Paroxysmal Extreme Pain Disorder

👪

Inheritance

1

Autosomal dominant HP:0000006

PEPD segregates as an autosomal dominant trait; affected individuals are heterozygous for a gain-of-function SCN9A missense variant, and the international series ascertained 77 affected individuals across 15 families.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:17679678 SUPPORT Human Clinical

"To describe the clinical phenotype of paroxysmal extreme pain disorder (previously called familial rectal pain syndrome), an autosomal dominant condition recently shown to be a sodium channelopathy involving SCN9A."

States the inheritance mode and the causative gene for the disorder in the defining international clinical series.

PMID:20301342 SUPPORT Human Clinical

"SCN9A neuropathic pain syndromes are inherited in an autosomal dominant manner. Each child of an individual with an NPS-causing variant in SCN9A has a 50% chance of inheriting the variant."

GeneReviews GENETIC COUNSELING section, giving the transmission risk used in counselling. Completes the mining of this chapter, whose other three sections are already cited on the phenotype, diagnosis and treatment blocks.

◈

Mechanistic Hypotheses

1

PEPD and inherited erythromelalgia as a biophysical continuum

pepd_iem_continuum EMERGING

Evidence balance 1 support

The two syndromes are conventionally treated as non-overlapping, defined by impaired inactivation (PEPD) versus enhanced activation (IEM). A variant has been reported that produces both defects in the same channel and a mixed clinical phenotype, arguing that PEPD and IEM are ends of a physiological continuum rather than discrete entities. If correct, the clinical separation is a consequence of which biophysical parameter a given variant perturbs most strongly, not of two distinct disease mechanisms — and mixed phenotypes should be curated as such rather than forced into one syndrome.

Show evidence (1 reference)

PMID:18945915 SUPPORT In Vitro

"These observations indicate that IEM and PEPD mutants are part of a physiological continuum that can produce a continuum of clinical phenotypes."

States the continuum hypothesis and the single-variant evidence on which it rests.

⚙

Pathophysiology

5

SCN9A Missense Variant Impairing Nav1.7 Fast Inactivation

A heterozygous missense variant in SCN9A alters residues governing fast inactivation of Nav1.7. Eight such variants were identified across 11 families and two sporadic cases in the founding genetic study. The lesion is mechanistically specific: it is not a generic gain of function but a selective failure of the channel to close after opening, which is what separates PEPD from the allelic erythromelalgia variants that instead shift the activation threshold.

nociceptor CL:0000198

voltage-gated sodium channel activity GO:0005248 ⇑ GAIN OF FUNCTION

Downstream

Persistent Non-Inactivating Nav1.7 Sodium Current The variant channel fails to inactivate fully, so a fraction of the sodium current persists after depolarization.

Show evidence (1 reference)

PMID:17145499 SUPPORT Human Clinical

"A genome-wide linkage search followed by mutational analysis of the candidate gene SCN9A, which encodes hNa(v)1.7, identified eight missense mutations in 11 families and 2 sporadic cases."

Establishes SCN9A missense variation as the causal lesion and quantifies the allelic series in the defining cohort.

Persistent Non-Inactivating Nav1.7 Sodium Current

Patch-clamp analysis of PEPD mutant channels shows reduced fast inactivation and a resulting persistent inward sodium current. Because this current flows during and after depolarization rather than lowering the threshold for depolarization, it produces sustained rather than merely facilitated firing — the biophysical signature that distinguishes PEPD from inherited erythromelalgia and that predicts its selective carbamazepine response.

nociceptor CL:0000198

voltage-gated sodium channel activity GO:0005248 ⇑ GAIN OF FUNCTION

Downstream

Nociceptor and Autonomic Neuron Hyperexcitability Persistent sodium current lowers the threshold for repetitive firing in Nav1.7-expressing sensory and sympathetic neurons.

Show evidence (2 references)

PMID:17145499 SUPPORT In Vitro

"Functional analysis in vitro of three of these mutant Na(v)1.7 channels revealed a reduction in fast inactivation, leading to persistent sodium current."

Direct electrophysiological demonstration of the persistent-current mechanism in PEPD mutant channels.

PMID:18945915 SUPPORT In Vitro

"Na(V)1.7 mutations that impair inactivation produce a different, nonoverlapping syndrome, paroxysmal extreme pain disorder (PEPD), characterized by rectal, periocular, and perimandibular pain."

Confirms impaired inactivation as the PEPD-specific mechanism and ties it to the syndrome's characteristic pain territory.

Nociceptor and Autonomic Neuron Hyperexcitability

Nav1.7 is expressed in sympathetic and trigeminal ganglion neurons as well as in dorsal root ganglion nociceptors, and PEPD variants render both classes hyperexcitable. This dual distribution is what makes PEPD an autonomic as well as a pain disorder, and explains why the autonomic manifestations — flushing, harlequin colour change, bradycardic syncope — dominate the neonatal presentation before the pain paroxysms declare themselves.

nociceptor CL:0000198 autonomic neuron CL:0000107

action potential GO:0001508 ↑ INCREASED

Downstream

Trigger-Evoked Pain Paroxysms Hyperexcitable nociceptors fire in prolonged bursts when their territory is stimulated.

Paroxysmal Sympathetic Dysregulation Hyperexcitable sympathetic neurons produce episodic vasomotor and cardiovagal instability.

