Familial_Episodic_Pain_Syndrome_With_Predominantly_Lower_Limb_Involvement

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Inheritance

1

Autosomal dominant HP:0000006

Heterozygous gain-of-function missense variants segregate with the pain phenotype through multiple generations; unaffected relatives do not carry them.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:30549873 SUPPORT Human Clinical

"This unique phenotype was inherited in an autosomal-dominant mode"

States the inheritance mode across six multigenerational Japanese families.

PMID:39058404 SUPPORT Human Clinical

"This variant was confirmed in other affected members but not in the unaffected father"

Segregation in a four-generation pedigree, with the variant absent from the unaffected parent.

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Discussions and Knowledge Gaps

2

What determines whether a gain-of-function SCN11A variant causes episodic pain or congenital insensitivity to pain?

KNOWLEDGE GAP OPEN gain_of_function_degree_threshold

Attached to

pathophysiology#Hyperpolarized NaV1.9 Activation with Enlarged Window Current genetic#SCN11A

Both phenotypes arise from gain of function in the same channel, and at Leu811 they arise from different substitutions of the same residue. The proposed explanation is that moderate gain of function lowers the firing threshold while extreme gain of function depolarizes the membrane far enough to inactivate the sodium channels needed to fire at all. No study has measured a quantitative boundary between the two regimes, so a novel variant with demonstrated gain of function cannot yet be assigned to a phenotype on biophysics alone. This matters clinically because the two conditions have opposite management.

Show evidence (2 references)

PMID:26645915 SUPPORT In Vitro

"we propose a model in which the physiological consequence of a mutation, that is, augmented versus absent pain, is critically dependent on the type of NaV1.9 hyperactivity"

States the proposal as a model rather than a demonstrated threshold, which is precisely the gap.

PMID:39058404 SUPPORT Computational

"Thus, we speculate that p.Leu811Phe may lead to current leakage, while p.Leu811Pro can increase the current through Nav1.9"

The authors' own hedging ("we speculate") shows the divergence is not yet mechanistically settled even for the one residue where both phenotypes are observed.

Why do episodes attenuate spontaneously around adolescence when the causal variant is present for life?

KNOWLEDGE GAP OPEN age_dependent_remission_mechanism

Attached to

progression#Spontaneous attenuation around adolescence pathophysiology#Nociceptor Hyperexcitability with Reduced Firing Threshold

The remission is the most clinically important fact about this disease - it is why the prognosis is benign - and no mechanism has been demonstrated. The germline variant does not change, so the attenuation must come from something acquired or developmental: changing NaV1.9 expression, changing nociceptor properties, or changing central processing. A fourth candidate is proposed in the literature and is the most uncomfortable one, because it makes the good news and the bad news the same event: long-term NaV1.9 dysfunction may itself degenerate the unmyelinated fibres, so pain could remit because the fibres carrying it are being lost. That would tie this gap directly to the small-fibre histopathology curated in this entry. It is offered speculatively by its authors and has not been measured across the relevant age range in patients, nor in the knock-in mice, which are studied at six to eight weeks.

Show evidence (2 references)

PMID:30549873 SUPPORT Human Clinical

"Affected participants were characterized by infantile recurrent pain episodes, with spontaneous mitigation around adolescence"

Establishes the phenomenon that lacks a demonstrated mechanism.

PMID:36051609 SUPPORT Human Clinical

"long-term dysfunction of the Nav1.9 channel may cause degeneration of the unmyelinated fibers in FEPS3 patient with pain remission"

The one candidate mechanism the literature offers for the remission, hedged by its own authors as a possibility rather than a finding.

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Pathophysiology

6

Heterozygous SCN11A Gain-of-Function Variant

A germline missense variant in one SCN11A allele alters the NaV1.9 channel protein. The variant class matters: these are point substitutions that change gating, not alleles that remove the channel.

Genetic context variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION

Downstream

Hyperpolarized NaV1.9 Activation with Enlarged Window Current The substitution alters channel gating directly, as measured by voltage clamp on the mutant channel.

Show evidence (1 reference)

PMID:26645915 SUPPORT Human Clinical

"Gain-of-function mutations in the human SCN11A-encoded voltage-gated Na(+) channel NaV1.9 cause severe pain disorders"

States the causal relationship between gain-of-function SCN11A variants and pain disorders.

Hyperpolarized NaV1.9 Activation with Enlarged Window Current

The mutant channel opens at more negative potentials than wild type and carries a larger persistent or window current, so more channels are open near the resting potential. This is the whole biophysical lesion; everything downstream follows from it.

sodium ion transmembrane transport GO:0035725 ↑ INCREASED

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

plasma membrane GO:0005886

Downstream

Depolarized Resting Membrane Potential in Nociceptors Sustained subthreshold sodium influx near rest shifts the resting potential in the depolarizing direction.

Show evidence (2 references)

PMID:31551682 SUPPORT In Vitro

"significantly increases current density and hyperpolarizes voltage-dependence of activation by 10 mV, enabling a larger window current"

Quantifies the shift and the enlarged window current for a disease allele.

PMID:39836077 SUPPORT In Vitro

"Nav1.9 exhibited the most hyperpolarized activation, while its fast inactivation resembled the depolarized inactivation of Nav1.8"

Establishes the wild-type baseline that the disease variants shift further, from a systematic comparison across nine channel subtypes.

Depolarized Resting Membrane Potential in Nociceptors

Small-diameter dorsal root ganglion neurons sit closer to threshold than they should. NaV1.9 is the channel that normally sets this potential, which is why a gating change in it moves the resting potential rather than the action potential upstroke.

nociceptor CL:0000198 dorsal root ganglion sensory neuron CL:0000101

membrane depolarization GO:0051899 ↑ INCREASED

Animal models

Scn11a F802C and F1125S knock-in mice Mouse recapitulates Both lines show the raised resting membrane potential and increased firing that define this node, which is how the two human variants were assigned gain-of-function status.

Downstream

Nociceptor Hyperexcitability with Reduced Firing Threshold A membrane closer to threshold fires on smaller inputs and fires more often.

Show evidence (2 references)

PMID:31551682 SUPPORT In Vitro

"Current-clamp recordings in DRG neurons shows that N816K channels depolarize RMP of small DRG neurons by 7 mV"

Quantifies the resting-potential shift in the relevant neuron type.

PMID:39836077 SUPPORT In Vitro

"Nav1.9, as it produces large persistent currents, is attributed a role in determining the resting membrane potential"

Establishes why this channel, and not another sodium channel, is the one that moves the resting potential.

Nociceptor Hyperexcitability with Reduced Firing Threshold

Nociceptors fire action potentials at lower stimulus intensities and at higher frequencies. Crucially the hyperexcitability persists at cold temperatures, where normal nociceptor firing is suppressed - which is the cellular explanation for a pain syndrome that is triggered by cold.

nociceptor CL:0000198

neuronal action potential GO:0019228 ↑ INCREASED

dorsal root ganglion UBERON:0000044

Animal models

Scn11a R222S knock-in mouse Mouse recapitulates Reproduces both the cellular defect - increased input impedance and evoked firing frequency in dorsal root ganglion neurons - and a behavioural correlate of the thermal sensitivity.

