'Medusa head ataxia': the expanding spectrum of Purkinje cell antibodies in autoimmune cerebellar ataxia. Part 2: Anti-PKC-gamma, anti-GluR-delta2, anti-Ca/ARHGAP26 and anti-VGCC

Abstract

Serological testing for anti-neural autoantibodies is important in patients presenting with idiopathic cerebellar ataxia, since these autoantibodies may indicate cancer, determine treatment and predict prognosis. While some of them target nuclear antigens present in all or most CNS neurons (e.g. anti-Hu, anti-Ri), others more specifically target antigens present in the cytoplasm or plasma membrane of Purkinje cells (PC). In this series of articles, we provide a detailed review of the clinical and paraclinical features, oncological, therapeutic and prognostic implications, pathogenetic relevance, and differential laboratory diagnosis of the 12 most common PC autoantibodies (often referred to as 'Medusa head antibodies' due their characteristic somatodendritic binding pattern when tested by immunohistochemistry). To assist immunologists and neurologists in diagnosing these disorders, typical high-resolution immunohistochemical images of all 12 reactivities are presented, diagnostic pitfalls discussed and all currently available assays reviewed. Of note, most of these antibodies target antigens involved in the mGluR1/calcium pathway essential for PC function and survival. Many of the antigens also play a role in spinocerebellar ataxia. Part 1 focuses on anti-metabotropic glutamate receptor 1-, anti-Homer protein homolog 3-, anti-Sj/inositol 1,4,5-trisphosphate receptor- and anti-carbonic anhydrase-related protein VIII-associated autoimmune cerebellar ataxia (ACA); part 2 covers anti-protein kinase C gamma-, anti-glutamate receptor delta-2-, anti-Ca/RhoGTPase-activating protein 26- and anti-voltage-gated calcium channel-associated ACA; and part 3 reviews the current knowledge on anti-Tr/delta notch-like epidermal growth factor-related receptor-, anti-Nb/AP3B2-, anti-Yo/cerebellar degeneration-related protein 2- and Purkinje cell antibody 2-associated ACA, discusses differential diagnostic aspects, and provides a summary and outlook.

Fig. 1

Expression of PKCγ in the human cerebellum as demonstrated by IHC (modified image from the Human Protein Atlas image database [20])

Fig. 2

Binding of anti-PKCγ from a patient with ACA to a monkey cerebellum tissue section. The patient antibody was detected by use of a goat anti-human IgG secondary antibody labelled with Alexa Fluor® 488 (green)

Fig. 3

Expression of GluRδ2 in the human cerebellum as demonstrated by IHC (modified image from the Human Protein Atlas image database [20])

Fig. 4

Binding of anti-GluRδ2 from a patient with ACA to a monkey cerebellum tissue section. The patient antibody was detected by use of a goat anti-human IgG secondary antibody labelled with Alexa Fluor® 488 (green)

Fig. 5

Expression of ARHGAP26 in the human cerebellum as demonstrated by IHC (modified image from the Human Protein Atlas image database [20])

Fig. 6

Binding of IgG from a patient with ARHGAP26-Ab-positive ACA to a mouse cerebellum tissue section. An Alexa Fluor® 488-labelled goat anti-human IgG antibody (green fluorescence) was used to visualise bound patient IgG. ML = molecular layer, PCL = Purkinje cell layer, WM = white matter, GL = granular layer, P = pia mater. Image taken from Jarius et al. [22]

Fig. 7

Expression of Ca_v2.1 in the mouse cerebellum as detected by IHC (modified image from Mallmann RT et al. Ablation of Ca(V)2.1 voltage-gated Ca²⁺ channels in mouse forebrain generates multiple cognitive impairments. PLoS One 2013 Oct 31;8(10):e78598 doi: 10.1371/journal.pone.0078598. © 2013 Mallmann et al.). Note that IHC is not an established method for the detection of anti-VGCC autoantibodies, which are usually determined by RIA