Gephyrin Neurological Autoimmunity.

Pantuliano, Maria Chiara; Arlt, Friederike A; Arenson, Naomi; Basuroski, Irena Dujmovic; Dubey, Divyanshu; Lesnick, Connie E; Mills, John R; Pittock, Sean J et al. · Ann Neurol · 2026

case_series · Level IV

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Abstract

Gephyrin is a postsynaptic scaffold protein essential for inhibitory neurotransmission. Gephyrin-immunoglobulin G (IgG) was reported, decades ago, in a single case of paraneoplastic stiff-person-like syndrome, but its broader clinical relevance remains unknown. While investigating unclassified synaptic IgGs mimicking amphiphysin-IgG, we identified gephyrin-IgG in 3 patients using human protein microarray. Gephyrin specificity was confirmed using confocal tissue-based immunofluorescence assay, cell-based assay, and Western blot. The 3 patients, all female, had: encephalitis (2) and myeloneuropathy and breast cancer (1). All had inflammatory cerebrospinal fluid and abnormal magnetic resonance imaging, and improved following immunotherapy. Gephyrin-IgG is associated with a treatable autoimmune neurological disease, sometimes paraneoplastic. ANN NEUROL 2026.