Transcobalamin Receptor Autoantibodies in Central Vitamin B12 Deficiency

Abstract

Vitamin B12 is critical for hematopoiesis and myelination.1Deficiency can cause neurologic deficits including loss of coordination, spasticity, and cognitive decline.2,3,4However, 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 B12in 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.

A Brief Overview of the Diagnosis and Treatment of Cobalamin (B12) Deficiency

“…80,81 An intriguing recent study has demonstrated that (auto)antibodies against the CD320 (transcobalamin) receptor may interfere with the proper uptake of cobalamin into the brain. 82 Long-term studies clearly indicate that treatment with pharmacological doses of B12 and the corresponding increase in serum B12 concentrations do not increase mortality risk. 83 Treatment with parenteral B12 during pregnancy and lactation is safe, and should not be postponed or stopped.…”