Clinical Chemistry 54: 633-641, 2008.
First published February 29, 2008; 10.1373/clinchem.2007.099986
(Clinical Chemistry. 2008;54:633-641.)
© 2008 American Association for Clinical Chemistry, Inc.
Clinical Utility of Monoamine Neurotransmitter Metabolite Analysis in Cerebrospinal Fluid
Keith Hyland
Medical Neurogenetics, Atlanta, GA.
Address correspondence to the author at: Medical Neurogenetics, One Dunwoody Park, Suite 250, Atlanta, GA 30338. Fax 678-507-5669, e-mail khyland{at}medicalneurogenetics.com.
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Abstract
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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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Introduction
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Peripheral measurements of monoamine neurotransmitters (serotonin and the catecholamines, dopamine and norepinephrine) and their metabolites in either plasma or urine have been used most often to look at mechanisms in hypotension or hypertension, and as screening procedures to detect and monitor neuroblastoma and pheochromocytoma(1)(2)(3). Measurement of these neurotransmitters and metabolites in peripheral fluids, although useful for these disorders, rarely has benefit for the investigation of disorders that primarily affect the central nervous system (CNS).1
This review is therefore not designed to cover the use of monoamine and metabolite analysis in the periphery, but rather is limited to the clinical utility of their measurement in cerebrospinal fluid (CSF) as this relates to human disease within the CNS.
Pathways for the synthesis and catabolism of serotonin and the catecholamines are shown in Fig. 1
. The major metabolites of these neurotransmitters that appear in human CSF are homovanillic acid (HVA) for dopamine, 5-hydroxyindoleacetic acid (5HIAA) for serotonin, and 3-methoxy,4-hydroxyphenylglycol (MHPG) for norepinephrine; the concentrations of these are thought to reflect the overall turnover of the neurotransmitters within the CNS(4). Measurement of monoamine metabolites in CSF can therefore be used to establish a "snapshot" of serotonin and catecholamine metabolism at one particular time that may provide an indication of disease mechanisms that affect the neurotransmitter pathways.
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Figure 1. Disorders and associated CSF metabolite patterns found in the catecholamine and serotonin biosynthetic and catabolic pathways.
1, GTP cyclohydrolase; 2, 6-pyruvoyltetrahydropterin synthase; 3, sepiapterin reductase; 4, tyrosine hydroxylase; 5, dihydropteridine reductase; 6, tryptophan hydroxylase; 7, aromatic L-amino acid decarboxylase; 8, monoamine oxidase; 9, dopamine β-hydroxylase; 10, catechol-O-methyltransferase; 11, pyridox(am)ine phosphate oxidase. NH2P3, dihydroneopterin triphosphate; 6PTP, 6-pyruvoyltetrahydropterin; qBH2, quinonoid dihydrobiopterin; TYR, tyrosine; TRYP, tryptophan; 5HTP, 5-hydroxytryptophan; 3OMD, 3-O-methyldopa. Solid lines, known inherited disorders; dashed line, site of a predicted inherited disorder; dashed arrows, >1 step is involved;  , decreased levels;  , increased levels.
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The monoamine neurotransmitters are involved in the control of a wide variety of neuronal functions. They regulate, among other things, psychomotor function (through involvement in the regulation of motor coordination), reward-driven learning, arousal, processing of sensory input, memory, appetite, emotional stability, sleep, mood, vomiting, sexual behavior, and secretion of anterior pituitary and other hormones(5)(6). In the field of neuropsychiatry, changes in CSF monoamine metabolite concentration have been linked to numerous disease phenotypes including depression(7), Alzheimer’s disease and Parkinson’s disease(8), obsessive compulsive disorder(9), and suicide(10). In these disorders, metabolite changes can be subtle, and often only statistical analysis of large populations allows differentiation from controls. For this reason, the measurement of monoamine metabolites in CSF from these patient populations is not of great clinical utility. Their measurement is of importance, however, for the diagnosis and monitoring of inherited disorders that affect the synthesis, action, and degradation of serotonin and the catecholamines. In these conditions, changes in monoamine metabolites are normally profound, particular patterns may be suggestive for individual conditions, and concentrations of metabolites can be used to monitor treatment outcomes(11).
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primary inherited disorders affecting serotonin and catecholamine metabolism
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The synthesis of serotonin and the catecholamines requires participation of 2 cofactors, tetrahydrobiopterin (BH4) for the activity of tyrosine hydroxylase and tryptophan hydroxylase and pyridoxal 5'-phosphate (PLP) for the activity of aromatic L-amino acid decarboxylase (AADC) (Fig. 1
). Tetrahydrobiopterin is formed in a 3-step pathway from GTP and involves the activities of GTP cyclohydrolase, 6-pyruvoyltetrahydropterin synthase, and sepiapterin reductase. After its oxidation in the 2 hydroxylase reactions, it is reduced back to the active form by the action of pterin-4
-carbinolamine dehydratase and dihydropteridine reductase (Fig. 1
)(12). Pathogenic mutations have been described in all the known enzymes involved in BH4 metabolism(13). As these mutations affect synthesis of both serotonin and the catecholamines, concentrations of 5HIAA, HVA, and MHPG are, in general, significantly decreased in CSF(14). An exception is found in dominantly inherited GTP cyclohydrolase deficiency (dopa-responsive dystonia)(15); in this disorder, it appears that the major impact is on the dopaminergic system, as an isolated decrease in HVA is observed(16).
