Journal Club:

Article: Shannon JR, Flattem NL, Jordan J, Jacob G, Black BK, Biaggioni I, Blakely RD, Robertson D. Orthostatic Intolerance and tachycardia associated with norepinephrine-transporter deficiency. N Engl J Med 2000; 342:541-9

A Literature Review by David S. Bell, MD, FAAP

Published in Lyndonville News, May 2000

Summary: In a recent issue of the New England Journal of Medicine, Dr. David Robertson and colleagues described an abnormality in a gene which causes orthostatic intolerance in three members of a family. The primary case was a woman with orthostatic intolerance (OI), characterized by rapid heart rate, difficulty breathing, cognitive difficulties, and fainting spells related to being in the upright position. Her identical twin had similar symptoms, again usually while standing.

Measurements of norepinephrine while lying down and standing up revealed "hyperadrenergic" orthostatic intolerance, meaning that there was an excessing blood level of norepinephrine while standing. Further testing revealed reduced norepinephrine clearance from the blood stream, and impaired increase of blood levels of norepinephrine after administration of tyramine. The authors analyzed the sequences of the norepinephrine-transporter gene and found an abnormality that impaired the function of this gene in the patient and her twin. They hypothesized that this specific genetic abnormality was the cause of the OI and that "Genetic or acquired deficits in norepinephrine inactivation may underlie hyperadrenergic states that lead to orthostatic intolerance."

Discussion and Opinion: I feel that this article is of tremendous importance to persons with CFS. Central to this issue is the relationship between OI and CFS, a subject discussed in another section of the newsletter. However, both illnesses are characterized by disorders of the autonomic nervous system, particularly excessive sympathetic activation in response to stimuli that should not be stressful, such as standing up.

In a paper written in 1988 the symptoms of CFS were compared to cocaine withdrawal1, which still remains as an excellent model for the illness. Interestingly, cocaine inhibits norepinephrine reuptake, thus acting in a similar manner to the gene deficit described in this paper. It is because of this deficit that patients experience symptoms suggestive of not enough norepinephrine (adrenaline) simultaneously with too much norepinephrine, a paradox, which underlies much of the confusion regarding CFS. It may be that a physiologic mishandling of norepinephrine lies at the root of both conditions.

It should be noted, however, that even if this study proves to be accurate, it is not likely to explain many cases of OI. The authors state that the abnormal gene sequence was not found in 254 other (unrelated) persons with OI. But the paper is of great importance as it is likely to be the explanation in at least two persons with OI. It is a start.

1. Lehrer JF, Hover LM. Fatigue Syndrome JAMA [Letter] 1988; 259:842-3.

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