Cerebrospinal fluid alterations of the serotonin product, 5‐hydroxyindolacetic acid, in neurological disorders

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.

Cerebrospinal Fluid Neopterin Analysis in Neuropediatric Patients: Establishment of a New Cut Off-Value for the Identification of Inflammatory-Immune Mediated Processes

“…These results may be explained because neopterin is also produced intrathecally by different glial brain cells, acting as a possible link among inflammation, neurodegeneration and regeneration [24], [25]. These events can be found in primary inflammatory processes but are also commonly involved in some neurological acquired and unknown etiology diseases, in which neuroimaging reflects CNS damage.…”

Autism associated with low 5-hydroxyindolacetic acid in CSF and the heterozygous SLC6A4 gene Gly56Ala plus 5-HTTLPR L/L promoter variants

“…Moreover, several authors have reported no difference for 5HIAA in CSF measured in autistic patients (for an overview see [17]), which is in contradiction to our routine determination of 5HIAA in CSF in patients with autistic disorders where we find a significant percentage of patients with low 5HIAA (unpublished observation). On the other hand, several other laboratories reported recently on isolated low 5HIAA level in CSF from patients with neurological disorders and neuro-psychiatric disturbances, including ASD (without identifying an underlying genetic cause) [25].…”

Protective activity of α-lactoalbumin (ALAC), a whey protein rich in tryptophan, in rodent models of epileptogenesis

“…Agents that increase extracellular 5-HT levels, such as 5-hydroxytryptophan (5-HTP) and/or SSRIs, inhibit generalized tonic-clonic seizures as well as focal seizures, including hippocampal and lateral geniculate nucleus-kindled seizures and spontaneous seizures occurring after pilocarpine-induced SE, whereas, they increase absence seizures (for a review see Bagdy et al, 2007). In humans, a link between altered 5-HT, seizures and epilepsy is suggested by the finding of reduced levels of 5-HT metabolites in the cerebrospinal fluid of patients with seizure disorders (De Grandis et al, 2010), reduced in vivo 5-HT binding, mostly to 5-HT 1A receptors, in patients with chronic epilepsy (Merlet et al, 2004) and a possibly compensatory increase in 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) content in cortex tissue resected from patients with pharmacoresistant epilepsy (Naffah-Mazzacoratti et al, 1996). Based on these findings, the suggestion has been made that modulation of serotoninergic function could represent an innovative approach to the treatment of AED-refractory epilepsy (Lo¨scher and Leppik, 2002).…”

“…In particular, serotoninergic deficits increase seizure predisposition in mammals, whereas 5-HT can exert anticonvulsant effects (Bagdy et al, 2007). Accordingly, low levels of 5-HT metabolites were found in the cerebrospinal fluid of some patients with seizure disorders (De Grandis et al, 2010), and clinical observations suggest a potential seizuresuppressing effect of selective 5-HT reuptake inhibitors (SSRIs) (Albano et al, 2006). Other lines of evidence suggest that some forms of epilepsy may be related to decreased availability of the 5-HT precursor tryptophan (TRP) in the brain (Albano et al, 2006;Russo et al, 2009).…”