Case Control Analysis of Glycine Receptor Autoimmunity (P5.125)

Objective: To report our experience with an in-house developed cell-based assay for IgG antibody targeting the alpha-1 subunit of glycine receptor (GlyRα1) among patients and control subjects. Background: GlyRα1antibody is a biomarker of spinal and brainstem hyperexcitability (stiff-person spectrum [SPS] disorders) which includes classical SPS, limited SPS (e.g. stiff-limb), progressive encephalomyelitis with rigidity and myoclonus (PERM) and hyperekplexia. Design/Methods: HEK293 cells were transfected with a plasmid encoding GlyRα1subunit or were non-transfected and exposed to serum or CSF. Patients (n=20) were GlyRα1antibody positive from physician requests (2013–2016). Controls (n=240 total) were subjects with serum (n=190: 100 healthy adults; 40 healthy children; 50 patients with non-organ specific immunopathies) or CSF (n=50: 30 adults with normal pressure hydrocephalus; 20 children with hereditary neurological disorders). Results: GlyRα1 antibody positivity was found in none of the CSF controls and 8 of 190 serum controls (4%: 5 healthy, 2 with polyclonal hypergammaglobulinemia and 1 with SLE). Of the 20 patients, 1 had a functional neurological disorder (GlyRα1 antibody positive in serum only). The remaining 19 patients had organic SPS spectrum disorders. Ten were male, median age of symptom onset was 51 years. Six patients had GAD65 antibody coexisting (median value: 60.2 nmol/L; range, 0.04–3861). GlyRα1-IgG was detected in serum in 18/19 patients (3/11 were also positive in CSF) and in CSF alone in 1 patient. Phenotypes included PERM (8), SPS (5), stiff-limb (5), and hyperekplexia (1). Neuropsychiatric symptoms (anxiety only [10], anxiety and depression [5], and cognitive dysfunction [3]) coincided with SPS symptoms in 50% of patients. Neoplasms were identified in 4 patients: thymoma (2); Hodgkin lymphoma (1) and ovarian adenocarcinoma (1). Objective neurologic improvement occurred in 15/17 immunotherapy-treated patients (88%), although 2 with PERM died. Conclusions: In the context of SPS spectrum disorders, GlyRα1antibody is a biomarker of an immunotherapy-responsive neurological disease. Study Supported by: Funding: Mayo Clinic Center for Individualized Medicine and Department of Laboratory Medicine and Pathology. Disclosure: Dr. Lopez-Chiriboga has nothing to disclose. Dr. Hinson has received (royalty or license fee or contractual rights) payments from Mayo Foundation. Dr. Bower has nothing to disclose. Dr. Matsumoto has nothing to disclose. Dr. Hassan has nothing to disclose. Dr. Basal has nothing to disclose. Dr. Lennon has received personal compensation from Mayo Foundation-licensed Laboratories. Dr. Pittock9s institution has received compensation for Dr. Pittock9s activities with Alexion Pharmaceuticals, Medimmune and Chugai Pharma USA. Dr. Pittock and Dr. Pittock9s institution stand to receive patent payments that relate to patents for functional AQP4/NMO-IgG assays and NMO-IgG as a cancer marker. Dr. Pittock has received research support from NIH, Alexion Pharmaceuticals and Medimmune related to autoimmune NMO/AQP4 channelopathy. Dr. McKeon has received research support from MedImmune and Euroimmun.