The DOI matches its Crossref record; 35 of the 35 references it cites were found in a registry or an index; 2 of the 19 sources its claims cite were checked for support.
Orthostatic Intolerance and Tachycardia Associated with Norepinephrine-Transporter Deficiency
Open accessAbstract
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.
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TL;DR
In a woman with orthostatic intolerance and her identical twin, the authors found evidence of impaired norepinephrine reuptake, including a heterozygous Ala457Pro mutation in the norepinephrine transporter gene that nearly abolished transporter function. The mutation tracked with higher standing heart rates and plasma norepinephrine and lower DHPG:norepinephrine ratios in relatives, suggesting a hyperadrenergic mechanism for some orthostatic intolerance.
Key findings
- The proband had a standing plasma norepinephrine concentration of 923 pg/mL versus 439±129 pg/mL in normal subjects, reduced systemic norepinephrine clearance of 1.56 versus 2.42±0.71 L/min, and a blunted plasma norepinephrine rise after tyramine of 12 versus 56±21 pg/mL.
- Plasma DHPG:norepinephrine ratios were low in the proband and her twin compared with normal subjects: supine 3.06 and 2.41 versus 5.52, and upright 1.05 and 1.17 versus 3.44.
- The proband was heterozygous for a G237C mutation in exon 9 of the norepinephrine transporter gene, producing Ala457Pro; expressed mutant transporter showed 2 percent or less of wild-type uptake activity, corresponding to more than 98 percent loss of function.
- The mother and four siblings were heterozygous for the mutation; heterozygous relatives had significantly higher standing heart rates and upright plasma norepinephrine concentrations and significantly lower DHPG:norepinephrine ratios, but none had the full syndrome. The mutation was absent in 254 unrelated persons.
Methods
- Case-family study of a 33-year-old proband with orthostatic intolerance, her identical twin, nine siblings, and their mother; clinical measurements included supine and upright blood pressure, heart rate, plasma catecholamines, tyramine challenge, and tritiated norepinephrine infusion with nitroprusside to assess spillover and clearance.
- Genetic and functional work included sequencing of norepinephrine-transporter gene exons, expression of wild-type and Ala457Pro cDNA in Chinese-hamster-ovary cells for tritiated norepinephrine uptake, and allele-specific oligonucleotide hybridization for genotyping.
- Comparisons used 10 normal subjects for blood pressure, heart rate, and catecholamines, 9 for tyramine response, and 8 for norepinephrine spillover and clearance; paired and unpaired t-tests were used with two-sided P values.
Limitations
- The paper states that the Ala457Pro mutation was not found in 254 unrelated persons and does not explain all cases of orthostatic intolerance; heterozygous relatives showed some abnormalities but none had the full syndrome, so other genetic or environmental factors likely contributed.
- Evident from the text: the study is very small, centered on one proband and her twin with limited family and normal comparison groups, and lacks independent replication.
- The functional evidence comes from heterologous cell expression rather than patient tissue, and the case-family design limits generalizability.
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Claims the paper makes
45 Own result · 21 Own interpretation · 11 No full text of the sources · 2 No basis given · 1 Supported · 1 Couldn’t confirm · 1 Not checked yet · 1 Own method · accuracy not yet measured
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“A deficiency of the norepinephrine transporter may explain several of the clinical findings in patients with this disorder: the high heart rate in the supine position, the high plasma concentration of norepinephrine in association with the relatively low plasma concentration of dihydroxyphenylglycol, the impaired response of norepinephrine to tyramine, 13 the reduced systemic clearance of norepine”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [13] Jacob G, 1999, Circulation source
- Could not verifycites [27] Furlan R, 1998, Circulation sourceExperimental — accuracy not yet measured
The Autonomic Control section reports elevated supine norepinephrine and tachycardia, but proposes a possible central nervous system abnormality rather than a norepinephrine-transporter deficiency. Searches for transporter deficiency, tyramine, and dihydroxyphenylglycol found no passage in our copy addressing the claimed explanation. (LLM, conf=0.76)
hedgedconditionalSingle case- Asserted: passes — The authors put it forward as true.
