Citations 2
Novel risk loci in LGI1-antibody encephalitis: genome-wide association study discovery and validation cohorts
Elliott, Katherine S. , Gilbert, Edmund , Harper, Andrew R. , Sempere, Vicente Peris, Pinto, Anne‐Laurie , Rayner, N. William, Mentzer, Alexander J. , Delanty, Norman, Picard, Géraldine , Titulaer, Maarten J. , Kuhlenbäeumer, Gregor, Mignot, Emmanuel , Cavelleri, Gianpiero L, Irani, Sarosh R. , Cavalleri, Gianpiero L. , Mentzer, Alexander J , Handel, Adam , Melzer, Nico , Lee, Soon-Tae , Leypoldt, Frank , Honnorat, Jérôme , Mignot, Emmanuel , Irani, Sarosh R , Cavalleri, Gianpiero L , Titulaer, Maarten J , Binks, Sophie , Muñiz‐Castrillo, Sergio , Araujo, Tânia Kawasaki de , Brown, Andrew , Chong, Amanda Yoon-Yee , Band, Gavin , Costantino, Félicie , Rogemond, Véronique , Handel, Adam E. , Lee, Soon‐Tae , Honnorat, Jérôme , Knight, Julian Charles
Brain | October 24, 2024 | Volume: 148 | Issue: 3 | Pages: 737-745
Abstract Encephalitis with antibodies to leucine-rich glioma-inactivated 1 (LGI1-Ab-E) is a common form of autoimmune encephalitis, presenting with seizures and neuropsychiatric changes, predominantly in older males. More than 90% of patients carry the human leukocyte antigen (HLA) class II allele, HLA-DRB1*07:01. However, this is also present in 25% of healthy controls. Therefore, we hypothesized the presence of additional genetic predispositions. In this genome-wide association study and meta-analysis, we studied a discovery cohort of 131 French LGI1-Ab-E and a validation cohort of 126 American, British and Irish LGI1-Ab-E patients, ancestry-matched to 2613 and 2538 European controls, respectively. Outside the known major HLA signal, we found two single nucleotide polymorphisms at genome-wide significance (P < 5 × 10−8), implicating PTPRD, a protein tyrosine phosphatase, and LINC00670, a non-protein coding RNA gene. Meta-analysis defined four additional non-HLA loci, including the protein coding COBL gene. Polygenic risk scores with and without HLA variants proposed a contribution of non-HLA loci. In silico network analyses suggested LGI1 and PTPRD-mediated interactions via the established receptors of LGI1, ADAM22 and ADAM23. Our results identify new genetic loci in LGI1-Ab-E. These findings present opportunities for mechanistic studies and offer potential markers of susceptibility, prognostics and therapeutic responses.
Detection of High‐Risk Paraneoplastic Antibodies against TRIM9 and TRIM67 Proteins
Bartley, Christopher M. , Ngo, Thomas , Ζεκερίδου, Αναστασία , Dandekar, Ravi , Muñiz‐Castrillo, Sergio , Alvarenga, Bonny D. , Tubati, Asritha , Pinto, Anne‐Laurie , Browne, Weston D., Hullett, Patrick W. , Terrelonge, Mark , Yang, Binxia , Montalvo, Mayra , Kung, Andrew F. , Shah, Maulik , Geschwind, Michael D. , Pittock, Sean J. , Wilson, Michael R. , Pittock, S J , Zekeridou, Anastasia , Muñiz-Castrillo, Sergio , Honnorat, Jérôme , Wilson, Michael R , Do, Le-Duy , Zorn, Kelsey C , Browne, Weston, Schubert, Ryan D. , Piquet, Amanda L. , Mann, Sabrina A , Gelfand, Jeffrey M. , DeRisi, Joseph L , Honnorat, Jérôme , Pleasure, Samuel J
Annals of Neurology | August 26, 2023 | Volume: 94 | Issue: 6 | Pages: 1086-1101
ObjectiveCo‐occurring anti‐tripartite motif‐containing protein 9 and 67 autoantibodies (TRIM9/67‐IgG) have been reported in only a very few cases of paraneoplastic cerebellar syndrome. The value of these biomarkers and the most sensitive methods of TRIM9/67‐IgG detection are not known.MethodsWe performed a retrospective, multicenter study to evaluate the cerebrospinal fluid and serum of candidate TRIM9/67‐IgG cases by tissue‐based immunofluorescence, peptide phage display immunoprecipitation sequencing, overexpression cell‐based assay (CBA), and immunoblot. Cases in which TRIM9/67‐IgG was detected by at least 2 assays were considered TRIM9/67‐IgG positive.ResultsAmong these cases (n = 13), CBA was the most sensitive (100%) and revealed that all cases had TRIM9 and TRIM67 autoantibodies. Of TRIM9/67‐IgG cases with available clinical history, a subacute cerebellar syndrome was the most common presentation (n = 7/10), followed by encephalitis (n = 3/10). Of these 10 patients, 70% had comorbid cancer (7/10), 85% of whom (n = 6/7) had confirmed metastatic disease. All evaluable cancer biopsies expressed TRIM9 protein (n = 5/5), whose expression was elevated in the cancerous regions of the tissue in 4 of 5 cases.InterpretationTRIM9/67‐IgG is a rare but likely high‐risk paraneoplastic biomarker for which CBA appears to be the most sensitive diagnostic assay. ANN NEUROL 2023;94:1086–1101