Characterisation of TRIM46 autoantibody-associated paraneoplastic neurological syndrome

Valencia‐Sánchez, Cristina; Knight, Andrew M.; Hammami, M.; Guo, Yong; Mills, John R.; Kryzer, Thomas J.; Piquet, Amanda L.; Amin, Anik; Heinzelmann, Morgan; Lucchinetti, Claudia F.; Lennon, Vanda A.; McKeon, Andrew; Pittock, Sean J.; Dubey, Divyanshu

doi:10.1136/jnnp-2021-326656

Cited by 31 publications

(19 citation statements)

References 11 publications

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“…By TBIF, AIS-specific immunoreactivity has only been reported with CSF or serum from patients with TRIM46 (9, 29) or βIV-spectrin ( 12 , 40 ) autoimmune neurological disorders. In contrast, we have not observed AIS immunostaining with CSF and serum from patients with systemic autoimmunity, cancer without neurological illness, or healthy controls ( 9 ).…”

Section: Discussioncontrasting

confidence: 68%

“…Case 2 was identified as part of a screen for TRIM46 autoimmunity ( 9 ). CSF was screened at a 1:4 dilution and produced a similar AIS and NoR-like pattern of immunoreactivity throughout the murine brain ( Supplementary Figure 1A ) but was negative for TRIM46 on the cell-based assay.…”

Section: Resultsmentioning

confidence: 99%

“…Instead, research testing identified a high-titer antibody to AnkG that decreased in titer during convalescence. AnkG is enriched in the AIS and NoR, subcellular structures with similar molecular profiles that are targeted by autoantibodies in diverse autoimmune neurological disorders including antibodies that bind to gangliosides ( 23 ), neurofascins ( 24 , 25 ), CASPR ( 26 ), CASPR2 ( 27 , 28 ), TRIM46 ( 9 , 29 ), and βIV-spectrin ( 12 ). Grouping autoantibody-mediated neurological patients by target epitope may reveal unappreciated relationships between target epitope and clinical characteristics ( 30 , 31 ).…”

Section: Discussionmentioning

confidence: 99%

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Dual ankyrinG and subpial autoantibodies in a man with well-controlled HIV infection with steroid-responsive meningoencephalitis: A case report

et al. 2023

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Neuroinvasive infection is the most common cause of meningoencephalitis in people living with human immunodeficiency virus (HIV), but autoimmune etiologies have been reported. We present the case of a 51-year-old man living with HIV infection with steroid-responsive meningoencephalitis whose comprehensive pathogen testing was non-diagnostic. Subsequent tissue-based immunofluorescence with acute-phase cerebrospinal fluid revealed anti-neural antibodies localizing to the axon initial segment (AIS), the node of Ranvier (NoR), and the subpial space. Phage display immunoprecipitation sequencing identified ankyrinG (AnkG) as the leading candidate autoantigen. A synthetic blocking peptide encoding the PhIP-Seq-identified AnkG epitope neutralized CSF IgG binding to the AIS and NoR, thereby confirming a monoepitopic AnkG antibody response. However, subpial immunostaining persisted, indicating the presence of additional autoantibodies. Review of archival tissue-based staining identified candidate AnkG autoantibodies in a 60-year-old woman with metastatic ovarian cancer and seizures that were subsequently validated by cell-based assay. AnkG antibodies were not detected by tissue-based assay and/or PhIP-Seq in control CSF (N = 39), HIV CSF (N = 79), or other suspected and confirmed neuroinflammatory CSF cases (N = 1,236). Therefore, AnkG autoantibodies in CSF are rare but extend the catalog of AIS and NoR autoantibodies associated with neurological autoimmunity.

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Section: Discussioncontrasting

confidence: 68%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Dual ankyrinG and subpial autoantibodies in a man with well-controlled HIV infection with steroid-responsive meningoencephalitis: A case report

et al. 2023

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“… 1 However, whether βIV-spectrin antibodies are a diagnostic marker of paraneoplastic neuropathy is unknown. During a study of anti-TRIM46 neurologic syndromes, 2 we identified 2 TRIM46-negative cases whose antibodies putatively localized to the axon initial segment (AIS) in the cortex ( Figure 1A ) and node of Ranvier (NoR) in cerebellar white matter and optic tract (not shown). Case 1, a woman in her 70s, developed gait instability, distal lower extremity numbness, and paresthesias 6 months after being diagnosed with high-grade uterine and fallopian serous carcinoma.…”

mentioning

confidence: 99%

βIV-Spectrin Autoantibodies in 2 Individuals With Neuropathy of Possible Paraneoplastic Origin

Bartley

Ngo

Alvarenga

et al. 2022

Neurol Neuroimmunol Neuroinflamm

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ObjectiveTo identify the autoantigen in 2 individuals with possible seronegative paraneoplastic neuropathy.MethodsSerum and CSF were screened by tissue-based assay and panned for candidate autoantibodies by phage display immunoprecipitation sequencing (PhIP-Seq). The candidate antigen was validated by immunostaining knockout tissue and HEK 293T cell-based assay.ResultsCase 1 presented with gait instability, distal lower extremity numbness, and paresthesias after a recent diagnosis of serous uterine and fallopian carcinoma. Case 2 had a remote history of breast adenocarcinoma and presented with gait instability, distal lower extremity numbness, and paresthesias that progressed to generalized weakness. CSF and serum from both patients immunostained the axon initial segment (AIS) and node of Ranvier (NoR) of mice and enriched βIV-spectrin by PhIP-Seq. Patient CSF and serum failed to immunostain NoRs in dorsal root sensory neurons from βI/βIV-deficient mice. βIV-spectrin autoantibodies were confirmed by overexpression of AIS and nodal βIV-spectrin isoforms Σ1 and Σ6 by a cell-based assay. βIV-spectrin was not enriched in a combined 4,815 PhIP-Seq screens of healthy and other neurologic disease patients.DiscussionTherefore, βIV-spectrin autoantibodies may be a marker of paraneoplastic neuropathy.Classification of EvidenceThis study provides Class IV evidence that βIV-spectrin antibodies are specific autoantibody biomarkers for paraneoplastic neuropathy.

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“…4,9 TRIM46 antibodies against AIS have previously been described in patients with paraneoplastic autoimmune encephalitis. 8,9 Since TRIM46 is a cytosolic protein, neurological symptoms are likely caused by a T-cell-mediated response against TRIM46. 8,9 2.…”

mentioning

confidence: 99%

Frontotemporal dementia associated with intrathecal antibodies against axon initial segments

Endres

Schlump

Nickel

et al. 2022

Alzheimer's & Dementia

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Characterisation of TRIM46 autoantibody-associated paraneoplastic neurological syndrome

Cited by 31 publications

References 11 publications

Dual ankyrinG and subpial autoantibodies in a man with well-controlled HIV infection with steroid-responsive meningoencephalitis: A case report

Dual ankyrinG and subpial autoantibodies in a man with well-controlled HIV infection with steroid-responsive meningoencephalitis: A case report

βIV-Spectrin Autoantibodies in 2 Individuals With Neuropathy of Possible Paraneoplastic Origin

Frontotemporal dementia associated with intrathecal antibodies against axon initial segments

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