Nav1.9-null mouse Mouse perturbs Deleting the channel moves nociceptor excitability in the opposite direction to the disease: C-fibre electrical threshold rises by 55% and mechanical and thermal thresholds rise with it.

Downstream

Ectopic Nociceptive Signalling from Distal Limb Afferents Hyperexcitable afferents are inferred to generate amplified or ectopic nociceptive traffic; the transition from single-neuron excitability to a pain episode has not been recorded in patients.

Myenteric Neuron Hyperexcitability The same channel is preferentially expressed in myenteric neurons, so variants that reach that compartment produce enteric symptoms alongside the limb pain.

Show evidence (2 references)

PMID:30549873 SUPPORT Model Organism

"Electrophysiological studies using dorsal ganglion neurons showed significant increase of input impedance and firing frequency of evoked action potentials in p.R222S mice"

Measures the hyperexcitability directly in a knock-in model of a disease allele.

PMID:26645915 SUPPORT Model Organism

"cause cold-resistant hyperexcitability of nociceptors, suggesting a mechanistic basis for the temperature dependence of the pain phenotype"

Establishes the cold-resistant character of the hyperexcitability, which is what ties the cellular defect to the clinical trigger.

Ectopic Nociceptive Signalling from Distal Limb Afferents

Amplified nociceptive traffic from afferents innervating the distal limbs, predominantly the lower limbs. Large-fibre function is spared - nerve conduction studies, imaging and inflammatory markers are normal, and there is no joint pathology - so the acute episode is a signalling abnormality. That does not mean the nerve is structurally intact: a small-fibre lesion is demonstrable on skin biopsy in some patients, and is curated separately as histopathology.

sensory perception of pain GO:0019233 ↑ INCREASED

hindlimb UBERON:0002103

Downstream

Episodic pain The ectopic afferent traffic is experienced as the paroxysmal pain episode.

Lower limb pain The predominant site of the pain, and the feature the disease is named for.

Arthralgia Patients and families localize the pain to joints, though the lesion is in the afferent neuron rather than the joint; whether the perceived joint localization reflects afferent innervation territory is not established.

Show evidence (1 reference)

PMID:30549873 SUPPORT Human Clinical

"The affected joints, in an in- creasing order of frequency, include those in the knees, ankles, wrists, and elbows"

Establishes the distal and lower-limb-predominant distribution.

Myenteric Neuron Hyperexcitability

A variant-dependent branch. NaV1.9 is preferentially expressed in myenteric neurons, and in at least one allele the enteric compartment is affected alongside the limbs, producing episodic abdominal pain and chronic constipation. Most reported patients have no gastrointestinal involvement.

myenteric neuron CL:0007011

Downstream

Abdominal pain Hyperexcitable visceral afferents produce episodic abdominal pain.

Constipation Constipation accompanies the enteric involvement; whether it follows from altered myenteric motor control or from pain-related behaviour is not established.

Show evidence (2 references)

PMID:31551682 SUPPORT Human Clinical

"here we report a new Nav1.9 mutation, N816K, in a child with early-onset episodic pain in both legs, episodic abdominal pain, and chronic constipation"

The single reported case establishing the enteric branch.

PMID:24972070 SUPPORT INDIRECT Model Organism

"the voltage-gated sodium channel subtype NaV1.9 is expressed in half of gut-projecting rodent dorsal root ganglia sensory neurons"

Supports gut-projecting expression of the channel in a model system, which is the basis for expecting a visceral branch at all.

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Histopathology

1

Reduced intraepidermal nerve fibre density with unmyelinated axon degeneration

Skin biopsy in some patients shows reduced intraepidermal nerve fibre density and vacuolar degeneration of unmyelinated axons - a small-fibre neuropathy. This is the finding that qualifies the otherwise-true statement that investigation in this disease is normal: routine studies interrogate large fibres, and the lesion is in the small ones. It also matters for prognosis, since degeneration of the fibres carrying the pain has been proposed as a mechanism for the age-dependent remission.

Show evidence (1 reference)

PMID:36051609 SUPPORT Human Clinical

"Skin biopsies in some FEPS3 patients have revealed different degrees of reduction of intraepidermal nerve fiber density and vacuolar degeneration of unmyelinated axons, indicating small-fiber neuropathy"

Reports the histological lesion and names it as small-fibre neuropathy.

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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

7

Digestive 1

Constipation OCCASIONAL HP:0002019

Temporal: CHRONIC

Show evidence (1 reference)

PMID:31551682 SUPPORT Human Clinical

"episodic pain in both legs, episodic abdominal pain, and chronic constipation"

Records the constipation in the index case.

Integument 1

Hyperhidrosis OCCASIONAL HP:0000975

Show evidence (1 reference)

PMID:36051609 SUPPORT Human Clinical

"hyperhidrosis, constipation, and intestinal spasm can be concomitantly observed in some patients"

Lists the autonomic features observed alongside the pain.

Nervous System 1

Tremor OCCASIONAL HP:0001337

Deliberately left unconnected in the pathograph. Every other phenotype here is reached by a downstream edge from a mechanism node, but no mechanism has been proposed linking NaV1.9 to tremor, and this is a co-segregation observation in a single pedigree. Drawing an edge would assert a causal claim the source does not make.

Show evidence (1 reference)

PMID:28298626 SUPPORT Human Clinical

"We confirmed the presence of the SCN11A (c.673C>T) mutation in family members with episodic pain and essential tremor"

Reports the co-segregation of both phenotypes with the variant.

Constitutional 4

Episodic pain OBLIGATE HP:0032148

Show evidence (1 reference)

PMID:36051609 SUPPORT Human Clinical

"Familial episodic pain syndromes (FEPS) are one of the distinctive syndromes characterized by early-childhood onset of severe episodic pain mainly affecting the distal extremities and tend to attenuate or diminish with age"

States the defining episodic character and its distal distribution.

Lower limb pain VERY_FREQUENT HP:0012514

Show evidence (2 references)

PMID:30549873 SUPPORT Human Clinical

"The affected regions feel cold in the patients, and warming the lesions relieves the symptoms"

Records the cold sensation and the relief by warming, which is the discriminating feature against erythromelalgia.

PMID:36051609 SUPPORT Human Clinical

"Distal joints, occasionally proximal limbs and neck"

Gives the fuller distribution, which extends beyond the lower limbs the disease is named for.

Arthralgia FREQUENT HP:0002829

The quoted sentence reproduces a line-break hyphenation artifact present in the cached source, where the word "increasing" is split across a line. It is quoted exactly rather than repaired, because a snippet must be a true substring of the cited source.

Show evidence (1 reference)

PMID:30549873 SUPPORT Human Clinical

"The affected joints, in an in- creasing order of frequency, include those in the knees, ankles, wrists, and elbows"

Gives the joint distribution and its rank order.

Abdominal pain OCCASIONAL HP:0002027

Show evidence (1 reference)

PMID:31551682 SUPPORT Human Clinical

"a child with early-onset episodic pain in both legs, episodic abdominal pain, and chronic constipation"

The index case for the enteric branch of the phenotype.

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Genetic Associations

1

SCN11A

Gene: SCN11A hgnc:10583 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:30549873 SUPPORT Human Clinical

"p.R222S and p.R222H, were identified in SCN11A by linkage analysis"

Gene identification by linkage and exome sequencing in the founding Japanese families.

