Autoimmunity to Inhibitory Synaptic Proteins in Stiff-Person Spectrum of Symptoms (S52.003)

OBJECTIVE To determine the type and frequency of autoantibodies in a large series of patients with stiff-person spectrum of symptoms (SPSS). BACKGROUND SPSS associates with muscle rigidity and spasms. Autoantibodies against inhibitory synaptic proteins, including glutamic-acid decarboxylase (GAD65), amphiphysin, glycine receptor (GlyR), and gephyrin have been implicated in the development of the disorder. METHODS 163 patients with SPSS were included in the study. 87 serum samples, 11 CSF samples and 65 paired serum and CSF samples were examined using immunoblot (amphiphysin), immunohistochemistry (GAD65) and cell-based assays (GlyR, gephyrin and GABAa-receptor). Serum and/or CSF of 20 patients with neurodegenerative diseases and 150 with immune-mediated disorders (57 encephalitis associated to cell-surface antibodies, 83 GAD65 syndromes other than SPSS, and 10 anti-Hu-associated syndromes) served as controls. RESULTS 82/163 (50.3%) patients had antibodies against inhibitory synaptic proteins. When each of the proteins was considered, 53 (32.5%) had antibodies to GAD65, 22 (13.5%) GlyR, 4 (2.4%) GABAa-receptor and 3 (1.8%) amphiphysin. Three patients had antibodies against both, GlyR and GAD65, and 2 against GAD65 and GABAa-receptor. Antibodies to gephyrin were examined in 50 randomly selected patients and all were negative. Among the control groups, GlyR-antibodies were identified in 7/83 patients with GAD65-antibodies (4 cerebellar ataxia and 3 epilepsy), and 4/52 patients with cell-surface-antibodies (all 4 NMDAR). Preliminary clinical comparison between GAD65+ (30 patients) and GlyR+ (22 patients) showed that male gender (p<0.0001), brainstem signs (p=0.0013), sensory symptoms (p=0.0037) and pyramidal signs (p=0.0268, Fisher’s test) were more frequent in the GlyR group. CONCLUSIONS In our experience there is an ample repertoire of individual or coexistent antibodies to inhibitory synaptic proteins in patients with SPSS, including (by order of frequency) GAD65> GlyR> GABAa-receptor> amphyphisin. The GABAa-receptor is a novel antigen not previously reported in this disorder. Preliminary analysis suggests differences in clinical-immunological association. Study Supported by:Instituto CarlosIII CM12/00055, FIS PI11/01780 and PI12/00611, National Institutes of Health RO1NS077851 and Fundacio la Marato TV3 101530 Disclosure: Dr. Martinez-Hernandez has nothing to disclose. Dr. Gresa-Arribas has nothing to disclose. Dr. Petit-Pedrol has nothing to disclose. Dr. Arino has nothing to disclose. Dr. Saiz has received personal compensation for activities with Bayer Schering, Merck Serono, Biogen Idec, Sanofi-Aventis Pharmaceuticals Inc., Teva Neuroscience, and Novartis. Dr. Graus has nothing to disclose. Dr. Dalmau has received personal compensation in an editorial capacity for Up To Date. Dr. Dalmau has received royalty payments from Athena Diagnostics. Dr. Dalmau has received research support from Euroimmun.