Orthostatic intolerance is not necessarily related to a specific mutation (Ala457Pro) in the human norepinephrine transporter gene

Abstract

Background Orthostatic intolerance (OI) is a syndrome characterized by lightheadedness, palpitations, fatigue, blurred vision, dizziness, chest discomfort, cognitive impairment, and occasionally syncope. These symptoms usually occur after upright posture and are associated with tachycardia and high plasma concentrations of norepinephrine. It has been proposed that a mutation in exon 9 of the norepinephrine transporter gene (Ala457Pro), resulting in more than 98% loss of function compared with the wild type, might provide a pathogenetic mechanism to explain the clinical symptoms of patients with OI. Methods We studied 46 young men from military service who had sought medical advice because of dizziness while standing. Every patient underwent a tilt-table test, with monitoring of blood pressure, heart rate, and plasma catecholamines in supine position and during 30 minutes of standing. Fourteen patients showing the full-blown OI syndrome (30 bpm increase in heart rate and 600 pg/mL plasma norepinephrine levels while standing) underwent direct DNA sequencing of exon 9 of the norepinephrine-transporter gene. Results and conclusions The specific mutation (Ala457Pro) was not detected in any of the 14 OI patients. Based on these findings, we doubt that this specific genetic transport defect is a frequent cause of the impaired uptake of norepinephrine in OI patients. Its routine determination will therefore not be helpful to establish the clinical diagnosis of OI.