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Page 279 Jyonouchi. J Transl Genet Genom 2023;7:274-90 https://dx.doi.org/10.20517/jtgg.2023.32

IEIs causing autoinflammatory conditions affecting the brain
Recent progress in clinical and molecular immunology has revealed that there are many genetic variants
causing monogenic autoinflammatory diseases. Primary autoinflammatory diseases are characterized by
dysregulated innate immune responses caused by variants of genes associated with the regulation of non-
specific inflammatory responses exerted by innate immunity as the 1st line of immune defense. Since such
[38]
genes are also often closely associated with morphogenesis and plasticity of the nervous system , it is not
surprising that patients with monogenic autoinflammatory diseases often exhibit neuropsychiatric
symptoms and developmental delay. It is beyond the scope of this review to describe each group of
monogenic autoinflammatory diseases. Therefore, in this review, we describe representative
autoinflammatory diseases that are relatively common and often present with predominant
neuropsychiatric symptoms that may mimic ASD behavioral symptoms or, if they co-exist, will be
challenging for clinical management.

Variants of genes regulating activation of inflammasomes
In this category, we will mainly discuss autoinflammatory diseases caused by MEFV variants that cause
familial Mediterranean fever (FMF) and NLRP3 variants that cause cryopyrinopathies.

(1) FMF: FMF is one of the most common systemic autoinflammatory diseases and its gene (MEFV) was
[39]
initially cloned in 1997 . FMF affects populations of Mediterranean descent and its prevalence is reported
to be 1:500 to 1:1,000 in endemic countries . It was known to cause intermittent fever with serositis and
[40]
[41]
subsequent progressive amyloidosis, provided sterile inflammation is not managed properly . Self-limited
fever attacks are thought to be a hallmark of FMF. However, it became more evident that some FMF
patients with pathogenic MEFV gene variants do not present with classical fever attacks and can present
with clinical features mimicking vasculitis and Behçet disease . An atypical manifestation of FMF is now
[42]
well recognized and effects of genotypes and epigenetic regulations are implicated in its variable clinical
manifestations . One case report describes two heterozygous mutations of FMF in a high-functioning ASD
[43]
subject, and these genes may be contributing to muscle rigidity and other symptoms of the musculoskeletal
system in this patient . The pathogenesis of FMF is attributed to a gain of function (GOF) variant of
[44]
MEFV, which causes persistent activation of pyrin. Severe phenotypes are associated with autosomal
recessive (AR) homozygous MEFV variants and/or compound heterozygous AR mutations of MEFV .
[45]
[46]
Autosomal dominant (AD) GOF MEFV variants manifest more distinct clinical phenotypes . It is now
recognized that the presence of pathogenic variants of the MEFV genes aggravates autoimmune
[47]
conditions . We have encountered one patient who was diagnosed with autoimmune encephalitis with the
presence of ovarian teratoma, but this patient’s neuropsychiatric symptoms appeared to be affected by
severe musculoskeletal (MSK) pain symptoms. This patient was later found to have an AD, GOF MEFV
pathogenic variant: her MSK pain was brought under control with daily intake of colchicine and resultant
improvement of her neuropsychiatric symptoms.

(2) Cryopyrinopathyies: Activation of the NLRP3 inflammasome is triggered by signaling from non-specific
triggers of innate immunity, including danger-associated molecular patterns (DAMPS) and pathogen-
associated molecular patterns (PAMPS). These stimuli activate NLRP3 through the NF-kB signaling
pathway, resulting in the up-regulation of IL-1ß (interleukin-1ß) transcription, called priming, and
[45]
subsequent NLRP3 activation follows through multiple mechanisms . Activation of NLRP3 results in the
release of oxidized mitochondrial DNA that can then directly activate NLRP3 . AD, GOF mutations in
[48]
NLRP3 are known to manifest variable degrees of symptoms, called cryopyrin-associated periodic fever
syndrome (CAPS). CAPS is considered to be rare, occurring 1 to 3 per 1 million , but patients with milder
[49]
phenotypes may be present at a higher frequency. Familial cold autoinflammatory syndrome (FACS) is
manifested as intermittent delayed onset cold induced urticaria, often with fever and joint ache, and patients