Show evidence (2 references)

PMID:18945915 SUPPORT In Vitro

"Using current clamp, we show that A1632E renders dorsal root ganglion (DRG) and trigeminal ganglion neurons hyperexcitable."

Demonstrates that a variant carrying the PEPD impaired-inactivation defect makes both DRG and trigeminal neurons hyperexcitable, matching the disorder's sensory territory.

PMID:14985375 SUPPORT Human Clinical

"SCN9A, encoding a voltage-gated sodium channel alpha subunit predominantly expressed in sensory and sympathetic neurones, may play an important role in nociception and vasomotor regulation."

Establishes the sensory-plus-sympathetic expression pattern that accounts for the combined pain and autonomic output of this node.

Trigger-Evoked Pain Paroxysms

Attacks of excruciating deep burning pain, initially and most characteristically rectal, and later also ocular, submandibular or diffuse. The triggers are stimuli that mechanically or thermally activate the affected territory — defecation, cold wind, eating, and emotion — consistent with a lowered firing threshold rather than with spontaneous discharge alone.

sensory perception of pain GO:0019233 ↑ INCREASED

Downstream

Paroxysmal rectal pain

Ocular pain

Jaw pain

Show evidence (1 reference)

PMID:17679678 SUPPORT Human Clinical

"Later, the disorder is characterized by attacks of excruciating deep burning pain often in the rectal, ocular, or jaw areas, but also diffuse. Attacks are triggered by factors such as defecation, cold wind, eating, and emotion."

Documents the pain phenotype and its trigger profile in the defining 77-patient international series.

Paroxysmal Sympathetic Dysregulation

Episodic autonomic instability that dominates the neonatal and infantile phase: skin flushing in all affected individuals, harlequin (patchy or asymmetric) colour change and tonic non-epileptic attacks in most, and dramatic syncopes with bradycardia that sometimes reach asystole. It is this presentation, not the pain, that most often leads to an initial misdiagnosis of epilepsy, hyperekplexia, or reflex anoxic seizures.

autonomic neuron CL:0000107

Downstream

Flushing

Autonomic dysfunction with harlequin colour change

Syncope with bradycardia

Bradycardia

Tonic non-epileptic attacks

Show evidence (2 references)

PMID:17679678 SUPPORT Human Clinical

"Autonomic manifestations predominate initially, with skin flushing in all and harlequin color change and tonic attacks in most. Dramatic syncopes with bradycardia and sometimes asystole are common."

Establishes the autonomic arm as the presenting phenotype and records the frequency bands used for the individual phenotype entries.

PMID:17679678 SUPPORT Human Clinical

"It is most likely to be misdiagnosed as epilepsy and, particularly in infancy, as hyperekplexia and reflex anoxic seizures."

Documents the diagnostic confusion that follows from the autonomic and tonic-attack presentation.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

8

Cardiovascular 2

Syncope with bradycardia FREQUENT HP:0001279

Temporal: RECURRENT

Show evidence (1 reference)

PMID:17679678 SUPPORT Human Clinical

"Dramatic syncopes with bradycardia and sometimes asystole are common."

Documents syncope with bradycardia as a common manifestation, supporting a FREQUENT band.

Bradycardia HP:0001662

Show evidence (1 reference)

PMID:17679678 SUPPORT Human Clinical

"Dramatic syncopes with bradycardia and sometimes asystole are common."

Directly documents bradycardia, and its progression to asystole, during attacks.

Integument 1

Flushing OBLIGATE HP:0031284

Show evidence (1 reference)

PMID:17679678 SUPPORT Human Clinical

"Autonomic manifestations predominate initially, with skin flushing in all and harlequin color change and tonic attacks in most."

Reports skin flushing in all affected individuals in the defining series, directly supporting an OBLIGATE frequency band.

Nervous System 1

Autonomic dysfunction with harlequin colour change FREQUENT Abnormal autonomic nervous system physiology HP:0012332

Show evidence (2 references)

PMID:20301342 SUPPORT Human Clinical

"SCN9A-PEPD is characterized by neonatal or infantile onset of autonomic manifestations that can include skin flushing, harlequin (patchy or asymmetric) color change, tonic non-epileptic attacks (stiffening), and syncope with bradycardia."

GeneReviews lists harlequin colour change among the neonatal autonomic manifestations of PEPD.

PMID:17679678 SUPPORT Human Clinical

"with skin flushing in all and harlequin color change and tonic attacks in most"

Reports harlequin colour change in most affected individuals, supporting a FREQUENT band.

Constitutional 1

Ocular pain HP:0200026

Temporal: RECURRENT

Show evidence (1 reference)

PMID:20301342 SUPPORT Human Clinical

"Later manifestations are episodes of excruciating deep burning rectal, ocular, or submandibular pain accompanied by flushing (erythematous skin changes)."

GeneReviews lists ocular pain among the three characteristic PEPD attack territories.

Other 3

Paroxysmal rectal pain HP:0032150

Temporal: RECURRENT

Show evidence (1 reference)

PMID:17679678 SUPPORT Human Clinical

"Later, the disorder is characterized by attacks of excruciating deep burning pain often in the rectal, ocular, or jaw areas, but also diffuse."

Documents rectal pain as a cardinal, characteristic attack territory in the international series.

