Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency.

Background: Orthostatic intolerance is a syndrome characterized by lighthea dedness, fatigue, altered mentation, and syncope and associated with postur al tachycardia and plasma norepinephrine concentrations that are disproport ionately 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 me asured postural blood pressure, heart rate, plasma catecholamines, and syst emic norepinephrine spillover and clearance, and we sequenced the norepinep hrine-transporter gene and evaluated its function. Results: The patient had a high mean plasma norepinephrine concentration wh ile standing, as compared with the mean (+/-SD) concentration in normal sub jects (923 vs. 439+/-129 pg per milliliter [5.46 vs. 2.59+/-0.76 nmol per l iter]), reduced systemic norepinephrine clearance (1.56 vs. 2.42+/-0.71 lit ers per minute), impairment in the increase in the plasma norepinephrine co ncentration after the administration of tyramine (12 vs. 56+/-63 pg per mil liliter [0.07 vs. 0.33+/-0.37 pmol per liter]), and a disproportionate incr ease in the concentration of plasma norepinephrine relative to that of dihy droxyphenylglycol. Analysis of the norepinephrine-transporter gene revealed that the proband was heterozygous for a mutation in exon 9 (encoding a cha nge 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. Im pairment of synaptic norepinephrine clearance may result in a syndrome char acterized by excessive sympathetic activation in response to physiologic st imuli. The mutant allele in the proband's family segregated with the postur al heart rate and abnormal plasma catecholamine homeostasis. Conclusions: Genetic or acquired deficits in norepinephrine inactivation ma y underlie hyperadrenergic states that lead to orthostatic intolerance. (N Engl J Med 2000;342:541-9.) (C)2000, Massachusetts Medical Society.