Primary defects affecting the AADC gene also lead to decreases in all 3 CSF metabolites, as this enzyme is likewise involved in both pathways(17). In addition, there are elevations of L-dopa and 5-hydroxytrypophan, which are the substrates for the enzyme. L-Dopa can also be methylated using S-adenosylmethionine as the methyl group donor, and the product, 3-O-methyldopa, accumulates and provides a major indicator for decreased activity of AADC(17). Pyridox(am)ine phosphate oxidase (PNPO) is required for the maintenance of PLP levels within the CNS, and mutations in this enzyme lead to a deficiency of PLP and consequently to decreased activity of AADC and a similar metabolite pattern(18). Elevations of CSF threonine and glycine can also be seen, as PLP is required for their catabolism. In both primary AADC deficiency and PNPO deficiency, the accumulating 3-O-methyldopa can be further metabolized via transamination to form vanillactic acid, which can be detected on a urine organic acid screen(17)(18).
Tyrosine hydroxylase deficiency leads to specific decreases in HVA and MHPG but normal levels of 5HIAA, as serotonin synthesis is unaffected(19). Mutations in tryptophan hydroxylase have yet to be described, but an isolated decrease in 5HIAA can be predicted. Formation of norepinephrine relies on the activity of dopamine β-hydroxylase. This is a copper-containing enzyme, and deficiency of dopamine β-hydroxylase leads to increased HVA levels due to the accumulation of dopamine and its subsequent conversion to this metabolite(20). Catabolism of serotonin requires the activity of monoamine oxidase, and low levels of 5HIAA are predicted in this disorder(21). Catabolism of the catecholamines requires monoamine oxidase and catechol-O-methyltransferase (Fig. 1
), and again deficiencies of these enzymes likely lead to low CSF concentrations of HVA and MHPG. Monoamine metabolite profiles seen, or expected, in these disorders are summarized in Table 1
and indicated in Fig. 1
.
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Table 1. Metabolite patterns observed in CSF in the inherited disorders affecting catecholamine and serotonin metabolism.
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secondary abnormalities of serotonin and catecholamines
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It is important to emphasize that changes in CSF serotonin and catecholamine metabolites can occur as a consequence of problems in other areas of metabolism. Secondary changes have been described in posthypoxia(22), epilepsy(23), febrile convulsions(24), liver disease and viral infections(25), abnormalities of folate metabolism(26)(27), Lesch Nyhan syndrome(28), Down syndrome(29), urea cycle disorders(30), Rett syndrome(31), Menkes disease(32), and deficiencies of arginase(33) and phenylalanine hydroxylase(34). Isolated low concentrations of HVA have also been found in many neurological conditions where etiology is unclear(35)(36). This list is not comprehensive but does serve to demonstrate that other possibilities should be considered before making a diagnosis of a primary disorder of neurotransmitter monoamine metabolism when abnormal concentrations of CSF metabolites have been found.
Because monoamine metabolite profiles can be nonspecific, an absolute diagnosis of a primary defect in monoamine metabolism requires further investigation. Pituitary prolactin secretion is regulated by neurosecretory dopamine neurons in the hypothalamus that normally inhibit prolactin secretion. A finding of an increased serum prolactin can therefore provide further evidence of a central dopamine deficiency when low CSF HVA concentrations have been found(37). For tryptophan hydroxylase and tyrosine hydroxylase deficiency, genomic sequencing is required for absolute diagnosis, as there is no easily accessible tissue that can be used to measure enzyme activity. The CSF pattern seen in AADC deficiency is almost always diagnostic but may not differentiate between a primary AADC defect or secondary inhibition of the enzyme activity due to lack of PLP; PLP measurement in CSF may allow distinction between the two(18). AADC activity can be measured in plasma, and a finding of low activity is diagnostic for AADC deficiency. In the case of PNPO deficiency, plasma AADC activity can be increased, probably owing to upregulation of apoenzyme synthesis in the absence of the PLP cofactor. Genomic sequencing for AADC and PNPO may be used for final definitive confirmation.
Confirmation of monoamine oxidase-A deficiency is made by measurement of the enzyme activity in dexamethasone-stimulated fibroblasts or by sequencing(21). In patients with dopamine β-hydroxylase deficiency, activity of this enzyme is absent in plasma; however, there is genetically determined interindividual variation in plasma dopamine β-hydroxylase, with 3% to 4% of the normal adult population having near-zero concentrations(38). The disorder can be confirmed by the evaluation of the norepinephrine-to-dopamine ratio in plasma. Normally this ratio is around 10, but in patients with dopamine β-hydroxylase deficiency it is reduced to <0.1(20). Genomic sequencing is also available(39)(40).
