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Characterisation of TRIM46 autoantibody-associated paraneoplastic neurological syndrome
  1. Cristina Valencia-Sanchez1,
  2. Andrew M Knight2,
  3. M Bakri Hammami2,
  4. Yong Guo1,
  5. John R Mills2,
  6. Thomas J Kryzer2,
  7. Amanda L Piquet3,
  8. Anik Amin4,
  9. Morgan Heinzelmann4,
  10. Claudia F Lucchinetti1,
  11. Vanda A Lennon1,2,5,
  12. Andrew McKeon1,2,
  13. Sean J Pittock1,2,
  14. Divyanshu Dubey1,2
  1. 1Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA
  2. 2Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
  3. 3Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
  4. 4Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
  5. 5Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA
  1. Correspondence to Dr Divyanshu Dubey, Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA; Dubey.Divyanshu{at}mayo.edu

Abstract

Objectives To report the expanded neurological presentations and oncological associations of tripartite motif-containing protein 46 (TRIM46)-IgG seropositive patients.

Methods Archived sera/cerebrospinal fluid (CSF) were evaluated by tissue-based immunofluorescence assay to identify patients with identical axon initial segment (AIS)-specific staining pattern. Phage immunoprecipitation sequencing (PhIP-Seq) was used to identify the putative autoantigen.

Results IgG in serum (17) and/or CSF (16) from 25 patients yielded unique AIS-specific staining on murine central nervous system (CNS) tissue. An autoantibody specific for TRIM46 was identified by PhIP-Seq, and autoantigen specificity was confirmed by transfected COS7 cell-based assay. Clinical information was available for 22 TRIM46-IgG seropositive patients. Fifteen were female (68%). Median age was 67 years (range 25–87). Fifteen (68%) patients presented with subacute cerebellar syndrome (six isolated; nine with CNS accompaniments: encephalopathy (three), brainstem signs (two), myelopathy (two), parkinsonism (one)). Other phenotypes included limbic encephalitis (three), encephalopathy with/without seizures (two), myelopathy (two). Eighteen (82%) had cancer: neuroendocrine carcinomas (9; pancreatic (3), small-cell lung (4), oesophagus (1), endometrium (1)), adenocarcinomas (6; lung (2), ovarian (2), endometrial (1), breast (1)), sarcoma (2) and gastrointestinal tumour (1). Neurological symptoms in three followed immune checkpoint inhibitor (ICI) administration.

Conclusions This study supports TRIM46-IgG being a biomarker of paraneoplastic CNS disorders and expands the neurological phenotypes, oncological and ICI-related adverse event associations.

  • neuroimmunology
  • paraneoplastic syndrome

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Footnotes

  • Contributors CV-S contributed to acquisition and analysis of data, drafting the manuscript and figures. AMK, MBH, JRM, TJK, ALP, AA, MH, CFL, VAL, AM and SJP contributed to acquisition and analysis of data. YG contributed to acquisition and analysis of data and drafting figure 3. DD contributed to acquisition and analysis of data, conception, design and study supervision. All authors revised the manuscript critically for intellectual content and approved the final version.

  • Funding This work was supported by Mayo Clinic Center of Individualized Medicine Welch Award.

  • Competing interests CV-S, AMK, MBH, YG, JRM, AA and MH have no competing interests to disclose. TJK has a patent AQP4-IgG with royalties paid, a patent KLHL11, septin 5 and MAP1B IgG pending. ALP reports grants from University of Colorado, grants from Rocky Mountain MS Center, personal fees from Genentech/Roche, personal fees from Alexion. CFL received grants from National Institute of Health, National Multiple Sclerosis Society, National Institute of Neurological Disorders and Stroke, Kingsland Foundation, Biogen Idec. VAL has a patent AQP4-IgG with royalties paid, a patent KLHL11, septin 5 and MAP1B IgG pending. AM has patent pending for KLHL11, Septin 5, and MAP1B and GFAP IgGs as markers of neurological autoimmunity and paraneoplastic disorders. He has received research support from Alexion, Grifols, and Euroimmun but has not received personal compensation. SJP has a patent # 8889102 (Application # 12-678350) -Neuromyelitis Optica Autoantibodies as a Marker for Neoplasia issued, and a patent # 9891219B2 (Application # 12-573942) Methods for Treating Neuromyelitis Optica (NMO) by Administration of Eculizumab to an individual that is Aquaporin-4 (AQP4)-IgG Autoantibody positive issued. He has a patent pending for GFAP, Septin 5, MAP1B, KLHL11 and PDE10A IgGs as markers of neurological autoimmunity and paraneoplastic disorders. He has consulted for Alexion, Euroimmune, Medimmune, Astellas, Genetech, Sage Therapeutics, Prime Therapeutics. He has received research support from Grifols and Alexion. He has received research support from NIH, Guthy Jackson Charitable Foundation, Autoimmune Encephalitis Alliance. All compensation for consulting activities is paid directly to Mayo Clinic. DD has received research support from Center of Multiple Sclerosis and Autoimmune Neurology, Center of Individualized Medcine and Grifols pharmaceuticals. He has consulted for UCB and Astellas pharmaceuticals. All compensation for consulting activities is paid directly to Mayo Clinic. He has a patents pending for KLHL11-IgG and LUZP4-IgG as markers of testicular cancer and neurological autoimmunity.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.