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Ciolino et al. J Transl Genet Genom 2022;6:429-42 https://dx.doi.org/10.20517/jtgg.2022.15 Page 431

[8]
antibodies . Thus, autoimmune factors may cause or contribute to autistic symptoms in that group.
Marco et al. reported immune dysregulation in individuals with FXS and intrinsic microglia dysfunction in
[9]
those with Rett (RTT) syndrome . A brief report from 2020 indicated that the implementation of a
restricted diet by 4 months of age was successful in treating gastrointestinal problems in a boy with FXS and
ASD. Specifically, the dietary intervention was correlated with positive changes in laboratory findings, GI
[10]
issues, and behavioral symptoms . In an animal model of ASD from 2022 (studying Fmr1 knockout mice),
fatty acids had a significant effect on the behavioral and neuroimmune phenotype . Another study
[11]
demonstrated that allopregnanolone (an active positive allosteric modulator of GABA’s role on the GABAA
receptor) improved γ-amino butyric acid (GABA) metabolism. In Fragile-X-associated tremor/ataxia
syndrome (FXTAS), fatty acids improved cognitive ability and GABA metabolism .
[12]

Song et al. examined the administration of antioxidants to delay the onset of FXTAS, with the goal of
decreasing morbidity and treating the concomitant mitochondrial dysfunction . In 2014, Valenti et al.
[13]
proposed that mitochondria and radical oxygen species play a role in the pathogenesis of various known
genetic disorders (such as Down’s, RTT, and FXS) . The authors reviewed novel therapeutic approaches
[14]
[14]
involving the activation of mitochondrial function and the reduction of oxidative stress . In 2019, Müller
considered the presence of altered mitochondria and redox status in individuals with RTT syndrome, and
[15]
evaluated the use of medications such as antioxidants and scavengers to stabilize these issues .

THE ROLE OF GENETICS IN DIFFERENT MODELS OF ASD
Genetic models
In 2022, a study by Carlsson et al. examined a diverse range of models for the genetic and environmental
mechanisms of ASD. The authors stated, “Although highly heritable, environment also contributes to the
etiology of ASD” . According to the cumulative stress hypothesis and the three-hit concept, vulnerability
[16]
for a given condition is enhanced if adversities are accumulated during the early stages of life. In this
framework, genetic predisposition and the later-life environment are considered as the first and third hits,
[16]
respectively . In the multi-dimensional model of ASD, underlying genetic and environmental factors are
assumed to continuously affect the risk of developing ASD. In 2021, Torres emphasized the importance of
considering the brain-body connection and the contribution of the peripheral nervous system to mental
[17]
health . The author and her group combined the datasets from genes associated with mental illnesses with
well-known neurological disorders and with illnesses that are not directly associated with the nervous
systems and with manifestations of acquired Post-Traumatic Stress Syndrome Disorder (PTSD). They
included autism, schizophrenia and general, bipolar and unipolar depression. Among neurological
conditions, ataxias (e.g., cerebellar, spinocerebellar, progressive, and gait) and Parkinson’s disease were
taken into account. Among non-neurological disorders, they considered colon cancer, breast cancer,
diabetes, congenital heart disease, hematologic neoplasm, and several autoimmune disorders. The selection
was done to include neuromotor aspects, related to links between the brain and the peripheral nervous
system (mainly the autonomic nervous system). Torres reported as surprising the finding of contributions
of peripheral structures and organs to mental illness. She included in her work: “Tissues of the autonomic
nervous systems were maximally impacted by the removal of the genes associated with these mental
illnesses, as was the muscle-skeletal tissue among the top-ranked illnesses. Tissues associated with
subcortical brain regions necessary for motor control, learning, adaptation, and coordination (basal ganglia
and striatum) were highly impacted by the removal of the genes in both mental illnesses and neurological
disorders, along with those tissues important for memory (hippocampus), emotion (amygdala) and
regulation (hypothalamus)”.