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analytical methods
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Many different methods have been used to analyze serotonin, the catecholamines, and their metabolites in biological fluids. These include capillary electrophoresis(41), HPLC/MS(42), GC/MS(43), and HPLC with either fluorescence or electrochemical (EC) detection(44)(45). The current methods used to analyze CSF monoamines and metabolites in clinical and research laboratories rely mostly on reversed-phase HPLC coupled with EC detection(19)(46)(47)(48)(49)(50)(51)(52). These systems are highly sensitive and selective. Electrochemical detectors are now extremely stable and metabolites can be detected in the femtomole range. Selectivity is clearly demonstrated, as in many procedures CSF can be directly injected onto an HPLC column without prior derivatization of the samples(47)(49)(50).
Methods in general have used isocratic conditions and reversed-phase columns with or without the incorporation of ion pairing in the mobile phase(19)(46)(47)(48)(49)(50)(51). Changes in pH and organic modifier (usually methanol or acetonitrile) concentration markedly affect retention times of all metabolites and can be used to obtain optimum separation of any desired components. Accurate measurement of HVA and 5HIAA is easily obtained in all the systems described, but, MHPG is present in relatively small concentrations in CSF, and separation from other compounds can be challenging. The difficulties of measuring this compound accurately were evident in the large interlaboratory variations noted in a pilot quality control program(53). Partial purification of samples before analysis may alleviate this problem(19). Alternately, multielectrode coulometric electrochemical cells in series, with or without gradient elution, can be used to help resolve coeluting compounds by their current/voltage characteristics(54).
As well as the measurement of HVA, 5HIAA, and MHPG, there are occasions when other metabolite analysis may become important. As previously described, blockage of AADC leads to accumulation 3-O-methyldopa, which is the primary accumulating metabolite and, as such, it acts as a marker for this disease. In addition there is accumulation of 5-hydroxytryptophan and L-dopa(17). All of these compounds can be resolved and measured using a simple isocratic system(55) (Fig. 2
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Figure 2. Example chromatograms.
(a), Patients with aromatic L-amino acid decarboxylase deficiency; note the elevations of 3-O-methyldopa, 5-hydroxytryptophan, and L-dopa and the virtual absence of 5-hydroxyindoleacetic acid and homovanillic acid. (b), Patients with tyrosine hydroxylase deficiency; note the normal concentration of 5-hydroxyindoleacetic acid and the virtual absence of homovanillic acid. (c), Patients with tetrahydrobiopterin deficiency; note the absence of homovanillic acid and 5-hydroxyindoleacetic acid. (d), A patient with normal concentrations of 5-hydroxyindoleacetic acid and homovanillic acid who is receiving acetaminophen (*). (e), A mixture of standard compounds. 1, 3-methoxy-4-hydroxyphenylglycol; 2, L-dopa; 3, 5-hydroxyindoleacetic acid; 4, homovanillic acid; 5, 3-O-methyldopa; 6, 5-hydroxytryptophan. Chromatographic conditions: 20 µL CSF was injected onto a 250 by 4.6 mm Phenomenex, SpheraClone 5 µm ODS(2) column using an ESA 542 autosampler cooled to 4 °C. Compounds were eluted under isocratic conditions at a flow rate of 1.3 mL/min using an ESA 582 pump and mobile phase consisting of 0.05M potassium phosphate buffer (pH 2.7) containing 1 mmol/L octyl sodium sulfate, 54 µmol/L EDTA, and 14% methanol. Compounds were detected using an ESA Coulochem III dual electrode electrochemical detector. Electrode 1 was set at –0.05 mV, and compounds were oxidized at electrode 2, which was set at +400 mV.
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When investigating CSF for a possible defect in monoamine neurotransmitter metabolism, it is critical that one also examine CSF concentrations of the cofactor BH4 and its precursor neopterin. This is also achieved using HPLC with either fluorescence(14) or, in series, EC and fluorescence detection(56). Normally inherited defects in BH4 metabolism are detected at the time of newborn screening, as BH4 is also required for the activity of phenylalanine hydroxylase in the liver and a deficiency of the cofactor leads to hyperphenylalaninemia(14). In dominantly inherited GTP cyclohydrolase deficiency and in defects affecting sepiapterin reductase (the third enzyme in the BH4 synthesis pathway), hyperphenylalaninemia is absent. These conditions can be detected only by abnormal monoamine metabolite and pterin profiles in CSF(57).
Fig. 2
provides example chromatograms obtained from the analysis of CSF from patients with deficiencies of BH4, tyrosine hydroxylase, and aromatic L-amino acid decarboxylase using a simple isocratic reversed-phase HPLC system with coulometric EC detection. This system has been in use for >15 years in our clinical laboratory. More than 1000 samples can be analyzed without the need to change the analytical column. This system does not allow detection of MHPG, but in most instances where MHPG concentrations might be low, specific measurement of this compound is not required, as changes in HVA concentration are always also observed.
