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Abnormalities of the Serotonin-NAS-Melatonin Pathway in Autism Spectrum Disorders

Thursday, 2 May 2013: 16:00
Chamber Hall (Kursaal Centre)
C. Pagan1, H. Goubran Botros1, G. Huguet1, M. Leboyer2, R. Delorme3, J. M. Launay4 and T. Bourgeron5, (1)Neuroscience, Institut Pasteur, Paris, France, (2)INSERM U 955, Hôpital Chenevier-Mondor, Créteil, France, (3)Hôpital Robert Debré, PARIS, France, (4)Hôpital Lariboisière,, Paris, France, (5)Institut Pasteur CNRS URA 2182, Paris Diderot University, Paris, France

Autism spectrum disorders (ASD) are a heterogeneous group of severe developmental
disorders. In more than half of the patients, major sleep problems are present and
dramatically affect the quality of life of the patients and their family. The sleep problems are
thought to be heterogeneous and not specific to ASD, but they should not be neglected.
Indeed, they may constitute one of the first features detected in babies at risk for ASD. In
addition, the quantity and quality of sleep could be ameliorated by appropriate behavior
therapies and/or pharmacological treatments. One of the molecules that regulate the sleep-
wake cycle is melatonin. This molecule is synthesized through serotonin during the dark
phase of the day and is important for the circadian entrainment of the clock.


We previously showed that melatonin synthesis was reduced in patients with ASD. Here,
we explored all components of the serotonin-NAS-melatonin pathway in a large cohort of
patients with ASD, their parents and controls.


Serotonin, melatonin, the intermediate metabolite N-acetylserotonin (NAS), and the two
enzymes AANAT and ASMT was assessed in the blood (whole blood, plasma, or platelets
according to the parameters considered) of more than 193 patients with ASD, their first-
degree relatives (at least 226 parents and 60 unaffected sibs) and a group of more than 222


As previously described, patients with ASD displayed elevated blood serotonin. Taking
as a threshold the 90th percentile of the control group (680 nM), hyperserotonemia was
observed in 47% of patients with ASD. Serotonin was not found to be significantly elevated
in their first-degree relatives. In contrast, plasma melatonin was significantly decreased in
patients with ASD and their relatives compared to controls. Taking as a threshold the 10th
percentile of the control group (0.09 nM), melatonin deficit was observed in 63% of patients
with ASD, 35% of their parents and 31% of sibs. The melatonin decrease was associated
with significantly reduced activities of both enzymes involved in melatonin synthesis, AANAT
and ASMT, measured in blood platelets. Melatonin level was significantly correlated with
ASMT activity in all status groups, and the strongest correlation was observed for patients
with ASD (n=201, linear regression: r2=0.57, p<0.0001). Finally, the intermediate metabolite
NAS was significantly elevated in patients with ASD and in their relatives compared to the
control group. Taking as a threshold the 90th percentile of the control group (37.3 nmol/109
platelets), NAS was elevated in 60% of patients, 29% of parents and 35% of unaffected sibs.
Based on questioners, we showed that abnormal serotonin-NAS-melatonin pathway was
significantly associated with the presence of sleep disorders.


Low melatonin and increased NAS represent relevant biomarkers for a subset of patients
with ASD. These data also indicate that melatonin deficit and accumulation of NAS results
from a reduction of ASMT activity. These abnormalities have a complex inheritance and/or
a non-inherited component, but the high frequency of melatonin deficit observed in parents
suggests that this deficit may be a risk factor of having a child with ASD.

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