Jaw pain HP:0040264

Temporal: RECURRENT

Show evidence (1 reference)

PMID:20301342 SUPPORT Human Clinical

"Later manifestations are episodes of excruciating deep burning rectal, ocular, or submandibular pain accompanied by flushing (erythematous skin changes)."

GeneReviews lists submandibular pain among the three characteristic PEPD attack territories.

Tonic non-epileptic attacks FREQUENT Generalized tonic seizure HP:0010818

HPO has no term for a tonic non-epileptic (pseudo-seizure) attack, so the closest available descriptor, Generalized tonic seizure, is bound here. The cited sources are explicit that these attacks are NOT epileptic; the binding should not be read as asserting epilepsy, and the disorder's most common misdiagnosis is precisely that error.

Show evidence (1 reference)

PMID:20301342 SUPPORT Human Clinical

"tonic non-epileptic attacks (stiffening), and syncope with bradycardia"

GeneReviews records the tonic attacks and explicitly classifies them as non-epileptic, which is why the HP seizure term is used as the closest available descriptor rather than as a claim of epilepsy.

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Genetic Associations

1

SCN9A (Heterozygous gain-of-function missense variants in SCN9A that impair fast inactivation of Nav1.7 cause PEPD. The allelic series is distinct from, and biophysically opposite in mechanism to, the SCN9A variants causing inherited erythromelalgia, which shift activation to more negative potentials.)

Gene: SCN9A hgnc:10597 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:17145499 SUPPORT Human Clinical

"A genome-wide linkage search followed by mutational analysis of the candidate gene SCN9A, which encodes hNa(v)1.7, identified eight missense mutations in 11 families and 2 sporadic cases."

Establishes SCN9A as the causative gene through linkage plus mutational analysis across a 13-kindred cohort.

PMID:17145499 SUPPORT In Vitro

"PEPD and PE are allelic variants with distinct underlying biophysical mechanisms and represent a separate class of peripheral neuronal sodium channelopathy."

Documents the allelic relationship with primary erythermalgia and the distinct biophysical basis that separates the two disorders.

💊

Medical Actions

2

Carbamazepine

Action: Pharmacotherapy NCIT:C15986

Agent: carbamazepine CHEBI:3387

Carbamazepine selectively blocks the persistent sodium current produced by the inactivation-impaired PEPD channels and is effective in almost all patients who try it, although the response is usually incomplete. The selectivity is mechanistic rather than empirical: the same drug does not correct the hyperpolarized activation threshold of erythromelalgia variants and is not effective in that allelic disorder.

Mechanism Target:

INHIBITS Persistent Non-Inactivating Nav1.7 Sodium Current — Selective block of the non-inactivating component of the mutant Nav1.7 current.

Show evidence (1 reference)

PMID:17145499 SUPPORT In Vitro

"Carbamazepine, a drug that is effective in PEPD, but not PE, showed selective block of persistent current associated with PEPD mutants, but did not affect the negative activation threshold of a PE mutant."

Demonstrates the drug acting on precisely the biophysical defect this node encodes, and not on the allelic erythromelalgia defect.

Show evidence (1 reference)

PMID:17679678 SUPPORT Human Clinical

"Carbamazepine is effective in almost all who try it, but the response is often incomplete."

Reports the clinical efficacy and its limits in the defining international series.

Trigger avoidance and stool softeners

Action: Supportive Care NCIT:C15747

Non-pharmacological management aimed at the identified triggers: stool softeners and slow passage of stool to reduce rectal attacks, and avoidance of cold wind and other provoking stimuli.

Show evidence (1 reference)

PMID:20301342 SUPPORT Human Clinical

"Use of stool softeners and passing stool slowly to reduce the likelihood of triggering an attack."

GeneReviews recommends this trigger-avoidance strategy for PEPD specifically.

🔬

Diagnosis

1

Molecular genetic testing of SCN9A

Diagnosis is established by identifying a heterozygous pathogenic SCN9A variant in a proband with the characteristic phenotype. Because the neonatal presentation is autonomic rather than painful, testing is often not considered until the pain paroxysms declare themselves years later.

Show evidence (1 reference)

PMID:20301342 SUPPORT Human Clinical

"The diagnosis of SCN9A-NPS is established in a proband with a heterozygous pathogenic variant in SCN9A identified by molecular genetic testing."

GeneReviews states the molecular diagnostic criterion for the SCN9A neuropathic pain syndromes, of which PEPD is one.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Paroxysmal Extreme Pain Disorder:

Primary Erythermalgia

Overlapping Features The allelic SCN9A disorder caused by variants that shift Nav1.7 activation to more negative potentials. Distinguished from PEPD by distal-extremity rather than rectal/ocular/submandibular territory, heat provocation and cooling relief rather than defecation and cold wind, and by its lack of response to carbamazepine.

Show evidence (1 reference)

PMID:18945915 SUPPORT In Vitro

"Na(V)1.7 mutations that enhance activation produce inherited erythromelalgia (IEM), characterized by burning pain in the extremities"

States the biophysical and clinical basis on which the two allelic disorders are separated.

Epilepsy

Overlapping Features The most common misdiagnosis. The tonic non-epileptic attacks and syncopal episodes of infantile PEPD are frequently interpreted as seizures; in infancy hyperekplexia and reflex anoxic seizures are the other common misattributions.