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In the paper
“Norepinephrine clearance did not change appreciably after the nitroprusside infusion in either the proband (1.76 liters per minute) or the normal subjects (2.31±0.68liters per minute).”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Spillover and Clearance of Systemic Norepinephrine
plainSingle case- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In the proband and her twin, the plasma concentrations of dihydroxyphenylglycol, an intraneuronal metabolite of norepinephrine, 9 were low in relation to the plasma norepinephrine concentrations (ratio of dihydroxyphenylglycol to norepinephrine in the supine position, 3.06 in the proband and 2.41 in her twin, vs. 5.52 in the normal subjects; ratio in the upright position, 1.05 in the proband and 1”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Autonomic Responses
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In the paper
“Direct sequence analysis of the norepinephrinetransporter gene in the proband revealed no divergence from previously published sequences 14,18 in exons 1 through 8 and exons 10 through 15.”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Identification of a Functional Missense Mutation in the Norepinephrine-Transporter Gene
What the sources say
plainSingle case- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We evaluated a patient and her identical twin, both of whom had symptoms typical of orthostatic intolerance”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Conclusions
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“reduced systemic norepinephrine clearance (1.56 vs. 2.42±0.71liters per minute)”
- Also stated in: § Spillover and Clearance of Systemic Norepinephrine · plain
“norepinephrine clearance in the proband was less than half that in the normal subjects (1.56 vs. 2.42±0.71liters per minute).”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Results
plainSingle case- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Spillover and Clearance of Systemic Norepinephrine · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The patient had a high mean plasma nor- epinephrine 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±0.76nmol per liter])”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Results
plaincorrelationalSingle case- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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)”
- Also stated in: § T ABLE 1. B LOOD P RESSURE , H EART R ATE , AND P LASMA C ATECHOLAMINE C ONCENTRATIONS IN THE P ROBAND , H ER T WIN S ISTER , AND 10 U · plain
“The proband was heterozygous for both the C154A and the G237C polymorphisms (Fig. 2A).”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Results
plainSingle case- Asserted: passes — The authors put it forward as true.
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- Also stated in: § T ABLE 1. B LOOD P RESSURE , H EART R ATE , AND P LASMA C ATECHOLAMINE C ONCENTRATIONS IN THE P ROBAND , H ER T WIN S ISTER , AND 10 U · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The arterial plasma norepinephrine concentration at rest was slightly higher in the proband than in the normal subjects (280 pg per milliliter [1.66 nmol per liter] vs. 204±51 pg per milliliter [1.21±0.30nmol per liter]).”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Spillover and Clearance of Systemic Norepinephrine
plaincorrelationalSingle case- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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])”
- Also stated in: § Response to Tyramine · plain
“In the proband, the same dose of tyramine increased systolic blood pressure by 18 mm Hg but increased the plasma norepinephrine concentration by only 12 pg per milliliter (0.07 nmol per milliliter).”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Results
plainSingle case- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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- Also stated in: § Response to Tyramine · plain
- It may state two separate claims as one. 11
- Probably not a substantial claim. 2
Every source the paper cites for this claim was checked and supports it.
In the paper
“The dihydroxyphenylglycol then enters the circulation and can serve as a marker of norepinephrine uptake and monoamine oxidase activity 9 (Fig. 4).”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > DISCUSSION
What the sources say
- Supportedcites [9] source
The Introduction (p. 1) identifies DHPG as a norepinephrine metabolite present in human plasma. The Conclusions (p. 7) link plasma DHPG to neuronal norepinephrine uptake, and the DHPG/NE ratio discussion (p. 7) predicts a changed DHPG response when either uptake or monoamine oxidase is blocked. The paper presents this as information obtained from DHPG measured alongside norepinephrine, rather than as a standalone measure of enzyme activity. (LLM, conf=0.86)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In the normal subjects, the mean (±SD) systolic blood pressure increased by 19±2 mm Hg and the mean plasma norepinephrine concentration increased by 56 ±21 pg per milliliter (0.33±0.12 nmol per liter) in response to 3 mg of tyramine.”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Response to Tyramine
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The proband and her twin sister had normal autonomic reflexes, but their blood pressure and heart rate were variable (Fig. 1).”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Autonomic Responses
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Their heart rates while supine were slightly but not significantly greater than those of their family members with the wild-type genotype, but their heart rates while standing were significantly higher (Fig. 3A and 3B).”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Segregation of the Ala457Pro Mutation with a Phenotype
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Likewise, plasma norepinephrine concentrations in the supine position were somewhat higher and plasma norepinephrine concentrations in the upright position were significantly higher in the heterozygous family members than in those with the normal genotype (Fig. 3C and 3D).”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Segregation of the Ala457Pro Mutation with a Phenotype
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“In contrast, the Ala457Pro mutation renders the transporter nonfunctional and segregates with altered heart-rate regulation and altered norepinephrine metabolism.”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > DISCUSSION
