Transcobalamin Receptor Autoantibodies in Central Vitamin B12 Deficiency

Vitamin B12 is critical for hematopoiesis and myelination.[1][1] Deficiency can cause neurologic deficits including loss of coordination, spasticity, and cognitive decline.[2][2],[3][3],[4][4] However, diagnosis relies on vitamin B12 measurement in the blood which may not accurately reflect levels in the brain. Here, we discovered an autoimmune cause of vitamin B12 deficiency restricted to the central nervous system (CNS), termed autoimmune B12 central deficiency (ABCD). Using programmable phage display, we identified an autoantibody targeting the transcobalamin receptor (CD320) in a patient with progressive tremor, ataxia, and scanning speech. Patient immunoglobulins impaired cellular uptake of vitamin B12 in vitro . Despite normal serum levels, vitamin B12 was nearly undetectable in her cerebrospinal fluid (CSF). Immunosuppressive treatment and high-dose systemic vitamin B12 supplementation were associated with increased CSF B12 levels and clinical improvement. Autoantibodies targeting the same epitope of CD320 were identified in 7 other patients with neurologic deficits of unknown etiology and in 6 percent of healthy controls. In 132 paired serum and CSF samples, detection of anti-CD320 in the blood predicted B12 deficiency in the brain. These findings elucidate a new autoimmune cause of metabolic neurologic disease that may be amenable to immunomodulatory treatment and/or nutritional supplementation. ### Competing Interest Statement M.R.W. receives unrelated research grant funding from Roche/Genentech and Novartis, and received speaking honoraria from Genentech, Takeda, WebMD, and Novartis. J.D.R. reports being a founder and paid consultant for Delve Bio, Inc., and a paid consultant for the Public Health Company and Allen & Co. ### Funding Statement This study was funded by NIMH (R01MH122471), NINDS (U01NS120836; R35NS111644), Department of Defense (W81XWH-21-1-0979), National Multiple Sclerosis Society, Valhalla Foundation, and the Westridge Foundation. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: IRB of University of California, San Francisco gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors. [1]: #ref-1 [2]: #ref-2 [3]: #ref-3 [4]: #ref-4