I outline the methods required to analyze these metabolites together with details of specific sample handling requirements, sample stability, and interfering compounds, and I emphasize a need for age-related reference intervals. SUMMARY: Measured values of Monoamine metabolites in CSF provide only a single-time snapshot of the overall turnover of the Monoamine Neurotransmitters within the brain. Because these measurements reflect the average concentrations accumulated from all brain regions plus the regional changes that occur within the spinal cord, they may miss subtle abnormalities in particular brain regions or changes that occur on a minute-to-minute or diurnal basis. Clearly defined diagnosed disorders are currently limited to those affecting synthetic and catabolic pathways. In many cases, abnormal Monoamine metabolite concentrations are found in CSF and an underlying etiology cannot be found. Molecular screening of candidate genes related to steps in the neurotransmission process, including storage in presynaptic nerve vesicles, release, interaction with receptors, and reuptake, might be a fruitful endeavor in these cases.
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presentation diagnosis and treatment of the disorders of Monoamine Neurotransmitter metabolism
Seminars in Perinatology, 1999Co-Authors: Keith HylandAbstract:For many years, all of the described cases of Monoamine Neurotransmitter deficiency were associated with hyperphenylalaminemia that was generally detected at neonatal screening. It is now clear that inherited deficiency of Monoamines often occurs in the absence of hyperphenylalaninemia and that the normal battery of screening tests used to investigate individuals with suspected metabolic disease will not detect these cases. Diagnosis in this situation must rely heavily on clinical suspicion. This article, therefore, describes the presentation and clinical symptoms that results from defective Monoamine neurotransmission; outlines therapeutic approaches; and explains how cerebrospinal fluid profiles of Monoamine metabolites, their precursors, and the cofactor required for Monoamine synthesis can be used to pinpoint the exact site of the metabolic lesion.
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cerebrospinal fluid concentrations of pterins and metabolites of serotonin and dopamine in a pediatric reference population
Pediatric Research, 1993Co-Authors: Keith Hyland, Simon J. R. Heales, David W. Howells, Robert Surtees, Ann Bowron, I. SmithAbstract:ABSTRACT: 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.
Simon J. R. Heales - One of the best experts on this subject based on the ideXlab platform.
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Monoamine Neurotransmitter disorders clinical advances and future perspectives
Nature Reviews Neurology, 2015Co-Authors: J Ng, Simon J. R. Heales, Apostolos Papandreou, M. A. KurianAbstract:The Monoamine Neurotransmitter disorders are important genetic syndromes that cause disturbances in catecholamine (dopamine, noradrenaline and adrenaline) and serotonin homeostasis. These disorders result in aberrant Monoamine synthesis, metabolism and transport. The clinical phenotypes are predominantly neurological, and symptoms resemble other childhood neurological disorders, such as dystonic or dyskinetic cerebral palsy, hypoxic ischaemic encephalopathy and movement disorders. As a consequence, Monoamine Neurotransmitter disorders are under-recognized and often misdiagnosed. The diagnosis of Monoamine Neurotransmitter disorders requires detailed clinical assessment, cerebrospinal fluid Neurotransmitter analysis and further supportive diagnostic investigations. Prompt and accurate diagnosis of Neurotransmitter disorders is paramount, as many are responsive to treatment. The treatment is usually mechanism-based, with the aim to reverse disturbances of Monoamine synthesis and/or metabolism. Therapeutic intervention can lead to complete resolution of motor symptoms in some conditions, and considerably improve quality of life in others. In this Review, we discuss the clinical features, diagnosis and management of Monoamine Neurotransmitter disorders, and consider novel concepts, the latest advances in research and future prospects for therapy.
