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September 2022; 9 (5) RESEARCH ARTICLEOpen Access

Cerebellar Ataxia With Anti-DNER Antibodies

Outcomes and Immunologic Features

Elise Peter, Le Duy Do, Salem Hannoun, Sergio Muñiz-Castrillo, Alberto Vogrig, Valentin Wucher, Anne-Laurie Pinto, Naura Chounlamountri, Walaa Zakaria, Veronique Rogemond, Geraldine Picard, Julien-Jacques Hedou, Aditya Ambati, Agusti Alentorn, Alexandra Traverse-Glehen, Mario Manto, Dimitri Psimaras, Emmanuel Mignot, Francois Cotton, Virginie Desestret, Jérôme Honnorat, Bastien Joubert
First published August 8, 2022, DOI: https://doi.org/10.1212/NXI.0000000000200018
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Figures

  • Figure 1
    Figure 1 Longitudinal Volumetric Analysis of the Patients' Cerebellum

    (A) Boxplot showing the volumes of cerebellar white matter, cerebellar gray matter, and whole cerebellum at baseline and follow-up, in 10 patients with anti-DNER antibodies. Volumes are expressed as percentages of intracranial volume. There is a significant decrease of cerebellar gray matter and whole-cerebellum volumes at follow-up, compared with baseline, **p < 0.005. (B) Representative images of sagittal T1-weighted brain MRI at baseline and follow-up of a patient with favorable outcome (follow-up MRI 9 months after disease onset) and a patient with poor outcome (follow-up MRI 6 months after disease onset).

  • Figure 2
    Figure 2 Proteomic Analysis of the Cerebrospinal Fluid of Patients With DNER Ataxia

    Heatmap of CSF log2 expression of proteins shown as median Z-scores per protein in patients with anti-DNER antibodies (n = 5) compared with controls (n = 40). Overexpressed proteins were mainly related to immune response. Among them, overexpression of C-X-C motif chemokine 13 (CXCL-13) and CD48 is implicated in B-cell activation. Other immune-related proteins included complement component 2 (C2), interleukin-1 receptor type 2 (IL1R2), chemokine C-X-C motif chemokine 10 (CXCL10), pulmonary surfactant-associated protein D (SFtPD), and hepcidin (HAMP). Proteins of leukocyte migration were also overexpressed, including vascular cell adhesion protein 1 (VCAM-1), and integrin alpha1 and beta1 (ITGB1/ITGA1). Other overexpressed proteins likely reflected tissue lysis, including proteins involved in cell cycle or processing of proteins and RNA, such as heterogeneous nuclear ribonucleoproteins A2/B1 (HNRNPA2B1), SUMO-conjugating enzyme UBC9 (UBE2I), and acidic leucine-rich nuclear phosphoprotein 32 family member B (ANP32B). Underexpressed proteins were interferon gamma (IFNG), and proteins mostly related to neural development (such as neuronal growth regulator 1 or NEGR1 and the neurexins 1 and 3: NRXN1, NRXN3) or cell cycle (e.g., BH3-interacting domain death agonist [BID]).

  • Figure 3
    Figure 3 DNER Antibodies Bind DNER at the Surface of Purkinje Cells

    (A) Incubation of nonpermeabilized live organotypic cerebellar cultures with an anti–DNER-positive CSF shows punctuate cell-surface immunolabeling (top) that is not obtained with a control CSF (bottom). Purkinje cells were labeled with an anti-calbindin D-28K antibody (red). (B) Fixed and permeabilized organotypic cerebellar cultures labeled with an anti-DNER-positive CSF (green), a commercial anti-DNER antibody (purple), and calbindin D-28K (red). Commercial anti-DNER and human DNER-specific IgG demonstrate superposable staining of the dendrites and soma of Purkinje cells.

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