The serotonin-N-acetylserotonin-melatonin pathway as a biomarker for autism spectrum disorders.
Elevated whole-blood serotonin and decreased plasma melatonin (a circadian synchronizer hormone that derives from serotonin) have been reported independently in patients with autism spectrum disorders (ASDs). Here, we explored, in parallel, serotonin, melatonin and the intermediate N-acetylserotonin (NAS) in a large cohort of patients with ASD and their relatives. We then investigated the clinical correlates of these biochemical parameters. Whole-blood serotonin, platelet NAS and plasma melatonin were assessed in 278 patients with ASD, their 506 first-degree relatives (129 unaffected siblings, 199 mothers and 178 fathers) and 416 sex- and age-matched controls. We confirmed the previously reported hyperserotonemia in ASD (40% (35-46%) of patients), as well as the deficit in melatonin (51% (45-57%)), taking as a threshold the 95th or 5th percentile of the control group, respectively. In addition, this study reveals an increase of NAS (47% (41-54%) of patients) in platelets, pointing to a disruption of the serotonin-NAS-melatonin pathway in ASD. Biochemical impairments were also observed in the first-degree relatives of patients. A score combining impairments of serotonin, NAS and melatonin distinguished between patients and controls with a sensitivity of 80% and a specificity of 85%. In patients the melatonin deficit was only significantly associated with insomnia. Impairments of melatonin synthesis in ASD may be linked with decreased 14-3-3 proteins. Although ASDs are highly heterogeneous, disruption of the serotonin-NAS-melatonin pathway is a very frequent trait in patients and may represent a useful biomarker for a large subgroup of individuals with ASD.
1] Service de Biochimie et Biologie Moléculaire, Department of Biochemistry, University Hospital Lariboisière, AP-HP, INSERM U942, Paris, France [2] University Paris Descartes, Sorbonne Paris Cité, Paris, France [3] Human Genetics and Cognitive Functions, CNRS URA 2182 « Genes, Synapses and Cognition », Institut Pasteur, Paris, France [4] Fondation FondaMental, Créteil, France.
C
C
Pagan
1] Human Genetics and Cognitive Functions, CNRS URA 2182 « Genes, Synapses and Cognition », Institut Pasteur, Paris, France [2] Fondation FondaMental, Créteil, France [3] Department of Child and Adolescent Psychiatry, Robert-Debré Hospital, AP-HP, Paris, France [4] University Paris Diderot, Sorbonne Paris Cité, Paris, France.
R
R
Delorme
1] Service de Biochimie et Biologie Moléculaire, Department of Biochemistry, University Hospital Lariboisière, AP-HP, INSERM U942, Paris, France [2] University Paris Descartes, Sorbonne Paris Cité, Paris, France.
J
J
Callebert
Human Genetics and Cognitive Functions, CNRS URA 2182 « Genes, Synapses and Cognition », Institut Pasteur, Paris, France.
H
H
Goubran-Botros
1] Fondation FondaMental, Créteil, France [2] Department of Child and Adolescent Psychiatry, Robert-Debré Hospital, AP-HP, Paris, France.
F
F
Amsellem
1] Fondation FondaMental, Créteil, France [2] INSERM U955, Psychiatry Genetic, Créteil, France.
X
X
Drouot
1] Fondation FondaMental, Créteil, France [2] INSERM U955, Psychiatry Genetic, Créteil, France [3] Department of Psychiatry, University Hospital Henri Mondor, AP-HP, University Paris-Est Créteil, Créteil, France.
C
C
Boudebesse
1] Fondation FondaMental, Créteil, France [2] INSERM, CIC 1430 and Biological Resource Platform, Henri Mondor Hospital, AP-HP, Créteil, France.
K
K
Le Dudal
Fondation FondaMental, Créteil, France.
N
N
Ngo-Nguyen
Fondation FondaMental, Créteil, France.
H
H
Laouamri
1] Gillberg Neuropsychiatry Centre, University of Gothenburg, Goteborg, Sweden [2] Institute of Child Health, University College London, London, UK.
C
C
Gillberg
1] Fondation FondaMental, Créteil, France [2] INSERM U955, Psychiatry Genetic, Créteil, France [3] Department of Psychiatry, University Hospital Henri Mondor, AP-HP, University Paris-Est Créteil, Créteil, France.
M
M
Leboyer
1] Human Genetics and Cognitive Functions, CNRS URA 2182 « Genes, Synapses and Cognition », Institut Pasteur, Paris, France [2] Fondation FondaMental, Créteil, France [3] University Paris Diderot, Sorbonne Paris Cité, Paris, France.
T
T
Bourgeron
1] Service de Biochimie et Biologie Moléculaire, Department of Biochemistry, University Hospital Lariboisière, AP-HP, INSERM U942, Paris, France [2] University Paris Descartes, Sorbonne Paris Cité, Paris, France [3] Fondation FondaMental, Créteil, France.
J-M
JM
Launay
D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000097:blood; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000097:blood* / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008550:Melatonin / Q000097:blood*; D010290:Parents; D012701:Serotonin / Q000031:analogs & derivatives* / Q000097:blood*; D035781:Siblings; D015398:Signal Transduction / Q000502:physiology*
D015415:Biomarkers; D012701:Serotonin; D008550:Melatonin; C006389:N-acetylserotonin