Detection of <scp>High‐Risk</scp> Paraneoplastic Antibodies against <scp>TRIM9</scp> and <scp>TRIM67</scp> Proteins
Christopher M. Bartley, Thomas Ngo, Le Duy, Αναστασία Ζεκερίδου, Ravi Dandekar, Sergio Muñiz‐Castrillo, Bonny D. Alvarenga, Kelsey C. Zorn, Asritha Tubati, Anne‐Laurie Pinto, Weston D. Browne, Patrick W. Hullett, Mark Terrelonge, Ryan Schubert, Amanda L. Piquet, Binxia Yang, Mayra Montalvo, Andrew F. Kung, Sabrina A Mann, Maulik Shah, Michael D. Geschwind, Jeffrey M. Gelfand, Joseph L. DeRisi, Sean J. Pittock, Jérôme Honnorat, Samuel J. Pleasure, Michael R. Wilson
Abstract
OBJECTIVE: Co-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. METHODS: We 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. RESULTS: Among 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. INTERPRETATION: TRIM9/67-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.