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 4½ years. Low levels of the serotonin endmetabolite 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.

The serotonergic anatomy of the developing human medulla oblongata: Implications for pediatric disorders of homeostasis

“…Polymorphisms within the 5-HTTLPR promoter sequence, mutations in the coding sequence, or intronic mutations of the 5-HT transporter have been reported in autism (Murphy et al , 2008; Prasad et al , 2009). The case report of an autistic child with the heterozygous SLC64A gene Gly56Ala alteration plus the homozygous 5-HTTLPR L/L promoter variant is of special importance as daily oral treatment with 5-hydroxytryptophan (and carbidopa) led to marked clinical improvement in autistic behaviors and normalization of low 5-HIAA levels in the CSF (Adamsen et al , 2011). While the cognitive and emotional components of autism implicate an abnormal rostral 5-HT domain, the autonomic and respiratory components suggest an impaired caudal 5-HT domain as well.…”

Association between common alcohol dehydrogenase gene (ADH) variants and schizophrenia and autism

“…5-HIAA is an important metabolite of serotonin. Alterations in 5-HIAA levels variably associated with schizophrenia (Wieselgren and Lindstrom 1998) and autism (Adamsen et al 2011) have been interpreted as providing evidence of disturbances in serotonergic neurotransmission associated with these disorders (Cook and Leventhal 1996; Abi-Dargham et al 1997; Chugani 2004). Thus, it is conceivable that ADH1B and ADH1C are involved in serotonergic dysfunction associated with these disorders.…”

Evidencia de asociación entre el gen SLC6A4 y efectos epistáticos con variantes en HTR2A en la etiología del autismo en población antioqueña

“…La madre de este sujeto, sin síntomas, tenía genotipos Gly56Ala, pero era heterocigótica S/L para 5HTTLPR. Se postuló que el genotipo Gly56Ala-L/L predispone a un aumento en la recaptura de serotonina de la hendidura sináptica, lo cual puede ser un factor decisivo para el fenotipo autista (87).…”