title: Autism associated with low 5-hydroxyindolacetic acid in CSF and the heterozygous SLC6A4 gene Gly56Ala plus 5-HTTLPR L/L promoter variants.
abstract: The known Gly56Ala mutation in the serotonin transporter SERT (or 5-HTT), encoded by the SLC6A4 gene, causes increased serotonin reuptake and has been associated with autism and rigid-compulsive behavior. We report a patient with macrocephaly from birth, followed by hypotonia, developmental delay, ataxia and a diagnosis of atypical autism (PDD-NOS) in retrospect at the age of 4½years. Low levels of the serotonin end-metabolite 5-hydroxyindolacetic acid (5HIAA) in CSF were detected, and SLC6A4 gene analysis revealed the heterozygous Gly56Ala alteration and the homozygous 5-HTTLPR L/L promoter variant. These changes are reported to be responsible for elevated SERT activity and expression, suggesting that these alterations were responsible in our patient for low serotonin turnover in the central nervous system (CNS). Daily treatment with 5-hydroxytryptophan (and carbidopa) led to clinical improvement and normalization of 5HIAA, implying that brain serotonin turnover normalized. We speculate that the mutated 56Ala SERT transporter with elevated expression and basal activity for serotonin re-uptake is accompanied with serotonin accumulation within pre-synaptic axons and their vesicles in the CNS, resulting in a steady-state of lowered serotonin turnover and degradation by monoamine-oxidase (MAO) enzymes in pre-synaptic or neighboring cells.
authors.affiliation: Division of Chemistry and Biochemistry, Department of Pediatrics, University of Zürich, Switzerland.
authors.forename: Dea
authors.initials: D
authors.lastname: Adamsen
authors.forename: David
authors.initials: D
authors.lastname: Meili
authors.forename: Nenad
authors.initials: N
authors.lastname: Blau
authors.forename: Beat
authors.initials: B
authors.lastname: Thöny
authors.forename: Vincent
authors.initials: V
authors.lastname: Ramaekers
mesh_terms: D006916:5-Hydroxytryptophan / Q000627:therapeutic use; D019943:Amino Acid Substitution; D018687:Antidepressive Agents, Second-Generation / Q000627:therapeutic use; D001321:Autistic Disorder / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D002675:Child, Preschool; D005838:Genotype; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000134:cerebrospinal fluid*; D008297:Male; D009154:Mutation; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D018687:Antidepressive Agents, Second-Generation; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D006916:5-Hydroxytryptophan