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In Chinese-hamster-ovary cells that had been transiently transfected with cDNA encoding the human norepinephrine transporter, uptake of tritiated norepinephrine was 10 times that in vector-transfected cells, whereas in cells transfected with cDNA encoding the Ala457Pro mutation in the norepinephrine transporter, the uptake was 2 percent or less (Fig. 2D).”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > T ABLE 1. B LOOD P RESSURE , H EART R ATE , AND P LASMA C ATECHOLAMINE C ONCENTRATIONS IN THE P ROBAND , H ER T WIN S ISTER , AND 10 U
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Approximately 80 to 90 percent of the norepinephrine released into many synapses is cleared by this mechanism, and the remaining 10 to 20 percent spills over into the circulation or extraneuronal tissue.8”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Conclusions
What the sources say
- Not checked — no full text of the sourcecites [8] Esler M, 1990, Physiol Rev source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The reduced DHPG concentration in the neuron results in lower concentrations of this metabolite in the plasma and, consequently, a ratio of plasma DHPG to plasma norepinephrine that is lower than normal.”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: DHPG diffuses out of the neuron into the circulation.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All samples of genomic DNA were coded before genotype analysis in order to preserve the anonymity of the subjects.”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Genotyping of Ala457Pro Alleles
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Because acute pharmacologic blockade of the norepinephrine transporter causes a decrease in sympathetic outflow, 33 one would expect a decrease in sympathetic tone with a deficiency of the norepinephrine transporter.”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > DISCUSSION
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In persons with norepinephrine-transporter deficiency, the release of norepinephrine into the synaptic space is normal, but because of the decreased activity of the norepinephrine transporter, less than 80 percent of norepinephrine is taken up into the neuron that released it, so that the spillover into the circulation is greater than 20 percent.”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Approximately 80 percent of norepinephrine in the synaptic space is taken up by the norepinephrine transporter into the neuron that released it, and approximately 20 percent spills over into the circulation.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Because the substitution of proline disrupts alpha-helical secondary structures that are supported by alanine residues, this mutation may disrupt the transport of norepinephrine.”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > DISCUSSION
hedgedconditionalSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper relies on this without support.
The in vitro loss of norepinephrine transport caused by the Ala457Pro mutation reflects impaired norepinephrine clearance in the patients.
“nephrine transport was greatly diminished by the Ala457Pro mutation.”
The paper relies on this without support.
Under normal conditions, norepinephrine is released from vesicles in the neuron into the synaptic space, where it can interact with presynaptic and postsynaptic alpha- and beta-adrenergic receptors.
“Under normal conditions, norepinephrine is released from vesicles in the neuron into the synaptic space, where it can interact with presynaptic and postsynaptic a-and b-adrenergic receptors.”
The paper relies on this without support.
Approximately 80 percent of norepinephrine in the synaptic space is taken up by the norepinephrine transporter into the neuron that released it, and approximately 20 percent spills over into the circulation.
“Approximately 80 percent of the norepinephrine in the synaptic space is taken up by the norepinephrine transporter into the neuron that released it, and approximately 20 percent spills over into the circulation.”
The paper relies on this without support.
Norepinephrine taken up by the neuron that released it is preferentially converted to DHPG by monoamine oxidase; some is repackaged into synaptic vesicles.
“Norepinephrine taken up by the neuron that released it is preferentially converted to dihydroxyphenylglycol (DHPG) by monoamine oxidase; some is repackaged into the synaptic vesicles.”
The paper relies on this without support.
DHPG diffuses out of the neuron into the circulation.
“DHPG diffuses out of the neuron into the circulation.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Many patients with POTS have increased sympathetic nervous system tone measured with direct nerve recordings 5 or biochemically with an elevated plasma norepinephrine on standing 6–8.”
From Propranolol Decreases Tachycardia and Improves Symptoms in the Postural Tachycardia Syndrome: Less Is More (2009) · cites this paper as [8]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“With 1 notable exception of a particular mutation causing POTS in members of a single family, 37 no evidence supports a monogenic cause of POTS.”
From Diagnosis and management of postural orthostatic tachycardia syndrome (2022) · cites this paper as [37]
Experimental — accuracy not yet measuredIn the citing paper
“A very rare form of hyperadrenergic POTS is caused by a loss-of-function mutation in the gene for the norepinephrine transporter (NET) [54].”
From Postural tachycardia syndrome: beyond orthostatic intolerance (2015) · cites this paper as [54]
In the citing paper
“While many conditions, such as mast cell activation disorders (9), Ehlers-Danlos syndrome (10, 11), deconditioning (12), and genetic mutations of norepinephrine transporters (13), coexist with POTS, their downstream effects also funnel into these three principal pathophysiologic mechanisms.”
From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [13]
In the citing paper
“Shannon et al. (13) discovered a single missense mutation (ALA457Pro) in the norepinephrine transporter gene ( SLC6A2 ) that resulted in a 98% loss of function in the transporter and was present in two identical twins with POTS.”
From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [13]
In the citing paper
“Each twin had normal levels of supine plasma norepinephrine (269 pg/ml and 199 pg/ml), but standing plasma norepinephrine exceeded 900 pg/ml.”
