Clinical manifestations of the anti-IgLON5 disease

doi:10.1212/WNL.0000000000003887

. 2017 May 2;88(18):1736-1743.

doi: 10.1212/WNL.0000000000003887. Epub 2017 Apr 5.

Clinical manifestations of the anti-IgLON5 disease

Carles Gaig¹, Francesc Graus², Yarko Compta¹, Birgit Högl¹, Luis Bataller¹, Norbert Brüggemann¹, Caroline Giordana¹, Anna Heidbreder¹, Katya Kotschet¹, Jan Lewerenz¹, Stefan Macher¹, Maria J Martí¹, Teresa Montojo¹, Jesus Pérez-Pérez¹, Inmaculada Puertas¹, Caspar Seitz¹, Mateus Simabukuro¹, Nieves Téllez¹, Klaus-Peter Wandinger¹, Alex Iranzo¹, Guadalupe Ercilla¹, Lidia Sabater¹, Joan Santamaría¹, Josep Dalmau¹

Affiliations

¹ From the Neuroimmunology Program (C. Gaig, F.G., A.I., L.S., J.S., J.D.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Department of Neurology (C. Gaig, F.G., Y.C., M.J.M., A.I., J.S.), Multidisciplinary Sleep Disorders Unit (C. Gaig, A.I., J.S.), Parkinson's Disease & Movement Disorders Unit (Y.C., M.J.M.), and Department of Immunology (G.E.), Hospital Clinic, Barcelona, Spain; Department of Neurology (B.H.), Medical University of Innsbruck, Austria; Department of Neurology (L.B.), Hospital Universitari i Politècnic La Fe; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (L.B., L.S., J.D.), Valencia, Spain; Department of Neurology and Institute of Neurogenetics (N.P., K.-P.W.), University of Lübeck, Germany; Department of Movement Disorders and Neurology (C. Giordana), Centre Hospitalier Universitaire Nice, France; Department of Neurology (A.H.), Division of Sleep Medicine and Neuromuscular Disorders, University Hospital Muenster, Germany; Clinical Neurosciences (K.K.), St Vincent's Hospital, Melbourne, Australia; Department of Neurology (J.L.), Ulm University, Germany; Department of Neurology (S.M.), Medical University of Vienna, Austria; Department of Neurology (T.M.), Centre Hospitalier de Luxembourg; Department of Neurology (J.P.-P.), Hospital de la Santa Creu i Sant Pau, Barcelona; Department of Neurology (I.P.), Hospital La Paz, Madrid, Spain; Department of Neurology (C.S.), University Medical Center of the Johannes Gutenberg University Mainz, Germany; Neurology Division (M.S.), Hospital das Clínicas, São Paulo University, Brazil; Department of Neurology (N.T.), Hospital Clínico Universitario, Valladolid, Spain; Institute of Clinical Chemistry (K.-P.W.), University Hospital Schleswig-Holstein, Lübeck, Germany; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; and Institució Catalana de Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain.
² From the Neuroimmunology Program (C. Gaig, F.G., A.I., L.S., J.S., J.D.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Department of Neurology (C. Gaig, F.G., Y.C., M.J.M., A.I., J.S.), Multidisciplinary Sleep Disorders Unit (C. Gaig, A.I., J.S.), Parkinson's Disease & Movement Disorders Unit (Y.C., M.J.M.), and Department of Immunology (G.E.), Hospital Clinic, Barcelona, Spain; Department of Neurology (B.H.), Medical University of Innsbruck, Austria; Department of Neurology (L.B.), Hospital Universitari i Politècnic La Fe; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (L.B., L.S., J.D.), Valencia, Spain; Department of Neurology and Institute of Neurogenetics (N.P., K.-P.W.), University of Lübeck, Germany; Department of Movement Disorders and Neurology (C. Giordana), Centre Hospitalier Universitaire Nice, France; Department of Neurology (A.H.), Division of Sleep Medicine and Neuromuscular Disorders, University Hospital Muenster, Germany; Clinical Neurosciences (K.K.), St Vincent's Hospital, Melbourne, Australia; Department of Neurology (J.L.), Ulm University, Germany; Department of Neurology (S.M.), Medical University of Vienna, Austria; Department of Neurology (T.M.), Centre Hospitalier de Luxembourg; Department of Neurology (J.P.-P.), Hospital de la Santa Creu i Sant Pau, Barcelona; Department of Neurology (I.P.), Hospital La Paz, Madrid, Spain; Department of Neurology (C.S.), University Medical Center of the Johannes Gutenberg University Mainz, Germany; Neurology Division (M.S.), Hospital das Clínicas, São Paulo University, Brazil; Department of Neurology (N.T.), Hospital Clínico Universitario, Valladolid, Spain; Institute of Clinical Chemistry (K.-P.W.), University Hospital Schleswig-Holstein, Lübeck, Germany; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; and Institució Catalana de Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain. fgraus@clinic.ub.es.

