Recently, we reported on a newly discovered serum and CSF autoantibody in a patient with ACA . This new antibody bound selectively to Purkinje cell somata, dendrites, and axons on primate and murine cerebellum tissue sections, and was shown to target ARHGAP26. Here, we report on two newly diagnosed cases of anti-Ca/anti-ARHGAP26-positive ACA.
Occurrence of ARHGAP26 antibody-positive ACA led to the diagnosis of ovarian carcinoma in one of the patients reported here, suggesting a possible paraneoplastic aetiology of the condition. Paraneoplastic neurological disorders count among the most common causes of antibody-associated ACA [2, 3]. It is of note in this context that ARHGAP26 has been shown to be expressed in a subset of ovarian cancer tissues, partly at high levels, while it is absent or present only at low levels in normal ovarian tissue ; however, no tumour tissue from patient 1 was available for analysis in this study.
Antibodies previously demonstrated in patients with paraneoplastic ACA included anti-Hu , anti-Yo , anti-CV2/CRMP5 [7, 8], anti-Tr [9, 10], anti-Zic4 , anti-protein kinase C gamma (PKCγ) , anti-mGluR1 [13, 14], anti-PCA2 , anti-ANNA3 , or voltage-gated calcium channels (VGCC) . None of these antibodies was detected in the patient reported here.
Histologically, a diagnosis of undifferentiated carcinoma was made. However, as a caveat, elevated serum levels of neuron-specific enolase (NSE), a marker of neuroendocrine tumours, were detected. This is of potential interest since tumours of neuroendocrine differentiation such as small-cell lung cancer and neuroblastoma have previously been implicated in a wide range of paraneoplastic neurological disorders, including ACA [2, 18]. As no secondary carcinoma of neuroendocrine differentiation has been found in repeated follow-up examinations, we cannot exclude that the primary tumour contained neuroendocrine components that went unrecognized. Notably, ARHGAP26 has been found to be upregulated in neuroendocrine tumours . Alternatively, the elevated NSE serum levels might be of neuronal origin, reflecting the marked neuronal loss as detected on MRI.
In the second case reported here, the tumour status is unknown as the patient is lost to follow-up; however, the development of ACA was reportedly associated with unusual weight loss in this patient.
Now that it is clear that anti-ARHGAP26/GRAF is present in more patients with ACA, studies on the immunopathological impact of this new serum reactivity are warranted. So far, it is unknown whether the antibody itself causes neurological damage (as has been shown for some of the novel anti-CNS autoantibodies described over the past of couple of years ) or whether the antibody is merely a disease marker of ACA while the actual damage is T cell-mediated (as it is thought to be the case with the classical onco-neuronal antibodies). Of note, as in the index case, anti-Ca/anti-ARHGAP26 belonged to the complement-activating IgG1 subclass in the two new cases reported here, confirming that these new antibodies may possibly act on PCs via complement-dependent mechanisms. In this context, it is of note that patient 1 was, in addition to IgG, positive for IgM antibodies to ARHGAP26. IgM antibodies are generally known to be more potent activators of complement than IgG. Autoantibodies of the IgM class have been reported also in other autoimmune diseases of the CNS . By contrast, patient 2 as well as well as the index patient  were negative for ARHGAP26-IgM.
Our finding of high-titre anti-Ca/anti-ARHGAP26 antibodies in two additional patients with ACA strongly supports a role for autoimmunity against ARHGAP26 in the pathogenesis of this rare condition and proves that the index patient was not a singular case. Moreover, the finding of ovarian cancer in one of our patients suggests that anti-Ca/anti-ARHGAP26-positive ACA might be of paraneoplastic aetiology in some cases. In conclusion, testing for anti-Ca/anti-ARHGAP26 should be included in the diagnostic work-up of patients with ACA; while more cases have to be evaluated before a strict recommendation can be made as to whether broad tumour screening is generally required in patients with anti-Ca/ARHGAP26 antibody-positive ACA, non-harmful screening procedures such as ultrasound examination for ovarian cancer and, possibly, tumour marker testing seem warranted.