From the Centre National de Référence pour les Syndromes Neurologiques Paranéoplasiques (E.P., S.M.-C., A.V., A.-L.P., V.R., G.P., V.D.,J.H., B.J.), Hospices Civils de Lyon, Hôpital Neurologique, Bron, France; Synaptopathies and Autoantibodies (SynatAc) Team (E.P., L.D.D., S.M.-C., A.V., V.W., N.C., V.D., J.H., B.J.), Institut NeuroMyoGène-MeLis, INSERM U1314/CNRS UMR 5284, Université de Lyon, France; Medical Imaging Sciences Program (S.H., W.Z.), Division of Health Professions, Faculty of Health Sciences, American University of Beirut, Lebanon; Center for Sleep Sciences and Medicine (J.-J.H., Aditya Ambati, E.M.), Stanford University, Palo Alto, CA; Service de Neurologie 2-Mazarin (Agusti Alentorn, D.P.), Hôpitaux Universitaires La Pitié-Salpêtrière-Charles Foix, APHP; Inserm U1127 CNRS UMR 7225 (Agusti Alentorn, D.P.), Institut du Cerveau et de la Moelle épinière, ICM, Université Pierre-et-Marie-Curie, Sorbonne Universités, Paris, France; INSERM Unité Mixte de Recherche (UMR) S1052 (A.T.-G.), Centre National de la Recherche UMR 5286, Centre de Recherche en Cancérologie de Lyon, France; Département de Pathologie (A.T.-G.), Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre-Bénite Cedex, France; Service des Neurosciences (M.M.), UMons, Mons, Belgium; Service de Neurologie (M.M.), CHU-Charleroi, Charleroi, Belgium; Department of Radiology (F.C.), Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France; and Université Lyon 1 (F.C.), CREATIS-LRMN, CNRS/UMR/5220-INSERM U630, Villeurbanne, France.
Neurol Neuroimmunol Neuroinflamm. 2022 Aug 8;9(5). doi: 10.1212/NXI.0000000000200018. Print 2022 Sep.
There is no report on the long-term outcomes of ataxia with antibodies against Delta and Notch-like epidermal growth factor-related (DNER). We aimed to describe the clinical-immunologic features and long-term outcomes of patients with anti-DNER antibodies.
Patients tested positive for anti-DNER antibodies between 2000 and 2020 were identified retrospectively. In those with available samples, immunoglobulin G (IgG) subclass analysis, longitudinal cerebellum volumetry, human leukocyte antigen isotyping, and CSF proteomic analysis were performed. Rodent brain membrane fractionation and organotypic cerebellar slices were used to study DNER cell-surface expression and human IgG binding to the Purkinje cell surface.
Twenty-eight patients were included (median age, 52 years, range 19-81): 23 of 28 (82.1%) were male and 23 of 28 (82.1%) had a hematologic malignancy. Most patients (27/28, 96.4%) had cerebellar ataxia; 16 of 28 (57.1%) had noncerebellar symptoms (cognitive impairment, neuropathy, and/or seizures), and 27 of 28 (96.4%) became moderately to severely disabled. Half of the patients (50%) improved, and 32.1% (9/28) had no or slight disability at the last visit (median, 26 months; range, 3-238). Good outcome significantly associated with younger age, milder clinical presentations, and less decrease of cerebellar gray matter volumes at follow-up. No human leukocyte antigen association was identified. Inflammation-related proteins were overexpressed in the patients' CSF. In the rodent brain, DNER was enriched in plasma membrane fractions. Patients' anti-DNER antibodies were predominantly IgG1/3 and bound live Purkinje cells in vitro.
DNER ataxia is a treatable condition in which nearly a third of patients have a favorable outcome. DNER antibodies bind to the surface of Purkinje cells and are therefore potentially pathogenic, supporting the use of B-cell-targeting treatments.
目前尚无关于抗 Delta 和 Notch 样表皮生长因子相关蛋白（DNER）抗体的共济失调患者长期预后的报道。我们旨在描述抗 DNER 抗体患者的临床免疫特征和长期预后。
我们回顾性地确定了 2000 年至 2020 年期间检测到抗 DNER 抗体阳性的患者。对于有可用样本的患者，进行了免疫球蛋白 G（IgG）亚类分析、纵向小脑体积测量、人类白细胞抗原定型和 CSF 蛋白质组分析。使用鼠脑膜部分分离和器官型小脑切片研究 DNER 细胞表面表达和人 IgG 与人小脑浦肯野细胞表面的结合。
共纳入 28 例患者（中位年龄为 52 岁，范围为 19-81 岁）：28 例患者中 23 例（82.1%）为男性，23 例（82.1%）患有血液系统恶性肿瘤。大多数患者（27/28，96.4%）有小脑性共济失调；28 例患者中有 16 例（57.1%）有非小脑症状（认知障碍、神经病和/或癫痫发作），27 例（96.4%）患者中度至重度残疾。一半的患者（50%）好转，32.1%（9/28）在末次随访时无或轻度残疾（中位随访时间为 26 个月，范围为 3-238 个月）。良好的预后与年龄较小、临床表现较轻以及随访时小脑灰质体积减少较少显著相关。未发现人类白细胞抗原相关性。患者 CSF 中过表达与炎症相关的蛋白质。在鼠脑中，DNER 富含于质膜部分。患者的抗 DNER 抗体主要是 IgG1/3，在体外与活的浦肯野细胞结合。
DNER 共济失调是一种可治疗的疾病，近三分之一的患者有良好的预后。DNER 抗体与浦肯野细胞表面结合，因此具有潜在的致病性，支持使用 B 细胞靶向治疗。
