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.
BACKGROUND
Autoimmunity might be associated with or implicated in sleep and neurodegenerative disorders. We aimed to describe the features of a novel neurological syndrome associated with prominent sleep dysfunction and antibodies to a neuronal antigen.


METHODS
In this observational study, we used clinical and video polysomnography to identify a novel sleep disorder in three patients referred to the Sleep Unit of Hospital Clinic, University of Barcelona, Spain, for abnormal sleep behaviours and obstructive sleep apnoea. These patients had antibodies against a neuronal surface antigen, which were also present in five additional patients referred to our laboratory for antibody studies. These five patients had been assessed with polysomnography, which was done in our sleep unit in one patient and the recording reviewed in a second patient. Two patients underwent post-mortem brain examination. Immunoprecipitation and mass spectrometry were used to characterise the antigen and develop an assay for antibody testing. Serum or CSF from 298 patients with neurodegenerative, sleep, or autoimmune disorders served as control samples.


RESULTS
All eight patients (five women; median age at disease onset 59 years [range 52-76]) had abnormal sleep movements and behaviours and obstructive sleep apnoea, as confirmed by polysomnography. Six patients had chronic progression with a median duration from symptom onset to death or last visit of 5 years (range 2-12); in four the sleep disorder was the initial and most prominent feature, and in two it was preceded by gait instability followed by dysarthria, dysphagia, ataxia, or chorea. Two patients had a rapid progression with disequilibrium, dysarthria, dysphagia, and central hypoventilation, and died 2 months and 6 months, respectively, after symptom onset. In five of five patients, video polysomnography showed features of obstructive sleep apnoea, stridor, and abnormal sleep architecture (undifferentiated non-rapid-eye-movement [non-REM] sleep or poorly structured stage N2, simple movements and finalistic behaviours, normalisation of non-REM sleep by the end of the night, and, in the four patients with REM sleep recorded, REM sleep behaviour disorder). Four of four patients had HLA-DRB1*1001 and HLA-DQB1*0501 alleles. All patients had antibodies (mainly IgG4) against IgLON5, a neuronal cell adhesion molecule. Only one of the 298 controls, who had 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 in the two patients studied.


CONCLUSIONS
IgLON5 antibodies identify a unique non-REM and REM parasomnia with sleep breathing dysfunction and pathological features suggesting a tauopathy.


BACKGROUND
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.
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Lidia
L
Sabater
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Department of Neurology, Hospital Clinic, Barcelona, Spain; Multidisciplinary Sleep Disorders Unit, Hospital Clinic, Barcelona, Spain.
Carles
C
Gaig
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Neurological Tissue Bank of the Biobanc-Hospital Clinic-IDIBAPS, Barcelona, Spain.
Ellen
E
Gelpi
Department of Neurology, Hospital Universitari i Politècnic La Fe, Valencia, Spain; Instituto de Investigación Sanitaria La Fe, Valencia, Spain.
Luis
L
Bataller
Department of Neurology, Ulm University, Ulm, Germany.
Jan
J
Lewerenz
Instituto de Investigación Sanitaria La Fe, Valencia, Spain.
Estefanía
E
Torres-Vega
Department of Neurology, Hospital Morales Meseguer, Murcia, Spain.
Angeles
A
Contreras
Department of Neurology, Regional Hospital "Ca' Foncello" Treviso, Italy.
Bruno
B
Giometto
Department of Neurology, Hospital Clinic, Barcelona, Spain.
Yaroslau
Y
Compta
Multidisciplinary Sleep Disorders Unit, Hospital Clinic, Barcelona, Spain; Department of Respiratory Diseases, Hospital Clinic, Barcelona, Spain.
Cristina
C
Embid
Multidisciplinary Sleep Disorders Unit, Hospital Clinic, Barcelona, Spain; Department of Ear, Nose and Throat, Hospital Clinic, Barcelona, Spain.
Isabel
I
Vilaseca
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Department of Neurology, Hospital Clinic, Barcelona, Spain; Multidisciplinary Sleep Disorders Unit, Hospital Clinic, Barcelona, Spain.
Alex
A
Iranzo
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Joan
J
Santamaría
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
Josep
J
Dalmau
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Department of Neurology, Hospital Clinic, Barcelona, Spain. Electronic address: fgraus@clinic.ub.es.
Francesc
F
Graus
D000368:Aged; D001323:Autoantibodies / Q000096:biosynthesis* / Q000097:blood; D015816:Cell Adhesion Molecules, Neuronal / Q000276:immunology*; D018450:Disease Progression; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000097:blood; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D010266:Paraproteins / Q000276:immunology; D020447:Parasomnias / Q000175:diagnosis / Q000276:immunology* / Q000473:pathology; D017286:Polysomnography; D020923:REM Sleep Parasomnias / Q000175:diagnosis / Q000276:immunology / Q000473:pathology; D020181:Sleep Apnea, Obstructive / Q000175:diagnosis / Q000276:immunology* / Q000473:pathology; D013577:Syndrome; D024801:Tauopathies / Q000175:diagnosis / Q000276:immunology / Q000473:pathology; D016875:tau Proteins / Q000276:immunology
D001323:Autoantibodies; D015816:Cell Adhesion Molecules, Neuronal; C000591569:IgLON5 protein, human; D007074:Immunoglobulin G; C054369:MAPT protein, human; D010266:Paraproteins; D016875:tau Proteins