Metabotropic Glutamate Receptor Type 1 Autoantibody–Associated Cerebellitis

Marignier, Romain; Chenevier, F.; Rogemond, Véronique; Smitt, Peter Sillevis; Renoux, Christel; Cavillon, Gaëlle; Androdias, Géraldine; Vukusic, Sandra; Graus, Francesc; Honnorat, Jérôme; Confavreux, Christian

doi:10.1001/archneurol.2010.51

Cited by 108 publications

(91 citation statements)

References 13 publications

(15 reference statements)

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“…DISCUSSION The 9 Mayo Clinic mGluR-IgG autoimmune cases described share characteristics similar to the 5 previously published: a cerebellar degeneration-predominant phenotype in all and lymphoma encountered in a minority. [2][3][4][5] Notably, 4 of our 9 patients reported dysgeusia. mGluR1 localization also extends to circumvallate and foliate papillae of the posterior mammalian tongue, a region likely responsible for umami taste.…”

Section: Resultsmentioning

confidence: 72%

Metabotropic glutamate receptor type 1 autoimmunity

et al. 2016

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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. Metabotropic glutamate receptor 1 (mGluR1) is a G-protein-coupled receptor, activation of which facilitates long-term depression of parallel fiber-Purkinje cell synapses critical for cerebellar motor learning. 1 mGluR1-immunoglobulin G (IgG) autoantibody is a biomarker of autoimmune cerebellar ataxia, reported in a paraneoplastic context (usually lymphoma) or without neoplasm detected.2-5 Given the limited literature, we report 11 patients (with archived specimens and recorded histories) in whom mGluR1 autoimmunity was encountered, in order to determine the disease spectrum.METHODS Standard protocol approvals, registrations, and patient consents. This study was carried out with the approval of institutional review boards and written informed consents were obtained.Patients and assays. Nine patients were identified in the Mayo Clinic Neuroimmunology Laboratory by 2 mechanisms. All specimens were clinically submitted for paraneoplastic antibody evaluation. (1) Four patients were identified by reviewing archived descriptions of mouse tissue-based immunofluorescence assays (IFAs) for 1,074 patients with unclassified neural antibody staining (1996. Thirty-two patients had descriptions resembling the reported mGluR1-IgG staining pat...

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Section: Resultsmentioning

confidence: 72%

Metabotropic glutamate receptor type 1 autoimmunity

et al. 2016

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“…Furthermore, auto-antibodies to GluR␦2 are found in patients with acute cerebellar ataxia, acute cerebellitis, and steroid-responsive chronic cerebellitis (Shiihara et al, 2007;Shimokaze et al, 2007;Kubota and Takahashi, 2008;Fukuoka et al, 2012;Kinno et al, 2012;Matsumoto et al, 2012). Also, auto-antibodies to mGluR1 are associated with neoplastic cerebellar ataxia (Marignier et al, 2010;Sillevis Smitt et al, 2000;Coesmans et al, 2003). Pharmacological regulation of the GluR␦2/mGluR1/PKC␥/TRPC network identified here might therefore be therapeutic.…”

Section: Physiological Relevance Of Glur␦2-mglur1-pkc␥-trpc3 Interactmentioning

confidence: 64%

Glutamate Receptor δ2 Associates with Metabotropic Glutamate Receptor 1 (mGluR1), Protein Kinase Cγ, and Canonical Transient Receptor Potential 3 and Regulates mGluR1-Mediated Synaptic Transmission in Cerebellar Purkinje Neurons

Kato¹,

Knierman²,

Siuda³

et al. 2012

J. Neurosci.

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Cerebellar motor coordination and cerebellar Purkinje cell synaptic function require metabotropic glutamate receptor 1 (mGluR1, Grm1). We used an unbiased proteomic approach to identify protein partners for mGluR1 in cerebellum and discovered glutamate receptor ␦2 (GluR␦2, Grid2, Glu⌬2) and protein kinase C␥ (PKC␥) as major interactors. We also found canonical transient receptor potential 3 (TRPC3), which is also needed for mGluR1-dependent slow EPSCs and motor coordination and associates with mGluR1, GluR␦2, and PKC␥. Mutation of GluR␦2 changes subcellular fractionation of mGluR1 and TRPC3 to increase their surface expression. Fitting with this, mGluR1-evoked inward currents are increased in GluR␦2 mutant mice. Moreover, loss of GluR␦2 disrupts the time course of mGluR1-dependent synaptic transmission at parallel fiber-Purkinje cells synapses. Thus, GluR␦2 is part of the mGluR1 signaling complex needed for cerebellar synaptic function and motor coordination, explaining the shared cerebellar motor phenotype that manifests in mutants of the mGluR1 and GluR␦2 signaling pathways.

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“…However, subsequent reports have not confirmed this association. 49,50 Treatment of PCD involves treating the underlying HL. PCD associated with DNER Ag (in HL) does not respond as well when compared to the PCD related to other cell membrane antigens in other tumors.…”

Section: Neurological Paraneoplastic Phenomenamentioning

confidence: 99%

Paraneoplastic Manifestations of Lymphoproliferative Neoplasms

2016

Lymphoma and Chronic Lymphocytic Leukemias

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Paraneoplastic syndromes, although rare, have been associated with lymphoproliferative disorders. Hodgkin's lymphoma (HL) is the most common lymphoid neoplasm known to cause paraneoplastic syndromes. These syndromes can often be the earliest manifestation of the underlying malignancy, and treating the underlying lymphoma can cure the paraneoplastic disease. Paraneoplastic diseases reported in lymphoid malignancies can be broadly classified into hematological, neurological, and dermatological syndromes based on the organ systems that are predominantly involved. In addition, renal and hepatobiliary involvement has also been reported. The pathogenesis of the hematological paraneoplastic conditions primarily involves the production of autoantibodies by the neoplastic lymphocytes, which then subsequently leads to cytopenias. Cytoses are a result of cytokine produced by the neoplasms. The administration of corticosteroids along with chemotherapy for the underlying malignancy is the treatment of choice. Neurological paraneoplastic phenomena have been reported in both HL and non-Hodgkin's lymphoma (NHL). They are thought to be secondary to an immune-related process that is triggered by the underlying process. Both the central and the peripheral nervous systems can be affected. Often, treatment of the underlying malignancy with chemotherapy can result in reversal of the paraneoplastic syndrome. In peripheral neuropathies, muscle relaxants and analgesics are often used for symptomatic relief. Dermatological manifestations, pemphigus vulgaris in particular, often precedes the malignancy. Renal and hepatobiliary manifestations, although rare, are also associated with lymphomas.

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Metabotropic Glutamate Receptor Type 1 Autoantibody–Associated Cerebellitis

Cited by 108 publications

References 13 publications

Metabotropic glutamate receptor type 1 autoimmunity

Metabotropic glutamate receptor type 1 autoimmunity

Glutamate Receptor δ2 Associates with Metabotropic Glutamate Receptor 1 (mGluR1), Protein Kinase Cγ, and Canonical Transient Receptor Potential 3 and Regulates mGluR1-Mediated Synaptic Transmission in Cerebellar Purkinje Neurons

Paraneoplastic Manifestations of Lymphoproliferative Neoplasms

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