From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [13]
In the citing paper
“Alteration of norepinephrine metabolism, congenital or iatrogenic, is another well-described cause of hyperadrenergic POTS.”
From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [13]
In the citing paper
“One of the twins even became hypertensive with standing (13).”
From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [13]
In the citing paper
“In certain cases, it may be possible to recognize key endophenotypes (13, 73, 79).”
From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [13]
In the citing paper
“A loss of function single point mutation in the NET gene SLC6A2 was identified in one family with orthostatic tachycardia”
From Postural tachycardia syndrome – Diagnosis, physiology, and prognosis (2018) · cites this paper as Shannon et al., 2000
In the citing paper
“In a subgroup of these patients, a rare mutation of norepinephrine-transporter gene was found, resulting in reduced synaptic norepinephrine reuptake and excessive sympathetic activation [56].”
From Postural orthostatic tachycardia syndrome: clinical presentation, aetiology and management (2019) · cites this paper as [56]
In the citing paper
“The cardinal diagnostic features of this condition are exaggerated reflex increases in heart rate and plasma NE concentration with standing, 9 attributable in the kindred reported although not in the majority of patients with the condition to the NE transporter fault.”
From Phenotypic Evidence of Faulty Neuronal Norepinephrine Reuptake in Essential Hypertension (2000) · cites this paper as [9]
In the citing paper
“Near-total absence of activity of the neuronal NE transporter was recently reported in a family kindred with the postural tachycardia syndrome, in which a missense mutation of the NE transporter gene has been identified.9”
From Phenotypic Evidence of Faulty Neuronal Norepinephrine Reuptake in Essential Hypertension (2000) · cites this paper as [9]
In the citing paper
“We were encouraged in this line of thinking by the recent description of a missense mutation of the NE transporter gene in a family kindred with the postural tachycardia syndrome 9 in whom the exaggerated reflex increase in heart rate with standing, which is a cardinal feature of the disorder, was due to the NE transporter fault.”
From Phenotypic Evidence of Faulty Neuronal Norepinephrine Reuptake in Essential Hypertension (2000) · cites this paper as [9]
In the citing paper
“The transporter gene mutation recently described in the postural tachycardia syndrome kindred differs from the 5 identified earlier and is associated with almost total absence of transporter activity.9”
From Phenotypic Evidence of Faulty Neuronal Norepinephrine Reuptake in Essential Hypertension (2000) · cites this paper as [9]
In the citing paper
“It should be kept in mind that sinus tachycardia paroxysms may be due to anxiety as in panic disorder44 (epinephrine-mediated), norepinephrine reuptake inhibition45 (a very rare condition; norepinephrine-mediated) or drug intake (e.g. beta-agonists in asthma).”
From Sinus Tachycardia: a Multidisciplinary Expert Focused Review (2022) · cites this paper as [45]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Results
“12 vs. 56±63 pg per milliliter”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Response to Tyramine
“the mean plasma norepinephrine concentration increased by 56 ±21 pg per milliliter”
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Segregation of the Ala457Pro Mutation with a Phenotype
“The mother and four siblings (including the twin sister) were heterozygous for the mutant allele (Fig. 2E).”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > DISCUSSION
“the proband and nine family members (three family members with the Ala457Pro mutation and six with the normal genotype)”
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Results
“0.33± 0.37 pmol per liter”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Response to Tyramine
“0.33±0.12 nmol per liter”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
“norepinephrine clearance in the proband was less than half that in the normal subjects (1.56 vs. 2.42±0.71liters per minute)”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Spillover and Clearance of Systemic Norepinephrine
Reported 0.5 · recomputed 0.644628
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > DISCUSSION
“This change from cytosine to guanine results in a change from alanine to proline at amino acid position 457 (Ala457Pro).”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > T ABLE 1. B LOOD P RESSURE , H EART R ATE , AND P LASMA C ATECHOLAMINE C ONCENTRATIONS IN THE P ROBAND , H ER T WIN S ISTER , AND 10 U
“a missense mutation in which guanine was replaced by cytosine at position 237 (G237C)”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Response to Tyramine
“increased the plasma norepinephrine concentration by only 12 pg per milliliter (0.07 nmol per milliliter)”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Identification of a Functional Missense Mutation in the Norepinephrine-Transporter Gene
“To convert values for plasma norepinephrine to nanomoles per liter, multiply by 0.005911.”
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“Baroreflex dysfunction in the presence of residual sympathetic outflow may be partially responsible (Shannon et al, 2000b).”
BackgroundNausea and Vomiting Related to Autonomic Nervous System Disorders
Abell, T. L., & Parajuli, D. (2016) · Springer eBooks · doi:10.1007/978-3-319-34076-0_7 · Cited by 7
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Self-citationThe pathophysiology of chronic fatigue syndrome in adolescents
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“Postviral onset [16], association with autoimmune disorders [17, 18], and genetic causes [19, 20] have been implicated.”