PMID:36051609 SUPPORT Human Clinical

"FEPS at least includes four subtypes of FEPS1, FEPS2, FEPS3, and FEPS4, which are caused by mutations in the TRPA1, SCN10A, SCN11A, and SCN9A genes, respectively"

Places SCN11A as the FEPS3 gene within the four-subtype classification, which is what fixes this entry's scope.

Variants (7)

p.Arg222His

The most frequently reported allele and a founder mutation in the Tohoku region of Japan, seen in seven of forty-eight families in the largest series.

Functional effects

NaV1.9 voltage-gated sodium channel gating

Gain of function.

Show evidence (1 reference)

PMID:30557356 SUPPORT Human Clinical

"A founder mutation, SCN11A p.R222H was confirmed to be frequently observed in patients with FEP in the Tohoku region of Japan"

Establishes both the recurrence and the founder effect.

p.Arg222Ser

The second allele identified in the founding series, and the one modelled as a knock-in mouse.

Functional effects

NaV1.9 voltage-gated sodium channel gating

Gain of function, demonstrated in a knock-in mouse.

Show evidence (1 reference)

PMID:30549873 SUPPORT Model Organism

"These results suggest that the novel mutation reported herein is a gain-of-function mu- tation that causes infantile familial episodic pain"

Assigns the gain-of-function consequence from the knock-in mouse experiments.

p.Arg225Cys

Reported in a four-generation Chinese family in which early-onset episodic pain co-segregated with adult-onset essential tremor.

Functional effects

NaV1.9 voltage-gated sodium channel gating

Gain of function.

Show evidence (1 reference)

PMID:28298626 SUPPORT Human Clinical

"We identified a missense mutation of p.Arg225Cys in SCN11A in a four-generation Chinese family with early-onset familial episodic pain and adult onset familial essential tremor syndrome"

Reports the allele and the co-segregating tremor phenotype.

p.Phe814Cys and p.Phe1146Ser

Two novel alleles from the forty-two-family Japanese expansion series, each validated by an orthologous knock-in mouse.

Functional effects

NaV1.9 voltage-gated sodium channel gating

Gain of function, demonstrated by increased resting membrane potential and firing frequency in orthologous knock-in mice.

Show evidence (1 reference)

PMID:30557356 SUPPORT Model Organism

"These results suggest a higher level of excitability in the F802C or F1125S mice than in WT, and indicate that these novel mutations are gain of function mutations"

Functional validation of both alleles through their mouse orthologues.

p.Val1184Ala

Identified by exome sequencing in a European case with cold-aggravated peripheral pain, and the allele on which the cold-resistant hyperexcitability mechanism was demonstrated.

Functional effects

NaV1.9 voltage-gated sodium channel gating

Gain of function through hyperpolarized shift in voltage dependence of opening.

Show evidence (1 reference)

PMID:26645915 SUPPORT Human Clinical

"Applying whole-exome sequencing we here identify a missense change (p.V1184A) in NaV1.9, which leads to cold-aggravated peripheral pain in humans"

Reports the allele and its distinctive cold-aggravated phenotype.

p.Asn816Lys

Reported in a child with early-onset episodic pain in both legs together with episodic abdominal pain and chronic constipation, which is the allele linking the enteric branch of the phenotype to the channel.

Functional effects

NaV1.9 voltage-gated sodium channel gating

Gain of function through increased current density and a ten-millivolt hyperpolarizing shift in activation, enlarging the window current.

Show evidence (1 reference)

PMID:31551682 SUPPORT In Vitro

"Voltage-clamp recordings demonstrate that Nav1.9-N816K significantly increases current density and hyperpolarizes voltage-dependence of activation by 10 mV, enabling a larger window current"

Quantifies the biophysical gain of function for this allele.

p.Leu811Phe

A novel allele in a four-generation Japanese pedigree, and the more informative half of a residue that diverges by substitution: p.Leu811Phe causes episodic pain while p.Leu811Pro at the same residue causes congenital insensitivity to pain.

Functional effects

NaV1.9 voltage-gated sodium channel gating

Increases the structural stability of NaV1.9 and impedes the conformational changes required for normal gating, by molecular dynamics simulation.

Show evidence (2 references)

PMID:39058404 SUPPORT Human Clinical

"Sequencing of SCN9A, SCN10A, and SCN11A in the proband revealed a novel heterozygous variant of SCN11A: g.38894937G>A (c.2431C>T, p.Leu811Phe)"

Reports the allele and the genes excluded before it was called.

PMID:39058404 SUPPORT Computational

"Molecular dynamics simulations showed that p.Leu811Phe increased the structural stability of Nav1.9 and prevented the necessary conformational changes"

The proposed structural basis, from simulation rather than from electrophysiology.

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Medical Actions

2

Warming and Trigger Avoidance

Action: Supportive Care NCIT:C15747

Platform: Behavioral / lifestyle

The first-line and most effective intervention: warming the affected limb relieves an episode, and avoiding cold and fatigue reduces episode frequency. It is unusual for a behavioural measure to be first-line, and it follows directly from the mechanism - the trigger is the cold-resistant hyperexcitability, so removing the cold removes the drive.

Mechanism Target:

Nociceptor Hyperexcitability with Reduced Firing Threshold — Warming removes the thermal condition under which the mutant channel sustains firing.

Show evidence (1 reference)

PMID:30549873 SUPPORT Human Clinical

"The affected regions feel cold in the patients, and warming the lesions relieves the symptoms"

Reports symptomatic relief by warming in the founding families.

Show evidence (1 reference)

PMID:30549873 SUPPORT Human Clinical

"The affected regions feel cold in the patients, and warming the lesions relieves the symptoms"

The clinical observation that warming relieves the pain.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Platform: Other

Counselling for the fifty percent recurrence risk of an autosomal dominant condition, with cascade testing of at-risk relatives once a familial variant is known. Counselling can be unusually reassuring here, because the natural history is benign and remits with age.

Show evidence (1 reference)

PMID:39058404 SUPPORT Human Clinical

"This variant was confirmed in other affected members but not in the unaffected father"

Illustrates the familial segregation testing that cascade counselling rests on.

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Environmental Factors

2

Cold ambient exposure

Cold precipitates episodes and the affected region feels cold to the patient, while warming relieves the pain. The cellular counterpart is that gain-of-function NaV1.9 confers hyperexcitability that persists at cold temperatures, where nociceptor firing would normally be suppressed.

Show evidence (1 reference)

PMID:39058404 SUPPORT Human Clinical

"pain episodes can be triggered by fatigue, bad weather, and cold temperatures"

Records cold as a clinical trigger of episodes.

Mechanism Target:

TRIGGERS Nociceptor Hyperexcitability with Reduced Firing Threshold — Cold is the modality at which the mutant channel's hyperexcitability is retained, which is why cooling provokes rather than suppresses firing.

Show evidence (1 reference)

PMID:26645915 SUPPORT Model Organism

"cause cold-resistant hyperexcitability of nociceptors, suggesting a mechanistic basis for the temperature dependence of the pain phenotype"

Ties the cold trigger to the cellular mechanism explicitly.

Physical fatigue

Physical exertion and fatigue precipitate episodes; rest and warming mitigate them. Reported consistently across the Japanese families.

