Abstract
Although patients with low cerebrospinal fluid (CSF) serotonin metabolite levels have been reported, inborn errors of the rate-limiting enzyme of serotonin synthesis (tryptophan hydroxylase, TPH) have not been described so far. In this study we aimed to evaluate CSF alterations of the serotonin metabolite 5-hydroxyindolacetic acid (5-HIAA) in patients with neurological disorders and to explore a possible TPH deficiency in some of them. A total of 606 patients (286 males, 320 females, mean age 4 years and 6 months, SD 5 years and 7 months) underwent CSF analysis of neurotransmitter metabolites by reverse phase high performance liquid chromatography. Results were compared with values established in a control population. Patients’ medical records were reviewed to determine diagnosis and clinical features. A primary defect of biogenic amines was genetically investigated in indicated patients. Low 5-HIAA was seen in 19.3%. Of these, 22.2% showed inborn errors of metabolism (mitochondrial disorders being the most frequent at 10.2% of low 5-HIAA patients) and neurogenetic conditions. Other relatively frequent conditions were pontocerebellar hypoplasia (4.3%), Rett syndrome (4.3%), and among congenital nonetiologically determined conditions, epilepsy including epileptic encephalopathies (26.4%), leukodystrophies (6.8%), and neuropsychiatric disturbances (4.2%). Mutational analysis of the TPH2 gene, performed in five candidate patients, was negative. Although frequency of secondary alteration of 5-HIAA was relatively high in patients with neurological disorders, this finding was more frequently associated with some neurometabolic disorders, epileptic encephalopathies, and neuropsychiatric disturbances. No inborn errors of TPH were found. Due to serotonin’s neurotrophic role and to ameliorate symptoms, a supplementary treatment with 5-hydroxytriptophan would seem advisable in these patients.
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References
Airaksinen E, Tuomisto L, Riikonen R (1992) The concentrations of GABA, 5-HIAA and HVA in the cerebrospinal fluid of children with infantile spasms and the effects of ACTH treatment. Brain Dev 14:386–390
Alenina N, Kiric D, Todiras M et al. (2009) Growth retardation and altered autonomic control in mice lacking brain serotonin. Proc Nat Acad Sci USA 105:10332–10337
Assmann B, Kohler M, Hoffman G, Heales S, Surtees R (2002) Selective decrease in central nervous system serotonin turnover in children with dopa-nonresponsive dystonia. Pediatr Res 52:91–94
Duarte S, Sanmarti F, Gonzalez V et al. (2008) Cerebrospinal fluid pterins and neurotransmitters in early severe epileptic encephalopathies. Brain Dev 30:106–111
García-Cazorla A, Serrano M, Pérez-Dueñas B et al. (2007) Secondary abnormalities of neurotransmitters in infant with neurological disorders. Dev Med Child Neurol 49:740–744
García-Cazorla A, Duarte S, Serrano M et al. (2008) Mitochondrial diseases mimicking neurotransmitter defects. Mitochondrion 8:273–278
Herlenius E, Lagercrantz H (2001) Neurotransmitters and neuromodulators during early human development. Early Hum Dev 65:21–37
Hyland K, Surtees RA, Heales SJ, Bowron A, Howells DW, Smith I (1993) Cerebrospinal fluid concentrations of pterins and metabolites of serotonin and dopamine in a pediatric reference population. Pediatr Res 34:10–14
Kölker S, Sauer SW, Hoffmann GF, Müller I, Morath MA, Okun JG (2008) Pathogenesis of CNS involvement in disorders of amino and organic acid metabolism. J Inherit Metab Dis 31:194–204
Langlais PJ, Wardlow ML, Yamamoto H (1991) Changes in CSF neurotransmitters in infantile spasms. Pediatr Neurol 7:440–445
Naumann M, Gotz M, Reiners K, Lange KW, Riederer P (1996) Neurotransmitters in CSF of idiopathic adult-onset dystonia: reduced 5HIIA levels as evidence of impaired serotoninergic metabolism. J Neural Transm 103:1083–1091
Ohno Y, Hibino H, Lossin C, Inanobe A, Kurachi Y (2007) Inhibition of astroglial Kir4.1 channels by selective serotonin reuptake inhibitors. Brain Res 1178:44–51
Ormazabal A, García-Cazorla A, Fernandez Y, Fernandez-Alvarez E, Campistol J, Artuch R (2005) HLPC with electrochemical and fluorescence detection procedures for the diagnosis of inborn errors of biogenic amines and pterins. J Neurosci Methods 142:153–158
Placidi GP, Oquendo MA, Malone KM, Huang YY, Ellis SP, Mann JJ (2001) Aggressivity, suicide attempts, and depression: relationship to cerebrospinal fluid monoamine metabolite levels. Biol Psychiatry 50:783–791
Pons R (2009) The phenotypic spectrum of paediatric neurotransmitter diseases and infantile parkinsonism. J Inherit Metab Dis 32:321–332
Ramaekers VT, Senderek J, Häusler M et al (2001) A novel developmental syndrome responsive to 5-hydroxytryptophan and carbidopa. Mol Genet Metab 73:179–187
Van Der Heyden JC, RotteveelJJ, Wevers RA (2003) Decreased homovanillic acid concentrations in cerebrospinal fluid in children without a known defect in dopamine metabolism. Eur J Paediatr Neurol 7(1):31–37
Walitza S, Renner TJ, Dempfle A et al. (2005) Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in attention-deficit/hyperactivity disorder. Mol Psychiatry 10:1126–1132
Zhang X, Gainetdinov RR, Beaulieu JM et al. (2005) Loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron 45:11–16
Acknowledgments
We greatly appreciate the collaboration of the patients and their families in the study. CIBERER is an initiative of the ISCIII (MICINN, Spain), and part of this work resulted from an Intramural Project between CIBERER Units 703 and 736. This work was funded by the grants FIS PS09/01132 and FIS PI070548. R.A. is supported by the Programa de Intensificación de Actividad Investigadora of FIS.
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Communicated by: Sedel Frederic
Competing interest: None declared
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De Grandis, E., Serrano, M., Pérez-Dueñas, B. et al. Cerebrospinal fluid alterations of the serotonin product, 5-hydroxyindolacetic acid, in neurological disorders. J Inherit Metab Dis 33, 803–809 (2010). https://doi.org/10.1007/s10545-010-9200-9
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DOI: https://doi.org/10.1007/s10545-010-9200-9