Feb. 28, 2000 We do it countless times every day-stand up after sitting or lying down. For patients with orthostatic intolerance though, this simple action causes racing hearts, nausea, headache, dizziness, even fainting. In short, a "head-rush" that just won't end.
Now, researchers at Vanderbilt University Medical Center have identified the first genetic defect in this syndrome-a mutation that cripples the norepinephrine transporter. This discovery is doubly exciting as it represents the first mutation in this family of transporter proteins that has been linked to a human disease.
The findings, reported on February 24th in the New England Journal of Medicine, offer a new explanation for some forms of orthostatic intolerance and suggest different treatment strategies for this common clinical problem. "The discovery of this gene defect may lead to new understanding of blood pressure control and how extreme fluctuations in blood pressure can cause irregular heart rhythms. Since the norepinephrine transporter system is the target site for a number of drugs, including tricyclic antidepressants and amphetamines, this finding may also lead to new insights into the mechanisms of these drugs," said Dr. Claude Lenfant, director of the National Heart, Lung, and Blood Institute.
Orthostatic intolerance, characterized by an increase in heart rate (at least 30 beats per minute) on standing, affects more than 500,000 people-more women than men-in the United States. It is the most common disorder of the autonomic nervous system, the system that makes instantaneous adjustments to blood pressure and heart rate in order to counteract gravity's pull when we stand up. Orthostatic intolerance goes by other names including soldier's heart, neurocirculatory asthenia, and mitral valve prolapse, and it bears many similarities to chronic fatigue syndrome.
One of the biochemical irregularities of orthostatic intolerance is high blood levels of the neurotransmitter norepinephrine.
"If norepinephrine is high, there are really only two explanations-either a lot more is being released from neurons, or a lot less is being cleared away," said Dr. David Robertson, professor of Medicine, Pharmacology, and Neurology, and director of the Clinical Research Center.
Most attempts to explain the abnormal levels of norepinephrine observed in orthostatic intolerance have focused on alterations in its release from neurons. Robertson and his colleagues in the Autonomic Dysfunction Center decided to look at the other side of the equation and ask if there were changes in norepinephrine removal.
"That was not really being done," Robertson said. "When we looked, we found that there was reduced norepinephrine clearance in a significant percentage of patients with orthostatic intolerance."
The norepinephrine transporter, a sort of molecular vacuum cleaner, is the molecule that removes most of the released norepinephrine from the synapse, leading Robertson to suspect that it might be faulty in some patients with orthostatic intolerance. When he encountered a patient whose identical twin sister also had symptoms of orthostatic intolerance, he recognized the opportunity to look for a genetic defect.
Robertson paired with Randy D. Blakely, Ph.D., Allan D. Bass Professor of Pharmacology and director of the Center for Molecular Neuroscience, to search for mutations in the norepinephrine transporter gene. Blakely participated in cloning the norepinephrine transporter in 1991 and has studied it and related neurotransmitter transporters ever since.
Nancy L. Flattem, a medical student in Blakely's group, hunted for a mutation by isolating DNA from the original patient's blood, sequencing the norepinephrine transporter gene, and comparing it to the normal sequence. She found a mutation that changed one 'letter' of the DNA code and resulted in a transporter protein that no longer worked.
The patient is 'heterozygous' for the mutation, meaning that she has one normal copy of the norepinephrine transporter gene and one copy with the mutation. Flattem also examined DNA samples from the patient's mother and nine siblings and found that the mother and four siblings (including the twin sister) were also heterozygous for the mutation.
While Flattem probed the DNA sequence, Dr. John R. Shannon, instructor of Medicine, investigated cardiovascular responses in the family members. The ones who share the transporter mutation also share characteristics of orthostatic intolerance-elevated heart rate and norepinephrine levels on standing.
Linking a genetic defect in the norepinephrine transporter to orthostatic intolerance is significant, Robertson said. "It focuses our understanding of this disorder in a new direction and shifts our attention for treatment options to entirely different kinds of drugs."
The particular transporter mutation that the researchers found was not present in any of 254 unrelated individuals, including normal controls and patients with orthostatic intolerance, indicating that it does not explain all cases of orthostatic intolerance. Robertson and Blakely believe that mutations in other regions of the transporter and in other genes will be linked to orthostatic intolerance.
"What had been speculation now clearly has a framework for looking carefully at other adrenergic (norepinephrine-related) genes in orthostatic intolerance," Blakely said.
The findings are also important as the first to connect a neurotransmitter transporter genetic defect to a clinical disease.
"We think this is the tip of an iceberg with respect to transporter defects," Blakely said. "There are a large number of candidate mutations (catalogued by geneticists) in the norepinephrine transporter gene that may be clinically relevant. And of course the norepinephrine transporter has its brothers and sisters in the gene family-like the serotonin and dopamine transporters-that have not yet been genetically linked to clinical disorders but which serve as major targets for antidepressants and cocaine."
The studies were supported by the National Heart, Lung, and Blood Institute, the National Institute of Mental Health, NASA (astronauts experience orthostatic intolerance on return to Earth), and Vanderbilt's Nathan Blaser Shy-Drager Research Program.
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