Abstract Details

Title Seizure-related 6 homolog like 2 (SEZ6L2) autoimmunity: Neurologic syndrome and antibody effects

Topic Autoimmune Neurology

Presentation(s) S7 - Autoimmune and Paraneoplastic Neurologic Disorders: Diagnosis, Epidemiology, and Pathophysiology (2:32 PM-2:40 PM)

Poster/Presentation
Number 004

Objective To describe the clinical syndrome of four new patients with seizure-related 6 homolog like 2 antibodies (SEZ6L2-ab), study the antibody characteristics, and evaluate their effects on neuronal cultures.

Background

SEZ6L2 is a type 1 transmembrane protein highly expressed in the brain, particularly in the hippocampus and cerebellum, and in many types of cancer. Antibodies against SEZ6L2 had been previously identified in 2 patients with cerebellar ataxia. Studies on cell lines transfected with SEZ6L2 and AMPA glutamate receptor 1 (GluA1) showed that these 2 proteins are binding partners.

Design/Methods SEZ6L2-ab were initially identified in serum and CSF of a patient with cerebellar ataxia by immunohistochemistry on rat brain sections and immunoprecipitation from rat cerebellar neurons. We used a cell-based assay (CBA) of HEK293 cells transfected with SEZ6L2 to test the serum of 95 patients with unclassified neuropil antibodies, 331 with different neurological disorders, and 10 normal subjects. Additional studies included characterization of IgG subclasses and the effects of SEZ6L2-ab on cultures of rat hippocampal neurons.

Results

In addition to the index patient, SEZ6L2-ab were identified by CBA in 3/95 patients with unclassified neuropil antibodies but in none of the 341 controls. The median age of the four patients was 62 years (range: 54-69) and two were female. Patients presented with subacute gait ataxia, dysarthria and mild extrapyramidal symptoms. Initial brain MRI was normal and CSF pleocytosis was found in only one patient. None improved with immunotherapy. SEZ6L2-ab recognized conformational epitopes. IgG4 SEZ6L2-abs was found in all four patients, and it was the predominant subclass in two. SEZ6L2-abs did not alter the number of total or synaptic SEZ6L2 or GluA1 clusters on the surface of hippocampal neurons.

Conclusions SEZ6L2-ab associate with a subacute cerebellar syndrome with frequent extrapyramidal symptoms. The potential pathogenic effect of the antibodies is not mediated by internalization of the antigen.

Authors/Disclosures
Mar Guasp, MD (Hospital Clínic Barcelona - IDIBAPS) PRESENTER	Dr. Guasp has nothing to disclose.
	No disclosure on file
	No disclosure on file
Eugenia Martinez-Hernandez, MD (Hospital Clinic Barcelona)	Dr. Martinez-Hernandez has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion. Dr. Martinez-Hernandez has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB. Dr. Martinez-Hernandez has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Argenx. The institution of Dr. Martinez-Hernandez has received research support from Instituto de Salud Carlos III. Dr. Martinez-Hernandez has received personal compensation in the range of $500-$4,999 for serving as a support for attending meetings with Sanofi. Dr. Martinez-Hernandez has received personal compensation in the range of $500-$4,999 for serving as a support for attending meetings and speaker honoraria with UCB. Dr. Martinez-Hernandez has received personal compensation in the range of $500-$4,999 for serving as a speaker honoraria with Alexion. Dr. Martinez-Hernandez has received personal compensation in the range of $0-$499 for serving as a speaker honoraria with Terumo. Dr. Martinez-Hernandez has received personal compensation in the range of $500-$4,999 for serving as a support for attending meetings with Janssen. Dr. Martinez-Hernandez has received personal compensation in the range of $500-$4,999 for serving as a support for attending meetings with CSL Behring.
Sonali Singh	No disclosure on file
Albert Saiz (Hospital Clinico De Barcelona)	Albert Saiz has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Albert Saiz has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Horizon Therapeutics. Albert Saiz has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck. Albert Saiz has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Janseen. Albert Saiz has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Albert Saiz has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for novartis. Albert Saiz has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biogen.
	No disclosure on file
Lorena Garcia, MD	Lorena Garcia, MD has nothing to disclose.
Jan Verschuuren, MD, PhD (Leiden University Medical Center)	The institution of Dr. Verschuuren has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Argenx. The institution of Dr. Verschuuren has received personal compensation in the range of $0-$499 for serving as a Consultant for Rapharma. Dr. Verschuuren has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Argenx. The institution of Dr. Verschuuren has received research support from Argenx.
Rachel J. Saunders-Pullman, MD (Mount Sinai Beth Israel, Neurology, Downtown Union Square)	The institution of Dr. Saunders-Pullman has received research support from NIH, Bigglesworth Family Foundation, Empire Clinical Research Investigatory Program.
Liliana A. Ramirez-Gomez, MD, FAAN (Wang Ambulatory Care Center)	The institution of Dr. Ramirez-Gomez has received research support from NIA-NIH.
Michael D. Geschwind, MD, PhD, FAAN (UCSF)	Dr. Geschwind has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Brainstorm Cell Therapeutics, Inc.. Dr. Geschwind has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Walter Grubb. Dr. Geschwind has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Gerson Lehrman Group. Dr. Geschwind has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Reata Pharmaceuticals, Inc..
Josep O. Dalmau, MD, PhD, FAAN	Dr. Dalmau has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Astellas Research Institute of America. Dr. Dalmau has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Janssen Research & Development . Dr. Dalmau has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for ��ɫ��. An immediate family member of Dr. Dalmau has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Nature. The institution of Dr. Dalmau has received research support from Sage Therapeutics. The institution of Dr. Dalmau has received research support from Edmond J.Safra Foundation . The institution of Dr. Dalmau has received research support from La Caixa Foundation. The institution of Dr. Dalmau has received research support from Spanish Ministry of Health (ISCIII). The institution of Dr. Dalmau has received research support from Euroimmun, Inc. Dr. Dalmau has received intellectual property interests from a discovery or technology relating to health care. An immediate family member of Dr. Dalmau has received intellectual property interests from a discovery or technology relating to health care. Dr. Dalmau has received intellectual property interests from a discovery or technology relating to health care. An immediate family member of Dr. Dalmau has received intellectual property interests from a discovery or technology relating to health care. Dr. Dalmau has received publishing royalties from a publication relating to health care. Dr. Dalmau has received publishing royalties from a publication relating to health care. Dr. Dalmau has received publishing royalties from a publication relating to health care.
	No disclosure on file
Francesc R. Graus, MD (IDIBAPS)	Dr. Graus has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for MedLink. Dr. Graus has received intellectual property interests from a discovery or technology relating to health care.

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