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“For example, the pathogenesis of POTS mainly involves high catecholamine status,([11]) overexcitement of sympathetic activity,([27]) low central blood volume,([23,28]) and excessive vasodilation.”
BackgroundSyncope: An Evidence-Based Approach
Iwai, S. (2013) · Springer eBooks · doi:10.1007/978-1-4471-4441-0_40 · Cited by 5
The incidence of postural orthostatic tachycardia syndrome in the population of Zagreb, Croatia
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“The increase in NE may be caused by a reduced clearance of synaptic NE due to the NE transporter deficiency, however this pathophysiological mechanism has been genetically confirmed in only one family (26).”
Arterial hypertension in the elderly
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“Dysfunction of NE clearance or altered NET density has been associated with attention deficit, depression, and cardiovascular disorders (Esler et al., 1981; Hadley et al., 1995; Klimek et al., 1997; Merlet et al., 1992; Shannon et al., 2000).”
BackgroundAtomoxetine-induced hyperadrenergic postural tachycardia syndrome: a case report
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“[3] reported that the loss of function of the SLC6A2 (noradrenaline transporter) gene could be the cause of hyperadrenergic POTS.”
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“However, for a minority of patients, alterations to the norepinephrine transporter or autoantibodies to adrenergic receptors may cause primary hyperadrenergic POTS [55].”
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The genetic landscape of pediatric postural orthostatic tachycardia syndrome
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“Genetic defects in a norepinephrine transporter gene manifests a phenotype with many overlapping clinical features with orthostatic intolerance, and blocking this transporter with reboxetine reproduced many orthostatic intolerance symptoms and signs in normal subjects [112,113].”
BackgroundThe postural tachycardia syndrome: When to consider it in adolescents
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“The most striking evidence for the important role of NETs in humans is the recent identification of a coding mutation in a proband with disrupted NE homeostasis.(17) The proband with profound orthostatic intolerance is found to be heterozygous for the mutation that results in diminished NET activity.”
InfluentialVerschure, D. O., Baas, F., van Eck‐Smit, B. L. F., Somsen, G. A., & Verberne, H. J. (2016) · Journal of Nuclear Cardiology · doi:10.1007/s12350-016-0722-x · Cited by 4
“In a familial form of idiopathic POTS a SNP of the SLC6A2 gene in exon 9 that resulted in loss of function of theNETwas associatedwith increased NE plasma levels and increased heart rate.(10,11) The cardiac sympathetic system is one of the neurohormonal compensation mechanisms that plays an important role in the patho…”
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“7 DISCUSSION 8 Being a key regulator of 5-HT neurotransmission, SERT stands out as the only 9 monoamine transporter for which no loss-of-function missense mutation has been 10 linked to diseased states (37, 53, 60-62).”
BackgroundSelf-citationNeurocardiogenic Syncope: Mechanisms, Evaluation and Treatment
Eltahawy, E. A., & Grubb, B. P. (2006) · Future Cardiology · doi:10.2217/14796678.2.3.325 · Cited by 3
“A landmark study by Shannon and colleagues has identified the exact genes responsible for this subgroup in one family with a number of severely affected members [72].”
BackgroundYuan, P., Lian, Z., Wang, Y., Zhang, C., Jin, H., Du, J., Huang, Y., & Liao, Y. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1280172 · Cited by 3
[Vasovagal syncope: from genetic to bedside].
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Perioperative care of an adolescent with postural orthostatic tachycardia syndrome
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“[6] Various other names have been given to this syndrome including chronic orthostatic intolerance, hyperadrenergic orthostatic tachycardia, familial orthostatic tachycardia, and orthostatic intolerance syndrome.[7] The diagnosis is made based on the development of the classic signs and symptoms and by the demonstrati…”
BackgroundResultInfluentialBeyond postural tachycardia syndrome
Mustafa, H. I., & Robertson, D. (2010) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.2009.180620 · Cited by 2
Self-citationNeurovegetative Regulation of the Vascular System
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Regulation of the Norepinephrine Transporter by Endothelins
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New indices from microneurography to investigate the arterial baroreflex
Laurin, A., Lloyd, M. G., Hachiya, T., Saito, M., Claydon, V. E., & Blaber, A. P. (2017) · Physiological Reports · doi:10.14814/phy2.13220 · Cited by 3
“Interestingly, although previous research has shown norepinephrine transporter deficiency associated with orthostatic intolerance (Jacob et al. 1999; Shannon et al. 2000), we did not detect a significant difference in response time between groups at baseline.”
