Anti-IgLON5 Disease

Josep Dalmau; Francesc Graus

doi:10.1017/9781108696722.016

Chapter 15 - Anti-IgLON5 Disease

from Section 3 - Specific Syndromes and Diseases

Published online by Cambridge University Press: 27 January 2022

Josep Dalmau and

Francesc Graus

Show author details

Josep Dalmau: Affiliation:
Universitat de Barcelona
Francesc Graus: Affiliation:
Universitat de Barcelona

Book contents

Get access

Summary

Anti-IgLON5 disease is a neurological disorder that associates with antibodies against IgLON5, a neuronal cell-adhesion protein of unknown function. Most patients develop a combination of prominent sleep alterations (non-rapid eye movement (NREM) and REM parasomnias with obstructive sleep apnoeas), bulbar dysfunction (dysarthria, dysphagia, vocal cord palsy, or episodes of respiratory failure), and gait instability. Initial autopsy studies showed deposits of phosphorylated tau protein predominantly in neurons of the tegmentum of the brainstem, suggesting a primary neurodegenerative disease. However, findings in subsequent studies have provided increasing support to an immune-mediated pathogenesis. First, there is a strong association with the human leukocyte antigen (HLA) haplotype DRB1*10:01–DQB1*05:01 which is present in ~60% of patients (compared to 2% in the normal population); second, recent autopsy studies showed absence of abnormal deposits of tau; and third, in live neurons in culture, IgLON5 antibodies cause an irreversible loss of surface IgLON5 clusters and changes in the cytoskeleton such as dystrophic neurites and axonal swellings. Taken together, these studies suggest that an antibody-mediated disruption of IgLON5 function leads to neurofilament and cytoskeletal alterations that can potentially result in tau accumulation.

Keywords

Anti-IgLON5 disease IgLON5 antibodies NREM parasomnias abnormal movements tauopathy sleep apnoea progressive supranuclear palsy

Type: Chapter
Information: Autoimmune Encephalitis and Related Disorders of the Nervous System , pp. 411 - 429

DOI: https://doi.org/10.1017/9781108696722.016 [Opens in a new window]

Publisher: Cambridge University Press

Print publication year: 2022

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Sabater, L, Gaig, C, Gelpi, E, et al. 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. Lancet Neurol 2014;13:575–586.Google Scholar

Lugaresi, E, Provini, F. Agrypnia excitata: clinical features and pathophysiological implications. Sleep Med Rev 2001;5:313–322.Google Scholar

Lugaresi, E, Provini, F, Cortelli, P. Agrypnia excitata. Sleep Med 2011;12(Suppl.2):S3–S10.Google Scholar

Provini, F, Marconi, S, Amadori, M, et al. Morvan chorea and agrypnia excitata: when video-polysomnographic recording guides the diagnosis. Sleep Med 2011;12:1041–1043.Google Scholar

Gaig, C, Iranzo, A, Cajochen, C, et al. Characterization of the sleep disorder of anti-IgLON5 disease. Sleep 2019;42:zsz133.Google Scholar

Gaig, C, Graus, F, Compta, Y, et al. Clinical manifestations of the anti-IgLON5 disease. Neurology 2017;88:1736–1743.CrossRef Google Scholar PubMed

Honorat, JA, Komorowski, L, Josephs, KA, et al. IgLON5 antibody: neurological accompaniments and outcomes in 20 patients. Neurol Neuroimmunol Neuroinflamm 2017;4:e385.Google Scholar

Escudero, D, Guasp, M, Arino, H, et al. Antibody-associated CNS syndromes without signs of inflammation in the elderly. Neurology 2017;89:1471–1475.Google Scholar

Cagnin, A, Mariotto, S, Fiorini, M, et al. Microglial and neuronal TDP-43 pathology in anti-IgLON5-related tauopathy. J Alzheimer Dis 2017;59:13–20.Google Scholar

Erro, ME, Sabater, L, Martinez, L, et al. Anti-IGLON5 disease: a new case without neuropathologic evidence of brainstem tauopathy. Neurol Neuroimmunol Neuroinflamm 2020;7:e651.Google Scholar

Landa, J, Gaig, C, Planagumà, J, et al. Effects of IgLON5 antibodies on neuronal cytoskeleton: a link between autoimmunity and neurodegeneration. Ann Neurol 2020;88:1023–1027.CrossRef Google Scholar PubMed

Haitao, R, Huiqin, L, Tao, Q, et al. Autoimmune encephalitis associated with vitiligo? J Neuroimmunol 2017;310:14–16.Google Scholar

