Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency.
Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency.
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DOI：
10.1056/nejm200002243420803
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发表时间：
2000-02-24
影响因子：
158.5
通讯作者：
Robertson, D
中科院分区：
文献类型：
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作者：
Shannon, JR;Flattem, NL;Robertson, D
背景：立位不耐受是一种以头晕、疲劳、精神状态改变和晕厥为特征的综合征，与体位性心动过速和血浆去甲肾上腺素浓度有关，与交感神经流出相关联，不成比例地高。方法：在一名立位耐受患者及其亲属中，我们测量了体位血压、心率、血浆儿茶酚胺和全身去甲肾上腺素的溢出和清除，并对去甲肾上腺素转运体基因进行了测序和功能评估。结果：患者站立时的平均血浆去甲肾上腺素浓度高于正常受试者的平均(+/-SD)浓度(923比439+/-129pg/毫升[5.46比2.59+/-0.76nmol/L])，全身去甲肾上腺素清除量降低(每分钟1.56升对2.42+/-0.71升)，给予酪胺后血浆去甲肾上腺素浓度升高的损害(每毫升12对56+/-63 pg[每毫升0.07对0.33+-0.37 pmoL])，血浆去甲肾上腺素浓度相对于二羟基苯乙二醇有不成比例的增加。对去甲肾上腺素转运蛋白基因的分析表明，先证者是外显子9的杂合子突变(在第237位编码从鸟嘌呤到胞嘧啶的变化)，与野生型基因相比，导致超过98%的功能丧失。突触去甲肾上腺素清除障碍可能导致一种综合征，其特征是对生理刺激的交感神经过度激活。先证者家族中的突变等位基因与体位心率和血浆儿茶酚胺代谢异常分离。结论：去甲肾上腺素失活的遗传或获得性缺陷可能是导致立位不耐受的高肾上腺素能状态的基础。(N Engl J Med 2000；342：541-9)(C)2000年，马萨诸塞州医学会。
Background: 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. (N Engl J Med 2000;342:541-9.) (C)2000, Massachusetts Medical Society.