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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 433

[26]
reversible . The reversibility would be closely related to the genetic susceptibility or risk, the amount and
severity of medical problems outside the brain that affect the brain (CMP), and the approach for addressing
CMP. The lack of treatment for CMP could adversely affect ASD symptoms trajectory and development.
CMP are also influenced by genetic susceptibility, such as risk related to genetic polymorphisms, genetic
mutations, and chromosomal alterations.

In a 16-year pediatric cohort study in Canada (1993-2010), Cawthorpe assessed the quantity of CMP in
individuals with ASD. CMP were diagnosed by a physician according to the International Classification of
Disease version 9 (ICD-9). The analysis included 111 female and 609 male participants with ASD.
According to this study, 28 ICD disorders were found before and 95 ICD disorders after an ASD diagnosis
in female participants, whereas 38 ICD disorders preceded and 234 ICD disorders proceeded ASD diagnosis
[27]
in male participants .
The chronic, dynamic, systemic encephalopathy framework
In this framework, genetic polymorphisms related to the immune system, mitochondrial dysfunction,
autoimmune susceptibility and genes expressed in tissues beyond the brain are important in terms of ASD
risk. Over the last decades, many behaviors have been assigned to ASD. However, some of these behaviors
may be the emerging symptomatology of an encephalopathy related to underlying medical problems
outside the brain, which can affect the brain through barrier permeabilities and other mechanisms.
Accordingly, gut and blood-brain barrier (BBB) permeabilities in ASD are receiving increasing attention
from researchers. The gut-brain-microbiota axis, gut-brain vagal connection, and the complex relationship
between behavior and immune system function is increasingly being taken into account. Allergies and food
intolerances are considered to have a large effect on the symptoms of ASD. In this sense, the evaluation,
detection, and treatment of CMP are extremely important, and healthcare practitioners should be aware of
the importance of medical problems such as diarrhea, constipation, vitamin deficiencies (D, B complex,
A-C-E), mitochondrial dysfunction, dysbiosis, inflammation, and autoimmune issues in individuals with
ASD . Pain or CMP may be strongly related to behavioral symptoms in individuals with ASD, in addition
[27]
to genes expressed in the brain. Indeed, many neurological and psychiatric issues have been correlated with
CMP outside the brain in individuals with ASD, and these may modulate the effect of the exposome on the
risk of CMP in this population.

Regression is defined as losing developmental skill(s) or ability/ies (among them language and social
engagement) that a child once had. Regression of up to 88% was reported in prospective studies about
[28]
infants who were at risk for ASD . Mitochondrial dysfunction has been linked to regression as well as
[29]
autoimmunity in ASD . Redox alterations and mitochondrial dysfunction have been considered to play a
[30]
role in the presentation of RTT [15,31] .
The static encephalopathy framework
Genetic testing may be critical in understanding individual complexity in several medical problems. For
example, epilepsy, movement disorders, and developmental delay are associated with a glucose transporter
type 1 (GLUT 1) deficiency. This has also been associated with impaired glucose transport across the BBB in
[32]
individuals with ASD .
The QT interval is the lapse from the beginning of the Q wave to the end of the T wave during ventricular
depolarization and repolarization in the heart. In long QT syndrome (LQTS), the heart takes more time to
return to the baseline between beats. Timothy syndrome is a congenital form of LQTS with syndactyly and
developmental delay. The prevalence of ASD in individuals with Timothy syndrome is nearly 70% of all
cases.