Update in Autoimmune Movement Disorders: Newly Described Antigen Targets in Autoimmune and Paraneoplastic Cerebellar Ataxia

Abstract

Movement disorders are a common feature of many antibody-associated neurological disorders. In fact, cerebellar ataxia is one of the most common manifestations of autoimmune neurological diseases. Some of the first autoantibodies identified against antigen targets include anti-neuronal nuclear antibody type 1 (ANNA-1 or anti-Hu) and Purkinje cell cytoplasmic antibody (PCA-1) also known as anti-Yo have been identified in paraneoplastic cerebellar degeneration. Historically these antibodies have been associated with an underlying malignancy; however, recently discovered antibodies can occur in the absence of cancer as well, resulting in the clinical syndrome of autoimmune cerebellar ataxia. The pace of discovery of new antibodies associated with autoimmune or paraneoplastic cerebellar ataxia has increased rapidly over the last few years, and pathogenesis and potential treatment options remains to be explored. Here we will review the literature on recently discovered antibodies associated with autoimmune and paraneoplastic cerebellar ataxia including adaptor protein-3B2 (AP3B2); inositol 1,4,5-trisphophate receptor type 1 (ITPR1); tripartite motif-containing (TRIM) proteins 9, 67, and 46; neurochondrin; neuronal intermediate filament light chain (NIF); septin 5; metabotropic glutamate receptor 2 (mGluR2); seizure-related 6 homolog like 2 (SEZ6L2) and homer-3 antibodies. We will review their clinical characteristics, imaging and CSF findings and treatment response. In addition, we will discuss two clinical case examples of autoimmune cerebellar ataxia.

Keywords: AP3B2 antibody; ITPR1 antibody; TRIM46 antibody; TRIM67 antibody; TRIM9 antibody; autoimmune cerebellar ataxia; mGluR2 antibody; paraneoplastic cerebellar ataxia.

Figure 1

T2 sequence of brain MRI demonstrating hemi-atrophy of the left cerebellum in addition to a 6 mm T2-hyperintense lesion near the cerebellar vermis on the left. Additional brain imaging not show any further T2/FLAIR (fluid-attenuated inversion recovery) abnormalities in the cerebellum, cerebrum or corpus callosum (sequences not shown).

Figure 2

(A) MRI sequences of T2/FLAIR (fluid-attenuated inversion recovery) with STIR (short tau inversion recovery; i.e. fat suppression) at the onset of neurological symptoms of vertigo and ataxia demonstrating a small T2, non-enhancing lesion (contrast imaging not shown) in the left medulla (thin, white arrow). (B) with T2/FLAIR MRI 3 months later demonstrating T2 changes seen bilaterally within the medulla (thin, white arrow) with no associated contrast enhancement. There is noted cerebellar atrophy, particularly seen in the superior cerebellum (thick, white arrow), compared to the MRI from 3 months prior.

Figure 3

Images of (A) 10x magnification and (B) 60x magnification of cerebellar tissue demonstrating antigen staining of the patient's Trim46 antibody (in green) and nuclei are in blue. (C) There are axon initial segments staining in green in the dentate gyrus and (D) in the cortex as well. Images courtesy of Dr. Christopher Bartley and team at University of San Francisco (USCF) Weill Institute for Neurosciences laboratory.