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Previous Volume 342:541-549 February 24, 2000 Number 8 Next

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ABSTRACT

Background Orthostatic intolerance is a syndrome characterized by lightheadedness, fatigue, altered mentation, and syncope and associated with postural tachycardia and plasma norepinephrine concentrations that are disproportionately high in relation to sympathetic outflow. We tested the hypothesis that impaired functioning of the norepinephrine transporter contributes to the pathophysiologic mechanism of orthostatic intolerance.

Methods In a patient with orthostatic intolerance and her relatives, we measured postural blood pressure, heart rate, plasma catecholamines, and systemic norepinephrine spillover and clearance, and we sequenced the norepinephrine-transporter gene and evaluated its function.

Results The patient had a high mean plasma norepinephrine concentration while standing, as compared with the mean (±SD) concentration in normal subjects (923 vs. 439±129 pg per milliliter [5.46 vs. 2.59±0.76 nmol per liter]), reduced systemic norepinephrine clearance (1.56 vs. 2.42±0.71 liters per minute), impairment in the increase in the plasma norepinephrine concentration after the administration of tyramine (12 vs. 56±63 pg per milliliter [0.07 vs. 0.33± 0.37 pmol per liter]), and a disproportionate increase in the concentration of plasma norepinephrine relative to that of dihydroxyphenylglycol. Analysis of the norepinephrine-transporter gene revealed that the proband was heterozygous for a mutation in exon 9 (encoding a change from guanine to cytosine at position 237) that resulted in more than a 98 percent loss of function as compared with that of the wild-type gene. Impairment of synaptic norepinephrine clearance may result in a syndrome characterized by excessive sympathetic activation in response to physiologic stimuli. The mutant allele in the proband's family segregated with the postural heart rate and abnormal plasma catecholamine homeostasis.

Conclusions Genetic or acquired deficits in norepinephrine inactivation may underlie hyperadrenergic states that lead to orthostatic intolerance.

Source Information

From the Autonomic Dysfunction Center (J.R.S., J.J., G.J., B.K.B., I.B., D.R.) and the Center for Molecular Neuroscience (N.L.F., R.D.B.), Departments of Medicine, Pharmacology, and Neurology, Vanderbilt University, Nashville.

Address reprint requests to Dr. Robertson at the General Clinical Research Center, AA3228 MCN, Vanderbilt University, Nashville, TN 37232-2195, or at david.robertson{at}mcmail.vanderbilt.edu.

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