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sample collection
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Measurement of neurotransmitter metabolites in CSF is of little value unless the method of collection and sample handling are carefully controlled. Age, height, diet, motility, concentration gradients, site of puncture, diurnal variations, and even season at time of birth have been suggested to affect measured concentrations(58)(59).
Obviously, in the clinical setting, it is not possible to control for all of the above factors, but these confounding issues should be considered if large research studies are being conducted. One of the most important factors in the clinical arena is the rostrocaudal gradient for HVA and 5HIAA within the spinal cord(11)(19)(60)(61). Values double with approximately every 5–10 mL of CSF drawn. For this reason, it is essential that patient data is compared to reference intervals obtained using the same fraction of CSF. Values for MHPG do not vary substantially with increased CSF volume drawn, so they presumably reflect spinal cord concentrations rather than those within the brain(19) It is necessary that every laboratory define its own specific collection protocol and ensure that samples are then collected appropriately.
It is also necessary to have age-related reference intervals to which results can be compared, as metabolite concentrations are high in the newborn period, rapidly drop during the first few months of life, and then slowly decrease with age (Fig. 3
, a and b; Table 2
)(47)(62). A clear linear relationship exists between concentrations of 5HIAA and HVA in CSF(19)(63), and this relationship does not change with the fraction of CSF collected. There is, however, a change in slope of the regression line for this relationship between data obtained from individuals 0 to 6 months of age and older than 6 months (Fig. 3
, c and d)(19). This change reflects a more rapid age-related drop in 5HIAA than HVA in the first 6 months of life. Provided HVA/5HIAA ratios are compared to the appropriate reference ratios, they can prove useful in detecting abnormalities in monoamine metabolism in situations where CSF has not been collected in an optimal fashion(19).
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Figure 3. Relationships between homovanillic acid, 5-hydroxyindoleacetic acid, and age.
(a), The effect of age on 5-hydroxyindoleacetic acid (5HIAA) concentration. (b), The effect of age on homovanillic acid (HVA) concentration. Note the rapid decrease in concentrations in the first few months of life, particularly for 5HIAA. (c), Linear relationship between 5HIAA and HVA in the first 6 months of life (1/slope = 1.73; r2 = 0.57; P < 0.0001). (d), Linear relationship between 5HIAA and HVA from 6 months to 15 years of age (1/slope = 3.2; r2 = 0.64; P < 0.0001). Note the change in slope, indicating that the ratio of HVA to 5HIAA increases approximately 2-fold after the first 6 months of life.
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sample stability
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Neurotransmitter metabolites are relatively stable in CSF, but blood contamination during collection of CSF can lead to oxidation of metabolites if the red blood cells are allowed to hemolyze. Blood contaminated samples should, therefore, be centrifuged as soon as possible after sample collection, and the clear CSF should be transferred to a new container before freezing. Metabolite concentrations during analysis are stable for at least 24 h if kept at 4 °C(19), and samples can be frozen and thawed several times without changes in 5HIAA and HVA(64). When stored at <–70 °C, all the metabolites are stable for at least 5 years without a need for antioxidant addition (K.H., unpublished observation).
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quality
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Commercial quality control materials are not available for use in the measurement of CSF monoamine metabolites, but they can easily be prepared by dilution or spiking of CSF. When preparing diluted specimens, it is important to realize that the dilution process decreases the endogenous antioxidants in CSF, which can lead to instability of metabolites. Preparation of quality control materials with low metabolite values should therefore be performed using artificial CSF containing 0.01 g/L ascorbic acid. In the clinical setting, suitable internal standards have not been found to ensure injection integrity. Therefore the use of spiked samples is recommended, where each sample is first run neat and then diluted 50:50 with the external standard and checked for appropriate recovery.
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interfering compounds and drug effects
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Using the HPLC system defined in Fig. 2
, I have analyzed >10 000 CSF samples from patients of all ages who have had a wide range of neurological and neuropsychiatric conditions. It is extremely rare to observe other compounds that interfere with the measurement of 5HIAA and HVA. None of the currently used anticonvulsants generate electrochemically active compounds that appear on the neurotransmitter metabolite chromatogram. Acetaminophen elutes at around 5 min but does not affect measurement of the desired compounds (Fig. 2
). Occasionally, small peaks that elute close to 3-O-methyldopa may be observed, but small changes in pH can be used to obtain clear separation if measurement of this compound is critical.
It is important to obtain a list of medications at the time of CSF collection. Sinemet (L-dopa with carbidopa) therapy leads to a large accumulation of 3-O-methyldopa. Also, serotonin reuptake inhibitors and certain antidepressants are known to influence CSF metabolite concentrations(65)(66), and it is likely that serotonin and catecholamine agonists and antagonists will affect metabolite concentrations.