ResultHarnish, P. R., Shastri, P., & Grubb, B. P. (2021) · Journal of Innovations in Cardiac Rhythm Management · doi:10.19102/icrm.2021.120503 · Cited by 3
&NA; (2006) · Obstetric Anesthesia Digest · doi:10.1097/00132582-200612000-00053 · Cited by 3
Orthostatic Hypotension and Orthostatic Intolerance
Mathias, C. J., & Galizia, G. (2010) · Elsevier eBooks · doi:10.1016/b978-1-4160-5583-9.00113-1 · Cited by 3
Vance, A. L. A., Costin, J., & Maruff, P. T. (2002) · European Child & Adolescent Psychiatry · doi:10.1007/s007870200004 · Cited by 3
The Postural Tachycardia Syndrome: Etiology, Diagnosis and Treatment
Grubb, B. P. (2002) · Springer eBooks · doi:10.1007/978-88-470-2103-7_7 · Cited by 3
Deolalikar, S., Neeraj, Pannu, A., & Pandian, J. D. (2019) · CHRISMED Journal of Health and Research · doi:10.4103/cjhr.cjhr_81_18 · Cited by 3
Therapeutic strategies for orthostatic intolerance:
Kára, T., & Somers, V. K. (2002) · The American Journal of Medicine · doi:10.1016/s0002-9343(02)01071-9 · Cited by 3
Complex breathlessness in postural tachycardia syndrome and autonomic dysfunction
Gall, N. P., & Reilly, C. C. (2022) · European Respiratory Society eBooks · doi:10.1183/2312508x.10013621 · Cited by 2
Unusual cause of acquired brain injury
Pande, S. D., Tan, J. H., & Lee, S. (2011) · BMJ Case Reports · doi:10.1136/bcr.01.2011.3715 · Cited by 2
“Literature reveals other descriptions for this condition such as soldier’s heart, neurocirculatory asthenia and MV prolapse syndrome.”
BackgroundEffects of Reboxetine on Sympathetic Neuroeffector Transmission in Rabbit Carotid Artery
Rasmussen, L. E., & Nedergaard, O. A. (2003) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.103.052233 · Cited by 2
“Observations in a family with a genetic form of orthostatic intolerance suggest that impairment in norepinephrine clearance can result from NET dysfunction (Shannon et al., 2000).”
BackgroundOrthostatic Intolerance Syndrome
Ahn, M. (2016) · International Journal of Arrhythmia · doi:10.18501/arrhythmia.2016.014 · Cited by 2
Chapter 8 Suspension Trauma and Fall-Arrest Harness Design
Hsiao, H. (2016) · Human factors and ergonomics · doi:10.1201/9781315373744-9 · Cited by 2
Mathias, C. J., & Freeman, R. L. (2003) · Elsevier eBooks · doi:10.1016/b978-012125831-3/50298-7 · Cited by 2
Go, S., Takahashi, R., Suzuki, S., Kasuga, A., Morıchı, S., Ishida, Y., Yamanaka, G., Kashiwagi, Y., & Kawashima, H. (2020) · Clinical Autonomic Research · doi:10.1007/s10286-020-00701-5 · Cited by 2
Diagnostic et traitement du syndrome de tachycardie orthostatique posturale
Raj, S. R., Fedorowski, A., & Sheldon, R. S. (2022) · Canadian Medical Association Journal · doi:10.1503/cmaj.211373-f · Cited by 1
Waheed, W., & Holmes, G. L. (2024) · Pediatric Neurology · doi:10.1016/j.pediatrneurol.2024.09.025 · Cited by 2
Examinations in Suspected Vasovagal Syncope
Vecchia, L. A. D., Barbic, F., Furlan, R., & Alboni, P. (2014) · Springer eBooks · doi:10.1007/978-3-319-09102-0_12 · Cited by 3
Thermodynamic first law efficiency of membrane proteins
Gür, M., Gölcük, M., Yilmaz, S. Z., & Taka, E. (2019) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2019.1577759 · Cited by 2
“…depression (Andersen, Kristensen, Bang-Andersen, & Stromgaard, 2009; Schafer, 1999), anxiety (Clausen et al., 2006; Hahn & Blakely, 2002), attention-deficit hyperactivity disorder (Waldman et al., 1998), orthostatic intolerance (Shannon et al., 2000) and Parkinson disease (Hahn & Blakely, 2002).”
BackgroundUpdate on Recent Developments in the Study of Disorders of Orthostatic Intolerance
Grubb, B. P., & KOSINSKI, D. J. (2001) · Cardiac Electrophysiology Review · doi:10.1023/a:1013266402646 · Cited by 2
“In a recent publication, Shannon et al. [ 9 ] demonstrated this disorder is likely due to a genetic or acquired defect in norepinephrine transporter gene.”
