A novel non-rapid-eye movement and rapid-eye-movement parasomnia with sleep breathing disorder associated with antibodies to IgLON5: a case series, characterisation of the antigen, and post-mortem study

Abstract

Summary Background Autoimmunity may be involved in sleep and neurodegenerative disorders. We aimed to describe a neurological syndrome with prominent sleep dysfunction and antibodies to a previously unknown neuronal antigen. Methods In this observational study, clinical and video-polysomnography (V- PSG) investigations identified a novel sleep disorder in three patients referred to the Sleep Unit of Hospital Clinic University of Barcelona for abnormal sleep behaviors and obstructive sleep apnea(OSA). They had antibodies against a neuronal surface antigen also present in five additional patients referred to our laboratory for antibody studies. These five patients had been evaluated with PSG and in two, the study was done or reviewed in our Sleep Unit. Two patients underwent postmortem brain examination. Immunoprecipitation and mass spectrometry were used to characterize the antigen and to develop a diagnostic test. Serum or CSF from 285 patients with neurodegenerative, sleep, or autoimmune disorders served as controls. Findings All eight patients (five women; range: 52–76 years, median 59) had abnormal sleep movements and behaviors and OSA confirmed by PSG. Six patients had a chronic evolution (range 2–12 years, median 5.5); in four the sleep disorder was the initial and most prominent feature, and in two it was preceded by gait instability, and followed by dysarthria, dysphagia, ataxia, or chorea. Two patients had a rapid evolution with disequilibrium, dysarthria, dysphagia, and central hypoventilation, and died two and six months after symptom onset. In 5/5 patients, the V-PSG reviewed in our Unit disclosed OSA, stridor, and abnormal sleep architecture with undifferentiated NREM sleep or poorly structured stage N2 with simple movements and finalistic behaviors, normalization of NREM sleep by the end of the night, and REM sleep behavior disorder. Four/4 patients carried the HLA-DRB1*1001 and HLA-DQB1*0501 alleles. All patients had antibodies (mainly IgG4) against IgLON5, member of a family of neuronal cell adhesion molecules. Only 1/285 controls (with progressive supranuclear palsy) had IgLON5 antibodies. Neuropathology showed neuronal loss and extensive deposits of hyperphosphorylated tau mainly involving the tegmentum of the brainstem and hypothalamus. Interpretation IgLON5-antibodies identify a unique NREM and REM parasomnia with sleep breathing dysfunction and pathological features suggesting a tauopathy. Funding Fondo de Investigaciones Sanitarias. Centros de Investigación Biomédica en Red de enfermedades neurodegenerativas (CIBERNED) and Respiratorias (CIBERES), Ministerio de Economía y Competitividad, Fundació la Marató TV3 and the National Institutes of Health.

Clinical manifestations of the anti-IgLON5 disease

“…1 Here we provide evidence that the antiIgLON5 disease can be readily suspected if one considers the combination of a distinctive sleep disorder in association with one or more of the following symptoms: bulbar dysfunction, gait difficulties, oculomotor abnormalities, chorea, or cognitive deterioration. As occurs in other neurologic disorders (e.g., multiple system atrophy [MSA] or PSP), the presentation of the antiIgLON5 disease is heterogeneous.…”

“…1,[5][6][7][8] The median age at diagnosis was 64 years (range 46-83) and the median time to diagnosis was 30 months (range 3-216). All patients were seen by one or more of the authors with a geographic distribution including Europe (20), Australia (1), and Brazil (1).…”

“…Video-PSG is essential to identify and define the complex sleep disorder and confirm the characteristic features of the disorder. 1 Other than the sleep disorder, the most common signs or symptoms at the initial visit included gait difficulty and bulbar dysfunction. The cause of gait problems is probably not uniform.…”

“…Additional features include association with human leukocyte antigen (HLA)-DRB1*10:01 and HLA-DQB1*05:01 alleles and postmortem findings consistent with a novel neuronal tauopathy predominantly involving the hypothalamus and tegmentum of the brainstem. 1,2 These findings place this disorder (named anti-IgLON5 disease) at the convergence of neurodegenerative and autoimmune mechanisms.…”

“…IgLON5 antibodies were screened by immunohistochemistry on frozen sections of rat brain and confirmed by cell-based assay (CBA) using HEK 293 cells transfected with IgLON5 (Origene, Rockville, MD). 1 Determination of IgLON5-IgG subclass was performed by CBA with specific fluorescein isothiocyanate-labeled secondary antibodies against the 4 IgG subclasses (The Binding Site, Birmingham, England). The relative percentage of each IgG subclass in an individual serum was calculated by flow cytometry as described in appendix e-1 at Neurology.org.…”