Paraneoplastic cerebellar ataxia and antibodies to metabotropic glutamate receptor 2

Ruiz‐García, Raquel; Martínez‐Hernández, Eugenia; Joubert, Bastien; Petit‐Pedrol, Mar; Pajarón-Boix, Elena; Fernández, Verónica; Salais, Lidia; Pozo, María del; Armangué, Thaís; Sabater, Lidia; Dalmau, Josep; Graus, Francesc

doi:10.1212/nxi.0000000000000658

Cited by 47 publications

(24 citation statements)

References 11 publications

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“…Malignancy was identified in both patients after the development of neurologic symptoms. Small-cell neuroendocrine cancer of unknown origin was discovered on inguinal node biopsy in the 78 year-old woman three years after symptom onset, and the young girl was found to have alveolar rhabdomyosarcoma one year later ( 25 ).…”

Section: Methodsmentioning

confidence: 99%

“…Metabotropic glutamate receptor 1 was the first to be identified in patients with cerebellar ataxia in the early 2000s. More recently in 2019, mGluR2 was described in two patients with subacute onset cerebellar ataxia (25). There are 8 subtypes of mGluRs divided into 3 subgroups: Group I includes mGluR1 and 5 in which both are autoimmune targets in cerebellar ataxia and encephalitis associated with Hodgkin lymphoma (41,42); Group II comprises of mGluR2 and 3; and Group III includes the remaining subtypes.…”

Section: Metabotropic Glutamate Receptor 2 (Mglur2)mentioning

confidence: 99%

“…There are 8 subtypes of mGluRs divided into 3 subgroups: Group I includes mGluR1 and 5 in which both are autoimmune targets in cerebellar ataxia and encephalitis associated with Hodgkin lymphoma (41,42); Group II comprises of mGluR2 and 3; and Group III includes the remaining subtypes. The main physiologic role of mGluR2 is to modulate glutamatergic and GABAergic synaptic transmission and mGluR2 antibodies could potentially alter these functions (25,43). Immunohistochemical studies in rat cerebellar cortex demonstrated mGluR2 and 3 immunoreactivity in the cerebellar cortex localizing to the Golgi cells with the majority of the Golgi cells distributed mainly in the Purkinje cell layer and superficial part of the granular layer (44).…”

Section: Metabotropic Glutamate Receptor 2 (Mglur2)mentioning

confidence: 99%

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

Garza¹,

Piquet²

2021

Front. Neurol.

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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.

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Section: Methodsmentioning

confidence: 99%

Section: Metabotropic Glutamate Receptor 2 (Mglur2)mentioning

confidence: 99%

Section: Metabotropic Glutamate Receptor 2 (Mglur2)mentioning

confidence: 99%

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

Garza¹,

Piquet²

2021

Front. Neurol.

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“…Samples that produced a neuropil immunostaining on rat brain immunohistochemistry were subsequently examined with two types of IIFAs: 1) the Autoimmune Encephalitis Mosaic 6 kit (Euroimmun, Lübeck Germany), following manufacturer's instructions and recommended dilutions (undiluted CSF and 1:10 serum), to test IgG antibodies against N-methyl-D-aspartate (NMDA) receptor (GluN1), a-amino-3-hydroxyl-5-methyl-4isoxazole-propionate (AMPA) receptor (GluA1, GluA2), gamma-aminobutyric (GABA) B receptor (B1 and B2 subunits), contactin-associated protein-like 2 (CASPR2), leucine-rich glioma-inactivated protein 1 (LGI1) and dipeptidyl-peptidase 6 (DPPX), 2) in-house IIFAs in which HEK293 cells were transfected with DNA constructs to express the following antigens: NMDA receptor (GluN1, GluN2), AMPA receptor (GluA1, GluA2), GABA B receptor (B1, B2), CASPR2, LGI1 (with and without disintegrin and metalloproteinase domain-containing protein 23 [ADAM23] co-transfection), GABA A receptor (a1, b3), metabotropic glutamate receptors mGluR1, mGluR2, mGluR5, Ig-Like Domain-Containing Protein 5 (IgLON5) or Seizure 6-like protein 2 (SEZ6L2) as previously described (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Briefly, sera and CSF were diluted in PBS-1% BSA (1:2 CSF and 1:40 serum) and incubated with stored pre-fixed transfected cells overnight, and with an antihuman IgG antibody conjugated with AF488 or AF594 (Invitrogen) for 1 hour.…”

Section: Indirect Immunofluorescence Assaysmentioning

confidence: 99%

Limitations of a Commercial Assay as Diagnostic Test of Autoimmune Encephalitis

et al. 2021

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Detection of neuronal surface antibodies (NSAb) is important for the diagnosis of autoimmune encephalitis (AE). Although most clinical laboratories use a commercial diagnostic kit (Euroimmun, Lübeck, Germany) based on indirect immunofluorescence on transfected cells (IIFA), clinical experience suggests diagnostic limitations. Here, we assessed the performance of the commercial IIFA in serum and CSF samples of patients with suspected AE previously examined by rat brain immunohistochemistry (Cohort A). Of 6213 samples, 404 (6.5%) showed brain immunostaining suggestive of NSAb: 163 (40%) were positive by commercial IIFA and 241 (60%) were negative. When these 241 samples were re-assessed with in-house IIFA, 42 (18%) were positive: 21 (9%) had NSAb against antigens not included in the commercial IIFA and the other 21 (9%) had NSAb against antigens included in the commercial kit (false negative results). False negative results occurred more frequently with CSF (29% vs 10% in serum) and predominantly affected GABABR (39%), LGI1 (17%) and AMPAR (11%) antibodies. Results were reproduced in a separate cohort (B) of 54 AE patients with LGI1, GABABR or AMPAR antibodies in CSF which were missed in 30% by commercial IIFA. Patients with discordant GABABR antibody results (positive in-house but negative commercial IIFA) were less likely to develop full-blown clinical syndrome; no significant clinical differences were noted for the other antibodies. Overall, NSAb testing by commercial IIFA led to false negative results in a substantial number of patients, mainly those affected by anti-LG1, GABABR or AMPAR encephalitis. If these disorders are suspected and commercial IIFA is negative, more comprehensive antibody studies are recommended.

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“…Another study by Ruiz-García and colleagues 28 described a novel neuronal cell surface antibody against the metabotropic glutamate receptor 2 (mGluR2) in 2 patients with paraneoplastic cerebellar ataxia. One of the patients was a 78-year-old woman with progressive cerebellar ataxia with an initial relapsing and remitting course who developed a small-cell cancer of unknown origin.…”

mentioning

confidence: 99%