Neurological Autoimmunity Associated With Homer-3 Antibody

Background and ObjectiveTo present 6 new cases with Homer-3 antibodies that expand their clinical spectra and to evaluate the effect of immunotherapy.MethodsPatients with suspected autoimmune cerebellar disorder were tested for rare autoimmune cerebellar ataxia (ACA) antibodies (anti-Tr(DNER)/Zic4/ITPR1/Homer-3/NCDN/PKCγ/PCA-2/AP3B2/mGluR1/ATP1A3 antibodies) using both cell-based and tissue-based assays. Patients with positive serum or CSF results who were diagnosed with ACA were registered and followed up. This study reports and analyzes cases with Homer-3 antibodies.ResultsOf the serum and CSF samples of 750 patients tested, 6 were positive for Homer-3 antibodies. All manifested subacute or insidious-onset cerebellar ataxia. Furthermore, 2 patients each exhibited encephalopathy, myeloradiculopathy, REM sleep behavior disorder, and autonomic dysfunction. Brain magnetic resonance images were normal (n = 1) or revealed cerebellar atrophy (n = 1), cerebellum and pons atrophy with the hot cross bun sign (n = 2), and bilateral cerebral abnormalities (n = 2). Definite leukocytosis was identified in the CSF of 2 patients, protein concentration elevation was observed in the CSF of 1 patient, and oligoclonal bands were present in 2 patients. All patients received immunotherapy, including corticosteroid, IV immunoglobulin, plasma exchange, and mycophenolate mofetil, after which the residual disability was still severe (modified Rankin Scale score ≥3 at the last follow-up in 4 patients and final Scale for the Assessment and Rating of Ataxia scores of 12–29), although 4 patients partially improved and 1 patient stabilized. The remaining 1 patient continued to deteriorate after repeated immunotherapy. Two patients relapsed.DiscussionDisorders associated with Homer-3 antibody can mimic multiple system atrophy with cerebellar features in both clinical and radiologic aspects. Accurate identification of autoimmune-mediated cases is critical. Timely, comprehensive immunotherapy is warranted, given the possibility of long-term clinical benefit.

Update in Autoimmune Movement Disorders: Newly Described Antigen Targets in Autoimmune and Paraneoplastic Cerebellar Ataxia

Movement disorders are a common feature of many antibody-associated neurological disorders. In fact, cerebellar ataxia is one of the most common manifestations of autoimmune neurological diseases. Some of the first autoantibodies identified against antigen targets include anti-neuronal nuclear antibody type 1 (ANNA-1 or anti-Hu) and Purkinje cell cytoplasmic antibody (PCA-1) also known as anti-Yo have been identified in paraneoplastic cerebellar degeneration. Historically these antibodies have been associated with an underlying malignancy; however, recently discovered antibodies can occur in the absence of cancer as well, resulting in the clinical syndrome of autoimmune cerebellar ataxia. The pace of discovery of new antibodies associated with autoimmune or paraneoplastic cerebellar ataxia has increased rapidly over the last few years, and pathogenesis and potential treatment options remains to be explored. Here we will review the literature on recently discovered antibodies associated with autoimmune and paraneoplastic cerebellar ataxia including adaptor protein-3B2 (AP3B2); inositol 1,4,5-trisphophate receptor type 1 (ITPR1); tripartite motif-containing (TRIM) proteins 9, 67, and 46; neurochondrin; neuronal intermediate filament light chain (NIF); septin 5; metabotropic glutamate receptor 2 (mGluR2); seizure-related 6 homolog like 2 (SEZ6L2) and homer-3 antibodies. We will review their clinical characteristics, imaging and CSF findings and treatment response. In addition, we will discuss two clinical case examples of autoimmune cerebellar ataxia.

Indirect immunofluorescent assay as an aid in the diagnosis of suspected immune mediated ataxias

Background and purpose Immune mediated cerebellar ataxias account for a substantial proportion of all progressive ataxias. A diagnostic serological test is not always available. This is particularly problematic in Primary Autoimmune Cerebellar Ataxia, hence the necessity for diagnostic criteria recently devised and published by an International Task Force. We present our experience in the use of a commercially available indirect immunofluorescence assay, intended to be used for the detection of antibodies associated with paraneoplastic neurological syndromes. Methods Retrospective review of patients with ataxia who underwent serological testing using this assay as part of their diagnostic evaluation. We were interested in 3 groups: suspected immune mediated ataxias, genetically confirmed ataxias and patients with cerebellar variant of multi-system atrophy (MSA-C). The indirect immunofluorescence assay was performed using commercially available monkey cerebellum slides and anti-human IgG FITC conjugated antiserum. Results A total of 300 patients that had this test and fitted into one of these 3 groups (immune ataxias 190, genetic ataxias 60, MSA-C 50) were identified. The prevalence of positive immunofluorescence but negative immunoblot was 172/190 (91%) in the suspected immune ataxia group, 3/60 (5%) in the genetic group and 2/50 (4%) in the MSA-C group. The difference between the first and the other groups was significant χ2 (1, N = 291) = 64.2, p < 00001. Conclusions This report demonstrates that a commercially available immunofluorescence assay can be used to provide additional diagnostic aid for suspected immune mediated ataxias and in particular Primary Autoimmune Cerebellar Ataxia where no diagnostic marker exists.

Autoantibody to the Rab6A/Rab6B in Autoimmune Cerebellar Ataxia Associated with Sjogren’s Syndrome

The authors have requested that this preprint be withdrawn due to erroneous posting.

Autoantibody to the Rab6A/Rab6B in Autoimmune Cerebellar Ataxia Associated with Sjogren’s Syndrome

Background To report a novel autoantibody against Purkinje cell in a patient with autoimmune cerebellar ataxia (ACA) associated to Sjogren’s syndrome (SS).Methods The Patients on one centre with cerebellar ataxia of unknown cause, who were tested positive with tissue-based indirect immunofluorescence assay (TBA) on rat cerebellum sections and negative for comprehensive anti-neural autoantibodies panel, were investigated for novel autoantibody identification. Among them, one patient with comorbid ACA and SS was qualified for further exploration. His-immunoprecipitation (HIP) combined with mass spectrometric (MS) analysis was used to identify the target antigen, which was confirmed by recombinant cell based assay (CBA) and antibody neutralization experiments. Results TBA of the patient’s serum and cerebrospinal fluid (CSF) for autoantibody testing revealed binding of IgG antibody, mainly IgG1, to Purkinje cell and granular layer of rat cerebellum. Rab6A was identified as the autoantigen by MS and Western blot, subsequently verified by CBA with HEK293 cells expressing human Rab6A/Rab6B. Furthermore, recombinant human Rab6A/Rab6B protein to neutralize the autoantibodies’ tissue reaction was performed by a parallel confirmed approach.Conclusion Autoantibody against Rab6A/Rab6B may be a novel biomarker in diagnosis of ACA, especially in patients with comorbid ACA and SS. The role of the antibody in mechanism of ACA warrants further study.