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Conclusions
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The measurement of monoamine metabolites in CSF is not ideal, as it provides a only single snapshot of one time point, and the measured values probably reflect average concentrations accumulated from all brain regions together with the regional changes that occur within the spinal cord. Thus, subtle abnormalities—in particular brain regions or changes that occur on a minute-to-minute or diurnal basis—may be missed. This limits the clinical utility of metabolite measurement in CSF to situations where the monoamine pathways are affected in a global manner leading to large changes in metabolite concentrations. Despite these drawbacks, CSF monoamine neurotransmitter metabolite analysis has become fairly routine in many research laboratories and in specialized clinical laboratories that search for changes that might indicate problems in this area of neurochemistry. Clearly defined diagnosed disorders have been limited to those affecting synthetic and catabolic pathways. The process of neurotransmission, however, requires other steps including storage in presynaptic nerve vesicles, release, interaction with receptors, and reuptake. In most animal models where each of these steps has been knocked out, the intracellular (and presumably extracellular) concentrations of neurotransmitters are profoundly changed(67)(68)(69)(70)(71). It is certain that these disorders occur in humans. In many cases, abnormal monoamine metabolite concentrations are found in CSF and an underlying etiology cannot be found. These are likely candidates for which molecular screening of candidate genes might be a fruitful endeavor.
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Acknowledgments
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Grant/Funding Support: This work was supported in part by a grant from the Pediatric Neurotransmitter Disease (PND) Association.
Financial Disclosures: K.H. is employed by Medical Neurogenetics LLC, a company that performs neurotransmitter monoamine metabolite analyses in cerebrospinal fluid.
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Footnotes
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1 Nonstandard abbreviations: CNS, central nervous system; CSF, cerebrospinal fluid; HVA, homovanillic acid; 5HIAA, 5-hydroxyindoleacetic acid; MHPG, 3-methoxy,4-hydroxyphenylglycol; BH4, tetrahydrobiopterin; PLP, pyridoxal 5'-phosphate; AADC, aromatic L-amino acid decarboxylase; PNPO, pyridox(am)ine phosphate oxidase; EC, electrochemical. 
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References
|
|---|
- Kema IP, de Vries EG, Muskiet FA. Clinical chemistry of serotonin and metabolites. J Chromatogr B Biomed Sci Appl 2000;747:33-48.[CrossRef][Medline]
[Order article via Infotrieve]
- Monsaingeon M, Perel Y, Simonnet G, Corcuff JB. Comparative values of catecholamines and metabolites for the diagnosis of neuroblastoma. Eur J Pediatr 2003;162:397-402.[Web of Science][Medline]
[Order article via Infotrieve]
- Reisch N, Peczkowska M, Januszewicz A, Neumann HP. Pheochromocytoma: presentation, diagnosis and treatment. J Hypertens 2006;24:2331-2339.[Web of Science][Medline]
[Order article via Infotrieve]
- Wester P, Bergstrom U, Eriksson A, Gezelius C, Hardy J, Winblad B. Ventricular cerebrospinal fluid monoamine transmitter and metabolite concentrations reflect human brain neurochemistry in autopsy cases. J Neurochem 1990;54:1148-1156.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Walther DJ, Bader M. A unique central tryptophan hydroxylase isoform. Biochem Pharmacol 2003;66:1673-1680.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Hyland K. Neurochemistry and defects of biogenic amine neurotransmitter metabolism. J Inherit Metab Dis 1999;22:353-363.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Bottiglieri T, Laundy M, Crellin R, Toone BK, Carney MW, Reynolds EH. Homocysteine, folate, methylation, and monoamine metabolism in depression. J Neurol Neurosurg Psychiatry 2000;69:228-232.[Abstract/Free Full Text]
- Hartikainen P, Reinikainen KJ, Soininen H, Sirvio J, Soikkeli R, Riekkinen PJ. Neurochemical markers in the cerebrospinal fluid of patients with Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis and normal controls. J Neural Transm Park Dis Dement Sect 1992;4:53-68.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Baumgarten HG, Grozdanovic Z. Role of serotonin in obsessive-compulsive disorder. Br J Psychiatry Suppl 1998;(35):13-20.
- Jokinen J, Nordstrom AL, Nordstrom P. The relationship between CSF HVA/5-HIAA ratio and suicide intent in suicide attempters. Arch Suicide Res 2007;11:187-192.[CrossRef][Medline]
[Order article via Infotrieve]
- Hyland K. The lumbar puncture for diagnosis of pediatric neurotransmitter diseases. Ann Neurol 2003;54(Suppl 6):S13-S17.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Thony B, Auerbach G, Blau N. Tetrahydrobiopterin biosynthesis, regeneration and functions. Biochem J 2000;347(Pt 1):1-16.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Thony B, Blau N. Mutations in the BH4-metabolizing genes GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase, sepiapterin reductase, carbinolamine-4a-dehydratase, and dihydropteridine reductase. Hum Mutat 2006;27:870-878.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Blau N, Thony B, Cotton RG, Hyland K. Disorders of tetrahydrobiopterin and related biogenic amines. Scriver CR Beaudet AL Sly WS Valle D eds. The Metabolic and Molecular Bases of Inherited Disease 2001:1725-1776 McGraw-Hill New York. .
