Abstract Details

Title Novel Septin Autoantibodies in Paraneoplastic Neurological Diseases

Topic Autoimmune Neurology

Presentation(s) P2 - Poster Session 02 (3:00 PM-4:00 PM)
C19 - Focus on Emerging Diagnostics (4:16 PM-4:26 PM)

Poster/Presentation
Number 1-054

Objective To identify novel septin-directed IgGs among previously unclassified neural autoantibodies (UNAs).

Background

Septins are a family of 13 different proteins involved in various cellular processes including cytoskeletal organization and vesicle trafficking. We have previously reported septin-5- and -7-IgGs in patients with neurological autoimmunity; paraneoplastic causation occurs infrequently (<20%). We report additional septin autoimmune targets identified in our UNA discovery pipeline.

Design/Methods

UNAs (538) were identified by TIIFA during routine testing from 03/2023 to 02/2025. Sixteen showed septin-5/-7-IgG-like staining patterns - characterized by synaptic cerebellar molecular layer predominance, and stronger thalamic than hippocampal or cortical signal - but were negative on corresponding cell-based assays (CBAs). All samples were screened for septin IgGs using protein microarrays and PhIP-Seq. Septin antigen specificity was confirmed with septin-specific CBAs and confocal TIIFA colocalization studies. Clinical data were retrospectively reviewed, tumor specimens assessed for septin expression, and live-cell binding tested in primary neuronal cultures.

Results

Six sera demonstrated reactivity to septin-3, septin-4, septin-6, or septin-9. Septin-3-IgG was detected in a cerebellar ataxia patient (consistent with prior report); our patient had spindle cell sarcoma. Septin-4-IgG was identified in 2 patients with cancer (thymoma and vulva squamous cell carcinoma) and brainstem syndromes, one responding to immunotherapy. Septin-4 expression was detected in the available thymoma tissue. Septin-6-IgG was detected in paraneoplastic encephalopathy with lung cancer. Septin-9-IgG was detected in 2 cases: 1 with coexisting septin-7-IgG and pancreatic adenocarcinoma-associated encephalopathy, and 1 with septin-9-IgG and immune checkpoint-inhibitor-related myeloradiculoplexopathy with squamous cell lung carcinoma. CSF was available only for the septin-3-IgG patient and showed strong positive binding to live rodent hippocampal neurons. Serum IgG showed no binding in any of the six patients.

Conclusions Septin autoimmunity is diverse, with specific septin reactivity relating to distinct clinical phenotypes. All patients in this cohort had associated malignancies, supporting the necessity for tumor screening.

Authors/Disclosures
Andrew McKeon, MD (Mayo Clinic) PRESENTER	The institution of Dr. McKeon has received research support from National Institutes of Health. Dr. McKeon has received intellectual property interests from a discovery or technology relating to health care. Dr. McKeon has received intellectual property interests from a discovery or technology relating to health care. Dr. McKeon has received publishing royalties from a publication relating to health care.
Friederike A. Arlt, MD	Dr. Arlt has received research support from Kompetenznetzwerk Peripherer Nerv (KKPNS).
Yong Guo	Yong Guo has nothing to disclose.
Michael Gilligan, MBBS	Dr. Gilligan has nothing to disclose.
Surendra Dasari	Surendra Dasari has nothing to disclose.
Reghann LaFrance-Corey	Miss LaFrance-Corey has nothing to disclose.
Connie Lesnick (Mayo Clinic)	Connie Lesnick has nothing to disclose.
Divyanshu Dubey, MD, FAAN (Mayo Clinic)	The institution of Dr. Dubey has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Argenx. The institution of Dr. Dubey has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Arialys. The institution of Dr. Dubey has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UCB . Dr. Dubey has received research support from Department of Defense . Dr. Dubey has received research support from Department of Defense . Dr. Dubey has received research support from UCB. Dr. Dubey has received research support from David J. Tomassoni ALS Research Grant Program . Dr. Dubey has received intellectual property interests from a discovery or technology relating to health care. Dr. Dubey has received intellectual property interests from a discovery or technology relating to health care. Dr. Dubey has received intellectual property interests from a discovery or technology relating to health care. Dr. Dubey has received intellectual property interests from a discovery or technology relating to health care.
John R. Mills, MD, PhD (Mayo Clinic)	The institution of Dr. Mills has received research support from Werfen Diagnostics. Dr. Mills has received intellectual property interests from a discovery or technology relating to health care.
Sean J. Pittock, MD, FAAN (Mayo Clinic Dept of Neurology)	Dr. Pittock has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Arialys. The institution of Dr. Pittock has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion. The institution of Dr. Pittock has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB. The institution of Dr. Pittock has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche/Genentech. The institution of Dr. Pittock has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Alexion/AstraZeneka. The institution of Dr. Pittock has received research support from NIH. Dr. Pittock has received intellectual property interests from a discovery or technology relating to health care. Dr. Pittock has received intellectual property interests from a discovery or technology relating to health care. Dr. Pittock has received publishing royalties from a publication relating to health care.
Anastasia Zekeridou, MD, PhD, FAAN (Neuroimmunology Laboratory, Mayo Clinic)	The institution of Dr. Zekeridou has received research support from Roche/Genentech. Dr. Zekeridou has received intellectual property interests from a discovery or technology relating to health care. Dr. Zekeridou has received intellectual property interests from a discovery or technology relating to health care. Dr. Zekeridou has received intellectual property interests from a discovery or technology relating to health care. Dr. Zekeridou has received intellectual property interests from a discovery or technology relating to health care.
Ramona Miske	Ramona Miske has received personal compensation for serving as an employee of Euroimmun. Ramona Miske has received intellectual property interests from a discovery or technology relating to health care.
Madeleine Scharf, PhD	Dr. Scharf has received personal compensation for serving as an employee of Euroimmun AG.
Elias T. Spiliotis, PhD	The institution of Dr. Spiliotis has received research support from NIH.

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