Movement disorders with neuronal antibodies: syndromic approach, genetic parallels and pathophysiology

Abstract

Movement disorders are a prominent and common feature in many autoantibody-associated neurological diseases, a group of potentially treatable conditions that can mimic infectious, metabolic or neurodegenerative disease. Certain movement disorders are likely to associate with certain autoantibodies; for example, the characteristic dyskinesias, chorea and dystonia associated with NMDAR antibodies, stiff person spectrum disorders with GAD, glycine receptor, amphiphysin or DPPX antibodies, specific paroxysmal dystonias with LGI1 antibodies, and cerebellar ataxia with various anti-neuronal antibodies. There are also less-recognized movement disorder presentations of antibody-related disease, and a considerable overlap between the clinical phenotypes and the associated antibody spectra. In this review, we first describe the antibodies associated with each syndrome, highlight distinctive clinical or radiological 'red flags', and suggest a syndromic approach based on the predominant movement disorder presentation, age, and associated features. We then examine the underlying immunopathophysiology, which may guide treatment decisions in these neuroimmunological disorders, and highlight the exceptional interface between neuronal antibodies and neurodegeneration, such as the tauopathy associated with IgLON5 antibodies. Moreover, we elaborate the emerging pathophysiological parallels between genetic movement disorders and immunological conditions, with proteins being either affected by mutations or targeted by autoantibodies. Hereditary hyperekplexia, for example, is caused by mutations of the alpha subunit of the glycine receptor leading to an infantile-onset disorder with exaggerated startle and stiffness, whereas antibodies targeting glycine receptors can induce acquired hyperekplexia. The spectrum of such immunological and genetic analogies also includes cerebellar ataxias and some encephalopathies. Lastly, we discuss how these pathophysiological considerations could reflect on possible future directions regarding antigen-specific immunotherapies or targeting the pathophysiological cascades downstream of the antibody effects.

Keywords: ataxia; chorea; movement disorders; neuronal antibodies; parkinsonism.

Figure 1

The different test systems for antibody detection. HEK = human embryonic kidney cell.

Figure 2

The three groups of neuronal antibodies and their pathogenic roles, examples, treatment responses and tumour associations. AMPAR = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; CASPR2 = contactin associated protein like 2; D2R = dopamine 2 receptor; DPPX = dipeptidyl peptidase like protein 6; GABA_AR and GABA_BR = gamma aminobutyric acid type A and type B receptors; GlyR = glycine receptor; LGI1 = leucine rich glioma inactivated protein 1; NMDAR = N-methyl-d-aspartate receptor.

Figure 3

Proteins of the calcium homeostasis and signalling network in Purkinje cells: parallels of genetic cerebellar ataxias and antibody-related autoimmunity. Upon parallel fibre stimulation, glutamate is released and binds to mGlur1, a G-protein-coupled surface receptor highly expressed at the perisynaptic site of Purkinje cells and involved in mediation of slow excitatory potentials and long-term depression. Its intracellular domain in turn interacts with Homer-3, which is a scaffolding protein relevant for mGlur1 clustering, and which crosslinks mGluR1 with ITPR1 in the smooth endoplasmic reticulum. Upon glutamate binding, mGluR1 activates of phospholipase C, an enzyme that cleaves phosphatidylinositol 4,5-bisphosphate in the plasma membrane to produce diacylglycerol and inositol trisphosphate (IP3). IP3 binds to ITPR1 and thereby induces calcium release from the endoplasmatic reticulum, which in turn activates protein kinase C γ (PKCγ) that desensitizes mGluR1 by phosphorylation and induces internalization of AMPA receptors (AMPAR). GluRδ2 is a key binding partner for mGluR1 and PKCγ, relevant for synaptic mGluR1 signalling and also involved in AMPAR trafficking. Similarly, activation of climbing fibres opens voltage gated calcium channels (VGCC) which mediate calcium influx and contribute to the signalling cascade, which results in reduction of AMPAR sensitivity at the synapse. Proteins that are targets of antibodies associated with cerebellar ataxia are in single-lined boxes, proteins that are also affected by mutations in genetic ataxias (Table 3) are highlighted in double-lined boxes, and existing evidence with regards to their pathogenic role is discussed in Table 3. AMPAR = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; CARP VIII = carbonic anhydrase VIII; ER = endoplasmic reticulum; GluRd2 = glutamate receptor delta 2; PKCg = protein kinase C gamma.

Figure 4

Potential future treatment approaches with antigen-specific immunotherapy.