Neuronal antibody targeting metabotropic glutamate receptor 8 in five cases and its pathogenicity

To characterize patients with autoantibodies against metabotropic glutamate receptor 8 (mGluR8) and assess the pathogenicity of these antibodies.

Anti-mGluR8 antibodies were detected via cell-based assay and immunoprecipitation. Clinical data from five anti-mGluR8-positive patients and previously reported cases with other anti-mGluR antibodies were reviewed. Patient-derived IgG was purified and absorbed using mGluR8-expressing or control HEK293T cells. Pathogenicity was tested in hippocampal neuron cultures and via passive transfer into mice, with ataxia evaluated using behavioral tests.

Five patients (4 male, median age 61) presented with subacute ataxia; other symptoms included dysarthria, ophthalmoplegia, dysphagia, and cognitive changes. Brain MRI showed cerebellar and cortical atrophy in all cases. Immunotherapy led to transient improvement in all patients, with stabilization in three of four with follow-up. In vitro, non-mGluR8-absorbed IgG reduced synaptic mGluR8 clusters. Mice injected with non-mGluR8-absorbed IgG developed transient ataxia peaking at 3-6 h and resolving within 24 h, correlating with antibody binding to Purkinje cells.

Anti-mGluR8 antibody is a novel possible biomarker for autoimmune ataxia, with its pathogenicity supported by passive transfer models.