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Cited by 595Cardiovascular Syncope and Autonomic DisordersHeart Rate Variability and Autonomic ControlCardiac electrophysiology and arrhythmias

Orthostatic Intolerance and Tachycardia Associated with Norepinephrine-Transporter Deficiency

Open access
Shannon, John R., Flattem, Nancy L., Jordan, Jens, Jacob, Giris, Black, Bonnie K., Biaggioni, Italo, Blakely, Randy D., Robertson, David·2000·New England Journal of Medicine
DOI 10.1056/nejm200002243420803
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Abstract

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.

AI snapshot

Written from the paper’s full text.

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.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1056/nejm200002243420803

Cites

35 of 35 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

2 of 19 cited sources checked · 1 supported · 0 flagged · accuracy not yet measured

  • Interpretationreasoning

    A deficiency of the norepinephrine transporter may explain several clinical findings in patients with orthostatic intolerance.

    “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”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [13] Jacob G, 1999, Circulation source
    • cites [27] Furlan R, 1998, Circulation source

      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)

      Experimental — accuracy not yet measured
  • Findingown data

    Norepinephrine clearance did not change appreciably after nitroprusside infusion in either the proband (1.76 L/min) or normal subjects (2.31±0.68 L/min).

    “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).”
    Quote in the paperSubstantial claim
  • Findingown data

    In the proband and her twin, plasma concentrations of dihydroxyphenylglycol were low in relation to plasma norepinephrine concentrations (ratio supine 3.06 and 2.41 vs 5.52 normal; upright 1.05 and 1.17 vs 3.44 normal).

    “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”
    Quote in the paperSubstantial claim
  • Findingown data

    Direct sequence analysis of the norepinephrine-transporter gene in the proband revealed no divergence from previously published sequences in exons 1 through 8 and exons 10 through 15.

    “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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [14] source
    • cites [18] source
  • Findingown data

    The proband and her identical twin both had symptoms typical of orthostatic intolerance.

    “We evaluated a patient and her identical twin, both of whom had symptoms typical of orthostatic intolerance”
    Quote in the paperSubstantial claim
  • May combine two claims. 11
  • Classified as probably not a substantial claim. 2

  • May combine two claims.

    Premisecitation

    Dihydroxyphenylglycol enters the circulation and can serve as a marker of norepinephrine uptake and monoamine oxidase activity.

    “The dihydroxyphenylglycol then enters the circulation and can serve as a marker of norepinephrine uptake and monoamine oxidase activity 9 (Fig. 4).”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Findingown data

    In normal subjects, 3 mg tyramine increased mean systolic blood pressure by 19±2 mm Hg and mean plasma norepinephrine concentration by 56±21 pg/mL.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The proband and her twin had normal autonomic reflexes, but their blood pressure and heart rate were variable.

    “The proband and her twin sister had normal autonomic reflexes, but their blood pressure and heart rate were variable (Fig. 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Heart rates while supine were slightly but not significantly greater in heterozygous family members than in wild-type family members, but heart rates while standing were significantly higher.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Plasma norepinephrine concentrations in the supine position were somewhat higher and in the upright position were significantly higher in heterozygous family members than in those with the normal genotype.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    The Ala457Pro mutation segregates with altered heart-rate regulation and altered norepinephrine metabolism.

    “In contrast, the Ala457Pro mutation renders the transporter nonfunctional and segregates with altered heart-rate regulation and altered norepinephrine metabolism.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In Chinese-hamster-ovary cells 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, uptake was 2 percent or less.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Approximately 80 to 90 percent of the norepinephrine released into many synapses is cleared by uptake into the neuron by the norepinephrine transporter, and the remaining 10 to 20 percent spills over into the circulation or extraneuronal tissue.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Esler M, 1990, Physiol Rev source

  • May combine two claims.

    Interpretationreasoning

    In persons with norepinephrine-transporter deficiency, reduced DHPG concentration in the neuron results in lower plasma DHPG concentrations and a lower-than-normal ratio of plasma DHPG to plasma norepinephrine.

    “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.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: DHPG diffuses out of the neuron into the circulation.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    All samples of genomic DNA were coded before genotype analysis in order to preserve the anonymity of the subjects.