Show evidence (1 reference)

PMID:17679678 SUPPORT Human Clinical

"It is most likely to be misdiagnosed as epilepsy and, particularly in infancy, as hyperekplexia and reflex anoxic seizures."

Names the differential diagnoses directly in the defining clinical series.

{ }

Source YAML

click to show

name: Paroxysmal Extreme Pain Disorder
creation_date: "2026-08-22T00:00:00Z"
description: >-
  Paroxysmal extreme pain disorder (PEPD), formerly called familial rectal pain
  syndrome, is an autosomal dominant sodium channelopathy caused by
  gain-of-function missense variants in SCN9A that impair fast inactivation of
  the nociceptor sodium channel Nav1.7, leaving a persistent (non-inactivating)
  sodium current. It presents in the neonatal period or infancy with autonomic
  manifestations — skin flushing, harlequin (patchy or asymmetric) colour change,
  tonic non-epileptic attacks, and syncope with bradycardia that can progress to
  asystole — and evolves into lifelong paroxysms of excruciating deep burning
  pain in rectal, ocular, and submandibular territory, triggered by defecation,
  cold wind, eating, and emotion. Carbamazepine is effective in almost all
  patients although the response is usually incomplete. PEPD is the
  impaired-inactivation member of the SCN9A neuropathic pain syndromes: it is
  allelic with, but biophysically and clinically distinct from, inherited
  erythromelalgia (hyperpolarized activation, distal-extremity, heat-triggered,
  carbamazepine-unresponsive) and SCN9A small-fibre neuropathy. Its early
  presentation is most often misdiagnosed as epilepsy, hyperekplexia, or reflex
  anoxic seizures.
category: Mendelian
parents:
- Channelopathy
- Peripheral Neuropathy
- hereditary disease
disease_term:
  preferred_term: paroxysmal extreme pain disorder
  term:
    id: MONDO:0008179
    label: paroxysmal extreme pain disorder
references:
- reference: PMID:20301342
  title: "SCN9A Neuropathic Pain Syndromes."
  tags:
  - GeneReviews
- reference: PMID:17679678
  title: "Paroxysmal extreme pain disorder (previously familial rectal pain syndrome)."
inheritance:
- name: Autosomal dominant
  description: >-
    PEPD segregates as an autosomal dominant trait; affected individuals are
    heterozygous for a gain-of-function SCN9A missense variant, and the
    international series ascertained 77 affected individuals across 15 families.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:17679678
    reference_title: "Paroxysmal extreme pain disorder (previously familial rectal pain syndrome)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To describe the clinical phenotype of paroxysmal extreme pain disorder
      (previously called familial rectal pain syndrome), an autosomal dominant
      condition recently shown to be a sodium channelopathy involving SCN9A.
    explanation: >-
      States the inheritance mode and the causative gene for the disorder in the
      defining international clinical series.
  - reference: PMID:20301342
    reference_title: "SCN9A Neuropathic Pain Syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SCN9A neuropathic pain syndromes are inherited in an autosomal dominant
      manner. Each child of an individual with an NPS-causing variant in SCN9A
      has a 50% chance of inheriting the variant.
    explanation: >-
      GeneReviews GENETIC COUNSELING section, giving the transmission risk used
      in counselling. Completes the mining of this chapter, whose other three
      sections are already cited on the phenotype, diagnosis and treatment
      blocks.
pathophysiology:
- name: SCN9A Missense Variant Impairing Nav1.7 Fast Inactivation
  description: >-
    A heterozygous missense variant in SCN9A alters residues governing fast
    inactivation of Nav1.7. Eight such variants were identified across 11
    families and two sporadic cases in the founding genetic study. The lesion is
    mechanistically specific: it is not a generic gain of function but a
    selective failure of the channel to close after opening, which is what
    separates PEPD from the allelic erythromelalgia variants that instead shift
    the activation threshold.
  role: trigger
  biological_scale: MOLECULAR
  conforms_to: "nociceptor_sodium_channel_excitability#Nociceptor Voltage-Gated Sodium Channel Variant"
  cell_types:
  - preferred_term: nociceptor
    term:
      id: CL:0000198
      label: pain receptor cell
  molecular_functions:
  - preferred_term: voltage-gated sodium channel activity
    term:
      id: GO:0005248
      label: voltage-gated sodium channel activity
    modifier: GAIN_OF_FUNCTION
  evidence:
  - reference: PMID:17145499
    reference_title: "SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A genome-wide linkage search followed by mutational analysis of the
      candidate gene SCN9A, which encodes hNa(v)1.7, identified eight missense
      mutations in 11 families and 2 sporadic cases.
    explanation: >-
      Establishes SCN9A missense variation as the causal lesion and quantifies
      the allelic series in the defining cohort.
  downstream:
  - target: Persistent Non-Inactivating Nav1.7 Sodium Current
    description: >-
      The variant channel fails to inactivate fully, so a fraction of the sodium
      current persists after depolarization.