BackgroundGonzález-Hermosillo, A., Márquez, M. F., Kostine, A., Jáuregui‐Renaud, K., & Cárdenas, M. (2004) · Springer eBooks · doi:10.1007/978-88-470-2137-2_81 · Cited by 2
Turakhia, M. P., Grubb, B. P., & Gregoratos, G. (2008) · Journal of Hospital Medicine · doi:10.1002/jhm.344 · Cited by 2
Brown, C. R., & Foster, J. D. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.03.22.586171 · Cited by 2
Orthostatic Tachycardia-Hypotensive Syndrome: A Novel Form of Orthostatic Intolerance in the Young
Numan, M. T., El‐Dokla, A., & Butler, I. J. (2025) · Pediatric Cardiology · doi:10.1007/s00246-025-03948-9 · Cited by 1
“We hypothesize that POTS, OTHS, and NCS are inter-related conditions within a spectrum of disorders characterized by dysregulation of the baroreflex-mediated sympathetic nervous system and parasympathetic withdrawal at the neurocardiovascular interface [5, 13–20].”
Heart rate variability analysis in postural orthostatic tachycardia syndrome: a case report
Russo, V., Crescenzo, I. D., Ammendola, E., Pagano, C., Savarese, C., Santangelo, L., & Calabrò, R. (2006) · Heart International · doi:10.4081/hi.2006.126 · Cited by 1
“Impairment of synaptic norepinephrine clearance could produce a state of excessive sympathetic activation in response to physiologic stimuli (9).”
BackgroundMonoamine Transporters in the Brain
Sitte, H. H., & Freissmuth, M. (2007) · Springer eBooks · doi:10.1007/978-0-387-30380-2_17 · Cited by 1
von Scheidt, W. (2009) · Elsevier eBooks · doi:10.1016/b978-3-437-42831-9.10009-9 · Cited by 1
Orthostatic Intolerance: Postural Tachycardia Syndrome
Park, K. (2009) · Annals of Clinical Neurophysiology · Cited by 1
Miller, S. M., Moos, W. H., Munk, B. H., & Munk, S. A. (2016) · Elsevier eBooks · doi:10.1016/b978-0-08-100625-2.00011-8 · Cited by 1
Antidepressant-Sensitive Norepinephrine Transporters
Hahn, M. K. (2011) · Elsevier eBooks · doi:10.1016/b978-0-12-386525-0.00008-1 · Cited by 1
Dizziness and Vertigo in the Adolescent
Goodkin, H. P., Taylor, J. W., & Ramirez‐Montealegre, D. (2018) · Elsevier eBooks · doi:10.1016/b978-0-323-55136-6.00006-x · Cited by 1
Liang, H., Chen, L., Chen, L., Fang, J., Yi, Y., Gao, Y., Huang, X., Chen, X., Liu, T., Pan, W., et al. (2025) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2025.1576740 · Cited by 1
“…and plasma renin activity (PRA) in patients with POTS were consistent with those of healthy individuals, POTS patients exhibit a signi fi cant reduction in norepinephrine transporter (NET) protein in peripheral sympathetic nerves and impaired synaptic norepinephrine clearance (26, 27).”
Familial Vasovagal Syncope: Clinical Characteristics and Potential Genetic Substrates
González-Hermosillo, A., Márquez, M. F., Vallejo, M., et al. (2006) · Springer eBooks · doi:10.1007/88-470-0371-7_87 · Cited by 1
“Recently, a missense mutation (converting alanine to proline) in the human NE transporter (NET) gene A457P, located on chromosome 16q12.2, was identified in an individual and her identical twin suffering from POTS [ 13 ].”
BackgroundDifferential Diagnosis of Vasovagal Syncope: Postural Orthostatic Tachycardia
Garland, E. M., & Raj, S. R. (2014) · Springer eBooks · doi:10.1007/978-3-319-09102-0_14 · Cited by 1
Síndrome de taquicardia postural ortostática
Guijarro, J. B., Ponce, M. A. D., Foncubierta, A., Pedrote, A. A., Barroso, R. C., & López, R. Á. (2009) · Revista Española de Geriatría y Gerontología · doi:10.1016/j.regg.2009.06.003 · Cited by 1
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Molecular cloning and functional expression of the murine noradrenaline transporter
Muck, A., Gilsbach, R., Löbbe-Werner, S., et al. (2007) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-007-0181-7 · Cited by 1
“2000), orthostatic intolerance (Hahn et al. 2003; Paczkowski et al. 2002; Shannon et al. 2000), depression (Borowsky and Hoffman 1995; Stöber et al.”
