IRAK4 Deficiency Presenting with Anti-NMDAR Encephalitis and HHV6 Reactivation

Shiho Nishimura,Yoko Mizoguchi,Sarosh R Irani,Kunihiko Moriya,Sonoko Sakata,Osamu Ohara,Anne Puel,Nobutsune Ishikawa,Masao Kobayashi,Jean-Laurent Casanova,Vanessa Sancho-Shimizu,Hidetoshi Takada,Miyuki Tsumura,Satoshi Okada,Capucine Picard,Hidenori Ohnishi,Zenichiro Kato,Yoshiyuki Kobayashi

doi:10.1007/s10875-020-00885-5

Abstract

IRAK4 deficiency is an inborn error of immunity predisposing patients to invasive pyogenic infections. Currently, there is no established simple assay that enables precise characterization of IRAK4 mutant alleles in isolation. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune condition that is characterized by psychiatric symptoms, involuntary movement, seizures, autonomic dysfunction, and central hypoventilation. It typically occurs in adult females associated with tumors. Only a few infantile cases with anti-NMDAR encephalitis have been so far reported. We identified a 10-month-old boy with IRAK4 deficiency presenting with anti-NMDAR encephalitis and human herpes virus 6 (HHV6) reactivation. The diagnosis of IRAK4 deficiency was confirmed by the identification of compound heterozygous mutations c.29_30delAT (p.Y10Cfs*9) and c.35G>C (p.R12P) in the IRAK4 gene, low levels of IRAK4 protein expression in peripheral blood, and defective fibroblastic cell responses to TLR and IL-1 (TIR) agonist. We established a novel NF-κB reporter assay using IRAK4-null HEK293T, which enabled the precise evaluation of IRAK4 mutations. Using this system, we confirmed that both novel mutations identified in the patient are deleterious. Our study provides a new simple and reliable method to analyze IRAK4 mutant alleles. It also suggests the possible link between inborn errors of immunity and early onset anti-NMDAR encephalitis.

Highlights

Toll-like receptors (TLRs) sense microbial products and play an important role in innate immunity [1]
We report a rare case of IRAK4 deficiency presenting with severe neurological sequelae associated with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis and human herpes virus 6 (HHV6) reactivation
As the development of anti-NMDAR encephalitis in infantile periods is quite rare, we suspected the presence of a genetic background in this patient

Summary

Introduction

Toll-like receptors (TLRs) sense microbial products and play an important role in innate immunity [1]. Activation of the TLR response results in increased production of inflammatory cytokines such as IL-6 and type I interferons, a key component of the anti-viral state, and secretion of chemokines to attract innate immune cells [2]. Extended author information available on the last page of the article deficiency, together with myeloid differentiation primary response gene 88 (MyD88) deficiency, is a primary immune deficiency that impairs IL-1R and TLR family signaling [3]. Patients with AR IRAK4 deficiency show a predominant susceptibility to invasive infections with pyogenic bacteria such as Streptococcus pneumoniae, Staphylococcus aureus, and Pseudomonas aeruginosa in early childhood, with severe and often fatal outcomes [4, 5]. Cells and patients with inherited MyD88 deficiency are indistinguishable from cells and patients with inherited

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Conclusion