- name: Persistent Non-Inactivating Nav1.7 Sodium Current
  description: >-
    Patch-clamp analysis of PEPD mutant channels shows reduced fast inactivation
    and a resulting persistent inward sodium current. Because this current flows
    during and after depolarization rather than lowering the threshold for
    depolarization, it produces sustained rather than merely facilitated firing —
    the biophysical signature that distinguishes PEPD from inherited
    erythromelalgia and that predicts its selective carbamazepine response.
  role: amplifier
  biological_scale: MOLECULAR
  conforms_to: "nociceptor_sodium_channel_excitability#Enhanced or Persistent Nociceptor Sodium Current"
  cell_types:
  - preferred_term: nociceptor
    term:
      id: CL:0000198
      label: pain receptor cell
  molecular_functions:
  - preferred_term: voltage-gated sodium channel activity
    term:
      id: GO:0005248
      label: voltage-gated sodium channel activity
    modifier: GAIN_OF_FUNCTION
  evidence:
  - reference: PMID:17145499
    reference_title: "SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Functional analysis in vitro of three of these mutant Na(v)1.7 channels
      revealed a reduction in fast inactivation, leading to persistent sodium
      current.
    explanation: >-
      Direct electrophysiological demonstration of the persistent-current
      mechanism in PEPD mutant channels.
  - reference: PMID:18945915
    reference_title: "NaV1.7 gain-of-function mutations as a continuum: A1632E displays physiological changes associated with erythromelalgia and paroxysmal extreme pain disorder mutations and produces symptoms of both disorders."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Na(V)1.7 mutations that impair inactivation produce a different,
      nonoverlapping syndrome, paroxysmal extreme pain disorder (PEPD),
      characterized by rectal, periocular, and perimandibular pain.
    explanation: >-
      Confirms impaired inactivation as the PEPD-specific mechanism and ties it
      to the syndrome's characteristic pain territory.
  downstream:
  - target: Nociceptor and Autonomic Neuron Hyperexcitability
    description: >-
      Persistent sodium current lowers the threshold for repetitive firing in
      Nav1.7-expressing sensory and sympathetic neurons.

- name: Nociceptor and Autonomic Neuron Hyperexcitability
  description: >-
    Nav1.7 is expressed in sympathetic and trigeminal ganglion neurons as well as
    in dorsal root ganglion nociceptors, and PEPD variants render both classes
    hyperexcitable. This dual distribution is what makes PEPD an autonomic as
    well as a pain disorder, and explains why the autonomic manifestations —
    flushing, harlequin colour change, bradycardic syncope — dominate the
    neonatal presentation before the pain paroxysms declare themselves.
  role: central_effector
  biological_scale: CELLULAR
  conforms_to: "nociceptor_sodium_channel_excitability#Nociceptor Action Potential Threshold and Firing"
  cell_types:
  - preferred_term: nociceptor
    term:
      id: CL:0000198
      label: pain receptor cell
  - preferred_term: autonomic neuron
    term:
      id: CL:0000107
      label: autonomic neuron
  biological_processes:
  - preferred_term: action potential
    term:
      id: GO:0001508
      label: action potential
    modifier: INCREASED
  evidence:
  - reference: PMID:18945915
    reference_title: "NaV1.7 gain-of-function mutations as a continuum: A1632E displays physiological changes associated with erythromelalgia and paroxysmal extreme pain disorder mutations and produces symptoms of both disorders."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Using current clamp, we show that A1632E renders dorsal root ganglion (DRG)
      and trigeminal ganglion neurons hyperexcitable.
    explanation: >-
      Demonstrates that a variant carrying the PEPD impaired-inactivation defect
      makes both DRG and trigeminal neurons hyperexcitable, matching the
      disorder's sensory territory.
  - reference: PMID:14985375
    reference_title: "Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SCN9A, encoding a voltage-gated sodium channel alpha subunit predominantly
      expressed in sensory and sympathetic neurones, may play an important role
      in nociception and vasomotor regulation.
    explanation: >-
      Establishes the sensory-plus-sympathetic expression pattern that accounts
      for the combined pain and autonomic output of this node.
  downstream:
  - target: Trigger-Evoked Pain Paroxysms
    description: >-
      Hyperexcitable nociceptors fire in prolonged bursts when their territory is
      stimulated.
  - target: Paroxysmal Sympathetic Dysregulation
    description: >-
      Hyperexcitable sympathetic neurons produce episodic vasomotor and
      cardiovagal instability.

- name: Trigger-Evoked Pain Paroxysms
  description: >-
    Attacks of excruciating deep burning pain, initially and most characteristically
    rectal, and later also ocular, submandibular or diffuse. The triggers are
    stimuli that mechanically or thermally activate the affected territory —
    defecation, cold wind, eating, and emotion — consistent with a lowered firing
    threshold rather than with spontaneous discharge alone.
  role: effector
  biological_scale: ORGANISM
  biological_processes:
  - preferred_term: sensory perception of pain
    term:
      id: GO:0019233
      label: sensory perception of pain
    modifier: INCREASED
  evidence:
  - reference: PMID:17679678
    reference_title: "Paroxysmal extreme pain disorder (previously familial rectal pain syndrome)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Later, the disorder is characterized by attacks of excruciating deep
      burning pain often in the rectal, ocular, or jaw areas, but also diffuse.
      Attacks are triggered by factors such as defecation, cold wind, eating, and
      emotion.
    explanation: >-
      Documents the pain phenotype and its trigger profile in the defining
      77-patient international series.
  downstream:
  - target: Paroxysmal rectal pain
  - target: Ocular pain
  - target: Jaw pain