- Ichinose H, Ohye T, Takahashi E, Seki N, Hori T, Segawa M, et al. Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene. Nat Genet 1994;8:236-242.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Furukawa Y. Genetics and biochemistry of dopa-responsive dystonia: significance of striatal tyrosine hydroxylase protein loss. Adv Neurol 2003;91:401-410.[Web of Science][Medline]
[Order article via Infotrieve]
- Hyland K, Surtees RA, Rodeck C, Clayton PT. Aromatic L-amino acid decarboxylase deficiency: clinical features, diagnosis, and treatment of a new inborn error of neurotransmitter amine synthesis. Neurology 1992;42:1980-1988.[Abstract/Free Full Text]
- Mills PB, Surtees RA, Champion MP, Beesley CE, Dalton N, Scambler PJ, et al. Neonatal epileptic encephalopathy caused by mutations in the PNPO gene encoding pyridox(am)ine 5'-phosphate oxidase. Hum Mol Genet 2005;14:1077-1086.[Abstract/Free Full Text]
- Brautigam C, Wevers RA, Jansen RJ, Smeitink JA, de Rijk-van Andel JF, Gabreels FJ, Hoffmann GF. Biochemical hallmarks of tyrosine hydroxylase deficiency. Clin Chem 1998;44:1897-1904.[Abstract/Free Full Text]
- Robertson D, Haile V, Perry SE, Robertson RM, Phillips JA, Biaggioni I. Dopamine beta-hydroxylase deficiency: a genetic disorder of cardiovascular regulation. Hypertension 1991;18:1-8.[Abstract/Free Full Text]
- Brunner HG, Nelen M, Breakefield XO, Ropers HH, van Oost BA. Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A. Science (Wash DC) 1993;262:578-580.[Abstract/Free Full Text]
- Hyland K, Peterschmitt MJ, Soull JS, Korsen MS, Gascon G, Gibson JB, et al. Confusing CSF neurochemical picture suggesting 6-pyruvoyltetrahydropterin synthase deficiency in neonates with probable hypoxic-ischemic encephalopathy. J Inherit Metab Dis 1999;22:18.
- Devinsky O, Emoto S, Goldstein DS, Stull R, Porter RJ, Theodore WH, Nadi NS. Cerebrospinal fluid and serum levels of dopa, catechols, and monoamine metabolites in patients with epilepsy. Epilepsia 1992;33:263-270.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Giroud M, Dumas R, Dauvergne M, D’Athis P, Rochette L, Beley A, Bralet J. 5-Hydroxyindoleacetic acid and homovanillic acid in cerebrospinal fluid of children with febrile convulsions. Epilepsia 1990;31:178-181.[Web of Science][Medline]
[Order article via Infotrieve]
- O’Kusky JR, Boyes BE, Walker DG, McGeer EG. Cytomegalovirus infection of the developing brain alters catecholamine and indoleamine metabolism. Brain Res 1991;559:322-330.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Clayton PT, Smith I, Harding B, Hyland K, Leonard JV, Leeming RJ. Subacute combined degeneration of the cord, dementia and parkinsonism due to an inborn error of folate metabolism. J Neurol Neurosurg Psychiatry 1986;49:920-927.[Abstract/Free Full Text]
- Ramaekers VT, Hausler M, Opladen T, Heimann G, Blau N. Psychomotor retardation, spastic paraplegia, cerebellar ataxia and dyskinesia associated with low 5-methyltetrahydrofolate in cerebrospinal fluid: a novel neurometabolic condition responding to folinic acid substitution. Neuropediatrics 2002;33:301-308.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Hyland K, Kasim S, Egami K, Arnold LA, Jinnah HA. Tetrahydrobiopterin deficiency and dopamine loss in a genetic mouse model of Lesch-Nyhan disease. J Inherit Metab Dis 2004;27:165-178.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Mann DM, Lincoln J, Yates PO, Brennan CM. Monoamine metabolism in Down syndrome. Lancet 1980;2:1366-1367.[Web of Science][Medline]
[Order article via Infotrieve]
- Hyman SL, Porter CA, Page TJ, Iwata BA, Kissel R, Batshaw ML. Behavior management of feeding disturbances in urea cycle and organic acid disorders. J Pediatr 1987;111:558-562.[Web of Science][Medline]
[Order article via Infotrieve]
- Wenk GL, Naidu S, Casanova MF, Kitt CA, Moser H. Altered neurochemical markers in Rett’s syndrome. Neurology 1991;41:1753-1756.[Abstract/Free Full Text]
- Kaler SG, Goldstein DS, Holmes C, Salerno JA, Gahl WA. Plasma and cerebrospinal fluid neurochemical pattern in Menkes disease. Ann Neurol 1993;33:171-175.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Hyland K, Smith I, Clayton PT, Leonard JV. Impaired neurotransmitter amine metabolism in arginase deficiency. J Neurol Neurosurg Psychiatry 1985;48:1188-1189.[Free Full Text]
- Guttler F, Lou H. Dietary problems of phenylketonuria: effect on CNS transmitters and their possible role in behaviour and neuropsychological function. J Inherit Metab Dis 1986;9 Suppl 2:169-177.
