beta IV-Spectrin Autoantibodies in 2 Individuals With Neuropathy of Possible Paraneoplastic Origin A Case Series

Objective To identify the autoantigen in 2 individuals with possible seronegative paraneoplastic neuropathy. Methods Serum and CSF were screened by tissue-based assay and panned for candidate autoantibodies by phage display immunoprecipitation sequencing (PhIP-Seq). The candidate antigen was validated by immunostaining knockout tissue and HEK 293T cell-based assay. Results Case 1 presented with gait instability, distal lower extremity numbness, and paresthesias after a recent diagnosis of serous uterine and fallopian carcinoma. Case 2 had a remote history of breast adenocarcinoma and presented with gait instability, distal lower extremity numbness, and paresthesias that progressed to generalized weakness. CSF and serum from both patients immunostained the axon initial segment (AIS) and node of Ranvier (NoR) of mice and enriched beta IV-spectrin by PhIP-Seq. Patient CSF and serum failed to immunostain NoRs in dorsal root sensory neurons from beta I/beta IV-deficient mice. beta IV-spectrin autoantibodies were confirmed by overexpression of AIS and nodal beta IV-spectrin isoforms sigma 1 and sigma 6 by a cell-based assay. beta IV-spectrin was not enriched in a combined 4,815 PhIP-Seq screens of healthy and other neurologic disease patients. Discussion Therefore, beta IV-spectrin autoantibodies may be a marker of paraneoplastic neuropathy. Classification of Evidence This study provides Class IV evidence that beta IV-spectrin antibodies are specific autoantibody biomarkers for paraneoplastic neuropathy.