Show evidence (1 reference)

PMID:30549873 SUPPORT Human Clinical

"The pain is often induced by fa- tigue and is a prelude of bad weather"

Establishes fatigue and impending weather change as episode triggers.

Mechanism Target:

TRIGGERS Ectopic Nociceptive Signalling from Distal Limb Afferents — Fatigue is a reproducible clinical trigger, but no mechanism connecting exertion to NaV1.9 activity has been demonstrated.

Show evidence (1 reference)

PMID:30549873 SUPPORT Human Clinical

"The pain is often induced by fa- tigue and is a prelude of bad weather"

Records fatigue as a trigger, from the clinical description of six families.

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Diagnosis

2

Sodium-channelopathy gene panel sequencing

The definitive diagnostic. Because FEPS1, FEPS2, FEPS3 and FEPS4 are clinically overlapping and separated only by genotype, a panel covering SCN11A, SCN10A, SCN9A and TRPA1 is a more sensible first test than single-gene sequencing, with exome or genome sequencing for panel-negative cases.

genetic testing NCIT:C15709

Show evidence (2 references)

PMID:36051609 SUPPORT Human Clinical

"FEPS at least includes four subtypes of FEPS1, FEPS2, FEPS3, and FEPS4, which are caused by mutations in the TRPA1, SCN10A, SCN11A, and SCN9A genes, respectively"

The four-gene overlap is what makes panel sequencing rather than single-gene testing the appropriate approach.

PMID:39058404 SUPPORT Human Clinical

"Sequencing of SCN9A, SCN10A, and SCN11A in the proband revealed a novel heterozygous variant of SCN11A"

A worked example of the panel approach reaching the diagnosis.

Quantitative sensory testing and nerve conduction studies

Nerve conduction studies are normal in most patients, which is a useful negative: it excludes a large-fibre neuropathy. Quantitative sensory testing is the informative one, showing abnormal cold and warm thresholds in some patients - the objective correlate of the thermal sensitivity that defines the syndrome clinically.

quantitative sensory testing NCIT:C155860

Show evidence (1 reference)

PMID:36051609 SUPPORT Human Clinical

"Nerve conduction studies were normal in most patients, while QST showed abnormal cold and warm temperature thresholds in some patients"

Gives both the normal large-fibre result and the abnormal thermal thresholds in one sentence.

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Progression

2

Infantile and early childhood onset

Age: Infancy to early childhood

Episodes begin in infancy or early childhood and are at their most frequent and severe during childhood, when they disrupt sleep, activity and schooling.

Show evidence (1 reference)

PMID:30549873 SUPPORT Human Clinical

"Affected participants were characterized by infantile recurrent pain episodes, with spontaneous mitigation around adolescence"

Gives both the onset and the natural history in one sentence.

Spontaneous attenuation around adolescence

Age: Adolescence

Episodes diminish or remit around adolescence without disease-modifying treatment. The mechanism of the age dependence is not established. This is what makes the long-term prognosis benign despite a severe childhood symptom burden.

Show evidence (1 reference)

PMID:39058404 SUPPORT Human Clinical

"FEPS appears in early childhood, gradually disappearing with age, and pain episodes can be triggered by fatigue, bad weather, and cold temperatures"

States the age-dependent remission together with the triggers.

📊

Prevalence

1

Japan

Cases In Literature Ultra Rare

Forty-eight Japanese families had been recruited by 2018, the largest series reported. No population rate has been estimated for this disorder anywhere, so the qualitative band is the only claim the sources support.

Show evidence (1 reference)

PMID:30557356 SUPPORT Human Clinical

"we recruited an additional 42 new unrelated Japanese FEP families, between March 2016 and March 2018"

Gives the size of the largest reported series.

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Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Familial_Episodic_Pain_Syndrome_With_Predominantly_Lower_Limb_Involvement:

Inherited erythromelalgia MONDO:0007571

Overlapping Features The differential most worth stating, because the two look superficially similar and are separated by a single bedside observation that runs the opposite way. Curated in this knowledge base as Primary_Erythermalgia. Erythromelalgia produces red, hot, hyperperfused extremities relieved by cooling; FEPS3 patients report that the affected region feels cold and that warming relieves the pain.

Show evidence (2 references)

PMID:29299961 SUPPORT Human Clinical

"by the permanent occurrence of extremely painful hyperperfused skin"

Gives the hyperperfused character of erythromelalgia, which is the direct opposite of the cold, warmth-relieved pain of this disorder and is what separates them at the bedside.

PMID:29299961 SUPPORT Human Clinical

"affecting SCN9A, SCN10A, and SCN11A coding for NaV1.7, NaV1.8, and NaV1.9"

Notes that erythromelalgia arises from the same three sodium-channel genes, so the gene alone does not distinguish the two conditions and the clinical thermal character has to.

Growing pains

Overlapping Features The differential a clinician actually faces first. A child with recurrent self-limited limb pain that resolves with age is far more likely to have benign growing pains than a sodium channelopathy; what separates them is a segregating family history in an autosomal dominant pattern, the reproducible cold and fatigue triggers, and a molecular diagnosis.

Show evidence (1 reference)

PMID:36051609 SUPPORT Human Clinical

"characterized by early-childhood onset of severe episodic pain mainly affecting the distal extremities and tend to attenuate or diminish with age"

The features quoted here are exactly the ones growing pains shares, which is what makes the distinction rest on family history and genotype rather than on the pain description.

Other familial episodic pain syndromes

Overlapping Features FEPS1 (TRPA1), FEPS2 (SCN10A) and FEPS4 (SCN9A) produce overlapping distal episodic pain and are separated only by sequencing. FEPS2 in particular also causes distal, predominantly lower-limb episodic pain, which is why a gene panel rather than single-gene testing is the sensible first test.

Show evidence (1 reference)

PMID:36051609 SUPPORT Human Clinical

"FEPS at least includes four subtypes of FEPS1, FEPS2, FEPS3, and FEPS4, which are caused by mutations in the TRPA1, SCN10A, SCN11A, and SCN9A genes, respectively"

Enumerates the sibling subtypes this entry must be distinguished from.

Congenital insensitivity to pain MONDO:0015364

Overlapping Features Curated in this knowledge base as Congenital_Insensitivity_to_Pain. Not a clinical mimic but the opposite phenotype from the same gene, and the reason variant interpretation here cannot rely on "gain of function" alone. Extreme gain of function produces sustained depolarization block and loss of firing; at the Leu811 residue the substitution decides which phenotype results.

Show evidence (1 reference)

PMID:39058404 SUPPORT Human Clinical

"On the other hand, the c.2432T>C (p.Leu811Pro) variant is known to cause congenital insensitivity to pain (CIP)"

Documents the opposite phenotype arising at the same residue.

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Animal Models

3

Scn11a R222S knock-in mouse

A knock-in mouse carrying one of the two alleles found in the founding Japanese families, generated in the same study that identified them.

Species

Mouse

Genotype

Scn11a p.R222S knock-in

Publication

PMID:30549873

Pathograph links

Nociceptor Hyperexcitability with Reduced Firing Threshold recapitulates fidelity: high Reproduces both the cellular defect - increased input impedance and evoked firing frequency in dorsal root ganglion neurons - and a behavioural correlate of the thermal sensitivity.

Limitations: The mouse cannot model the episodic, weather-triggered character of the human pain or its spontaneous remission in adolescence, which are the two features that define the syndrome clinically.

