Anti-Neuronal Nuclear Antibody 3 Autoimmunity Targets Dachshund Homolog 1

ObjectiveTo identify the autoantigen defined by Anti-Neuronal Nuclear Antibody-type 3 (ANNA3)-IgG and describe the clinical phenotype of seropositive patients.BackgroundANNA3 was described in 11 patients with multifocal neurological presentations and cancer; its detection is based on the characteristic immunofluorescence staining on mouse tissue sections; ignorance of the antigen's molecular identity has precluded its ready detection in clinical practice.Design/MethodsThis study was performed at the Mayo Clinic Neuroimmunology Laboratory. The ANNA3-IgG antigen, identified by immunoprecipitation and mass spectrometry as Dachshund-homolog 1 (DACH1), was confirmed by using a commercial DACH1-specific IgG for immunohistochemical colocalization, antigen-specific Western blot, transfected cell-based immunofluorescence, and immune absorption experiments. Clinical data were abstracted from patients' medical records or provided by referring physicians.ResultsIgG in 32 ANNA3 seropositive patient sera, but in none of 145 controls, bound to DACH1. Clinical information was available for 30 patients (median age, 63.5 years [range, 49-88]; 67% female). Neurological manifestations included neuropathy, 12; cognitive difficulties or encephalitis, 11; ataxia, 8; dysautonomia, 7 (two additionally had diarrhea and esophageal spasm); chorioretinopathy, 1. Clinical improvement was noted in 8 of 11, all treated with immunosuppressants or oncologic treatment. In two patients, the neurological syndrome appeared or worsened during immune checkpoint inhibitor cancer immunotherapy. A neoplasm was found in 27 patients (90%); fourteen were of neuroendocrine lineage. Coexisting neural autoantibodies were detected in 14 patients (47%), and most predicted a neuroendocrine tumor (specific for neuronal intermediate filaments, collapsin response-mediator protein-5, voltage-gated calcium channel [P/Q-type], ANNA1, SOX1, Purkinje-cell cytoplasmic autoantibody type 2/microtubule-associated-protein-1B).ConclusionsIgG specific for DACH1 is a serological biomarker of neurological autoimmunity and cancer in patients of middle-age or older. DACH1-IgG is a valuable addition to comprehensive autoimmune and paraneoplastic neural antibody evaluations in clinical practice.