Skip to main content Accessibility help
×
Hostname: page-component-586b7cd67f-tf8b9 Total loading time: 0 Render date: 2024-11-22T20:18:11.188Z Has data issue: false hasContentIssue false

Chapter 15 - Anti-IgLON5 Disease

from Section 3 - Specific Syndromes and Diseases

Published online by Cambridge University Press:  27 January 2022

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

Type
Chapter
Information
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;13:575586.Google Scholar
Lugaresi, E, Provini, F. Agrypnia excitata: clinical features and pathophysiological implications. Sleep Med Rev 2001;5:313322.Google Scholar
Lugaresi, E, Provini, F, Cortelli, P. Agrypnia excitata. Sleep Med 2011;12(Suppl.2):S3S10.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;12:10411043.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;88:17361743.CrossRefGoogle ScholarPubMed
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;89:14711475.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;59:1320.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;88:10231027.CrossRefGoogle ScholarPubMed
Haitao, R, Huiqin, L, Tao, Q, et al. Autoimmune encephalitis associated with vitiligo? J Neuroimmunol 2017;310:1416.Google Scholar
Ramanan, VK, Crum, BA, McKeon, A. Subacute encephalitis with recovery in IgLON5 autoimmunity. Neurol Neuroimmunol Neuroinflamm 2018;5:e485.CrossRefGoogle ScholarPubMed
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;91:180182.Google Scholar
Gaig, C, Compta, Y. Neurological profiles beyond the sleep disorder in patients with anti-IgLON5 disease. Curr Opin Neurol 2019;32:493499.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;43:268279.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;261:196206.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;31:762764.CrossRefGoogle Scholar
Haitao, R, Yingmai, Y, Yan, H, et al. Chorea and parkinsonism associated with autoantibodies to IgLON5 and responsive to immunotherapy. J Neuroimmunol 2016;300:910.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;46:922930.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;38:102103.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.CrossRefGoogle ScholarPubMed
Morales-Briceno, H, Cruse, B, Fois, AF, et al. IgLON5-mediated neurodegeneration is a differential diagnosis of CNS Whipple disease. Neurology 2018;90:11131115.CrossRefGoogle ScholarPubMed
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;7:708709.CrossRefGoogle ScholarPubMed
Baizabal-Carvallo, JF, Cardoso, F, Jankovic, J. Myorhythmia: phenomenology, etiology, and treatment. Mov Disord 2015;30:171179.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.CrossRefGoogle ScholarPubMed
Tao, QQ, Wei, Q, Song, SJ, Yin, XZ. Motor neuron disease-like phenotype associated with anti-IgLON5 disease. CNS Neurosci Therapeut 2018;24:13051308.Google Scholar
Muñoz-Lopetegi, A, Graus, F, Dalmau, J, Santamaria, J. Sleep disorders in autoimmune encephalitis. Lancet Neurol 2020;19:10101022.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;5:653656.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:e46e47.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;28:203206.Google Scholar
Montagna, P, Lugaresi, E. Agrypnia excitata: a generalized overactivity syndrome and a useful concept in the neurophysiopathology of sleep. Clin Neurophysiol 2002;113:552560.Google Scholar
Mahowald, MW, Schenck, CH. Status dissociatus: a perspective on states of being. Sleep 1991;14:6979.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;39:121132.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;16:552563.Google Scholar
Fanciulli, A, Wenning, GK. Multiple-system atrophy. N Engl J Med 2015;372:13751376.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;4:441443.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;20:677683.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;15:391404.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;404:3639.Google Scholar
Gelpi, E, Hoftberger, R, Graus, F, et al. Neuropathological criteria of anti-IgLON5-related tauopathy. Acta Neuropathol 2016;132:531543.Google Scholar
Grimwood, J, Gordon, LA, Olsen, A, et al. The DNA sequence and biology of human chromosome 19. Nature 2004;428:529535.Google Scholar
Karagogeos, D. Neural GPI-anchored cell adhesion molecules. Front Biosci 2003;8:s13041320.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;1224:111.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;27:893906.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;432:52875303.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;117:645658.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;15:21412156.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;10:7390.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;22:11511161.Google Scholar
Sollid, LM, Pos, W, Wucherpfennig, KW. Molecular mechanisms for contribution of MHC molecules to autoimmune diseases. Curr Opin Immunol 2014;31:2430.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;267:21512153.Google Scholar
Logmin, K, Moldovan, AS, Elben, S, Schnitzler, A, Groiss, SJ. Intravenous immunoglobulins as first-line therapy for IgLON5 encephalopathy. J Neurol 2019;266:10311033.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;141:263270.Google Scholar
Fuseya, K, Kimura, A, Yoshikura, N, et al. Corticobasal syndrome in a patient with anti-IgLON5 antibodies. Mov Disord Clin Pract 2020;7:557559.Google Scholar

Save book to Kindle

To save this book to your Kindle, first ensure [email protected] is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

  • Anti-IgLON5 Disease
  • Josep Dalmau, Universitat de Barcelona, Francesc Graus, Universitat de Barcelona
  • Book: Autoimmune Encephalitis and Related Disorders of the Nervous System
  • Online publication: 27 January 2022
  • Chapter DOI: https://doi.org/10.1017/9781108696722.016
Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

  • Anti-IgLON5 Disease
  • Josep Dalmau, Universitat de Barcelona, Francesc Graus, Universitat de Barcelona
  • Book: Autoimmune Encephalitis and Related Disorders of the Nervous System
  • Online publication: 27 January 2022
  • Chapter DOI: https://doi.org/10.1017/9781108696722.016
Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

  • Anti-IgLON5 Disease
  • Josep Dalmau, Universitat de Barcelona, Francesc Graus, Universitat de Barcelona
  • Book: Autoimmune Encephalitis and Related Disorders of the Nervous System
  • Online publication: 27 January 2022
  • Chapter DOI: https://doi.org/10.1017/9781108696722.016
Available formats
×