From dizziness to severe ataxia and dysarthria: New cases of anti-Ca/ARHGAP26 autoantibody-associated cerebellar ataxia suggest a broad clinical spectrum

Wallwitz, Ulrike; Brock, Sebastian; Schunck, Antje; Wildemann, Brigitte; Jarius, Sven; Hoffmann, F.

doi:10.1016/j.jneuroim.2017.05.011

Cited by 26 publications

(20 citation statements)

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“…An underlying tumor was only found in two of the seven previously reported cases ( 2 , 5 ), whereas all three of the here described patients had a cancer diagnosis before or revealed on further work-up. Autoantibodies targeting intracellular antigens are frequently associated with underlying malignancy and can precede cancer diagnosis by up to 15 months ( 12 , 13 ).…”

Section: Discussionmentioning

confidence: 42%

“…While one patient died of his prostate cancer, long-term outcome of the other patients remains to be seen. Previous cases reported little effect of immunosuppressive therapy at best, ideally stabilizing patients with the existing deficits ( 5 ). Long-term clinical follow-up and evaluation of patient outcome after immunosuppressive and tumor therapy should be addressed in future studies.…”

Section: Discussionmentioning

confidence: 98%

“…The previously described clinical spectrum associated with ARHGAP26 autoantibodies includes cerebellar ataxia, but also psychotic, affective and cognitive symptoms ( 1 – 5 ). In line with the initial context of cerebellar ataxia, immunohistochemistry revealed binding to cerebellar molecular layer and PC cytoplasm and membrane ( 1 ).…”

Section: Discussionmentioning

confidence: 98%

“…This notion was further supported by the report of a fifth case with recurrent psychotic episodes, but no signs of cerebellar ataxia ( 4 ). Recently, two more cases have been described including one with cerebellar ataxia and a history of both breast cancer and melanoma and a second case with cerebellar ataxia, tremor, myoclonus, depression, and mild cognitive deficits ( 5 ).…”

Section: Introductionmentioning

confidence: 99%

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Anti-ARHGAP26 Autoantibodies Are Associated With Isolated Cognitive Impairment

2018

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Autoantibodies against the RhoGTPase-activating protein 26 (ARHGAP26) were originally identified in the context of subacute autoimmune cerebellar ataxia. Further studies identified a wider clinical spectrum including psychotic, affective, and cognitive symptoms. Only a few patients reported so far had evidence of a tumor association. A prospective analysis between January 2015 and December 2017 at the Dept. of Neurology at Charité—Universitätsmedizin Berlin identified 14 patients with ARHGAP26 autoantibodies on a cell-based assay, of which three patients had additional brain immunohistochemistry staining of cerebellar molecular layer and Purkinje cells, who were therefore considered antibody-positive. In all three patients, ARHGAP26 autoantibodies were associated with tumors. In two patients, an isolated cognitive impairment without additional neurological deficits was observed. These cases thus further extend the clinical spectrum associated with ARHGAP26 autoantibodies and strengthen a potential paraneoplastic context.

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Section: Discussionmentioning

confidence: 42%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Anti-ARHGAP26 Autoantibodies Are Associated With Isolated Cognitive Impairment

2018

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“…Immunoglobulin‐G (IgG) autoantibodies specific for ρ GTPase activating protein 26 (ARHGAP26, also known as GTPase regulator associated with focal adhesion kinase [GRAF1]) have been reported in 10 patients to date 1–6 . Neurological manifestations in decreasing order of frequency included the following: gait ataxia (gait, 7, limb 4), dysarthria (5), nystagmus (5), dizziness (3), cognitive impairment (3), depression (3), hyperkplexia (2), ocular flutter (1), oscillopsia (1), and recurrent psychoses (1).…”

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confidence: 99%

GTPase Regulator Associated with Focal Adhesion Kinase 1 (GRAF1) Immunoglobulin‐Associated Ataxia and Neuropathy

