Anti-CD320 Autoantibodies and Central Nervous System Vitamin B12 Deficiency in Idiopathic Myelopathy.

Abstract

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. To describe a novel autoantibody associated with idiopathic myelopathy (IM) and report its clinical, radiographic, and metabolic characteristics. 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). Autoantibody status. Prevalence, clinical phenotype, CSF profile, and magnetic resonance imaging pattern of autoantibody-positive IM. 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. 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.