There is no singular etiology for ACA, as multiple conditions may trigger this syndrome, including paraneoplastic cerebellar degeneration [7], gluten ataxia [8], and post-infectious cerebellitis [9]. The first case of immune-mediated cerebellar ataxia was reported in 1868 [10]. Since then, multiple antibodies have been associated with this condition (e.g., antibodies against Yo, Hu, Tr, CV2, Ri, Ma2, voltage-gated calcium channel, and GAD65) [11–13]. However, ARHGAP26 was only identified as an autoimmune target in 2010 [1].
The GTPase activating protein ARHGAP26 is highly expressed in the PC of the cerebellum and a subset of hippocampal neurons [2–4, 14]. This localization may explain the symptoms of ARHGAP26 autoantibody-associated ACA. In the present case, the primary symptom was ataxia, which may have been triggered by the activity of ARHGAP26 autoantibodies in the cerebellum. Moreover, until now, the reported age of onset for ARHGAP26 autoantibody-associated ACA has been between 24 and 84 years, suggesting it is more prevalent in adults. However, our patient was only 28 months old, indicating that ARHGAP26 autoantibody-associated ACA may occur at any age.
Only three of the patients in the previously reported cases underwent both serum and CSF ARHGAP26 autoantibody testing, and the results for all these patients were positive for both samples. The remaining seven patients underwent serum antibody testing only, and were also positive, but the presence of the antibody in the CSF could not be confirmed. Previously, Jarius et al. determined intrathecal synthesis of ARHGAP26 antibodies in patients with positive CSF and proposed that only testing the serum sample was sufficient in some cases, but that CSF testing may be necessary if test results for serum samples are hampered by nonspecific background or additional autoantibodies [2].
In the present report, we describe the first patient with cerebellar ataxia associated with the presence of anti-ARHGAP26 autoantibodies and medulloblastoma. Three cases of ARHGAP26 autoantibody-associated ACA have been reported, wherein ARHGAP26 antibodies were detected in both serum and CSF samples of patients. However, this is the first reported case where only the patient’s serum sample tested positive for ARHGAP26 antibodies, whereas the CSF sample did not. Because there are only few patients in whom double sample tests were performed in previously reported cases, it is possible to make a diagnosis for patients with only positive serum sample without CSF outcomes. Thus, we propose that when CSF cannot be tested simultaneously, positive ARHGAP26 antibodies in the serum also have sufficient diagnostic significance, but double sample tests are necessary to explore pathogenic relevance.
Paraneoplastic neurological disorders are the most common causes of antibody-associated ACA [7, 15]. Of the ten reported cases, five had a history of suspected extra-nervous system tumors, specifically ovarian, breast, and prostate cancers, melanoma (in the same patient with breast cancer), B-cell lymphoma, and gastric adenocarcinoma [1, 3, 16–19]. Our patient had a medulloblastoma originating from the cerebellar vermis, which had not been reported in patient with ARHGAP26 autoantibody-associated ACA previously. Medulloblastoma can cause ataxia; thus, we hypothesize that the ataxia in this patient was caused both by the activity of ARHGAP26 antibodies in the cerebellum and the medulloblastoma. However, other associations between ARHGAP26 antibodies and medulloblastoma are still unknown.
Only serum anti-ARHGAP26 antibody positivity was confirmed for patients with a tumor. As most of the patients did not undergo CSF testing, it remains unknown if the antibodies were also present in the CSF of these patients. Our patient tested positive for anti-ARHGAP26 antibody in the serum sample only, highlighting the need for more studies on the clinical implications of the presence of serum or CSF anti-ARHGAP26 autoantibodies and tumors in patients with ACA.
In this report, we describe the first case of a child with anti-ARHGAP26 autoantibody-associated cerebellar ataxia and medulloblastoma. This case may further the understanding of anti-ARHGAP26 autoantibody-associated cerebellar ataxia, its age of onset, and associated tumors. This case might suggest a potential connection between ARHGAP26 antibodies and tumors such as medulloblastoma in patient with ACA.Therefore, we recommend anti-ARHGAP26 antibody testing and cancer screening for patients diagnosed with ACA. Moreover, we propose that simultaneous CSF and serum testing may help elucidate the connection between the presence of a tumor and anti-ARHGAP26 antibodies in the CSF or serum samples. However, in some cases, testing only serum samples may be sufficient for the diagnosis. Although, double sample tests are necessary to explore pathogenic relevance.