- name: Paroxysmal Sympathetic Dysregulation
  description: >-
    Episodic autonomic instability that dominates the neonatal and infantile
    phase: skin flushing in all affected individuals, harlequin (patchy or
    asymmetric) colour change and tonic non-epileptic attacks in most, and
    dramatic syncopes with bradycardia that sometimes reach asystole. It is this
    presentation, not the pain, that most often leads to an initial misdiagnosis
    of epilepsy, hyperekplexia, or reflex anoxic seizures.
  role: effector
  biological_scale: ORGANISM
  cell_types:
  - preferred_term: autonomic neuron
    term:
      id: CL:0000107
      label: autonomic neuron
  evidence:
  - reference: PMID:17679678
    reference_title: "Paroxysmal extreme pain disorder (previously familial rectal pain syndrome)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autonomic manifestations predominate initially, with skin flushing in all
      and harlequin color change and tonic attacks in most. Dramatic syncopes
      with bradycardia and sometimes asystole are common.
    explanation: >-
      Establishes the autonomic arm as the presenting phenotype and records the
      frequency bands used for the individual phenotype entries.
  - reference: PMID:17679678
    reference_title: "Paroxysmal extreme pain disorder (previously familial rectal pain syndrome)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is most likely to be misdiagnosed as epilepsy and, particularly in
      infancy, as hyperekplexia and reflex anoxic seizures.
    explanation: >-
      Documents the diagnostic confusion that follows from the autonomic and
      tonic-attack presentation.
  downstream:
  - target: Flushing
  - target: Autonomic dysfunction with harlequin colour change
  - target: Syncope with bradycardia
  - target: Bradycardia
  - target: Tonic non-epileptic attacks

phenotypes:
- name: Paroxysmal rectal pain
  category: Clinical
  description: >-
    Attacks of excruciating deep burning rectal pain, the feature that gave the
    disorder its former name of familial rectal pain syndrome. Typically
    triggered by defecation.
  phenotype_term:
    preferred_term: Paroxysmal rectal pain
    term:
      id: HP:0032150
      label: Paroxysmal rectal pain
    temporality: RECURRENT
  evidence:
  - reference: PMID:17679678
    reference_title: "Paroxysmal extreme pain disorder (previously familial rectal pain syndrome)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Later, the disorder is characterized by attacks of excruciating deep
      burning pain often in the rectal, ocular, or jaw areas, but also diffuse.
    explanation: >-
      Documents rectal pain as a cardinal, characteristic attack territory in the
      international series.
- name: Ocular pain
  category: Clinical
  description: >-
    Periocular attacks of burning pain, one of the three characteristic attack
    territories.
  phenotype_term:
    preferred_term: Ocular pain
    term:
      id: HP:0200026
      label: Ocular pain
    temporality: RECURRENT
  evidence:
  - reference: PMID:20301342
    reference_title: "SCN9A Neuropathic Pain Syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Later manifestations are episodes of excruciating deep burning rectal,
      ocular, or submandibular pain accompanied by flushing (erythematous skin
      changes).
    explanation: >-
      GeneReviews lists ocular pain among the three characteristic PEPD attack
      territories.
- name: Jaw pain
  category: Clinical
  description: >-
    Submandibular or perimandibular attacks of burning pain, often triggered by
    eating.
  phenotype_term:
    preferred_term: Jaw pain
    term:
      id: HP:0040264
      label: Jaw pain
    temporality: RECURRENT
  evidence:
  - reference: PMID:20301342
    reference_title: "SCN9A Neuropathic Pain Syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Later manifestations are episodes of excruciating deep burning rectal,
      ocular, or submandibular pain accompanied by flushing (erythematous skin
      changes).
    explanation: >-
      GeneReviews lists submandibular pain among the three characteristic PEPD
      attack territories.
- name: Flushing
  category: Clinical
  frequency: OBLIGATE
  description: >-
    Erythematous skin flushing, often restricted to the territory of the attack.
    It was present in every affected individual in the 77-patient international
    series, which is the basis for the OBLIGATE frequency band.
  phenotype_term:
    preferred_term: Flushing
    term:
      id: HP:0031284
      label: Flushing
  evidence:
  - reference: PMID:17679678
    reference_title: "Paroxysmal extreme pain disorder (previously familial rectal pain syndrome)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autonomic manifestations predominate initially, with skin flushing in all
      and harlequin color change and tonic attacks in most.
    explanation: >-
      Reports skin flushing in all affected individuals in the defining series,
      directly supporting an OBLIGATE frequency band.
- name: Autonomic dysfunction with harlequin colour change
  category: Clinical
  frequency: FREQUENT
  description: >-
    Harlequin (patchy or asymmetric) colour change of the skin, reflecting
    unilateral sympathetic vasomotor discharge. Present in most affected
    individuals in the international series.
  phenotype_term:
    preferred_term: Abnormal autonomic nervous system physiology
    term:
      id: HP:0012332
      label: Abnormal autonomic nervous system physiology
  evidence:
  - reference: PMID:20301342
    reference_title: "SCN9A Neuropathic Pain Syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SCN9A-PEPD is characterized by neonatal or infantile onset of autonomic
      manifestations that can include skin flushing, harlequin (patchy or
      asymmetric) color change, tonic non-epileptic attacks (stiffening), and
      syncope with bradycardia.
    explanation: >-
      GeneReviews lists harlequin colour change among the neonatal autonomic
      manifestations of PEPD.
  - reference: PMID:17679678
    reference_title: "Paroxysmal extreme pain disorder (previously familial rectal pain syndrome)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      with skin flushing in all and harlequin color change and tonic attacks in
      most
    explanation: >-
      Reports harlequin colour change in most affected individuals, supporting a
      FREQUENT band.
- name: Syncope with bradycardia
  category: Clinical
  frequency: FREQUENT
  description: >-
    Dramatic syncopal episodes accompanied by bradycardia, which in some patients
    progresses to asystole. This is the feature most likely to be mistaken for
    reflex anoxic seizures in infancy.
  phenotype_term:
    preferred_term: Syncope
    term:
      id: HP:0001279
      label: Syncope
    temporality: RECURRENT
  evidence:
  - reference: PMID:17679678
    reference_title: "Paroxysmal extreme pain disorder (previously familial rectal pain syndrome)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dramatic syncopes with bradycardia and sometimes asystole are common.
    explanation: >-
      Documents syncope with bradycardia as a common manifestation, supporting a
      FREQUENT band.
- name: Bradycardia
  category: Clinical
  description: >-
    Cardiovagal slowing accompanying the syncopal episodes, sometimes reaching
    asystole, and reflecting autonomic rather than primary cardiac pathology.
    The sources report it in the context of syncope; they do not separately
    report bradycardia during the pain paroxysms.
  phenotype_term:
    preferred_term: Bradycardia
    term:
      id: HP:0001662
      label: Bradycardia
  evidence:
  - reference: PMID:17679678
    reference_title: "Paroxysmal extreme pain disorder (previously familial rectal pain syndrome)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dramatic syncopes with bradycardia and sometimes asystole are common.
    explanation: >-
      Directly documents bradycardia, and its progression to asystole, during
      attacks.
- name: Tonic non-epileptic attacks
  category: Clinical
  frequency: FREQUENT
  description: >-
    Episodes of tonic stiffening in infancy that are not epileptic in origin.
    Their resemblance to seizures is the main driver of the frequent initial
    misdiagnosis of epilepsy; EEG during attacks does not show ictal change.
  phenotype_term:
    preferred_term: Generalized tonic seizure
    term:
      id: HP:0010818
      label: Generalized tonic seizure
  evidence:
  - reference: PMID:20301342
    reference_title: "SCN9A Neuropathic Pain Syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      tonic non-epileptic attacks (stiffening), and syncope with bradycardia
    explanation: >-
      GeneReviews records the tonic attacks and explicitly classifies them as
      non-epileptic, which is why the HP seizure term is used as the closest
      available descriptor rather than as a claim of epilepsy.
  notes: >-
    HPO has no term for a tonic non-epileptic (pseudo-seizure) attack, so the
    closest available descriptor, Generalized tonic seizure, is bound here. The
    cited sources are explicit that these attacks are NOT epileptic; the binding
    should not be read as asserting epilepsy, and the disorder's most common
    misdiagnosis is precisely that error.