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Clinical Features and Pharmacotherapy of Childhood Monoamine Neurotransmitter Disorders
Pediatric Drugs, 2014Co-Authors: J Ng, Simon J. R. Heales, M. A. KurianAbstract:Childhood Neurotransmitter disorders are increasingly recognised as an expanding group of inherited neurometabolic syndromes. They are caused by disturbance in synthesis, metabolism, and homeostasis of the Monoamine Neurotransmitters, including the catecholamines (dopamine, norepinephrine, and epinephrine) and serotonin. Disturbances in Monoamine neurotransmission will lead to neurological symptoms that often overlap with clinical features of other childhood neurological disorders (such as hypoxic ischaemic encephalopathy, cerebral palsy, other movement disorders, and paroxysmal conditions); consequently, Neurotransmitter disorders are frequently misdiagnosed. The diagnosis of Neurotransmitter disorders is made through detailed clinical assessment, analysis of cerebrospinal fluid Neurotransmitters, and further supportive diagnostic investigations. Early and accurate diagnosis of Neurotransmitter disorders is important, as many are amenable to therapeutic intervention. The principles of treatment for Monoamine Neurotransmitter disorders are mainly directly derived from understanding these metabolic pathways. In disorders characterized by enzyme deficiency, we aim to increase Monoamine substrate availability, boost enzyme co-factor levels, reduce Monoamine breakdown, and replace depleted levels of Monoamines with pharmacological analogs as clinically indicated. Most Monoamine Neurotransmitter disorders lead to reduced levels of central dopamine and/or serotonin. Complete amelioration of motor symptoms is achievable in some disorders, such as Segawa’s syndrome, and, in other conditions, significant improvement in quality of life can be attained with pharmacotherapy. In this review, we provide an overview of the clinical features and current treatment strategies for childhood Monoamine Neurotransmitter disorders.
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the Monoamine Neurotransmitter disorders an expanding range of neurological syndromes
Lancet Neurology, 2011Co-Authors: M. A. Kurian, Paul Gissen, Peter E Clayton, Simon J. R. Heales, Martin SmithAbstract:Summary The Monoamine Neurotransmitter disorders consist of a rapidly expanding heterogeneous group of neurological syndromes characterised by primary and secondary defects in the biosynthesis degradation, or transport of dopamine, norepinephrine, epinephrine, and serotonin. Disease onset can occur any time from infancy onwards. Clinical presentation depends on the pattern and severity of Neurotransmitter abnormalities, and is predominated by neurological features (encephalopathy, epilepsy, and pyramidal and extrapyramidal motor disorders) that are primarily attributed to deficiency of cerebral dopamine, serotonin, or both. Many Neurotransmitter disorders mimic the phenotype of other neurological disorders (eg, cerebral palsy, hypoxic ischaemic encephalopathy, paroxysmal disorders, inherited metabolic diseases, and genetic dystonic or parkinsonian syndromes) and are, therefore, frequently misdiagnosed. Early clinical suspicion and appropriate investigations, including analysis of Neurotransmitters in CSF, are essential for accurate clinical diagnosis. Treatment strategies focus on the correction of Monoamine deficiency by replacement of Monoamine precursors, the use of Monoamine analogues, inhibition of Monoamine degradation, and addition of enzyme cofactors to promote Monoamine production.
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cerebrospinal fluid concentrations of pterins and metabolites of serotonin and dopamine in a pediatric reference population
Pediatric Research, 1993Co-Authors: Keith Hyland, Simon J. R. Heales, David W. Howells, Robert Surtees, Ann Bowron, I. SmithAbstract:ABSTRACT: 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.
Bruce N Ames - One of the best experts on this subject based on the ideXlab platform.
