Cytokine-related and sodium channel polymorphism as candidate predisposing factors for childhood encephalopathy FIRES/AERRPS

Abstract Febrile infection-related epilepsy syndrome (FIRES), or acute encephalitis with refractory, repetitive partial seizures (AERRPS), is an epileptic encephalopathy beginning with fever-mediated seizures. The etiology remains unclear. To elucidate the genetic background of FIRES/AERRPS (hereafter FIRES), we recruited 19 Japanese patients, genotyped polymorphisms of the IL1B , IL6 , IL10 , TNFA , IL1RN , SCN1A and SCN2A genes, and compared their frequency between the patients and controls. For IL1RN , the frequency of a variable number of tandem repeat (VNTR) allele, RN2, was significantly higher in the patients than in controls ( p  = 0.0067), and A allele at rs4251981 in 5′ upstream of IL1RN with borderline significance (p  = 0.015). Haplotype containing RN2 was associated with an increased risk of FIRES (OR 3.88, 95%CI 1.40–10.8, p  = 0.0057). For SCN1A , no polymorphisms showed a significant association, whereas a missense mutation, R1575C, was found in two patients. For SCN2A , the minor allele frequency of G allele at rs1864885 was higher in patients with borderline significance ( p  = 0.011). We demonstrated the association of IL1RN haplotype containing RN2 with FIRES, and showed a possible association of IL1RN rs4251981 G > A and SCN2A rs1864885 A > G, in Japanese patients. These preliminary findings suggest the involvement of multiple genetic factors in FIRES, which needs to be confirmed by future studies in a larger number of FIRES cases.