Day and nighttime excretion of 6-sulphatoxymelatonin in adolescents and young adults with autistic disorder

Laboratory of Psychology of Perception, CNRS UMR 8158, Paris Descartes University, Paris, France.
Psychoneuroendocrinology (Impact Factor: 4.94). 05/2012; 37(12). DOI: 10.1016/j.psyneuen.2012.04.013
Source: PubMed


BACKGROUND: Several reports indicate that nocturnal production of melatonin is reduced in autism. Our objective was to examine whether melatonin production is decreased during the whole 24-h cycle, whether the melatonin circadian rhythm is inverted, and whether the reduction in melatonin production is related to the severity of autistic behavioral impairments. METHOD: Day and nighttime urinary excretion of 6-sulphatoxymelatonin (6-SM) was examined during a 24-h period in post-pubertal individuals with autism (N=43) and typically developing controls (N=26) matched for age, sex and pubertal stage. RESULTS: Low 6-SM excretion (mean±SEM) was observed in autism, both at daytime (0.16±0.03 vs. 0.36±0.05μg/h, p<0.01), nighttime (0.52±0.07 vs. 1.14±0.23μg/h, p<0.05), and during 24h (8.26±1.27 vs. 18.00±3.43μg/24-h collection, p<0.001). Intra-individual nighttime-daytime differences (delta values) in 6-SM excretion were smaller in individuals with autism than in controls (0.36±0.07 vs. 0.79±0.23μg/h, p<0.05). Nocturnal excretion of 6-SM was negatively correlated with autism severity in the overall level of verbal language (Spearman ρ=-0.30, p<0.05), imitative social play (Spearman ρ=-0.42, p<0.05), and repetitive use of objects (Spearman ρ=-0.36, p<0.05). CONCLUSION: A deficit in melatonin production is present both at daytime and at nighttime in individuals with autism, particularly in the most severely affected individuals. These results highlight interest in potential therapeutic uses of melatonin in autistic disorder, especially in individuals with severe autistic impairment and/or low urinary 6-SM excretion.