Ramanan, VK, Crum, BA, McKeon, A. Subacute encephalitis with recovery in IgLON5 autoimmunity. Neurol Neuroimmunol Neuroinflamm 2018;5:e485.CrossRef Google Scholar PubMed

Werner, J, Jelcic, I, Schwarz, EI, et al. Anti-IgLON5 disease: A new bulbar-onset motor neuron mimic syndrome. Neurol Neuroimmunol Neuroinflamm 2021;8:e962.Google Scholar

Gaig, C, Iranzo, A, Santamaria, J, Graus, F. The sleep disorder in Anti-lgLON5 disease. Curr Neurol Neurosci Rep 2018;18:41.Google Scholar

Schoberl, F, Levin, J, Remi, J, et al. IgLON5: a case with predominant cerebellar tau deposits and leptomeningeal inflammation. Neurology 2018;91:180–182.Google Scholar

Gaig, C, Compta, Y. Neurological profiles beyond the sleep disorder in patients with anti-IgLON5 disease. Curr Opin Neurol 2019;32:493–499.Google Scholar

Schroder, JB, Melzer, N, Ruck, T, et al. Isolated dysphagia as initial sign of anti-IgLON5 syndrome. Neurol Neuroimmunol Neuroinflamm 2017;4:e302.Google Scholar

Bonello, M, Jacob, A, Ellul, MA, et al. IgLON5 disease responsive to immunotherapy. Neurol Neuroimmunol Neuroinflamm 2017;4:e383.Google Scholar

Nutt, JG, Marsden, CD, Thompson, PD. Human walking and higher-level gait disorders, particularly in the elderly. Neurology 1993;43:268–279.Google Scholar

Demain, A, Westby, GW, Fernandez-Vidal, S, et al. High-level gait and balance disorders in the elderly: a midbrain disease? J Neurol 2014;261:196–206.Google Scholar

Bruggemann, N, Wandinger, KP, Gaig, C, et al. Dystonia, lower limb stiffness, and upward gaze palsy in a patient with IgLON5 antibodies. Mov Disord 2016;31:762–764.CrossRef Google Scholar

Haitao, R, Yingmai, Y, Yan, H, et al. Chorea and parkinsonism associated with autoantibodies to IgLON5 and responsive to immunotherapy. J Neuroimmunol 2016;300:9–10.Google Scholar

Litvan, I, Agid, Y, Jankovic, J, et al. Accuracy of clinical criteria for the diagnosis of progressive supranuclear palsy (Steele–Richardson–Olszewski syndrome). Neurology 1996;46:922–930.Google Scholar

Mangesius, S, Sprenger, F, Hoftberger, R, et al. IgLON5 autoimmunity tested negative in patients with progressive supranuclear palsy and corticobasal syndrome. Parkinsonism Relat Disord 2017;38:102–103.Google Scholar

Gaig, C, Compta, Y, Heidbreder, A, et al. Frequency and characterization of movement disorders in anti-IgLON5 disease. Neurology 2021;97:e1367–e1381.Google Scholar

Simabukuro, MM, Sabater, L, Adoni, T, et al. Sleep disorder, chorea, and dementia associated with IgLON5 antibodies. Neurol Neuroimmunol Neuroinflamm 2015;2:e136.CrossRef Google Scholar PubMed

Morales-Briceno, H, Cruse, B, Fois, AF, et al. IgLON5-mediated neurodegeneration is a differential diagnosis of CNS Whipple disease. Neurology 2018;90:1113–1115.CrossRef Google Scholar PubMed

Vetter, E, Olmes, DG, Linker, R, Seifert, F. Teaching video NeuroImages: facial myokymia and myorhythmia in anti-IgLON5 disease – the bitten lip. Neurology 2018;91:e1659.Google Scholar

Peeters, I, Wiels, W, De Raedt, S, Flamez, A. Unusual head movements in Anti-IgLON5 disease. Mov Disord Clin Pract 2020;7:708–709.CrossRef Google Scholar PubMed

Baizabal-Carvallo, JF, Cardoso, F, Jankovic, J. Myorhythmia: phenomenology, etiology, and treatment. Mov Disord 2015;30:171–179.Google Scholar

Montagna, M, Amir, R, De Volder, I, et al. IgLON5-associated encephalitis with atypical brain magnetic resonance imaging and cerebrospinal fluid changes. Front Neurol 2018;9:329.CrossRef Google Scholar PubMed

