Orthostatic intolerance (OI) or postural tachycardia syndrome (POTS) is a 
syndrome primarily affecting young females, and is characterized by 
lightheadedness, palpitations, fatigue, altered mentation, and syncope primarily 
occurring with upright posture and being relieved by lying down. There is 
typically tachycardia and raised plasma norepinephrine levels on upright 
posture, but little or no orthostatic hypotension. The pathophysiology of OI is 
believed to be very heterogeneous. Most studies of the syndrome have focused on 
abnormalities in norepinephrine release. Here the hypothesis that abnormal 
norepinephrine transporter (NET) function might contribute to the 
pathophysiology in some patients with OI was tested. In a proband with 
significant orthostatic symptoms and tachycardia, disproportionately elevated 
plasma norepinephrine with standing, impaired systemic, and local clearance of 
infused tritiated norepinephrine, impaired tyramine responsiveness, and a 
dissociation between stimulated plasma norepinephrine and DHPG elevation were 
found. Studies of NET gene structure in the proband revealed a coding mutation 
that converts a highly conserved transmembrane domain Ala residue to Pro. 
Analysis of the protein produced by the mutant cDNA in transfected cells 
demonstrated greater than 98% reduction in activity relative to normal. NE, 
DHPG/NE, and heart rate correlated with the mutant allele in this family.
CONCLUSION: These results represent the first identification of a specific 
genetic defect in OI and the first disease linked to a coding alteration in a 
Na+/Cl(-)-dependent neurotransmitter transporter. Identification of this 
mechanism may facilitate our understanding of genetic causes of OI and lead to 
the development of more effective therapeutic modalities.