Download full-text


Available from: George M Anderson, Sep 13, 2014
27 Reads
  • Source
    • "Quite unlike the common WBS profile of talkativeness, overfriendliness and mild to moderate intellectual disability, both patients displayed severe impairments in verbal communication and social interaction, together with severe intellectual disability, and, more specifically, met the criteria for autism. In addition, both patients exhibited platelet hyperserotonemia and low nocturnal urinary melatonin excretion, neurochemical phenotypes associated with autism [20,22,23,33]. Thus, behavioral and neurochemical phenotypes typically associated with autism were observed in these two patients with WBS. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Deletion of the Williams-Beuren syndrome (WBS) critical region (WBSCR), at 7q11.23, causes a developmental disorder commonly characterized by hypersociability and excessive talkativeness and often considered the opposite behavioral phenotype to autism. Duplication of the WBSCR leads to severe delay in expressive language. Gene--dosage effects on language development at 7q11.23 have been hypothesized. Molecular characterization of the WBSCR was performed by fluorescence in situ hybridization and high-resolution single-nucleotide polymorphism array in two individuals with severe autism enrolled in a genetic study of autism who showed typical WBS facial dysmorphism on systematic clinical genetic examination. The serotonin transporter promoter polymorphism (5-HTTLPR, locus SLC6A4) was genotyped. Platelet serotonin levels and urinary 6-sulfatoxymelatonin excretion were measured. Behavioral and cognitive phenotypes were examined. The two patients had common WBSCR deletions between proximal and medial low copy repeat clusters, met diagnostic criteria for autism and displayed severe impairment in communication, including a total absence of expressive speech. Both patients carried the 5-HTTLPR ss genotype and exhibited platelet hyperserotonemia and low melatonin production. Our observations indicate that behaviors and neurochemical phenotypes typically associated with autism can occur in patients with common WBSCR deletions. The results raise intriguing questions about phenotypic heterogeneity in WBS and regarding genetic and/or environmental factors interacting with specific genes at 7q11.23 sensitive to dosage alterations that can influence the development of social communication skills. Thus, the influence of WBSCR genes on social communication expression might be dramatically modified by other genes, such as 5-HTTLPR, known to influence the severity of social communication impairments in autism, or by environmental factors, such as hyperserotonemia, given that hyperserotonemia is found in WBS associated with autism but not in WBS without autism. In this regard, WBS provides a potentially fruitful model with which to develop integrated genetic, cognitive, behavioral and neurochemical approaches to study genotype--phenotype correlations, possible gene--environment interactions and genetic background effects. The results underscore the importance of considering careful clinical and molecular genetic examination of individuals diagnosed with autism.
    Molecular Autism 08/2013; 4(1):29. DOI:10.1186/2040-2392-4-29 · 5.41 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Autism is known to be associated with hyperserotoninemia and, more recently, with decreased blood melatonin level. Melatonin is a neurohormone synthesized from serotonin and involved in circadian rhythms and sleep regulations. Thus, serotonin and melatonin are two ends of a biochemical pathway, and little is known concerning all the steps of this pathway in patients with Autism Spectrum Disorders. Moreover, the clinical relevance of these biochemical endophenotypes remains to be determined. Objectives: Here we explore the serotonin-melatonin pathway in a large cohort of patients with ASD, in order to (i) better characterize the biochemical abnormalities of this pathway in ASD, (ii) determine the clinical correlates of these biochemical abnormalities, and (iii) assess the relevance of these biochemical parameters as biomarkers for ASD diagnosis. Methods: The five parameters related to the serotonin-melatonin pathway, i.e. serotonin, arylalkylamine N-acetyltransferase (AA-NAT) enzyme activity, N-acetylserotonin, acetylserotonin methyltransferase (ASMT) enzyme activity, and melatonin, were measured in the blood of 203 patients with ASD, their unaffected relatives (291 parents and 92 sibs), and age- and sex-matched controls. Biochemical data were correlated with clinical data obtained from ADI-R for 117 patients. Results: Patients with ASD display elevated blood serotonin and N-acetylserotonin levels (p<0,001) compared to controls and unaffected relatives, and decreased ASMT activity and melatonin levels (p<0,001) compared to controls. When confronted to clinical data, melatonin deficiency appears significantly associated with stereotyped behavior (ADI-R axis D, p=0,003). Finally, comparisons between ASD patients, controls and unaffected sibs on the one hand, and between autism and Asperger syndrome on the other hand, reveal that hyperserotoninemia is a relevant biomarker of autism, with good specificity and sensitivity. Conclusions: This study confirms the previously reported major abnormalities of the serotonin-melatonin pathway in ASD. The typical biochemical profile of ASD patients suggests a deficit of the ASMT enzyme, consistent with our previous work. Serotonin and melatonin are both clinically relevant parameters, serotonin as a specific biomarker of autism, and melatonin for behavioral correlates. These results highlight the clinical interest of the serotonin –melatonin pathway in ASD, and its potential role as a susceptibility factor to autism.
    International Meeting for Autism Research 2010; 05/2010
  • [Show abstract] [Hide abstract]
    ABSTRACT: Biological rhythms are crucial phenomena that are perfect examples of the adaptation of organisms to their environment. A considerable amount of work has described different types of biological rhythms (from circadian to ultradian), individual differences in their patterns and the complexity of their regulation. In particular, the regulation and maturation of the sleep-wake cycle have been thoroughly studied. Its desynchronization, both endogenous and exogenous, is now well understood, as are its consequences for cognitive impairments and health problems. From a completely different perspective, psychoanalysts have shown a growing interest in the rhythms of psychic life. This interest extends beyond the original focus of psychoanalysis on dreams and the wake-sleep cycle, incorporating central theoretical and practical psychoanalytic issues related to the core functioning of the psychic life: the rhythmic structures of drive dynamics, intersubjective developmental processes and psychic containment functions. Psychopathological and biological approaches to the study of infantile autism reveal the importance of specific biological and psychological rhythmic disturbances in this disorder. Considering data and hypotheses from both perspectives, this paper proposes an integrative approach to the study of these rhythmic disturbances and offers an etiopathogenic hypothesis based on this integrative approach.
    Journal of Physiology-Paris 03/2013; 107(4). DOI:10.1016/j.jphysparis.2013.03.009 · 1.90 Impact Factor
Show more