    “All samples of genomic DNA were coded before genotype analysis in order to preserve the anonymity of the subjects.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationcitation

    One would expect a decrease in sympathetic tone with a deficiency of the norepinephrine transporter.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    In persons with norepinephrine-transporter deficiency, the release of norepinephrine into the synaptic space is normal, but because of decreased transporter activity, less than 80 percent of norepinephrine is taken up into the neuron that released it, so spillover into the circulation is greater than 20 percent.

    “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.”
    Quote in the paperSubstantial claim
    • 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.

  • May combine two claims.

    Interpretationreasoning

    The substitution of proline disrupts alpha-helical secondary structures supported by alanine residues, so the Ala457Pro mutation may disrupt norepinephrine transport.

    “Because the substitution of proline disrupts alpha-helical secondary structures that are supported by alanine residues, this mutation may disrupt the transport of norepinephrine.”
    Quote in the paperSubstantial claim
13 of 13

  • 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.”
5 of 5

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?

  • Many POTS patients have increased sympathetic nervous system tone, measured by direct nerve recordings or elevated standing plasma norepinephrine.

    “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]

    The Results report elevated standing plasma norepinephrine in the proband, and the Discussion says central sympathetic tone seems increased in many patients with orthostatic intolerance. But the paper does not establish elevated standing norepinephrine as a measure of increased sympathetic outflow in many POTS patients; its clearance analysis shows that reduced norepinephrine removal contributed to the proband’s elevated level. The direct-nerve-recording portion is attached to a different citation in the citing sentence. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • With one notable exception of a particular mutation causing POTS in members of a single family, no evidence supports a monogenic cause of POTS.

    “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]

    The Segregation section identifies the Ala457Pro mutation in the proband’s family and associates it with elevated standing heart rates. But the Discussion says other genetic or environmental factors contributed to the full syndrome in the two affected women; it does not establish the mutation as a sole, monogenic cause. The citation is attached to the family-mutation exception, not the sentence’s broader claim about other causes of POTS. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • A very rare form of hyperadrenergic POTS is caused by a loss-of-function mutation in the gene for the norepinephrine transporter (NET).

    “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]

  • Many conditions such as mast cell activation disorders, Ehlers-Danlos syndrome, deconditioning, and genetic mutations of norepinephrine transporters coexist with POTS, and their downstream effects funnel into the three principal pathophysiologic mechanisms.

    “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]

  • Shannon et al. 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.

    “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]

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.

  • Tyramine-response variability differs between sections

    Major

    The abstract gives the normal subjects' plasma norepinephrine response as 56±63 pg per milliliter, whereas the Results give 56±21 pg per milliliter for the same response.

  • Family mutation counts disagree

    Major

    The Results identify the mother and four siblings as mutation carriers, but Figure 3 describes only three mutation-carrying family members among the nine relatives assessed, with six assigned the normal genotype.

  • Abstract uses the wrong concentration unit for the tyramine response

    Major

    For the normal subjects' tyramine response, the abstract reports 0.33 pmol per liter, while the Results report 0.33 nmol per liter. Those units differ by a factor of 1,000.

  • Reported clearance is not less than half the comparison value

    Minor

    The proband's clearance of 1.56 liters per minute is about 64% of the normal-subject mean of 2.42 liters per minute, not less than half.

    Reported 0.5 · recomputed 0.644628

  • Mutation direction reverses in the Figure 2 caption

    Minor

    The Results describe a guanine-to-cytosine substitution at position 237, but the figure caption calls it a cytosine-to-guanine change.

  • Proband's tyramine-response conversion uses milliliters instead of liters

    Minor

    The Results express the proband's 12-pg-per-milliliter increase as 0.07 nmol per milliliter, but the paper's stated conversion factor yields approximately 0.07 nmol per liter.

6 of 6

Cites

Flagged first, then by citations

Research works printed but not linked: 6

  1. Low PA, 1995, Neurology, 45, S19
  2. Apparsundaram S, 1998, J Pharmacol Exp Ther, 287, 733
  3. Davis D, 1987, Circ Res, 61, I87
  4. Tung CS, 1983, J Pharmacol Exp Ther, 227, 484
  5. Esler MD, 1991, Am J Physiol, 260, R817
  6. Shannon JR, 1998, Circulation, 98, I

Cited by

Sorted by citations

Related

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)
ORCID
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
DOI
10.1056/nejm200002243420803
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
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 › Surgery › 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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