John V Pluvinage, David Acero-Garces, Giacomo Greco, Carson E Moseley, Sukhman Sidhu, Kelsey C Zorn, Sravani Kondapavulur, Sonam Mohan, John Neely, Stefano Masciocchi, Pietro Businaro, Alexis García Sarreón, Ariadna Gifreu Fraixinó, Krista McCutcheon, Colette Caspar, Richard Dela Rosa, Colin Zamecnik, Asritha Tubati, Andoni I Asencor, Madina Tugizova, Felicia Chow, Alexandra Galati, Yair Mina, Camilo Toro, Min Kang, Chu-Yueh Guo, Sarah F Wesley, Kathryn Kvam, Sydney Lee, Ahmed Abdelhak, Thomas Martin, Yun-Han Huang, Sarah B Berman, Jenny Linnoila, John Engstrom, Andrew McCaddon, Ari J Green, Ralph Green, Bruce A C Cree, Stephen L Hauser, Joseph L DeRisi, Samuel J Pleasure, Jeffrey M Gelfand, Gary Álvarez Bravo, Matteo Gastaldi, Carlos A Pardo, Michael R Wilson, UCSF Neurohospitalist Division, and the, and the, Megan Richie, Vanja Douglas, Maulik Shah, Elan L Guterman, Avindra Nath, Catherine G Suen, Martineau Louine, Leah Zuroff, Josiah Gerdts, Mary Karalius, Alyssa Nylander, Carolyn Bevan, Max Liu, Iyas Daghlas, Leena Suleiman, Todd Nguyen, Benjamin Meyer, Karen Ibarra
In this study, autoimmune vitamin B12 central deficiency was associated with IM. Screening for anti-CD320 antibodies followed by metabolic confirmation of a CNS-restricted vitamin B12 deficiency may be considered in the diagnostic evaluation of myelopathy.
IMPORTANCE: Disorders affecting the spinal cord (myelopathies) can cause severe disability. Despite diagnostic advances, approximately 12% to 18% of myelopathy cases continue to elude an etiological diagnosis, hampering effective treatment.
OBJECTIVE: To describe a novel autoantibody associated with idiopathic myelopathy (IM) and report its clinical, radiographic, and metabolic characteristics.
DESIGN, SETTING, AND PARTICIPANTS: This retrospective case-control study was conducted from May 2014 to October 2025 at 4 tertiary care centers. Biofluids from 148 patients diagnosed with IM were evaluated based on clinical evidence of myelopathy without an identified etiology. Biofluids from patients with other neurological diseases (ONDs; n = 32) or known autoimmune myelitis (n = 30) were used for comparison. Proteomewide phage display was used to discover novel autoantibodies. Targeted immunoassays were used to screen for a candidate autoantibody. Downstream metabolites were measured in the cerebrospinal fluid (CSF).
EXPOSURE: Autoantibody status.
MAIN OUTCOMES AND MEASURES: Prevalence, clinical phenotype, CSF profile, and magnetic resonance imaging pattern of autoantibody-positive IM.
RESULTS: Autoantibodies targeting the transcobalamin receptor (CD320) responsible for cellular transport of vitamin B12 were identified in 18 of 32 individuals with IM (56%) in a discovery cohort (mean [SD] age, 54 [14] years; 19 male). Bioactive vitamin B12 concentration was decreased in the CSF of individuals with positive anti-CD320 test results compared with that of control individuals with ONDs (mean [SD], 15.1 [2.3] pmol/L vs 22.9 [10.7] pmol/L; P = .03), indicative of autoimmune vitamin B12 central deficiency. Compared to individuals with IM and negative anti-CD320 test results, those with IM and positive anti-CD320 test results demonstrated a higher frequency of subacute time course (n = 10 [56%] vs n = 1 [7%]; P = .008), normal CSF profile (n = 15 [83%] vs n = 7 [50%]; P = .04), and dorsolateral spinal cord abnormalities on magnetic resonance imaging (n = 11 [61%] vs n = 1 [7%]; P = .003). In 2 independent validation cohorts comprising 91 and 25 patients with IM, anti-CD320 was detected in 41 (45%) and 12 (48%) patients, respectively. Comorbid anti-CD320 antibodies were detected in a smaller proportion of patients with other known autoimmune etiologies of myelopathy. Five individuals with IM and positive anti-CD320 test results received vitamin B12 supplementation with or without concurrent immunosuppression, and 4 of 5 showed clinical improvement.
CONCLUSIONS AND RELEVANCE: In this study, autoimmune vitamin B12 central deficiency was associated with IM. Screening for anti-CD320 antibodies followed by metabolic confirmation of a CNS-restricted vitamin B12 deficiency may be considered in the diagnostic evaluation of myelopathy.