Readouts

Evoked action potential firing frequency in DRG neurons

Direction: INCREASED

Interpretation: The direct electrophysiological correlate of the hyperexcitability node.

Show evidence (1 reference)

PMID:30549873 SUPPORT Model Organism

"showed significant increase of input impedance and firing frequency of evoked action potentials in p.R222S mice"

Reports the measurement in the knock-in model.

Behavioural sensitivity to hot and cold stimuli

Direction: INCREASED

Interpretation: Whole-animal correlate showing the cellular change reaches behaviour.

Show evidence (1 reference)

PMID:30549873 SUPPORT Model Organism

"Behavioral tests showed that p.R222S mice were significantly more hypersensitive to hot and cold stimuli"

Reports the behavioural readout.

Show evidence (1 reference)

PMID:30549873 SUPPORT Model Organism

"Next, we generated a knock-in mouse model harboring one of the mutations (p.R222S)"

Establishes that the model carries an actual patient allele, which is what makes it informative for this node.

Scn11a F802C and F1125S knock-in mice

Knock-in mice for the mouse orthologues of two novel human alleles, generated specifically to classify those variants functionally.

Species

Mouse

Genotype

Scn11a p.F802C or p.F1125S knock-in (orthologues of human p.F814C and p.F1146S)

Publication

PMID:30557356

Pathograph links

Depolarized Resting Membrane Potential in Nociceptors recapitulates fidelity: high Both lines show the raised resting membrane potential and increased firing that define this node, which is how the two human variants were assigned gain-of-function status.

Limitations: The alleles modelled are the mouse orthologous residues rather than the human variants themselves, and several action-potential parameters and the current threshold did not differ from wild type, so the effect is narrower than a global excitability increase.

Readouts

Resting membrane potential in DRG neurons

Direction: INCREASED

Interpretation: The defining measurement for this node, in both knock-in lines.

Show evidence (1 reference)

PMID:30557356 SUPPORT Model Organism

"Dissected neurons of F802C and F1125S mice showed increased resting membrane potentials and firing frequency of the action potentials (APs) by high input-current stimulus compared with WT mice"

Reports the resting-potential and firing measurements in both lines.

Show evidence (1 reference)

PMID:30557356 SUPPORT Model Organism

"These results suggest a higher level of excitability in the F802C or F1125S mice than in WT, and indicate that these novel mutations are gain of function mutations"

The authors' own conclusion that the models establish gain of function.

Nav1.9-null mouse

The loss-of-function counterpart. It does not model the disease - it carries the opposite lesion - but it establishes what NaV1.9 normally contributes, which is the necessity half of the causal argument the gain-of-function knock-ins make from the sufficiency side.

Species

Mouse

Genotype

Scn11a knockout

Publication

PMID:27780178

Pathograph links

Nociceptor Hyperexcitability with Reduced Firing Threshold perturbs fidelity: moderate Deleting the channel moves nociceptor excitability in the opposite direction to the disease: C-fibre electrical threshold rises by 55% and mechanical and thermal thresholds rise with it.

Limitations: This is an inverted model. It removes the channel rather than carrying a disease variant, so it can support the direction of the mechanism but cannot recapitulate the syndrome, and no inference about the episodic phenotype can be drawn from it.

Readouts

C-fibre electrical threshold

Direction: INCREASED

Interpretation: Threshold rises on channel deletion, the mirror image of the reduced threshold that defines the node in disease.

Show evidence (1 reference)

PMID:27780178 SUPPORT INDIRECT Model Organism

"the electrical threshold of NaV1.9 KO C fibers was elevated by 55% and the median von Frey threshold was 32 mN in contrast to 8 mN in wild types"

Quantifies the inverse effect; it supports the mechanism by inversion rather than by recapitulation.

Show evidence (1 reference)

PMID:27780178 SUPPORT INDIRECT Model Organism

"NaV1.9 presumably contributes to acute thermal and mechanical nociception in mice, most likely through increasing the excitability"

Establishes the channel's normal excitability role, which is what makes the inverted model informative for this node.

