From the Neuroimmunology Program (J.L., M.G., M.P.-P., E.M.-H., J.P., A.S., J.D., L.S., F.G.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Service of Neurology (M.G., E.M.-H., A.S., J.D.), Hospital Clinic, Barcelona; Centro de Investigación Biomédica en Red (M.G., J.D., L.S.), Enfermedades Raras (CIBERER); Immunology Department (R.R.-G.), Centre Diagnòstic Biomèdic, Hospital Clinic, Barcelona; Neurology Department (L.G.-F.), Hospital General San Jorge, Huesca, Spain; Leiden University Medical Center (J.V.), Leiden, The Netherlands; Icahn School of Medicine (R.S.-P.), Mount Sinai Beth Israel, New York; Massachussetts General Hospital (L.R.-G.), Department of Neurology, Boston; UCSF Department of Neurology Memory and Aging Center (M.D.G.), San Francisco, CA; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; Institució Catalana de Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain; and Dr. Petit-Pedrol is now with Interdisciplinary Institute for Neuroscience, UMR 5297, Université de Bordeaux, Bordeaux, France.
Neurol Neuroimmunol Neuroinflamm. 2020 Nov 3;8(1). doi: 10.1212/NXI.0000000000000916. Print 2021 Jan.
To describe the clinical syndrome of 4 new patients with seizure-related 6 homolog like 2 antibodies (SEZ6L2-abs), study the antibody characteristics, and evaluate their effects on neuronal cultures.
SEZ6L2-abs were initially identified in serum and CSF of a patient with cerebellar ataxia by immunohistochemistry on rat brain sections and immunoprecipitation from rat cerebellar neurons. We used a cell-based assay (CBA) of HEK293 cells transfected with to test the serum of 95 patients with unclassified neuropil antibodies, 331 with different neurologic disorders, and 10 healthy subjects. Additional studies included characterization of immunoglobulin G (IgG) subclasses and the effects of SEZ6L2-abs on cultures of rat hippocampal neurons.
In addition to the index patient, SEZ6L2-abs were identified by CBA in 3/95 patients with unclassified neuropil antibodies but in none of the 341 controls. The median age of the 4 patients was 62 years (range: 54-69 years), and 2 were female. Patients presented with subacute gait ataxia, dysarthria, and mild extrapyramidal symptoms. Initial brain MRI was normal, and CSF pleocytosis was found in only 1 patient. None improved with immunotherapy. SEZ6L2-abs recognized conformational epitopes. IgG4 SEZ6L2-abs were found in all 4 patients, and it was the predominant subclass in 2. SEZ6L2-abs did not alter the number of total or synaptic SEZ6L2 or the AMPA glutamate receptor 1 (GluA1) clusters on the surface of hippocampal neurons.
SEZ6L2-abs associate with a subacute cerebellar syndrome with frequent extrapyramidal symptoms. The potential pathogenic effect of the antibodies is not mediated by internalization of the antigen.
描述 4 例新的与癫痫相关的 SEZ6L2 抗体（SEZ6L2-abs）患者的临床综合征，研究抗体特征，并评估其对神经元培养物的影响。
SEZ6L2-abs 最初通过免疫组织化学方法在大鼠脑切片上和从大鼠小脑神经元中免疫沉淀鉴定为患者血清和 CSF 中的小脑共济失调抗体。我们使用转染的 HEK293 细胞的基于细胞的测定（CBA）来测试 95 例未分类神经丝抗体患者、331 例不同神经疾病患者和 10 例健康受试者的血清。其他研究包括鉴定免疫球蛋白 G（IgG）亚类和 SEZ6L2-abs 对大鼠海马神经元培养物的影响。
除了索引患者，CBA 还在 95 例未分类神经丝抗体患者中的 3 例中鉴定出 SEZ6L2-abs，但在 341 例对照中均未鉴定出。4 例患者的中位年龄为 62 岁（范围：54-69 岁），2 例为女性。患者表现为亚急性步态共济失调、构音障碍和轻度锥体外系症状。初始脑 MRI 正常，仅 1 例患者发现 CSF 白细胞增多。免疫治疗均未改善。SEZ6L2-abs 识别构象表位。所有 4 例患者均发现 IgG4 SEZ6L2-abs，其中 2 例为主要亚类。SEZ6L2-abs 不会改变海马神经元表面的总 SEZ6L2 或突触 SEZ6L2 或 AMPA 谷氨酸受体 1（GluA1）簇的数量。
SEZ6L2-abs 与经常伴有锥体外系症状的亚急性小脑综合征相关。抗体的潜在致病作用不是通过抗原内化介导的。
