Two new cases of anti-Ca (anti-ARHGAP26/GRAF) autoantibody-associated cerebellar ataxia

Abstract

Recently, we discovered a novel serum and cerebrospinal fluid (CSF) autoantibody (anti-Ca) to Purkinje cells in a patient with autoimmune cerebellar ataxia (ACA) and identified the RhoGTPase-activating protein 26 (ARHGAP26; alternative designations include GTPase regulator associated with focal adhesion kinase pp125, GRAF, and oligophrenin-1-like protein, OPHN1L) as the target antigen. Here, we report on two new cases of ARHGAP26 autoantibody-positive ACA that were first diagnosed after publication of the index case study. While the index patient developed ACA following an episode of respiratory infection with still no evidence for malignancy 52 months after onset, neurological symptoms heralded ovarian cancer in one of the patients described here. Our finding of anti-Ca/anti-ARHGAP26 antibodies in two additional patients supports a role of autoimmunity against ARHGAP26 in the pathogenesis of ACA. 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, and an underlying tumour should be considered in patients presenting with anti-Ca/ARHGAP26 antibody-positive ACA.

Figure 1

Magnetic resonance imaging of the brain, patient 1. Sagittal (A, T1 weighted) and coronal (B, FLAIR T2 weighted) MRI showing cortical atrophy in the cerebellar hemispheres and the inferior vermis with enlargement of the cerebellar sulci, the fourth ventricle and the inferior cerebellar cistern, but no atrophy of the cerebral cortex, midbrain, or pons.

Figure 2

Indirect immunofluorescence (IIF) on mouse cerebellum tissue sections revealed the typical anti-Ca staining pattern as previously described[1]. GL, granular layer; PC, Purkinje cell layer; ML, molecular layer. Interneurons are spared (arrowheads).

Figure 3

Anti-Ca antibodies belonged mainly to the IgG1 and IgG2 subclasses (left and middle panels). Patient 1 was, in addition, positive for anti-Ca antibodies of the IgM class (right panel) and patient 2 for anti-Ca antibodies of the IgA class (not shown).

Figure 4

Binding of serum IgG to human recombinant full-length ARHGAP26 as demonstrated in a dot blot assay. OND, other neurological diseases.

Figure 5

Preadsorption of the patients’ sera with recombinant human full-length ARHGAP26 but not preadsorption with a control protein resulted in complete disappearance of the typical anti-Ca cerebellar staining pattern as detected by IIF (left panel: binding of serum IgG from patient 1 to a cerebellum tissue section before preadsorption with ARHGAP26, right panel: after preadsorption with ARHGAP26).