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. 2022 Feb;93(2):196-200.
doi: 10.1136/jnnp-2021-326656. Epub 2021 Dec 17.

Characterisation of TRIM46 autoantibody-associated paraneoplastic neurological syndrome

Cristina Valencia-Sanchez  1 , Andrew M Knight  2 , M Bakri Hammami  2 , Yong Guo  1 , John R Mills  2 , Thomas J Kryzer  2 , Amanda L Piquet  3 , Anik Amin  4 , Morgan Heinzelmann  4 , Claudia F Lucchinetti  1 , Vanda A Lennon  1   2   5 , Andrew McKeon  1   2 , Sean J Pittock  1   2 , Divyanshu Dubey  6   2
Affiliations

Characterisation of TRIM46 autoantibody-associated paraneoplastic neurological syndrome

Cristina Valencia-Sanchez et al. J Neurol Neurosurg Psychiatry. 2022 Feb.

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.

Keywords: neuroimmunology; paraneoplastic syndrome.

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Conflict of interest statement

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.

Figures

Figure 1
Figure 1
Distinct immunofluorescence pattern of patient IgG binding to mouse tissues, confirmation of tipartite motif-containing protein 46 (TRIM46) as the target antigen. (A) Patient IgGs yielded an indirect immunofluorescence staining pattern characterised by staining of the axonal initial segment in cerebellar Purkinje neurons at ×20 magnification (A1), cerebral cortex at ×20 (A2) and hippocampus at ×10 (A3). (B) Dual immunostaining yielded by a commercial mouse IgG specific for TRIM46 (B1) and by a patient’s IgG (B2), binding to the axonal initial segment of Purkinje neurons; merged image (B3). (C) GFP-tagged TRIM46 protein expressed in transfected COS7 cells (C1), and patient IgG binding (C2); merged image (C3)
Figure 2
Figure 2
Expression of tripartite motif-containing protein 46 (TRIM46) in breast carcinoma tissue. H&E stain shows excised breast carcinoma tissue at different magnifications (A–D, G). The poorly differentiated tumour tissue (B, C) shows no TRIM46 expression on immunohistochemistry (E, F). However, the peripheral tumour tissue with better differentiation (D, G) shows TRIM46 immunoreactivity (H, I). Another example of peripheral relative normal tissue shows TRIM46 in the epithelium (J). Normal breast control tissue is negative for TRIM46 (K, L). Scale bars: 100 μm (A), 50 μm (B, D, E, H, K), 20 μm (C, F, G, I, J, L).
Figure 3
Figure 3
Characteristic brain images from three TRIM46-IgG seropositive patients. Brain images of three TRIM46-IgG seropositive patients. (A) MRI, sagittal T1 sequence, showing cerebellar atrophy in a patient who presented with subacute cerebellar ataxia, and was diagnosed with small cell lung cancer 4 years after neurological symptom onset. (B) Axial FLAIR-T2 sequences of a patient with endometrial carcinoma on treatment with pembrolizumab, who presented with a subacute cerebellar and brainstem syndrome. At onset of symptoms, a T2-hyperintense area in the anterior left medulla was observed (B1). Ten weeks later, she had developed cerebellar atrophy and T2 signal hyperintensity in the left pulvinar (B2). (C) Axial FLAIR-T2 sequence showing medial right temporal lobe T2-hyperintensity in a patient with lung adenocarcinoma treated with pembrolizumab, who presented with limbic encephalitis. TRIM46, tripartite motif-containing protein 46.
See this image and copyright information in PMC

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