Tao, QQ, Wei, Q, Song, SJ, Yin, XZ. Motor neuron disease-like phenotype associated with anti-IgLON5 disease. CNS Neurosci Therapeut 2018;24:1305–1308.Google Scholar

Muñoz-Lopetegi, A, Graus, F, Dalmau, J, Santamaria, J. Sleep disorders in autoimmune encephalitis. Lancet Neurol 2020;19:1010–1022.Google Scholar

Blinder, T, Lewerenz, J. Cerebrospinal fluid findings in patients with autoimmune encephalitis: a systematic analysis. Front Neurol 2019;10:804.Google Scholar

Moreno-Estebanez, A, Garcia-Ormaechea, M, Tijero, B, et al. Anti-IgLON5 disease responsive to immunotherapy: a case report with an abnormal MRI. Mov Disord Clin Pract 2018;5:653–656.Google Scholar

Rossling, R, Pehl, D, Lingnau, M, Pruss, H. A case of CLIPPERS challenging the new diagnostic criteria. Brain 2018;141:e12.Google Scholar

Hasselbacher, K, Steffen, A, Wandinger, KP, Bruggemann, N. IgLON5 antibodies are infrequent in patients with isolated sleep apnea. Eur J Neurol 2018;25:e46–e47.Google Scholar

Gaig, C, Ercilla, G, Daura, X, et al. HLA and microtubule-associated protein tau H1 haplotype associations in anti-IgLON5 disease. Neurol Neuroimmunol Neuroinflamm 2019;6:e605.Google Scholar

Iranzo, A, Santamaria, J. Severe obstructive sleep apnea/hypopnea mimicking REM sleep behavior disorder. Sleep 2005;28:203–206.Google Scholar

Montagna, P, Lugaresi, E. Agrypnia excitata: a generalized overactivity syndrome and a useful concept in the neurophysiopathology of sleep. Clin Neurophysiol 2002;113:552–560.Google Scholar

Mahowald, MW, Schenck, CH. Status dissociatus: a perspective on states of being. Sleep 1991;14:69–79.Google Scholar

Fernandez-Arcos, A, Iranzo, A, Serradell, M, Gaig, C, Santamaria, J. The clinical phenotype of idiopathic rapid eye movement sleep behavior disorder at presentation: a study in 203 consecutive patients. Sleep 2016;39:121–132.Google Scholar

Boxer, AL, Yu, JT, Golbe, LI, et al. Advances in progressive supranuclear palsy: new diagnostic criteria, biomarkers, and therapeutic approaches. Lancet Neurol 2017;16:552–563.Google Scholar

Fanciulli, A, Wenning, GK. Multiple-system atrophy. N Engl J Med 2015;372:1375–1376.Google Scholar

Montojo, T, Piren, V, Benkhadra, F, et al. Gaze palsy, sleep and gait disorder, as well as Tako-Tsubo syndrome in a patient with IgLON5 antibodies. Mov Disord Clin Pract 2017;4:441–443.Google Scholar

Brunetti, V, Della Marca, G, Spagni, G, Iorio, R. Immunotherapy improves sleep and cognitive impairment in anti-IgLON5 encephalopathy. Neurol Neuroimmunol Neuroinflamm 2019;6:e577.Google Scholar

Schwartz, MA, Selhorst, JB, Ochs, AL, et al. Oculomasticatory myorhythmia: a unique movement disorder occurring in Whipple’s disease. Ann Neurol 1986;20:677–683.Google Scholar

Chung, HY, Wickel, J, Voss, A, et al. Autoimmune encephalitis with anti-IgLON5 and anti-GABAB-receptor antibodies: a case report. Medicine (Baltimore) 2019;98:e15706.Google Scholar

Graus, F, Titulaer, MJ, Balu, R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016;15:391–404.Google Scholar

Hongo, Y, Iizuka, T, Kaneko, A, et al. An autopsy case of MM2-thalamic subtype of sporadic Creutzfeldt–Jakob disease with Lewy bodies presenting as a sleep disorder mimicking anti-IgLON5 disease. J Neurol Sci 2019;404:36–39.Google Scholar

Gelpi, E, Hoftberger, R, Graus, F, et al. Neuropathological criteria of anti-IgLON5-related tauopathy. Acta Neuropathol 2016;132:531–543.Google Scholar

Grimwood, J, Gordon, LA, Olsen, A, et al. The DNA sequence and biology of human chromosome 19. Nature 2004;428:529–535.Google Scholar

Karagogeos, D. Neural GPI-anchored cell adhesion molecules. Front Biosci 2003;8:s1304–1320.Google Scholar

