The classical approach to autism spectrum disorders (ASD) is often limited to considering their neuro-functional aspects. However, recent scientific literature has shown that ASDs also affect many body systems and apparatuses such as the immune system, the sensory-motor system, and the gut-brain axis. The connective tissue, a common thread linking all these structures, may have a pathogenetic role in the multisystem involvement of ASD. Depending on its different anatomical sites, the connective tissue performs functions of connection and support; furthermore, it acts as a barrier between the external and internal environments, regulating the interchange between the two and performing immunological surveillance. The connective tissue shares a close relationship with the central nervous system, the musculoskeletal system and the immune system. Alterations in brain connectivity are common to various developmental disorders, including ASD, and for this reason here we put forward the hypothesis that alterations in the physiological activity of microglia could be implicated in the pathogenesis of ASD. Also, muscle hypotonia is likely to clinically correlate with an altered sensoriality and, in fact, discomfort or early muscle fatigue are often reported in ASDs. Furthermore, patients with ASD often suffer from intestinal dysfunctions, malabsorption and leaky gut syndrome, all phenomena that may be linked to reduced intestinal connectivity. In addition, at the cutaneous and subcutaneous levels, ASDs show a greater predisposition to inflammatory events due to the lack of adequate release of anti-inflammatory mediators. Alveolar-capillary dysfunctions have also been observed in ASD, most frequently interstitial inflammations, immune-mediated forms of allergic asthma, and bronchial hyper-reactivity. Therefore, in autism, altered connectivity can result in phenomena of altered sensitivity to environmental stimuli. The following interpretative model, that we define as the "connectivome theory," considers the alterations in connective elements of common mesodermal origin located in the various organs and apparatuses and entails the evaluation and interpretation of ASDs through also highlighting somatic elements. We believe that this broader approach could be helpful for a more accurate analysis, as it is able to enrich clinical evaluation and define more multidisciplinary and personalized interventions.
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