PMID: 28381508
PMCID: PMC5409845
DOI: 10.1212/WNL.0000000000003887

Clinical manifestations of the anti-IgLON5 disease

Carles Gaig et al. Neurology. 2017.

. 2017 May 2;88(18):1736-1743.

doi: 10.1212/WNL.0000000000003887. Epub 2017 Apr 5.

Authors

Affiliations

¹ From the Neuroimmunology Program (C. Gaig, F.G., A.I., L.S., J.S., J.D.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Department of Neurology (C. Gaig, F.G., Y.C., M.J.M., A.I., J.S.), Multidisciplinary Sleep Disorders Unit (C. Gaig, A.I., J.S.), Parkinson's Disease & Movement Disorders Unit (Y.C., M.J.M.), and Department of Immunology (G.E.), Hospital Clinic, Barcelona, Spain; Department of Neurology (B.H.), Medical University of Innsbruck, Austria; Department of Neurology (L.B.), Hospital Universitari i Politècnic La Fe; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (L.B., L.S., J.D.), Valencia, Spain; Department of Neurology and Institute of Neurogenetics (N.P., K.-P.W.), University of Lübeck, Germany; Department of Movement Disorders and Neurology (C. Giordana), Centre Hospitalier Universitaire Nice, France; Department of Neurology (A.H.), Division of Sleep Medicine and Neuromuscular Disorders, University Hospital Muenster, Germany; Clinical Neurosciences (K.K.), St Vincent's Hospital, Melbourne, Australia; Department of Neurology (J.L.), Ulm University, Germany; Department of Neurology (S.M.), Medical University of Vienna, Austria; Department of Neurology (T.M.), Centre Hospitalier de Luxembourg; Department of Neurology (J.P.-P.), Hospital de la Santa Creu i Sant Pau, Barcelona; Department of Neurology (I.P.), Hospital La Paz, Madrid, Spain; Department of Neurology (C.S.), University Medical Center of the Johannes Gutenberg University Mainz, Germany; Neurology Division (M.S.), Hospital das Clínicas, São Paulo University, Brazil; Department of Neurology (N.T.), Hospital Clínico Universitario, Valladolid, Spain; Institute of Clinical Chemistry (K.-P.W.), University Hospital Schleswig-Holstein, Lübeck, Germany; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; and Institució Catalana de Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain.
² From the Neuroimmunology Program (C. Gaig, F.G., A.I., L.S., J.S., J.D.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Department of Neurology (C. Gaig, F.G., Y.C., M.J.M., A.I., J.S.), Multidisciplinary Sleep Disorders Unit (C. Gaig, A.I., J.S.), Parkinson's Disease & Movement Disorders Unit (Y.C., M.J.M.), and Department of Immunology (G.E.), Hospital Clinic, Barcelona, Spain; Department of Neurology (B.H.), Medical University of Innsbruck, Austria; Department of Neurology (L.B.), Hospital Universitari i Politècnic La Fe; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (L.B., L.S., J.D.), Valencia, Spain; Department of Neurology and Institute of Neurogenetics (N.P., K.-P.W.), University of Lübeck, Germany; Department of Movement Disorders and Neurology (C. Giordana), Centre Hospitalier Universitaire Nice, France; Department of Neurology (A.H.), Division of Sleep Medicine and Neuromuscular Disorders, University Hospital Muenster, Germany; Clinical Neurosciences (K.K.), St Vincent's Hospital, Melbourne, Australia; Department of Neurology (J.L.), Ulm University, Germany; Department of Neurology (S.M.), Medical University of Vienna, Austria; Department of Neurology (T.M.), Centre Hospitalier de Luxembourg; Department of Neurology (J.P.-P.), Hospital de la Santa Creu i Sant Pau, Barcelona; Department of Neurology (I.P.), Hospital La Paz, Madrid, Spain; Department of Neurology (C.S.), University Medical Center of the Johannes Gutenberg University Mainz, Germany; Neurology Division (M.S.), Hospital das Clínicas, São Paulo University, Brazil; Department of Neurology (N.T.), Hospital Clínico Universitario, Valladolid, Spain; Institute of Clinical Chemistry (K.-P.W.), University Hospital Schleswig-Holstein, Lübeck, Germany; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; and Institució Catalana de Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain. fgraus@clinic.ub.es.

PMID: 28381508
PMCID: PMC5409845
DOI: 10.1212/WNL.0000000000003887

Abstract

Objective: To report the presentation, main syndromes, human leukocyte antigen (HLA) association, and immunoglobulin G (IgG) subclass in the anti-IgLON5 disease: a disorder with parasomnias, sleep apnea, and IgLON5 antibodies.