- Van Der Heyden JC, Rotteveel JJ, Wevers RA. Decreased homovanillic acid concentrations in cerebrospinal fluid in children without a known defect in dopamine metabolism. Eur J Paediatr Neurol 2003;7:31-37.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Garcia-Cazorla A, Serrano M, Perez-Duenas B, Gonzalez V, Ormazabal A, Pineda M, et al. Secondary abnormalities of neurotransmitters in infants with neurological disorders. Dev Med Child Neurol 2007;49:740-744.[Web of Science][Medline]
[Order article via Infotrieve]
- Spada M, Ferraris S, Ferrero GB, Sartore M, Lanza C, Perfetto F, et al. Monitoring treatment in tetrahydrobiopterin deficiency by serum prolactin. J Inherit Metab Dis 1996;19:231-233.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Dunnette J, Weinshilboum R. Inheritance of low immunoreactive human plasma dopamine-beta-hydroxylase: radioimmunoassay studies. J Clin Invest 1977;60:1080-1087.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Garland EM, Hahn MK, Ketch TP, Keller NR, Kim CH, Kim KS, et al. Genetic basis of clinical catecholamine disorders. Ann N Y Acad Sci 2002;971:506-514.[Web of Science][Medline]
[Order article via Infotrieve]
- Timmers HJ, Deinum J, Wevers RA, Lenders JW. Congenital dopamine-beta-hydroxylase deficiency in humans. Ann N Y Acad Sci 2004;1018:520-523.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Chiu TC, Lin YW, Huang YF, Chang HT. Analysis of biologically active amines by CE. Electrophoresis 2006;27:4792-4807.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Manini P, Andreoli R, Cavazzini S, Bergamaschi E, Mutti A, Niessen WM. Liquid chromatography-electrospray tandem mass spectrometry of acidic monoamine metabolites. J Chromatogr B Biomed Sci Appl 2000;744:423-431.[CrossRef][Medline]
[Order article via Infotrieve]
- Parnetti L, Gottfries J, Karlsson I, Langstrom G, Gottfries CG, Svennerholm L. Monoamines and their metabolites in cerebrospinal fluid of patients with senile dementia of Alzheimer type using high performance liquid chromatography and gas chromatography-mass spectrometry. Acta Psychiatr Scand 1987;75:542-548.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Tsunoda M. Recent advances in methods for the analysis of catecholamines and their metabolites. Anal Bioanal Chem 2006;386:506-514.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Peaston RT, Weinkove C. Measurement of catecholamines and their metabolites. Ann Clin Biochem 2004;41:17-38.[Abstract/Free Full Text]
- Hyland K, Smith I, Howells DW, Clayton PT, Leonard JV. The determination of pterins, biogenic amine metabolites and aromatic amino acids in cerebrospinal fluid using isocratic reverse phase liquid chromatography with in series dual cell coulometric electrochemical and fluorescence detection: use in the study of inborn errors of dihydropteridine reductase and 5,10-methylenetetrahydrofolatye reductase. Wachter H Curtius HCh Pfleiderer W eds. Biochemical and Clinical Aspects of Pteridines 1985;Vol. 4:85-99 Gruyter New York. .
