The alpha-3 subunit encoded by the CHRNA3 gene is a crucial component of ganglionic acetylcholine receptors, which convey efferent sympathetic and parasympathetic activity to postganglionic autonomic neurons and are required to maintain blood pressure while standing. Antagonistic alpha-3 subunit antibodies abolish sympathetic and parasympathetic traffic and can cause autonomic failure.1,2 Pathogenic CHRNA3 variants have been identified in rare patients with autonomic failure and severe orthostatic hypotension.3 In a patient with a previously undescribed combination of mutated alleles, we conducted detailed investigations to delineate the mechanism mediating cardiovascular autonomic dysfunction. We hypothesized that postganglionic autonomic nerves innervating the cardiovascular system are intact but disconnected from central autonomic input.