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Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiencyBACKGROUND: 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.
Document ID
20040141660
Acquisition Source
Legacy CDMS
Document Type
Reprint (Version printed in journal)
Authors
Shannon, J. R.
(Vanderbilt University Nashville 37232-2195, United States)
Flattem, N. L.
Jordan, J.
Jacob, G.
Black, B. K.
Biaggioni, I.
Blakely, R. D.
Robertson, D.
Date Acquired
August 22, 2013
Publication Date
February 24, 2000
Publication Information
Publication: The New England journal of medicine
Volume: 342
Issue: 8
ISSN: 0028-4793
Subject Category
Aerospace Medicine
Funding Number(s)
CONTRACT_GRANT: MH58921
CONTRACT_GRANT: PO1 HL56693
CONTRACT_GRANT: RR00095
Distribution Limits
Public
Copyright
Other
Keywords
Non-NASA Center
NASA Program Biomedical Research and Countermeasures
Case Reports
NASA Discipline Regulatory Physiology

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