{ }

Source YAML

click to show

name: Familial_Episodic_Pain_Syndrome_With_Predominantly_Lower_Limb_Involvement
category: Mendelian
creation_date: '2026-09-01T23:30:00Z'
description: >-
  Familial episodic pain syndrome 3 (FEPS3) is an autosomal dominant
  channelopathy caused by heterozygous gain-of-function missense variants in
  SCN11A, which encodes the tetrodotoxin-resistant voltage-gated sodium channel
  NaV1.9. NaV1.9 has the most hyperpolarized activation of any voltage-gated
  sodium channel and carries a large persistent current, so it sets the resting
  membrane potential of nociceptors rather than driving the action potential
  upstroke. A gain-of-function variant shifts activation further towards
  hyperpolarized potentials and enlarges the window current, depolarizing the
  resting potential of small-diameter dorsal root ganglion neurons, lowering
  their firing threshold, and rendering them hyperexcitable in a way that
  persists at cold temperatures. The clinical result is paroxysmal, severe pain
  of the distal limbs and predominantly the lower limbs, lasting fifteen to
  thirty minutes and recurring several times a day, triggered by fatigue, cold
  and falling weather. The affected region feels cold and warming it relieves
  the pain - the inverse of erythromelalgia, and the most useful bedside
  discriminator. Onset is in infancy or early childhood and episodes attenuate
  spontaneously around adolescence, so long-term disability is low and life
  expectancy is unaffected. Routine investigation is normal - nerve conduction
  studies, imaging and inflammatory markers - and there is no joint pathology
  despite the pain being localized to joints. The small fibres are a different
  matter: skin biopsy in some patients shows reduced intraepidermal nerve fibre
  density and degeneration of unmyelinated axons, so the disease is not purely
  a signalling abnormality.
disease_term:
  preferred_term: familial episodic pain syndrome with predominantly lower limb involvement
  term:
    id: MONDO:0014247
    label: familial episodic pain syndrome with predominantly lower limb involvement
synonyms:
- Familial episodic pain syndrome 3
- FEPS3
- SCN11A-related familial episodic pain
- Infantile limb pain episodes
- Paroxysmal limb intolerable pain
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Heterozygous gain-of-function missense variants segregate with the pain
    phenotype through multiple generations; unaffected relatives do not carry
    them.
  evidence:
  - reference: PMID:30549873
    reference_title: "[Paroxysmal limb intolerable pain (infantile pain episodes associated with novel Nav1.9 mutations in familial episodic pain syndrome)]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This unique phenotype was inherited in an autosomal-dominant mode
    explanation: States the inheritance mode across six multigenerational Japanese
      families.
  - reference: PMID:39058404
    reference_title: "Familial Episodic Pain Syndrome: A Japanese Family Harboring the Novel Variant c.2431C>T (p.Leu811Phe) in SCN11A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This variant was confirmed in other affected members but not in the unaffected
      father
    explanation: Segregation in a four-generation pedigree, with the variant absent
      from the unaffected parent.
genetic:
- name: SCN11A
  gene_term:
    preferred_term: SCN11A
    term:
      id: hgnc:10583
      label: SCN11A
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:30549873
    reference_title: "[Paroxysmal limb intolerable pain (infantile pain episodes associated with novel Nav1.9 mutations in familial episodic pain syndrome)]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: p.R222S and p.R222H, were identified in SCN11A by linkage analysis
    explanation: Gene identification by linkage and exome sequencing in the founding
      Japanese families.
  - reference: PMID:36051609
    reference_title: "Familial Episodic Pain Syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: FEPS at least includes four subtypes of FEPS1, FEPS2, FEPS3, and FEPS4,
      which are caused by mutations in the TRPA1, SCN10A, SCN11A, and SCN9A genes,
      respectively
    explanation: Places SCN11A as the FEPS3 gene within the four-subtype classification,
      which is what fixes this entry's scope.
  variants:
  - name: p.Arg222His
    description: The most frequently reported allele and a founder mutation in the
      Tohoku region of Japan, seen in seven of forty-eight families in the largest
      series.
    functional_effects:
    - function: NaV1.9 voltage-gated sodium channel gating
      description: Gain of function.
    evidence:
    - reference: PMID:30557356
      reference_title: "Familial episodic limb pain in kindreds with novel Nav1.9 mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: A founder mutation, SCN11A p.R222H was confirmed to be frequently observed
        in patients with FEP in the Tohoku region of Japan
      explanation: Establishes both the recurrence and the founder effect.
  - name: p.Arg222Ser
    description: The second allele identified in the founding series, and the one modelled
      as a knock-in mouse.
    functional_effects:
    - function: NaV1.9 voltage-gated sodium channel gating
      description: Gain of function, demonstrated in a knock-in mouse.
    evidence:
    - reference: PMID:30549873
      reference_title: "[Paroxysmal limb intolerable pain (infantile pain episodes associated with novel Nav1.9 mutations in familial episodic pain syndrome)]."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: These results suggest that the novel mutation reported herein is a
        gain-of-function mu- tation that causes infantile familial episodic pain
      explanation: Assigns the gain-of-function consequence from the knock-in mouse
        experiments.
  - name: p.Arg225Cys
    description: Reported in a four-generation Chinese family in which early-onset
      episodic pain co-segregated with adult-onset essential tremor.
    functional_effects:
    - function: NaV1.9 voltage-gated sodium channel gating
      description: Gain of function.
    evidence:
    - reference: PMID:28298626
      reference_title: "Gain-of-function mutation p.Arg225Cys in SCN11A causes familial episodic pain and contributes to essential tremor."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: We identified a missense mutation of p.Arg225Cys in SCN11A in a four-generation
        Chinese family with early-onset familial episodic pain and adult onset familial
        essential tremor syndrome
      explanation: Reports the allele and the co-segregating tremor phenotype.
  - name: p.Phe814Cys and p.Phe1146Ser
    description: Two novel alleles from the forty-two-family Japanese expansion series,
      each validated by an orthologous knock-in mouse.
    functional_effects:
    - function: NaV1.9 voltage-gated sodium channel gating
      description: Gain of function, demonstrated by increased resting membrane potential
        and firing frequency in orthologous knock-in mice.
    evidence:
    - reference: PMID:30557356
      reference_title: "Familial episodic limb pain in kindreds with novel Nav1.9 mutations."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: These results suggest a higher level of excitability in the F802C or
        F1125S mice than in WT, and indicate that these novel mutations are gain of
        function mutations
      explanation: Functional validation of both alleles through their mouse orthologues.
  - name: p.Val1184Ala
    description: Identified by exome sequencing in a European case with cold-aggravated
      peripheral pain, and the allele on which the cold-resistant hyperexcitability
      mechanism was demonstrated.
    functional_effects:
    - function: NaV1.9 voltage-gated sodium channel gating
      description: Gain of function through hyperpolarized shift in voltage dependence
        of opening.
    evidence:
    - reference: PMID:26645915
      reference_title: "Cold-aggravated pain in humans caused by a hyperactive NaV1.9 channel mutant."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Applying whole-exome sequencing we here identify a missense change (p.V1184A)
        in NaV1.9, which leads to cold-aggravated peripheral pain in humans
      explanation: Reports the allele and its distinctive cold-aggravated phenotype.
  - name: p.Asn816Lys
    description: Reported in a child with early-onset episodic pain in both legs together
      with episodic abdominal pain and chronic constipation, which is the allele linking
      the enteric branch of the phenotype to the channel.
    functional_effects:
    - function: NaV1.9 voltage-gated sodium channel gating
      description: Gain of function through increased current density and a ten-millivolt
        hyperpolarizing shift in activation, enlarging the window current.
    evidence:
    - reference: PMID:31551682
      reference_title: "A Novel Gain-of-Function Nav1.9 Mutation in a Child With Episodic Pain."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Voltage-clamp recordings demonstrate that Nav1.9-N816K significantly
        increases current density and hyperpolarizes voltage-dependence of activation
        by 10 mV, enabling a larger window current
      explanation: Quantifies the biophysical gain of function for this allele.
  - name: p.Leu811Phe
    description: >-
      A novel allele in a four-generation Japanese pedigree, and the more
      informative half of a residue that diverges by substitution: p.Leu811Phe
      causes episodic pain while p.Leu811Pro at the same residue causes
      congenital insensitivity to pain.
    functional_effects:
    - function: NaV1.9 voltage-gated sodium channel gating
