NEURONAL NICOTINIC ACH RECEPTOR ANTIBODY IN SUBACUTE AUTONOMIC NEUROPATHY AND CANCER-RELATED SYNDROMES

Background: Autoantibodies specific for the acetylcholine receptor (AC hR) of skeletal muscle (containing the al subunit) impair neuromuscula r transmission in myasthenia gravis (MG). AChRs mediating fast synapti c transmission through autonomic ganglia are structurally similar to m uscle AChR, but contain the alpha 3 subunit. We propose that ganglioni c AChR autoimmunity may cause dysautonomia. Objective: To test serum o f patients with autonomic neuropathy for autoantibodies of neuronal ga nglionic AChR specificity. Methods: We developed an immunoprecipitatio n radioassay by complexing epibatidine (I-125-labeled high affinity ag onist) to a Triton X-100-solubilized AChR antigen from peripheral neur oblastoma membranes. Monoclonal rat immunoglobulins (IgG) specific for muscle or neuronal AChRs validated the assay's specificity. We tested serum from 52 healthy subjects, 12 patients with subacute autonomic n europathy, and 248 patients with other neurologic disorders. Results: Twelve patients had antibodies that bound unequivocally to ganglionic AChR. Five had subacute autonomic neuropathy, and three (of six tested ) had Isaacs' syndrome; four of these eight had a carcinoma (lung, bla dder, rectum, thyroid). The remaining four seropositive patients (two Lambert-Eaton syndrome, one dementia, one sensory neuronopathy) all ha d Ca2+ channel antibodies and three had small cell lung carcinoma. No healthy subject had ganglionic AChR antibodies, nor did 62 patients wi th AChr and muscle AChR antibodies. Conclusion: Neuronal AChR antibodi es are a novel serologic marker of neurologic autoimmunity. The pathog enicity of neuronal AChR autoantibodies in autonomic neuropathy, Isaac s' syndrome, or other neurologic disorders remains to be shown, as has been demonstrated for muscle AChR antibodies in MG. An autoimmune and potentially paraneoplastic etiology is implicated in seropositive pat ients.