Page 68 - Read Online

Page 275 Jyonouchi. J Transl Genet Genom 2023;7:274-90 https://dx.doi.org/10.20517/jtgg.2023.32

INTRODUCTION
Various genetic analysis has indicated that there are multiple ASD risk variants. These variants are reported
in genes associated with both brain morphogenesis and neuronal plasticity affecting the signaling pathways,
including chromatin remodeling, and Wnt/Notch pathways . Genes involving regulating oxidative stress
[1]
and the associated metabolic pathways also affect neuronal growth. Therefore, variants of these genes are
[1]
implicated in ASD pathogenesis as well . Recent studies of gene-protein interactions and other regulatory
factors of transcription and translation, like microRNA (miRNA), are also implicated in the epigenetic basis
[2]
of ASD development . In such changes, the immune system is thought to play a crucial role in the onset
and progress of ASD, partly through the generation of immune-mediated neuroinflammation . The role of
[2]
neuroinflammation in ASD pathogenesis is best documented in the animal model of ASD called maternal
immune activation (MIA), in which maternal sterile inflammation induced by injection of endotoxin during
[3,4]
the 2nd trimester has been shown to cause impaired neuropsychiatric development in offspring .
Candidate genes for ASD risk are often those involved in the regulation of gene expression in epigenetic
pathways . Likewise, environmental factors that affect epigenetic regulation are also implicated in ASD risk.
[2]
For example, valproate, an anti-seizure medication and a well-known risk factor of ASD through fetal
exposure, is known to affect a histone modification enzyme and folic acid metabolism . The resultant
[2,5]
[6]
epigenetic changes last for a prolonged time, as shown in animal models of MIA . In the MIA model,
maternal inflammation was triggered by endotoxin, causing sterile inflammation. Therefore, lasting effects
on the immune system and the brain are thought to be mediated by its effects on innate immunity. Apart
from the study of ASD pathogenesis, lasting changes in innate immunity following potent immune stimuli
are known to involve epigenetic changes and are often referred to as innate immune memory . In
[7,8]
summary, there may be underlying mechanisms involving gene variants that may cause immune activation
and resultant chronic inflammation in some ASD subjects, manifesting multi-organ phenotypes. In that
regard, research on IEIs provides valuable information.

The study of IEIs has revealed a genetic basis for autoinflammatory and immunodysregulatory conditions,
which often involve the central nervous system (CNS): this is partly due to the onset of inflammation during
the early stage of brain development . Mechanisms of neuroinflammation associated with IEIs often
[9]
involve dysregulated innate immune responses. Understanding such mechanisms has shed light on the role
of neuroinflammation in the pathogenesis of common neuropsychiatric conditions, including ASD. In this
review, IEIs that could present with ASD-like behavioral symptoms will be summarized along with
currently available treatment measures for each IEI condition. Such information may be helpful when
considering exploring advanced genetic testing for ASD subjects. In addition, treatment measures used for
specific IEI may be applicable for ASD subjects if they carry gene variants that can affect their clinical
manifestations.

IEI ASSOCIATED WITH NEURODEVELOPMENTAL CONDITIONS
IEI causing thymic defect and multiple pathways associated with the neuroimmune network
Syndromes that affect the morphogenesis of multiple organs and chromatin remodeling often present with a
puzzling array of clinical features. Both the immune and nervous systems are frequently affected. In
addition, these two systems have an intricate network of cells that are essential for both morphogenesis and
organ functions, by utilizing overlapping mechanisms of actions. In this section, we describe well-
recognized syndromes that could develop ASD-like clinical features and could be initially diagnosed with
ASD as a primary diagnosis. Since these patients are vulnerable to recurrent infection and
autoimmune/autoinflammatory complications, early diagnosis and proper management of these syndromes
will help minimize the hazardous effects of immune-mediated inflammation or other complications in the
brain.