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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 435

Over the last 5 years, many articles have been published in high-quality journals with new evidence
supporting the formation of models beyond the genetic model (GM) and neurodiversity model (NM). One
example is Panisi et al., who established that the epidemiological and clinical findings in ASD cannot be
explained by the GM . They supported the development of a “more fluid conception, integrating genetics,
[46]
environment, and epigenetics as a whole”. Indeed, a complex interplay of immune activation, dysbiosis, and
mitochondrial impairment/oxidative stress could affect neurodevelopment during pregnancy and
throughout life, leading to a concept of whole-body dysfunction in ASD. The authors proposed a
“multidisciplinary approach and interdisciplinary sharing of knowledge”.

[47]
[48]
Special issues of the Journal of Personalized Medicine about ASD in 2021 and 2022 include a plethora
of information about these topics from different research groups around the world. Recent manuscripts
[49]
have correlated ASD and autoimmune issues as autoimmune encephalitis and presented sociological
[50]
aspects and clinical challenges for treating CMP in people diagnosed with ASD . There is a clear need for
models that take into account the complexity and heterogeneity of ASD and introduce new meaning to the
role of CMP. Even authors who support conventional models are aware of the need for a revised
approach . For instance, Chen et al. concluded that, “there is a need to pause, rethink, and discuss an
[51]
[51]
intervention research agenda that better addresses the developmental and dynamic nature of Autism, and to
adopt methodological approaches that support the shift of focus from macro- to micro-level change, as well
as from static to dynamic prediction of change”. Recent reviews have emphasized the reemerging roles of
the immune system in ASD . Even when these aspects appear in the open literature, they are not
[52]
frequently analyzed in terms of clinical practice. Instead, research is frequently focused on searching for
biomarker(s) linked to certain genetic finding(s) to define epigenetics and then diagnosis and treatment.
The research focused on biomarkers derived from genetic studies at the brain only ignores the possibility
that the CMP, outside and at the brain, are the result of multiple genetic vulnerabilities interacting in
parallel and in sequence with the environment (water, air, soil) and the exposome (food, infections,
medications during the first 3 years of life, anesthesia, xenobiotics, and other biological stress sources)
through epigenetics. Therefore, the research does not focus on enhancing the daily life of the person with
ASD and the way in which his/her family addresses multiple CMP, their consequences, and concomitant
neurological and psychiatric medical problems as a whole.

Scheme 1 shows the different approaches in the GM and AIM for the detection of Groups/Subgroups in
people with ASD. Today, research about biomarkers in the GM is in the early stages because few validation
studies have been conducted, and the available studies did not consider biomarkers using adequate
[53]
comparison groups . After almost 50 years of continuous research, we are at the beginning of the third of
six steps, as shown in Scheme 1.

In the AIM, the CMP at the whole body level are first considered, properly diagnosed, and treated
(including but not limited to GI issues, allergies or sensitivities to food composition, infections, dysbiosis,
nutritional, metabolic, mitochondrial, biochemical, endocrinological, immune, and autoimmune issues, and
oxidative stress). The responses to treatment of the CMP would produce data regarding ASD groups and
subgroups and potentially reveal groups of biomarkers within subgroups. Neurological and psychiatric
medical issues are considered in the AIM in terms of individual presentation and severity. With this
stratification, research about genetic vulnerabilities (mutations and polymorphisms) is guaranteed and
genetic testing has an important place. However, even if the treatment of a CMP via the AIM does not
change ASD symptoms, the treatment is likely to improve the quality of life of the patient. In contrast, in the
GM, there is no clinical exploration regarding medical issues outside the brain, and CMP may remain
undetected, undiagnosed, and untreated.