‘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.

GRAF2, WDR44, and MICAL1 mediate Rab8/10/11–dependent export of E-cadherin, MMP14, and CFTR ΔF508

“…In recent years, proteins of the GRAF family have attracted attention because they are mutated in cancer (Li et al, 2017;Aissani et al, 2015;Bozóky et al, 2013;Qian et al, 2010) and have been associated with neuropsychiatric diseases (Barresi et al, 2010;Jarius and Wildemann, 2015;Dahm et al, 2014), but little mechanistic information has been published. We show here that direct binding of proline-rich regions of MICAL1 and WDR44 to the SH3 domain of GRAF1/2 allows GRAF-mediated trafficking to be controlled by Rab8, Rab10, and Rab11 (see model in Fig.…”

Neurologic Autoimmunity in the Era of Checkpoint Inhibitor Cancer Immunotherapy

“…3 Autoantibodies specific for GTPase regulator associated with focal adhesion kinase 1(GRAF1) and carbonic anhydraseerelated protein (CARP) VIII have been reported in rare cases of ovarian cancererelated cerebellar ataxia. [50][51][52] Antineuronal nuclear autoantibody type 2-IgG and amphiphysin-IgG predict breast carcinoma. ANNA2 -IgG is specific for NOVA1 and NOVA2 RNA-binding proteins and amphiphysin IgG for a protein involved in retrieval of neurotransmitter-vesicle membranes from the plasma membrane following exocytosis.…”

Autoimmune Vestibulocerebellar Syndromes

“…The main presentation is subacute cerebellar ataxia with limb and gait ataxia, horizontal nystagmus, dysarthria, and oscillopsia. 120 Extracerebellar symptoms such as hyperekplexia, mood symptoms, and cognitive decline have also been reported. 121 Brain MRI shows atrophy at approximately 4 months from the onset of symptoms, but it is typically normal initially.…”