Pittock

Alfugham

O’Connor

et al. 2020

Movement Disord Clin Pract

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Background Background: To date, 10 patients with GTPase Regulator Associated with Focal Adhesion Kinase 1/ Rho GTPase Activating Protein 26-Immunoglobulin (GRAF1/ARHGAP26-IgG) associated neurological disorders have been described, most with ataxia. Objective Objective: To report the clinical, oncological, and radiological associations of GRAF1 autoantibodies. Methods Methods: We identified 17 patients whose serum and/or cerebrospinal fluid IgG was confirmed to target GRAF1/ ARHGAP26-IgG by both tissue-based immunofluorescence and transfected cell-based assay. Clinical information was available on 14 patients. Results Results: The median age at neurological symptom onset was 51 years, and 8 (47%) were men. The predominant clinical features were subacute progressive cerebellar ataxia (13) or peripheral neuropathy (2). Magnetic resonance imaging brain (7 available) showed cerebellar atrophy (4, 1 also cerebrum and brainstem atrophy). Of 7 cerebrospinal fluids available for testing, 5 showed pleocytosis with oligoclonal bands in 3. Squamous cell carcinoma was observed in 3 patients (head and neck [2], lung [1]). Conclusion Conclusion: GTPase Regulator Associated with Focal Adhesion Kinase 1 autoimmunity manifests commonly with subacute ataxia and cerebellar degeneration with a potential association with squamous cell carcinoma. Peripheral neuropathy may also be encountered. Cases in this series responded poorly to immunotherapy. Immunoglobulin-G (IgG) autoantibodies specific for ρ GTPase activating protein 26 (ARHGAP26, also known as GTPase regulator associated with focal adhesion kinase [GRAF1]) have been reported in 10 patients to date. 1-6 Neurological manifestations in decreasing order of frequency included the following: gait ataxia (gait, 7, limb 4), dysarthria (5), nystagmus (5), dizziness (3), cognitive impairment (3), depression (3), hyperkplexia (2), ocular flutter (1), oscillopsia (1), and recurrent psychoses (1). Half of the patients had a tumor, including ovarian cancer (1), breast cancer (1), melanoma (1), B cell lymphoma (1) prostate adenocarcinoma (1), and gastric adenocarcinoma (1), suggesting that this is a paraneoplastic antibody biomarker. 1-6 Here we describe the clinical and oncological associations of an additional 14 GRAF1-IgG-seropositive patients. Methods The Mayo Clinic institutional review board approved this study (08-06647). This is a retrospective, clinical-serological cohort study approved by the institutional review board of Mayo Clinic, with a waiver of consent for clinical data obtained as part of serologic test validation (study 08-00647). All Mayo Clinic patients whose medical records were analyzed provided written consent for medical research.

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Detection of High‐Risk Paraneoplastic Antibodies against TRIM9 and TRIM67 Proteins

Bartley,

Ngo,

et al. 2023

Annals of Neurology

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Co‐occurring anti‐tripartite motif‐containing protein 9 and 67 autoantibodies (TRIM9/67‐IgG) have been reported in only a very few cases of paraneoplastic cerebellar syndrome. The value of these biomarkers and the most sensitive methods of TRIM9/67‐IgG detection are not known. We performed a retrospective, multi‐center study to evaluate the cerebrospinal fluid (CSF) and serum of candidate TRIM9/67‐IgG cases by tissue‐based immunofluorescence (TBIF), peptide phage display immunoprecipitation sequencing (PhIP‐Seq), overexpression cell‐based assay (CBA), and immunoblot. Cases in whom TRIM9/67‐IgG was detected by at least two assays were considered TRIM9/67‐IgG positive. Among these cases (N=13), CBA was the most sensitive (100%) and revealed that all cases had TRIM9 and TRIM67 autoantibodies. Of TRIM9/67‐IgG cases with available clinical history, a subacute cerebellar syndrome was the most common presentation (N = 7/10), followed by encephalitis (N = 3/10). Of these ten, 70% had comorbid cancer (7/10), 85% of whom (N = 6/7) had confirmed metastatic disease. All evaluable cancer biopsies expressed TRIM9 protein (N = 5/5), whose expression was elevated in the cancerous regions of the tissue in 4 of 5 cases. TRIM9/67‐IgG are rare but likely high‐risk paraneoplastic biomarkers for which CBA appears to be the most sensitive diagnostic assay.This article is protected by copyright. All rights reserved.

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From dizziness to severe ataxia and dysarthria: New cases of anti-Ca/ARHGAP26 autoantibody-associated cerebellar ataxia suggest a broad clinical spectrum

Cited by 26 publications

References 10 publications

Anti-ARHGAP26 Autoantibodies Are Associated With Isolated Cognitive Impairment

Anti-ARHGAP26 Autoantibodies Are Associated With Isolated Cognitive Impairment

GTPase Regulator Associated with Focal Adhesion Kinase 1 (GRAF1) Immunoglobulin‐Associated Ataxia and Neuropathy

Detection of High‐Risk Paraneoplastic Antibodies against TRIM9 and TRIM67 Proteins

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