2026 American Academy of Neurology Autoimmune Abstract Website

Bruna de Freitas Dias¹, Eric Yu², Sergio Muniz-Castrillo³, Frank Leypoldt⁴, Gregor Kuhlenbäumer⁴, Livia Dutra⁵, Soon-Tae Lee⁶, Kon Chu⁶, Maarten Titulaer⁷, Anna Bastiaansen⁷, Enrique Gomez Figueroa⁸, Jose Flores-Rivera⁹, Graciela Ordoñez-Lozano¹⁰, Hannah Jones¹¹, Russell Dale¹², Josep Dalmau¹³, Thais Armangue¹⁴, Alexander Sandweiss¹⁵, Ivan Chinn¹⁵, Eyal Muscal¹⁵, Sarosh Irani¹⁶, Sophie Binks¹⁷, Adam Al-Diwani¹⁸, Carsten Finke¹⁹, Harald Pruss²⁰, Michael Wilson²¹, Greer Waldrop²¹, Anne-Laurie Pinto²², Geraldine Picard²², Emmanuel Mignot²
¹Department of Neurology, Stanford University, Stanford, CA, United States, ²Stanford Center for Sleep Science and Medicine, Stanford University, Palo Alto, CA, United States, ³Neurology Department, Hospital Universitario 12 de Octubre, Madrid, Spain, ⁴Neuroimmunology, Institute of Clinical Chemistry and Department of Neurology, Christian-Albrechts-University/University Hospital Schleswig-Holstein, Kiel, Germany, ⁵Instituto de Ensino e Pesquisa, Hospital Israelita Albert Einstein, São Paulo, Brazil, ⁶Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea, ⁷Department of Neurology, Erasmus University Medical Center, Rotterdam, the Netherlands, ⁸Department of Neurology, Hospital Civil de Guadalajara, Guadalajara, Mexico, ⁹National Institute of Neurology and Neurosurgery, Mexico City, Mexico, ¹⁰Neuroimmunology Laboratory, Instituto Nacional de Neurología y Neurocirugía, Mexico City, ¹¹Starship Hospital, Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand, ¹²Kids Neuroscience Centre, Children’s Hospital at Westmead clinical school, University of Sydney, Sydney, NSW, Australia, ¹³IDIBAPS-CaixaResearch Institute, Hospital Clínic de Barcelona, Barcelona, Spain, ¹⁴IDIBAPS-CaixaResearch Institute, Hospital Clínic de Barcelona, Barcelona, Spain; Pediatric Neuroimmunology Unit, Department of Neurology, Sant Joan de Déu Children's Hospital, ERN-RITA, University of Barcelona, Barcelona, Spain, ¹⁵Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States, ¹⁶Department of Neurology, John Radcliffe Hospital, Oxford, United Kingdom; Departments of Neurology and Neurosciences, Mayo Clinic, Jacksonville, FL, United States, ¹⁷Department of Neurology, John Radcliffe Hospital, Oxford, United Kingdom; Nuffield Department of Clinical Neurosciences, University of Oxford, ¹⁸University Department of Psychiatry, University of Oxford, Oxford, UK; National Institute for Health Research (NIHR) Oxford Health Biomedical Research Centre, Oxford Health NHS Foundation Trust, Oxford, UK, ¹⁹Department of Neurology and Experimental Neurology, Charité, Universitatsmedizin Berlin, Berlin, Germany, ²⁰Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany, ²¹Department of Neurology, School of Medicine, University of California-San Francisco (UCSF), San Francisco, United States, ²²French Reference Centre on Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, Hôpital Neurologique, MeLiS-UCBL-CNRS UMR 5284. INSERM U1314, University Claude Bernard Lyon 1, Lyon 69008, France

Objective:

To identify the genetic risk factors underlying anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) through a large multi-ethnic GWAS.

Background:

The genetic predisposition to NMDARE remains poorly understood. Previous studies in different ethnic populations have yielded heterogeneous findings involving HLA and non-HLA loci. A large multi-ethnic study was needed to clarify the genetic architecture underlying NMDARE.

Design/Methods:

We performed a GWAS followed by PCA–based control matching in a cohort of 817 NMDARE patients and 11,620 healthy controls. Samples from France (n=256), Germany (n=224), Mexico (n=63), South Korea (n=63), the Netherlands (n=50), Brazil (n=42), Spain (n=36), the UK (n=30), New Zealand (n=25), the US (n=21), and Australia (n=7) were included. WGS was conducted in 20 Caucasian case-control pairs, ACP2-homozygous. Clinical and longitudinal data were also analyzed.

Results:

Among cases, 77% were female, 58% Caucasian, with a mean age of onset of 25.4 ± 14.4 years; 19.5% had ovarian teratoma. Three major association peaks were identified: the NR1H3/ACP2 region (rs11039155, β=0.768, SE=0.079, p=3.5×10⁻²²), DMXL2 (rs2124876, β=−0.391, SE=0.060, p=6.1×10⁻¹¹), and HLA-DRB1 (rs9271146, β=0.319, SE=0.063, p=4.6×10⁻⁷). The ACP2 signal showed a recessive effect (OR=13.4, p=7.8×10⁻²³). ACP2-homozygous patients (n=57) were 84% Caucasian, all females of reproductive age, and 96.5% without ovarian teratomas. WGS in 20 ACP2-homozygous cases and controls did not reveal any effect. Compared with non-ACP2 carriers matched by sex, ethnicity, and age, ACP2-homozygous patients had more seizures (92%vs77%, p=0.002), more speech disturbance (88%vs57%), more abnormal EEGs (92%vs75%, p=0.02), less pleocytosis (28%vs49%, p=0.02), and lower mRS scores at follow-up (0.95 ± 0.91 vs 1.46 ± 1.39, p=0.008), with no differences in mortality, ICU admission, or relapse rates.

Conclusions:

This study identifies HLA and non-HLA risk loci for NMDARE. DMXL2 represents a novel association present across ethnicities. The ACP2-homozygous subgroup, predominantly Caucasian females, appears to have a milder disease course. These findings identify potential biomarkers and provide insight into disease pathophysiology.