Helmholtz Gemeinschaft

Search
Browse
Statistics
Feeds

Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency

Item Type:Article
Title:Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency
Creators Name:Shannon, J.R. and Flattem, N.L. and Jordan, J. and Jacob, G. and Black, B.K. and Biaggioni, I. and Blakely, R.D. and Robertson, D.
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.
Keywords:Amino Acid Sequence, Base Sequence, Blood Pressure, Carrier Proteins, Heart Rate, Methoxyhydroxyphenylglycol, Molecular Sequence Data, Missense Mutation, Norepinephrine, Norepinephrine Plasma Membrane Transport Proteins, Pedigree, Posture, Amino Acid Sequence Homology, Symporters, Syncope, Tachycardia
Source:New England Journal of Medicine
ISSN:0028-4793
Publisher:Massachusetts Medical Society (U.S.A.)
Volume:342
Number:8
Page Range:541-549
Date:24 February 2000
Official Publication:http://content.nejm.org/cgi/content/abstract/342/8/541
PubMed:View item in PubMed

Repository Staff Only: item control page

Open Access
MDC Library