genetic:
- name: SCN9A
  gene_term:
    preferred_term: SCN9A
    term:
      id: hgnc:10597
      label: SCN9A
  relationship_type: CAUSATIVE
  association: >-
    Heterozygous gain-of-function missense variants in SCN9A that impair fast
    inactivation of Nav1.7 cause PEPD. The allelic series is distinct from, and
    biophysically opposite in mechanism to, the SCN9A variants causing inherited
    erythromelalgia, which shift activation to more negative potentials.
  evidence:
  - reference: PMID:17145499
    reference_title: "SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A genome-wide linkage search followed by mutational analysis of the
      candidate gene SCN9A, which encodes hNa(v)1.7, identified eight missense
      mutations in 11 families and 2 sporadic cases.
    explanation: >-
      Establishes SCN9A as the causative gene through linkage plus mutational
      analysis across a 13-kindred cohort.
  - reference: PMID:17145499
    reference_title: "SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      PEPD and PE are allelic variants with distinct underlying biophysical
      mechanisms and represent a separate class of peripheral neuronal sodium
      channelopathy.
    explanation: >-
      Documents the allelic relationship with primary erythermalgia and the
      distinct biophysical basis that separates the two disorders.

diagnosis:
- name: Molecular genetic testing of SCN9A
  description: >-
    Diagnosis is established by identifying a heterozygous pathogenic SCN9A
    variant in a proband with the characteristic phenotype. Because the neonatal
    presentation is autonomic rather than painful, testing is often not
    considered until the pain paroxysms declare themselves years later.
  evidence:
  - reference: PMID:20301342
    reference_title: "SCN9A Neuropathic Pain Syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of SCN9A-NPS is established in a proband with a heterozygous
      pathogenic variant in SCN9A identified by molecular genetic testing.
    explanation: >-
      GeneReviews states the molecular diagnostic criterion for the SCN9A
      neuropathic pain syndromes, of which PEPD is one.

