Address for correspondence: David Robertson, M.D., Autonomic Dysfunction Center, AA3228 MCN, Vanderbilt University, Nashville, TN 37232-2195. Voice: 615-343-6499; fax: 615-343-8649.
david.robertson{at}mcmail.vanderbilt.edu
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 dissociataion 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.
