Autism Spectrum Disorders (ASD) are defined by three core symptoms: social interaction impairments, language impairments, and stereotyped behavior and restricted interests. Beyond this definition lie extremely diverse clinical situations, in terms of symptoms severity as well as comorbidities and associated features. The aetiology of ASD is considered to be mostly genetic, but the molecular mechanisms involved seem to be complex and heterogeneous, and the genotype-phenotype associations elusive. One possible strategy for decomposing the clinical and genetic complexity is to focus on endophenotypes, or intermediate phenotypes, to define more homogeneous pathophysiological categories. Among many biological endophenotypes reported in ASD, the increase of blood serotonin is well documented but still unexplained. Deficits in melatonin (which chemically derives from serotonin) have also been described. The aim of this work was to characterize the impairments of the serotonin-melatonin pathway in ASD, and to address their mechanisms and clinical correlates. Based on a comprehensive assessment of the serotonin-melatonin pathway from blood samples in a large cohort of 200 patients with ASD and their relatives, the prevalence of hyperserotonemia in ASD was estimated to be 45%, and that of melatonin deficit about 60%. Impairments of serotonin catabolism were shown, as well as impairments of melatonin synthesis, thus providing biochemical mechanisms for both endophenotypes. Abnormal melatonin synthesis, which may involve an increase in N-acetylserotonin, was confirmed on pineal gland and gastro-intestinal tract samples (i.e. the major sources of melatonin and serotonin) from patients with ASD. The genes involved in melatonin synthesis (coding for AANAT and ASMT enzymes) were studied in ASD and in related neurodevelopmental disorders. Abnormal melatonin synthesis may be associated with sleep disorders, frequently observed in patients with ASD
