Metabotropic glutamate receptor type 1 autoimmunity: Clinical features and treatment outcomes

Abstract

Objective: To describe retrospectively the clinical associations of immunoglobulin G (IgG) targeting metabotropic glutamate receptor 1 (mGluR1-IgG).

Methods: Specimens of 9 patients evaluated on a service basis in the Mayo Clinic Neuroimmunology Laboratory by tissue-based immunofluorescence assay (IFA) yielded a robust, synaptic immunostaining pattern consistent with mGluR1-IgG (serum, 9; CSF, 2 available). Transfected HEK293 cell-based assay (CBA) confirmed mGluR1 specificity in all 11 specimens. A further 2 patients were detected in Germany primarily by CBA.

Results: The median symptom onset age for the 11 patients was 58 years (range 33-81 years); 6 were male. All 9 Mayo Clinic patients had subacute onset of cerebellar ataxia, 4 had dysgeusia, 1 had psychiatric symptoms, and 1 had cognitive impairment. All were evaluated for malignancy, but only 1 was affected (cutaneous T-cell lymphoma). One developed ataxia post-herpes zoster infection. Head MRIs were generally atrophic or normal-appearing, and CSF was inflammatory in just 1 of 5 tested, though mGluR1-IgG was detected in both specimens submitted. Five patients improved (attributable to immunotherapy in 4, spontaneously in 1), 3 stabilized (attributable to immunotherapy in 2, cancer therapy in 1), and 1 progressively declined (untreated). The 2 German patients had ataxia, but fulfilled multiple sclerosis diagnostic criteria (1 relapsing-remitting, 1 progressive). However, both had histories of hematologic malignancy (acute lymphocytic leukemia and mantle cell lymphoma), and had mGluR1-IgG detected in serum by CBA (weakly positive on tissue-based IFA).

Conclusions: mGluR1 autoimmunity represents a treatable form of cerebellar ataxia. Dysgeusia may be a diagnostic clue. Paraneoplastic, parainfectious, or idiopathic causes may occur.

Figure. Metabotropic glutamate receptor 1 (mGluR1) antibody tissue- and cell-based assays

Indirect immunofluorescence assays, tissue-based (A, cerebellum; B, cerebrum) and cell-based (C, mGluR1-transfected; D, mock-transfected) demonstrate mGluR1–immunoglobulin G (IgG) in patient serum. The synaptic CNS pattern of mGluR1-IgG immunoreactivity is most prominent in the molecular layer (M) of cerebellum, thalamus (T), and hippocampus (CA3 region and dentate gyrus [DG]). Granular layer of cerebellum (G) is dark. Serum is reactive with mGluR1-transfected cells (C), but not mock-transfected cells (D).