      description: Increases the structural stability of NaV1.9 and impedes the conformational
        changes required for normal gating, by molecular dynamics simulation.
    evidence:
    - reference: PMID:39058404
      reference_title: "Familial Episodic Pain Syndrome: A Japanese Family Harboring the Novel Variant c.2431C>T (p.Leu811Phe) in SCN11A."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Sequencing of SCN9A, SCN10A, and SCN11A in the proband revealed a novel
        heterozygous variant of SCN11A: g.38894937G>A (c.2431C>T, p.Leu811Phe)'
      explanation: Reports the allele and the genes excluded before it was called.
    - reference: PMID:39058404
      reference_title: "Familial Episodic Pain Syndrome: A Japanese Family Harboring the Novel Variant c.2431C>T (p.Leu811Phe) in SCN11A."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: Molecular dynamics simulations showed that p.Leu811Phe increased the
        structural stability of Nav1.9 and prevented the necessary conformational changes
      explanation: The proposed structural basis, from simulation rather than from
        electrophysiology.
  notes: >-
    Variants are point missense throughout; no frameshift, nonsense or
    structural variant has been reported for the episodic-pain phenotype, which
    is consistent with a mechanism that requires an altered channel rather than
    an absent one. The most instructive fact in the allelic series is that
    SCN11A is pleiotropic in a graded way: moderate gain of function gives
    episodic pain, while extreme gain of function gives congenital insensitivity
    to pain through sustained depolarization block. Leu811 shows this within a
    single residue.
pathophysiology:
- name: Heterozygous SCN11A Gain-of-Function Variant
  biological_scale: MOLECULAR
  conforms_to: "nociceptor_sodium_channel_excitability#Nociceptor Voltage-Gated Sodium Channel Variant"
  description: >-
    A germline missense variant in one SCN11A allele alters the NaV1.9 channel
    protein. The variant class matters: these are point substitutions that
    change gating, not alleles that remove the channel.
  genetic_context:
    functional_impact_category: GAIN_OF_FUNCTION
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
  evidence:
  - reference: PMID:26645915
    reference_title: "Cold-aggravated pain in humans caused by a hyperactive NaV1.9 channel mutant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Gain-of-function mutations in the human SCN11A-encoded voltage-gated Na(+)
      channel NaV1.9 cause severe pain disorders
    explanation: States the causal relationship between gain-of-function SCN11A variants
      and pain disorders.
  downstream:
  - target: Hyperpolarized NaV1.9 Activation with Enlarged Window Current
    causal_link_type: DIRECT
    description: The substitution alters channel gating directly, as measured by voltage
      clamp on the mutant channel.
    evidence:
    - reference: PMID:26645915
      reference_title: "Cold-aggravated pain in humans caused by a hyperactive NaV1.9 channel mutant."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Electrophysiological analysis reveals that p.V1184A shifts the voltage
        dependence of channel opening to hyperpolarized potentials thereby conferring
        gain-of-function characteristics to NaV1.9
      explanation: Direct measurement of the gating change caused by the variant.
- name: Hyperpolarized NaV1.9 Activation with Enlarged Window Current
  biological_scale: MOLECULAR
  conforms_to: "nociceptor_sodium_channel_excitability#Enhanced or Persistent Nociceptor Sodium Current"
  description: >-
    The mutant channel opens at more negative potentials than wild type and
    carries a larger persistent or window current, so more channels are open
    near the resting potential. This is the whole biophysical lesion; everything
    downstream follows from it.
  molecular_functions:
  - preferred_term: voltage-gated sodium channel activity
    term:
      id: GO:0005248
      label: voltage-gated sodium channel activity
    modifier: GAIN_OF_FUNCTION
  biological_processes:
  - preferred_term: sodium ion transmembrane transport
    term:
      id: GO:0035725
      label: sodium ion transmembrane transport
    modifier: INCREASED
  cellular_components:
  - preferred_term: plasma membrane
    term:
      id: GO:0005886
      label: plasma membrane
  evidence:
  - reference: PMID:31551682
    reference_title: "A Novel Gain-of-Function Nav1.9 Mutation in a Child With Episodic Pain."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: significantly increases current density and hyperpolarizes voltage-dependence
      of activation by 10 mV, enabling a larger window current
    explanation: Quantifies the shift and the enlarged window current for a disease
      allele.
  - reference: PMID:39836077
    reference_title: "Nociceptor sodium channels shape subthreshold phase, upstroke, and shoulder of action potentials."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Nav1.9 exhibited the most hyperpolarized activation, while its fast inactivation
      resembled the depolarized inactivation of Nav1.8
    explanation: Establishes the wild-type baseline that the disease variants shift
      further, from a systematic comparison across nine channel subtypes.
  downstream:
  - target: Depolarized Resting Membrane Potential in Nociceptors
    causal_link_type: DIRECT
    description: Sustained subthreshold sodium influx near rest shifts the resting
      potential in the depolarizing direction.
    evidence:
    - reference: PMID:26645915
      reference_title: "Cold-aggravated pain in humans caused by a hyperactive NaV1.9 channel mutant."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Mutated channels diminish the resting membrane potential of mouse primary
        sensory neurons and cause cold-resistant hyperexcitability of nociceptors
      explanation: Links the gating change to the resting-potential change in sensory
        neurons.
- name: Depolarized Resting Membrane Potential in Nociceptors
  biological_scale: CELLULAR
  description: >-
    Small-diameter dorsal root ganglion neurons sit closer to threshold than
    they should. NaV1.9 is the channel that normally sets this potential, which
    is why a gating change in it moves the resting potential rather than the
    action potential upstroke.
  cell_types:
  - preferred_term: nociceptor
    term:
      id: CL:0000198
      label: pain receptor cell
  - preferred_term: dorsal root ganglion sensory neuron
    term:
      id: CL:0000101
      label: sensory neuron
  biological_processes:
  - preferred_term: membrane depolarization
    term:
      id: GO:0051899
      label: membrane depolarization
    modifier: INCREASED
  evidence:
  - reference: PMID:31551682
    reference_title: "A Novel Gain-of-Function Nav1.9 Mutation in a Child With Episodic Pain."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Current-clamp recordings in DRG neurons shows that N816K channels depolarize
      RMP of small DRG neurons by 7 mV
    explanation: Quantifies the resting-potential shift in the relevant neuron type.
  - reference: PMID:39836077
    reference_title: "Nociceptor sodium channels shape subthreshold phase, upstroke, and shoulder of action potentials."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Nav1.9, as it produces large persistent currents, is attributed a role
      in determining the resting membrane potential
    explanation: Establishes why this channel, and not another sodium channel, is the
      one that moves the resting potential.
  downstream:
  - target: Nociceptor Hyperexcitability with Reduced Firing Threshold
    causal_link_type: DIRECT
    description: A membrane closer to threshold fires on smaller inputs and fires more
      often.
    evidence:
    - reference: PMID:31551682
      reference_title: "A Novel Gain-of-Function Nav1.9 Mutation in a Child With Episodic Pain."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: reduce current threshold of firing an action potential and render DRG
        neurons hyperexcitable
      explanation: States the step from resting-potential change to reduced threshold
        and hyperexcitability.
- name: Nociceptor Hyperexcitability with Reduced Firing Threshold
  biological_scale: CELLULAR
  conforms_to: "nociceptor_sodium_channel_excitability#Nociceptor Action Potential Threshold and Firing"
  description: >-
    Nociceptors fire action potentials at lower stimulus intensities and at
    higher frequencies. Crucially the hyperexcitability persists at cold
    temperatures, where normal nociceptor firing is suppressed - which is the
    cellular explanation for a pain syndrome that is triggered by cold.
  cell_types:
  - preferred_term: nociceptor
    term:
      id: CL:0000198
      label: pain receptor cell
  biological_processes:
  - preferred_term: neuronal action potential
    term:
      id: GO:0019228
      label: neuronal action potential
    modifier: INCREASED
  locations:
  - preferred_term: dorsal root ganglion
    term:
      id: UBERON:0000044
      label: dorsal root ganglion
  evidence:
  - reference: PMID:30549873
    reference_title: "[Paroxysmal limb intolerable pain (infantile pain episodes associated with novel Nav1.9 mutations in familial episodic pain syndrome)]."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Electrophysiological studies using dorsal ganglion neurons showed significant
      increase of input impedance and firing frequency of evoked action potentials
      in p.R222S mice
    explanation: Measures the hyperexcitability directly in a knock-in model of a disease
      allele.
  - reference: PMID:26645915
