Paraneoplastic Cerebellar Ataxia and Antibodies to Metabotropic Glutamate Receptor 2 (2689)

Objective: To report the presence of a new neuronal-surface antibody against the metabotropic glutamate receptor 2 (mGluR2-Ab) in two patients with paraneoplastic cerebellar ataxia. Background: In autoimmune encephalitis there is an extensive number of autoantibodies against neuronal cell surface or synaptic receptors that associate with a good response to immunotherapy. However, in autoimmune cerebellar ataxias the occurrence of similar autoantibodies is rare. Design/Methods: mGluR2-Ab were initially characterized by immunohistochemistry on rat brain and confirmed by immunofluorescence on HEK293 cells transfected with mGluR2. Additional studies included analysis of potential cross-reactivity with other mGluR’s, expression of mGluR2 in patients’ tumors, and the effects of mGluR2-Ab on cultures of rat hippocampal neurons. Results: Patient 1 was a 78-year-old woman with chronic cerebellar ataxia with an initial relapsing-remitting course who developed a small-cell tumor of unknown origin. Patient 2 was a 3-year-old girl who presented a steroid-responsive acute cerebellitis preceding the diagnosis of an alveolar rhabdomyosarcoma. Patients’ serum and CSF showed a characteristic immunostaining of hippocampus and cerebellum in rat brain sections and immunolabeled the cell surface of live rat hippocampal neurons. HEK 293 cells transfected with mGluR1, 2, 3, and 5 confirmed that patients’ antibodies only recognized mGluR2. mGluR2-Ab were not detected in 160 controls, 120 with paraneoplastic, autoimmune, or degenerative ataxias and 40 with autoimmune encephalitis and antibodies against mGluR5 or unknown antigens. Expression of mGluR2 in tumors was confirmed by immunohistochemistry using a commercial mGluR2-Ab. Incubation of live rat hippocampal neurons with CSF of patient 2 did not modify the density of surface mGluR2 clusters. Conclusions: mGluR2-Ab are a novel biomarker of a treatable type of paraneoplastic cerebellar ataxia. The potential pathogenic effect of the antibodies is not mediated by down regulation or internalization of neuronal surface mGluR2. Disclosure: Dr. Ruiz-Garcia has nothing to disclose. Dr. Martinez-Hernandez has nothing to disclose. Dr. Joubert has nothing to disclose. Dr. Petit-Pedrol has nothing to disclose. Dr. Sabater has nothing to disclose. Dr. Dalmau has received personal compensation in an editorial capacity for Editor: Neurology, Neuroimmunology, Neuroinflammation; and UpToDate. Dr. Dalmau has received royalty, license fees, or contractual rights payments from Euroimmune. Dr. Dalmau has received research support from Sage therapeutics. Dr. Graus has nothing to disclose.