- Hyland K, Surtees RA, Heales SJ, Bowron A, Howells DW, Smith I. Cerebrospinal fluid concentrations of pterins and metabolites of serotonin and dopamine in a pediatric reference population. Pediatr Res 1993;34:10-14.[Web of Science][Medline]
[Order article via Infotrieve]
- Scheinin M, Chang WH, Jimerson DC, Linnoila M. Measurement of 3-methoxy-4-hydroxyphenylglycol in human plasma with high-performance liquid chromatography using electrochemical detection. Anal Biochem 1983;132:165-170.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Ormazabal A, Garcia-Cazorla A, Fernandez Y, Fernandez-Alvarez E, Campistol J, Artuch R. HPLC with electrochemical and fluorescence detection procedures for the diagnosis of inborn errors of biogenic amines and pterins. J Neurosci Methods 2005;142:153-158.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Candito M, Nagatsu T, Chambon P, Chatel M. High-performance liquid chromatographic measurement of cerebrospinal fluid tetrahydrobiopterin, neopterin, homovanillic acid and 5-hydroxindoleacetic acid in neurological diseases. J Chromatogr B Biomed Appl 1994;657:61-66.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Yamamoto H. Changes in CSF neurotransmitters during the first year of life. Pediatr Neurol 1991;7:406-410.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Baig S, Halawa I, Qureshi GA. High performance liquid chromatography as a tool in the definition of abnormalities in monoamine and tryptophan metabolites in cerebrospinal fluid from patients with neurological disorders. Biomed Chromatogr 1991;5:108-112.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Brautigam C, Weykamp C, Hoffmann GF, Wevers RA. Neurotransmitter metabolites in CSF: an external quality control scheme. J Inherit Metab Dis 2002;25:287-298.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Matson WR, Langlais P, Volicer L, Gamache PH, Bird E, Mark KA. n-Electrode three-dimensional liquid chromatography with electrochemical detection for determination of neurotransmitters. Clin Chem 1984;30:1477-1488.[Abstract/Free Full Text]
- Hyland K, Clayton PT. Aromatic L-amino acid decarboxylase deficiency: diagnostic methodology. Clin Chem 1992;38:2405-2410.[Abstract/Free Full Text]
- Howells DW, Hyland K. Direct analysis of tetrahydrobiopterin in cerebrospinal fluid by high-performance liquid chromatography with redox electrochemistry: prevention of autoxidation during storage and analysis. Clin Chim Acta 1987;167:23-30.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Blau N, Bonafe L, Thony B. Tetrahydrobiopterin deficiencies without hyperphenylalaninemia: diagnosis and genetics of dopa-responsive dystonia and sepiapterin reductase deficiency. Mol Genet Metab 2001;74:172-185.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Bertilsson L, Asberg M. Amine metabolites in the cerebrospinal fluid as a measure of central neurotransmitter function: methodological aspects. Adv Biochem Psychopharmacol 1984;39:27-34.[Web of Science][Medline]
[Order article via Infotrieve]
- Chotai J, Murphy DL, Constantino JN. Cerebrospinal fluid monoamine metabolite levels in human newborn infants born in winter differ from those born in summer. Psychiatry Res 2006;145:189-197.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Blennow K, Wallin A, Gottfries CG, Mansson JE, Svennerholm L. Concentration gradients for monoamine metabolites in lumbar cerebrospinal fluid. J Neural Transm Park Dis Dement Sect 1993;5:5-15.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Kruesi MJ, Swedo SE, Hamburger SD, Potter WZ, Rapoport JL. Concentration gradient of CSF monoamine metabolites in children and adolescents. Biol Psychiatry 1988;24:507-514.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Blennow K, Wallin A, Gottfries CG, Karlsson I, Mansson JE, Skoog I, et al. Cerebrospinal fluid monoamine metabolites in 114 healthy individuals 18–88 years of age. Eur Neuropsychopharmacol 1993;3:55-61.[CrossRef][Medline]
[Order article via Infotrieve]
- Hyland K. Abnormalities of biogenic amine metabolism. J Inherit Metab Dis 1993;16:676-690.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Strawn JR, Ekhator NN, Geracioti TD, Jr. In-use stability of monoamine metabolites in human cerebrospinal fluid. J Chromatogr B Biomed Sci Appl 2001;760:301-306.[CrossRef][Medline]
[Order article via Infotrieve]
- Sheline Y, Bardgett ME, Csernansky JG. Correlated reductions in cerebrospinal fluid 5-HIAA and MHPG concentrations after treatment with selective serotonin reuptake inhibitors. J Clin Psychopharmacol 1997;17:11-14.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Bowden CL, Koslow SH, Hanin I, Maas JW, Davis JM, Robins E. Effects of amitriptyline and imipramine on brain amine neurotransmitter metabolites in cerebrospinal fluid. Clin Pharmacol Ther 1985;37:316-324.[Web of Science][Medline]
[Order article via Infotrieve]
- Giros B, Jaber M, Jones SR, Wightman RM, Caron MG. Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature (Lond) 1996;379:606-612.[CrossRef][Medline]
[Order article via Infotrieve]
- Xu F, Gainetdinov RR, Wetsel WC, Jones SR, Bohn LM, Miller GW, et al. Mice lacking the norepinephrine transporter are supersensitive to psychostimulants. Nat Neurosci 2000;3:465-471.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Bengel D, Murphy DL, Andrews AM, Wichems CH, Feltner D, Heils A, et al. Altered brain serotonin homeostasis and locomotor insensitivity to 3,4-methylenedioxymethamphetamine ("Ecstasy") in serotonin transporter-deficient mice. Mol Pharmacol 1998;53:649-655.[Abstract/Free Full Text]
- Wang YM, Gainetdinov RR, Fumagalli F, Xu F, Jones SR, Bock CB, et al. Knockout of the vesicular monoamine transporter 2 gene results in neonatal death and supersensitivity to cocaine and amphetamine. Neuron 1997;19:1285-1296.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Chen L, Zhuang X. Transgenic mouse models of dopamine deficiency. Ann Neurol 2003;54(Suppl 6):S91-102.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
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