Methods: This was a retrospective clinical analysis of 22 patients. The IgG subclass was determined using reported techniques.

Results: Patients' median age was 64 years (range 46-83). Symptoms that led to initial consultation included sleep problems (8 patients; 36%), gait abnormalities (8; 36%), bulbar dysfunction (3; 14%), chorea (2; 9%), and cognitive decline (1; 5%). By the time of diagnosis of the disorder, 4 syndromes were identified: (1) a sleep disorder with parasomnia and sleep breathing difficulty in 8 (36%) patients; (2) a bulbar syndrome including dysphagia, sialorrhea, stridor, or acute respiratory insufficiency in 6 (27%); (3) a syndrome resembling progressive supranuclear palsy (PSP-like) in 5 (23%); and (4) cognitive decline with or without chorea in 3 (14%). All patients eventually developed parasomnia, sleep apnea, insomnia, or excessive daytime sleepiness. HLA-DRB1*10:01 and HLA-DQB1*05:01 were positive in 13/15 (87%) patients; the DRB1*10:01 allele was 36 times more prevalent than in the general population. Among 16 patients with paired serum and CSF samples, 14 had IgLON5 antibodies in both, and 2 only in serum (both had a PSP-like syndrome). Twenty of 21 patients had IgG1 and IgG4 antibodies; the latter predominated in 16.

Conclusions: Patients with IgLON5 antibodies develop a characteristic sleep disorder preceded or accompanied by bulbar symptoms, gait abnormalities, oculomotor problems, and, less frequently, cognitive decline. IgG4 subclass antibodies predominate over IgG1; we confirm a strong association with the HLA-DRB1*10:01 allele.

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Figures

**Figure 1. Neurologic profile at diagnosis**
Clinical symptoms and immunologic features in the 22 patients with anti-IgLON5 disease classified according to the neurologic profile at diagnosis. PSG = polysomnography; PSP = progressive supranuclear palsy.

**Figure 2. Anti-IgLON5 immunoglobulin G (IgG) subclass distribution**
Subclasses of anti-IgLON5 IgG in the serum samples of 21 patients with anti-IgLON5 disease (IgG subclass analysis was not done in one patient due to lack of sample).

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Comment in

Cell surface antibody-associated neurodegeneration: The case of anti-IgLON5 antibodies.
Dale RC, Ramanathan S. Dale RC, et al. Neurology. 2017 May 2;88(18):1688-1690. doi: 10.1212/WNL.0000000000003931. Epub 2017 Apr 5. Neurology. 2017. PMID: 28381512 No abstract available.

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References

1. 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. - PMC - PubMed
1. Gelpi E, Höftberger R, Graus F, et al. . Neuropathological criteria of anti-IgLON5-related tauopathy. Acta Neuropathol 2016;132:531–543. - PMC - PubMed
1. van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988;19:604–607. - PubMed
1. Balas A, García-Sánchez F, Vicario JL. Allelic and haplotypic HLA frequency distribution in Spanish hematopoietic patients: implications for unrelated donor searching. Tissue Antigens 2011;77:45–53. - PubMed
1. Högl B, Heidbreder A, Santamaria J, Graus F, Poewe W. IgLON5 autoimmunity and abnormal behaviours during sleep. Lancet 2015;385:1590. - PubMed

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[1] 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. - PMC - PubMed

[2] 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. - PMC - PubMed

[3] Gelpi E, Höftberger R, Graus F, et al. . Neuropathological criteria of anti-IgLON5-related tauopathy. Acta Neuropathol 2016;132:531–543. - PMC - PubMed

[4] Gelpi E, Höftberger R, Graus F, et al. . Neuropathological criteria of anti-IgLON5-related tauopathy. Acta Neuropathol 2016;132:531–543. - PMC - PubMed

[5] van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988;19:604–607. - PubMed

[6] van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988;19:604–607. - PubMed

[7] Balas A, García-Sánchez F, Vicario JL. Allelic and haplotypic HLA frequency distribution in Spanish hematopoietic patients: implications for unrelated donor searching. Tissue Antigens 2011;77:45–53. - PubMed

[8] Balas A, García-Sánchez F, Vicario JL. Allelic and haplotypic HLA frequency distribution in Spanish hematopoietic patients: implications for unrelated donor searching. Tissue Antigens 2011;77:45–53. - PubMed

[9] Högl B, Heidbreder A, Santamaria J, Graus F, Poewe W. IgLON5 autoimmunity and abnormal behaviours during sleep. Lancet 2015;385:1590. - PubMed

[10] Högl B, Heidbreder A, Santamaria J, Graus F, Poewe W. IgLON5 autoimmunity and abnormal behaviours during sleep. Lancet 2015;385:1590. - PubMed

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Clinical manifestations of the anti-IgLON5 disease

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Clinical manifestations of the anti-IgLON5 disease

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