Tan, RPA, Leshchyns’ka, I, Sytnyk, V. Glycosylphosphatidylinositol-anchored immunoglobulin superfamily cell adhesion molecules and their role in neuronal development and synapse regulation. Front Molec Neurosci 2017;10:378.Google Scholar

Hashimoto, T, Yamada, M, Maekawa, S, Nakashima, T, Miyata, S. IgLON cell adhesion molecule Kilon is a crucial modulator for synapse number in hippocampal neurons. Brain Res 2008;1224:1–11.Google Scholar

Ranaivoson, FM, Turk, LS, Ozgul, S, et al. A proteomic screen of neuronal cell-surface molecules reveals IgLONs as Structurally conserved interaction modules at the synapse. Structure 2019;27:893–906.Google Scholar

Venkannagari, H, Kasper, JM, Misra, A, et al. Highly conserved molecular features in IgLONs contrast their distinct structural and biological outcomes. J Molec Biol 2020;432:5287–5303.Google Scholar

Vanaveski, T, Singh, K, Narvik, J, et al. Promoter-specific expression and genomic structure of IgLON family genes in mouse. Front Neurosci 2017;11:38.Google Scholar

Miyata, S, Matsumoto, N, Taguchi, K, et al. Biochemical and ultrastructural analyses of IgLON cell adhesion molecules, Kilon and OBCAM in the rat brain. Neuroscience 2003;117:645–658.Google Scholar

Struyk, AF, Canoll, PD, Wolfgang, MJ, et al. Cloning of neurotrimin defines a new subfamily of differentially expressed neural cell adhesion molecules. J Neurosci 1995;15:2141–2156.Google Scholar

Zacco, A, Cooper, V, Chantler, PD, et al. Isolation, biochemical characterization and ultrastructural analysis of the limbic system-associated membrane protein (LAMP), a protein expressed by neurons comprising functional neural circuits. J Neurosci 1990;10:73–90.Google Scholar

Sabater, L, Planaguma, J, Dalmau, J, Graus, F. Cellular investigations with human antibodies associated with the anti-IgLON5 syndrome. J Neuroinflammation 2016;13:226.Google Scholar

Huijbers, MG, Querol, LA, Niks, EH, et al. The expanding field of IgG4-mediated neurological autoimmune disorders. Eur J Neurol 2015;22:1151–1161.Google Scholar

Sollid, LM, Pos, W, Wucherpfennig, KW. Molecular mechanisms for contribution of MHC molecules to autoimmune diseases. Curr Opin Immunol 2014;31:24–30.Google Scholar

Leshchyns’ka, I, Sytnyk, V. Reciprocal interactions between cell adhesion molecules of the immunoglobulin superfamily and the cytoskeleton in neurons. Front Cell Dev Biol 2016;4:9.Google Scholar

Dale, RC, Tantsis, EM, Merheb, V, et al. Antibodies to MOG have a demyelination phenotype and affect oligodendrocyte cytoskeleton. Neurol Neuroimmunol Neuroinflamm 2014;1:e12.Google Scholar

Ryding, M, Gamre, M, Nissen, MS, et al. Neurodegeneration induced by anti-IgLON5 antibodies studied in induced pluripotent stem cell-derived human neurons. Cells 2021;10:837.Google Scholar

Grüter, T, Behrendt, V, Bien, CI, Gold, R, Ayzenberg, I. Early immunotherapy is highly effective in IgG1/IgG4 positive IgLON5 disease. J Neurol 2020;267:2151–2153.Google Scholar

Logmin, K, Moldovan, AS, Elben, S, Schnitzler, A, Groiss, SJ. Intravenous immunoglobulins as first-line therapy for IgLON5 encephalopathy. J Neurol 2019;266:1031–1033.Google Scholar

Nissen, MS, Blaabjerg, M. Anti-IgLON5 disease: a case with 11-year clinical course and review of the literature. Front Neurol 2019;10:1056.Google Scholar

Cabezudo-García, P, Mena-Vázquez, N, Estivill Torrús, G, Serrano-Castro, P. Response to immunotherapy in anti-IgLON5 disease: a systematic review. Acta Neurol Scand 2020;141:263–270.Google Scholar

Fuseya, K, Kimura, A, Yoshikura, N, et al. Corticobasal syndrome in a patient with anti-IgLON5 antibodies. Mov Disord Clin Pract 2020;7:557–559.Google Scholar

Book contents

Chapter 15 - Anti-IgLON5 Disease

Summary

Keywords

Access options

References

Save book to Kindle

Save book to Dropbox

Save book to Google Drive