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Jyonouchi. J Transl Genet Genom 2023;7:274-90 https://dx.doi.org/10.20517/jtgg.2023.32 Page 280

[41]
with Muckle-Wells syndrome (MWS) present with urticaria and sensory hearing loss . Neonatal-onset
multisystem inflammatory disease (NOMID) is characterized by an early onset of symptoms dominated by
neurological manifestations resembling serous meningitis [41,45] . Interestingly, patients with multiple sclerosis
(MS) are reported to have pathogenic, low-penetrance variants of MEFV and NLRP3 genes at a high
frequency .
[50]
Variants of NLRP and NLRC4 inflammasomes are also known to cause similar autoinflammatory diseases.
As seen in NOMID patients, severely affected patients with cryopyrinopathies are expected to develop
significant neurological symptoms mimicking serous meningitis that may result in significant
developmental delay and seizure disorders. Some patients with cryopyrinopathies develop behavioral
symptoms that overlap with ASD behavioral symptoms in our experience but respond dramatically to
treatment measures for cryopyrinopathies.

(3) Inflammasome blockers: The above-described pyrin and NLRP3-inflammatory disorders have been
treated with blockers of inflammasome activation with favorable clinical responses. Such treatment
measures may be applicable for ASD subjects in whom variants of these genes are found to have a role in
the regulation of underlying neuroinflammation. For FMF patients, colchicine has been the 1st line of
treatment for the past few decades. Colchicine inhibits the polymerization of microtubules, which is crucial
for chemotaxis and phagocytosis of innate immune cells [51,52] . Colchicine also inhibits NLRP3, subsequently
blocking IL-1ß induced inflammasome activation, and production of TNF-α (tumor necrosis factor-α) and
IL-6 [53,54] . Actions of colchicine on microtubes also inhibit neutrophil-platelet interactions, preventing
thrombosis triggered by neutrophilic inflammation [54,55] . These actions of colchicine indicate that colchicine
will be effective for controlling neutrophilic inflammation triggered by Th17 cells and/or other innate
immune cells. However, colchicine is a strong inhibitor of P450 3A4; thus, it will be necessary to evaluate
drug interactions with medications that patients are already taking. As for CAPS patients, IL-1 blockers are
[45]
the 1st line of treatment measures . Humanized monoclonal antibodies against IL-1ß (canakinumab) or
soluble IL-1ß receptor conjugated with the Fc portion of human IgG1 (rilonacept) have been used for long-
acting IL-1ß blockers . In contrast, anakinra, a IL-1 receptor antagonist (IL-1ra), is a recombinant protein
[56]
of naturally produced human IL-1ra that acts as a counter-regulatory mediator for controlling IL-1-induced
[57]
inflammation, blocking actions of both Il-1ß and IL-1 . Anakinra is short-acting, requiring daily
subcutaneous injection. However, it can penetrate intact blood-brain barriers (BBB): this unique property of
anakinra may be handy when it is required to control acute cytokine storms or CNS inflammation
associated with seizures. We have reported one case of treatment-resistant seizures and the favorable effects
of anakinra when used with a mTOR (mammalian target of rapamycin) blocker . Recent results of
[58]
randomized clinical trials of anakinra indicated attenuation of severe COVID-19 (coronavirus disease 2019)
in hospitalized patients [59,60] , although a recent metanalysis reported negative results of anakinra for severe
COVID-19 . It is also of note that CAPS patients are expected to suffer from more potent adjuvant effects
[61]
from vaccinations, but such effects are well attenuated with concurrent use of IL-1ß blockers .
[45]
As summarized, dysregulated activation of inflammasome pathways can present with a puzzling array of
clinical presentations, often including neuropsychiatric symptoms. Clinicians may need to pay attention to
possible genetic risk factors associated with inflammasome disorders in some ASD subjects if other clinical
features indicate autoinflammatory conditions, since blockers targeting inflammasome activation are readily
available and have good safety records .
[45]