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

Abstract

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.

GRAF1 integrates PINK1-Parkin signaling and actin dynamics to mediate cardiac mitochondrial homeostasis

“…With respect to neurodegenerative disease, it is notable that nearly all PD-associated mutations impact proteins that participate in mitochondrial quality control 52 , 63 , and GRAF1 was shown by others to be neuroprotective in a human Parkinson’s cell culture model (MPP + ‐treated dopaminergic neuroblastoma SK‐N‐SH cells) 64 . While related patient data are relatively scarce, 24 patients to date have been reported with GRAF1 autoimmunity, and of these cases, 83% of patients had cerebellar ataxia (a feature common in PD and related diseases), approximately 30% exhibited cerebellar atrophy and 1 patient had been diagnosed with early stage PD 65 . Thus, our studies provide a strong rationale for a more extensive exploration of the association between Arhgap26 polymorphisms and susceptibility to heart failure, PD, and perhaps other diseases that involve metabolic dysfunction 66 .…”

Neuronal antibodies in nonparaneoplastic autoimmune cerebellar ataxias

“…Rho GTPase activating protein 26 (ARHGAP26) antibodies, like ITPR1 antibodies, have been identified in patients with several neurological syndromes apart from cerebellar ataxia and associate with cancer in 37% of patients (Table 2) [46]. Neurochondrin antibodies are usually detected in patients younger than those with the other intracellular antibodies and 30% are children less than 14 years of age [47,48].…”