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adrenalectomy causes oxidative damage and Monoamine increase in the brain of rats and enhances immobilization stress induced oxidative damage and Neurotransmitter changes
International Journal of Stress Management, 1998Co-Authors: Jiankang Liu, Isao Yokoi, Stephanie J Doniger, Hideaki Kabuto, Akitane Mori, Bruce N AmesAbstract:The paradox that increased levels of glucocorticoids can either enhance or suppress the organism's defense against stress, has been an obstacle to formulating a unified picture of glucocorticoid function. To clarify the glucocorticoid paradox, we examined male Sprague-Dawley rats exposed to immobilization stress and/or bilateral adrenalectomy (ADX), and measured oxidative damage to lipid, protein, and DNA, as well as Monoamine Neurotransmitter turnover. ADX, which is similar to stress, induces an increase in lipid peroxidation and protein oxidation, accompanied by increased Monoamine Neurotransmitter turnover in several regions of the brain of rats. The effect of ADX is greater than that induced by short-term immobilization stress. In addition, ADX enhances stress-induced oxidative damage and increase of Monoamine Neurotransmitter turnover. These results, together with our previous finding that long-term stress causes oxidative damage to the brain, suggest that stress levels of glucocorticoids, or levels lower than basal, cause oxidative damage. However, basal levels of glucocorticoids appear to buffer against oxidative damage. These findings provide possible mechanisms to understand the glucocorticoid paradox, and support the stress-oxidative hypothesis of aging acceleration.
ペーターズ ダン - One of the best experts on this subject based on the ideXlab platform.
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its use as piperidine 4 acetamide derivatives and Monoamine Neurotransmitter reuptake inhibitors
2009Co-Authors: ニールセン エルセベット エステルガード, ペーターズ ダン, レッドローブ ジョン ポールAbstract:The present invention is useful as Monoamine Neurotransmitter re-uptake inhibitors, relates to novel piperidine-4-acetamide derivatives. In another aspect, the present invention relates to pharmaceutical compositions comprising a compound of the use of these compounds, and the present invention in therapy.
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novel 4 benz hydroxy their use as piperidine derivatives and Monoamine Neurotransmitter reuptake inhibitors tetraalkyl
2009Co-Authors: ニールセン エルセベット エステルガード, ペーターズ ダン, レッドローブ ジョン ポールAbstract:The present invention is useful as Monoamine Neurotransmitter re-uptake inhibitors, novel 4-benzhydryloxy of Formulas (I) - either piperidine derivatives, either or stereoisomers thereof stereoisomers thereof - tetraalkyl mixtures, or their N- oxide, or relates to a pharmaceutically acceptable salt thereof, wherein, 6,6-pentamethyl - not piperidine. In another aspect, this invention relates to a pharmaceutical compositions comprising a compound of the use of these compounds, and the present invention in therapy.
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novel piperidine 4 carboxylic acid phenyl alkyl their use as amide derivatives and Monoamine Neurotransmitter reuptake inhibitors
2009Co-Authors: ニールセン エルセベット エステルガード, ペーターズ ダン, レッドローブ ジョン ポールAbstract:The present invention Monoamine Neurotransmitter re-uptake useful novel piperidine-4-carboxylic acid phenyl as inhibitors - about amide derivatives - alkyl. In another aspect, the present invention is the use of these compounds in therapeutic methods, and to pharmaceutical compositions comprising a compound of the present invention.
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the novel carboxylic acid 4 phenylazo their use as phenyl ester derivatives and Monoamine Neurotransmitter reuptake inhibitors
2008Co-Authors: ニールセン エルセベット エステルガード, ペーターズ ダン, レッドローブ ジョン ポールAbstract:The present invention relates to a novel carboxylic acid 4-phenylazo useful expression as Monoamine Neurotransmitter re-uptake inhibitor (I) - relates phenyl ester derivatives. In another aspect, relates to the use of these compounds in a method for the present invention is treated, and to pharmaceutical compositions comprising a compound of the present invention.
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new chromen 2 one derivatives oyobi Monoamine Neurotransmitter reuptake inhibitors medicine toshite placing them roh use
2007Co-Authors: オルセン グンナー エム, ペーターズ ダン, ニールセン エルセベット エステルガード, レッドローブ ジョン ポールAbstract:The present invention relates to novel chromen-2-one derivatives useful expression as reuptake inhibitors of Monoamine Neurotransmitters (I). In another aspect, the present invention is the use of these compounds in therapeutic methods, and to pharmaceutical compositions containing the compounds of the present invention.