Genetic role in autoimmune encephalitis and paraneoplastic neurological syndromes

PURPOSE OF REVIEW: To synthesize evidence and recent advances concerning genetic contributors to autoimmune encephalitis (AE) and paraneoplastic neurological syndromes (PNS), relating these to disease processes and clinical management. RECENT FINDINGS: The known immunogenetic role of the human leucocyte antigen (HLA) region - critical to immune and infection response - was refined. A multiethnic IgLON5 study revealed DQ associations, surpassing those previously demonstrated with DR , and arguing for T cell involvement. In PNS with anti-Hu antibodies, a DQB1*02:01 ~ DRB1*03:01 haplotype was preferentially linked to a sensory neuropathy phenotype.Outside the HLA, there were genome-wide association studies (GWAS) in the two commonest AEs. The first AE GWAS with discovery and validation cohorts took place in leucine-rich glioma-inactivated 1-antibody encephalitis (LGI1-Ab-E). This identified a risk locus in PTPRD , a protein tyrosine phosphatase with dual immune and brain activity, and a polygenic risk score (PRS). In N -methyl- d -aspartate receptor-antibody encephalitis (NMDAR-Ab-E), a discovery-only cohort implicated the type 1 interferon pathway gene IFIH1. SUMMARY: Genetic status can perform as a biomarker or prioritize targets for drug development. The paucity of familial cases, the allele frequency of risk HLAs in healthy individuals, and the applicability of PRS, support a multihit model combining genetic and environmental risks.