treatments:
- name: Carbamazepine
  description: >-
    Carbamazepine selectively blocks the persistent sodium current produced by
    the inactivation-impaired PEPD channels and is effective in almost all
    patients who try it, although the response is usually incomplete. The
    selectivity is mechanistic rather than empirical: the same drug does not
    correct the hyperpolarized activation threshold of erythromelalgia variants
    and is not effective in that allelic disorder.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: carbamazepine
      term:
        id: CHEBI:3387
        label: carbamazepine
  target_mechanisms:
  - target: Persistent Non-Inactivating Nav1.7 Sodium Current
    treatment_effect: INHIBITS
    description: >-
      Selective block of the non-inactivating component of the mutant Nav1.7
      current.
    evidence:
    - reference: PMID:17145499
      reference_title: "SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Carbamazepine, a drug that is effective in PEPD, but not PE, showed
        selective block of persistent current associated with PEPD mutants, but
        did not affect the negative activation threshold of a PE mutant.
      explanation: >-
        Demonstrates the drug acting on precisely the biophysical defect this
        node encodes, and not on the allelic erythromelalgia defect.
  evidence:
  - reference: PMID:17679678
    reference_title: "Paroxysmal extreme pain disorder (previously familial rectal pain syndrome)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Carbamazepine is effective in almost all who try it, but the response is
      often incomplete.
    explanation: >-
      Reports the clinical efficacy and its limits in the defining international
      series.
- name: Trigger avoidance and stool softeners
  description: >-
    Non-pharmacological management aimed at the identified triggers: stool
    softeners and slow passage of stool to reduce rectal attacks, and avoidance
    of cold wind and other provoking stimuli.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301342
    reference_title: "SCN9A Neuropathic Pain Syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Use of stool softeners and passing stool slowly to reduce the likelihood of
      triggering an attack.
    explanation: >-
      GeneReviews recommends this trigger-avoidance strategy for PEPD
      specifically.

differential_diagnoses:
- name: Primary Erythermalgia
  description: >-
    The allelic SCN9A disorder caused by variants that shift Nav1.7 activation to
    more negative potentials. Distinguished from PEPD by distal-extremity rather
    than rectal/ocular/submandibular territory, heat provocation and cooling
    relief rather than defecation and cold wind, and by its lack of response to
    carbamazepine.
  evidence:
  - reference: PMID:18945915
    reference_title: "NaV1.7 gain-of-function mutations as a continuum: A1632E displays physiological changes associated with erythromelalgia and paroxysmal extreme pain disorder mutations and produces symptoms of both disorders."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Na(V)1.7 mutations that enhance activation produce inherited
      erythromelalgia (IEM), characterized by burning pain in the extremities
    explanation: >-
      States the biophysical and clinical basis on which the two allelic
      disorders are separated.
- name: Epilepsy
  description: >-
    The most common misdiagnosis. The tonic non-epileptic attacks and syncopal
    episodes of infantile PEPD are frequently interpreted as seizures; in infancy
    hyperekplexia and reflex anoxic seizures are the other common
    misattributions.
  evidence:
  - reference: PMID:17679678
    reference_title: "Paroxysmal extreme pain disorder (previously familial rectal pain syndrome)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is most likely to be misdiagnosed as epilepsy and, particularly in
      infancy, as hyperekplexia and reflex anoxic seizures.
    explanation: >-
      Names the differential diagnoses directly in the defining clinical series.

mechanistic_hypotheses:
- hypothesis_group_id: pepd_iem_continuum
  hypothesis_label: PEPD and inherited erythromelalgia as a biophysical continuum
  status: EMERGING
  description: >-
    The two syndromes are conventionally treated as non-overlapping, defined by
    impaired inactivation (PEPD) versus enhanced activation (IEM). A variant has
    been reported that produces both defects in the same channel and a mixed
    clinical phenotype, arguing that PEPD and IEM are ends of a physiological
    continuum rather than discrete entities. If correct, the clinical separation
    is a consequence of which biophysical parameter a given variant perturbs most
    strongly, not of two distinct disease mechanisms — and mixed phenotypes should
    be curated as such rather than forced into one syndrome.
  evidence:
  - reference: PMID:18945915
    reference_title: "NaV1.7 gain-of-function mutations as a continuum: A1632E displays physiological changes associated with erythromelalgia and paroxysmal extreme pain disorder mutations and produces symptoms of both disorders."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These observations indicate that IEM and PEPD mutants are part of a
      physiological continuum that can produce a continuum of clinical
      phenotypes.
    explanation: >-
      States the continuum hypothesis and the single-variant evidence on which it
      rests.

notes: >-
  Frequency bands on the autonomic phenotypes are taken from the 77-patient,
  15-family international series (PMID:17679678), which reports flushing in all
  affected individuals and harlequin colour change and tonic attacks in most.
  Attack-territory phenotypes (rectal, ocular, jaw) carry no frequency band: the
  series reports the territories qualitatively ("often in the rectal, ocular, or
  jaw areas") without per-site counts, so no band is derivable.

  Constipation is deliberately NOT curated as a phenotype. It is clinically
  plausible as avoidance of a known trigger, and stool softeners are recommended
  for PEPD, but no cited source reports constipation in these patients — the
  management recommendation establishes the trigger, not the phenotype.

📚

References & Deep Research

References

2

PMID:20301342

SCN9A Neuropathic Pain Syndromes.

No top-level findings curated for this source.

PMID:17679678

Paroxysmal extreme pain disorder (previously familial rectal pain syndrome).

No top-level findings curated for this source.

Paroxysmal Extreme Pain Disorder

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