Antibodies Against The Cell Adhesion Molecule IgLON5 Identify A Novel Tauopathy With NREM/REM Parasomnia And Sleep Breathing Disorder (S9.005)

OBJECTIVE/ BACKGROUND: We aimed to describe the clinical and neuropathological features of a disorder with prominent sleep symptoms associated with antibodies against a novel cell-surface protein and to characterize the autoantigen. DESIGN/METHODS: Eight patients with antibodies showing a similar reactivity with neuropil of rat brain were included in the study. Patients were assessed by clinical history and video-polysomnography (PSG). Postmortem brain examination was performed in two patients. Immunoprecipitation and mass spectrometry were used to identify the antigen. An assay with HEK293 cells was optimized to develop an unambiguous diagnostic test. As controls, we included 251 patients with neurodegenerative diseases, sleep disorders, autoimmune encephalitis, and multiple sclerosis. RESULTS: All patients developed a unique sleep disorder characterized by abnormal motor behaviors and obstructive sleep apnea with stridor. Video-PSG showed a disorder with undifferentiated or poorly structured stage N2 NREM sleep associated with simple and finalistic behaviors and periods of REM sleep behavior disorder. Normalization of NREM sleep characteristically occurred in the last part of the night. Four patients also developed severe gait instability. Other associated features included chorea, bulbar symptoms, and central hypoventilation. Pathological examination revealed a novel neuronal tauopathy without inflammation mainly involving the tegmentum of the brainstem and hypothalamus. All patients had serum and CSF antibodies (mainly IgG4) against a novel autoantigen that was identified as IgLON5, a member of a family of cell adhesion molecules involved in the control of synaptogenesis. The syndrome slowly progressed in years except in two patients who died in less than six months. Immunotherapy was not effective and six patients had sudden death. IgLON5 antibodies were detected in one of 251 controls. CONCLUSIONS: IgLON5 antibodies identify a novel tauopathy that associates with a sleep disorder characterized by NREM and REM parasomnia and sleep disordered breathing. Our findings emphasize a link between autoimmunity and neurodegeneration. Study Supported by: grants FIS (11/01780; PI12/00611), Fundacio la Marato TV3, and CIBERNED, Spain; and the NIH RO1NS077851, USA. Disclosure: Dr. Gaig has nothing to disclose. Dr. Sabater has nothing to disclose. Dr. Gelpi has nothing to disclose. Dr. Bataller has nothing to disclose. Dr. Lewerenz has nothing to disclose. Dr. Torres-Vega has nothing to disclose. Dr. Contreras has nothing to disclose. Dr. Giometto has nothing to disclose. Dr. Compta has nothing to disclose. Dr. Embid has nothing to disclose. Dr. Vilaseca has nothing to disclose. Dr. Iranzo has nothing to disclose. Dr. Santamaria 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. Dr. Graus has nothing to disclose.