BackgroundHereditary dysautonomias: current knowledge and collaborations for the future
Cuajungco, M. P., Ando, Y., Axelrod, F. B., Biaggioni, I., Goldstein, D. S., Guttmacher, A. E., Gwinn, K. A., Hahn, M. K., Hilz, M. J., Jacob, G., et al. (2003) · Clinical Autonomic Research · doi:10.1007/s10286-003-0098-2 · Cited by 1
“They have observed that PAF sufferers have SNS-independent hypertension, but MSA patients have SNS-dependent hypertension.”
BackgroundInfluentialSelf-citationA Case with Postural Tachycardia Syndrome.
Aoki, M., Ando, K., Miyazaki, T., Miyazaki, T., Nishihori, T., & Ito, Y. (2000) · Equilibrium Research · doi:10.3757/jser.59.593 · Cited by 1
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Scintigraphie cardiaque à la 123I-métaiodobenzylguanidine et cardiomyopathies : « le retour »
Agostini, D., Manrique, A., Hugentobler, A., Sabatier, R., Belin, A., Costo, S., Grollier, G., & Bouvard, G. (2007) · Médecine Nucléaire · doi:10.1016/j.mednuc.2007.07.003 · Cited by 1
Neuropathic Postural Tachycardia Syndrome
Low, P. A. (2004) · Elsevier eBooks · doi:10.1016/b978-012589762-4/50093-1 · Cited by 1
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Norepinephrine transporter function and tolerance to hypergravitational stress: A pilot study
Schroeder, C., Strempel, S., Boese, A., Hemmersbach, R., Tank, J., Luft, F. C., & Jordan, J. (2008) · Acta Astronautica · doi:10.1016/j.actaastro.2007.11.002 · Cited by 1
“Familial NET dysfunction is associated with orthostatic tachycardia [ 2 ].”
BackgroundSelf-citationChronische arterielle Hypotension
von Scheidt, W. (2000) · Springer eBooks · doi:10.1007/978-3-662-12156-6_39 · Cited by 1
Esler, M., Lambert, G. W., Thompson, J. M., Kaye, D. M., Hastings, J., Schwarz, R., Alvarenga, M. E., Richards, J., & Morris, M. J. (2004) · Elsevier eBooks · doi:10.1016/b978-012589762-4/50107-9 · Cited by 1
Lecheler, L., Hoffmann, F., Tank, J., & Jordan, J. (2021) · Hypertension · doi:10.1161/hypertensionaha.121.16578 · Cited by 1
Self-citationAutonomic Nervous System: General Overview
Keller, N. R., & Robertson, D. (2009) · Elsevier eBooks · doi:10.1016/b978-008045046-9.01508-4 · Cited by 1
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Familial Orthostatic Tachycardia due to Norepinephrine Transporter (SLC6A2) Deficiency
Hahn, M. K., Mazei‐Robison, M. S., Flattem, N. L., Shannon, J. R., Blakely, R., & Robertson, D. (2002) · Advances in behavioral biology · doi:10.1007/978-1-4757-3538-3_119 · Cited by 1
Self-citationMonoamine Transporter Pathologies
Sealover, N. R., & Barker, E. L. (2010) · Advances in neurobiology · doi:10.1007/978-1-4419-7104-3_6
“The hNET SNP A457P was discovered in a familial form of orthostatic intolerance (Hahn et al., 2003; Shannon et al., 2000).”
Background
Metadata
- Authors
- Shannon, J. R., Flattem, N. L., Jordan, J., Jacob, G., Black, B. K., Biaggioni, I., Blakely, R. D., & Robertson, D.
- Affiliations
- Vanderbilt University (US)
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2000-02-24
- Volume
- 342
- Issue
- 8
- Pages
- 541-549
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2133465432
- Cited by
- 594
- References
- 34
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 14 · 2023: 9 · 2022: 17 · 2021: 13 · 2020: 22 · 2019: 17 · 2018: 18 · 2017: 15 · 2016: 22 · 2015: 11 · 2014: 15 · 2013: 23 · 2012: 16
- FWCI
- 49.25
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (P01HL056693)
- National Institute of Mental Health (MH 58921, R01MH058921)
- National Center for Research Resources (RR00095)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Syncope and Autonomic Disorders
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- orthostatic intolerance, postural orthostatic tachycardia syndrome, norepinephrine transporter, plasma norepinephrine, norepinephrine clearance, hyperadrenergic state, sympathetic hyperactivity, plasma catecholamines, dihydroxyphenylglycol, loss-of-function mutations
- MeSH terms
- Adult, Amino Acid Sequence, Base Sequence, Blood Pressure, Carrier Proteins, Female, Heart Rate, Humans, Male, Methoxyhydroxyphenylglycol, Molecular Sequence Data, Norepinephrine, Pedigree, Posture, Syncope, Tachycardia, Sequence Homology, Amino Acid, Mutation, Missense, Symporters, Norepinephrine Plasma Membrane Transport Proteins
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