    reference_title: "Cold-aggravated pain in humans caused by a hyperactive NaV1.9 channel mutant."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: cause cold-resistant hyperexcitability of nociceptors, suggesting a mechanistic
      basis for the temperature dependence of the pain phenotype
    explanation: Establishes the cold-resistant character of the hyperexcitability,
      which is what ties the cellular defect to the clinical trigger.
  downstream:
  - target: Ectopic Nociceptive Signalling from Distal Limb Afferents
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Hyperexcitable afferents are inferred to generate amplified or ectopic
      nociceptive traffic; the transition from single-neuron excitability to a pain
      episode has not been recorded in patients.
    evidence:
    - reference: PMID:36051609
      reference_title: "Familial Episodic Pain Syndromes."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: Functional studies have revealed that all missense mutations in these
        genes are closely associated with the gain-of-function of cation channels
      explanation: Supports the general gain-of-function-to-pain reading across the
        FEPS genes without demonstrating the intervening step.
  - target: Myenteric Neuron Hyperexcitability
    causal_link_type: DIRECT
    description: >-
      The same channel is preferentially expressed in myenteric neurons, so
      variants that reach that compartment produce enteric symptoms alongside
      the limb pain.
    evidence:
    - reference: PMID:31551682
      reference_title: "A Novel Gain-of-Function Nav1.9 Mutation in a Child With Episodic Pain."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Nav1.9 is preferentially expressed in myenteric neurons, and small-diameter
        dorsal root ganglion (DRG) and trigeminal ganglion neurons including nociceptors
      explanation: Establishes the expression pattern that makes the enteric branch
        possible.
- name: Ectopic Nociceptive Signalling from Distal Limb Afferents
  biological_scale: TISSUE
  conforms_to: "nociceptor_sodium_channel_excitability#Nociceptor Hyperexcitability and Ectopic Firing"
  description: >-
    Amplified nociceptive traffic from afferents innervating the distal limbs,
    predominantly the lower limbs. Large-fibre function is spared - nerve
    conduction studies, imaging and inflammatory markers are normal, and there
    is no joint pathology - so the acute episode is a signalling abnormality.
    That does not mean the nerve is structurally intact: a small-fibre lesion is
    demonstrable on skin biopsy in some patients, and is curated separately as
    histopathology.
  locations:
  - preferred_term: hindlimb
    term:
      id: UBERON:0002103
      label: hindlimb
  biological_processes:
  - preferred_term: sensory perception of pain
    term:
      id: GO:0019233
      label: sensory perception of pain
    modifier: INCREASED
  evidence:
  - reference: PMID:30549873
    reference_title: "[Paroxysmal limb intolerable pain (infantile pain episodes associated with novel Nav1.9 mutations in familial episodic pain syndrome)]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The affected joints, in an in- creasing order of frequency, include those
      in the knees, ankles, wrists, and elbows
    explanation: Establishes the distal and lower-limb-predominant distribution.
  downstream:
  - target: Episodic pain
    causal_link_type: DIRECT
    description: The ectopic afferent traffic is experienced as the paroxysmal pain
      episode.
    evidence:
    - reference: PMID:30549873
      reference_title: "[Paroxysmal limb intolerable pain (infantile pain episodes associated with novel Nav1.9 mutations in familial episodic pain syndrome)]."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The pain typically lasts for 15-30 min and recurs several times a day
      explanation: Gives the episode duration and frequency that define the paroxysmal
        pattern.
  - target: Lower limb pain
    causal_link_type: DIRECT
    description: The predominant site of the pain, and the feature the disease is named
      for.
    evidence:
    - reference: PMID:31551682
      reference_title: "A Novel Gain-of-Function Nav1.9 Mutation in a Child With Episodic Pain."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: a child with early-onset episodic pain in both legs, episodic abdominal
        pain, and chronic constipation
      explanation: Records bilateral leg pain as the presenting complaint.
  - target: Arthralgia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Patients and families localize the pain to joints, though the lesion is in
      the afferent neuron rather than the joint; whether the perceived joint
      localization reflects afferent innervation territory is not established.
    evidence:
    - reference: PMID:30549873
      reference_title: "[Paroxysmal limb intolerable pain (infantile pain episodes associated with novel Nav1.9 mutations in familial episodic pain syndrome)]."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: The affected joints, in an in- creasing order of frequency, include
        those in the knees, ankles, wrists, and elbows
      explanation: Records the joint localization without asserting a joint pathology.
- name: Myenteric Neuron Hyperexcitability
  biological_scale: CELLULAR
  description: >-
    A variant-dependent branch. NaV1.9 is preferentially expressed in myenteric
    neurons, and in at least one allele the enteric compartment is affected
    alongside the limbs, producing episodic abdominal pain and chronic
    constipation. Most reported patients have no gastrointestinal involvement.
  cell_types:
  - preferred_term: myenteric neuron
    term:
      id: CL:0007011
      label: enteric neuron
  evidence:
  - reference: PMID:31551682
    reference_title: "A Novel Gain-of-Function Nav1.9 Mutation in a Child With Episodic Pain."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: here we report a new Nav1.9 mutation, N816K, in a child with early-onset
      episodic pain in both legs, episodic abdominal pain, and chronic constipation
    explanation: The single reported case establishing the enteric branch.
  - reference: PMID:24972070
    reference_title: "Multiple roles for NaV1.9 in the activation of visceral afferents by noxious inflammatory, mechanical, and human disease-derived stimuli."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: the voltage-gated sodium channel subtype NaV1.9 is expressed in half of
      gut-projecting rodent dorsal root ganglia sensory neurons
    explanation: Supports gut-projecting expression of the channel in a model system,
      which is the basis for expecting a visceral branch at all.
  downstream:
  - target: Abdominal pain
    causal_link_type: DIRECT
    description: Hyperexcitable visceral afferents produce episodic abdominal pain.
    evidence:
    - reference: PMID:31551682
      reference_title: "A Novel Gain-of-Function Nav1.9 Mutation in a Child With Episodic Pain."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: episodic pain in both legs, episodic abdominal pain, and chronic constipation
      explanation: Records the abdominal pain in the index case.
  - target: Constipation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Constipation accompanies the enteric involvement; whether it follows from
      altered myenteric motor control or from pain-related behaviour is not
      established.
    evidence:
    - reference: PMID:24972070
      reference_title: "Multiple roles for NaV1.9 in the activation of visceral afferents by noxious inflammatory, mechanical, and human disease-derived stimuli."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: We show that NaV1.9 is required for normal mechanosensation, for direct
        excitation and for sensitization of mouse colonic afferents
      explanation: Supports a role for the channel in colonic afferent function, from
        which a motility consequence is inferred rather than shown.
phenotypes:
- name: Episodic pain
  category: Neurological
  description: >-
    Paroxysmal, severe pain lasting fifteen to thirty minutes and recurring
    several times a day, with complete freedom from pain between episodes. This
    is the defining feature and is present in essentially all affected
    individuals.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Episodic pain
    term:
      id: HP:0032148
      label: Episodic pain
  evidence:
  - reference: PMID:36051609
    reference_title: "Familial Episodic Pain Syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Familial episodic pain syndromes (FEPS) are one of the distinctive syndromes
      characterized by early-childhood onset of severe episodic pain mainly affecting
      the distal extremities and tend to attenuate or diminish with age
    explanation: States the defining episodic character and its distal distribution.
- name: Lower limb pain
  category: Neurological
  description: >-
    Pain predominantly in the lower limbs, most often the knees and ankles, with
    the wrists and elbows affected less frequently. The affected region feels
    cold to the patient and warming it relieves the pain. The distribution is
    not strictly confined to the legs: the review characterizes FEPS3 pain as
    affecting distal joints and occasionally the proximal limbs and neck, so the
    lower-limb predominance in the disease name is a tendency rather than a
    boundary.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Lower limb pain
    term:
      id: HP:0012514
      label: Lower limb pain
  evidence:
  - reference: PMID:30549873
    reference_title: "[Paroxysmal limb intolerable pain (infantile pain episodes associated with novel Nav1.9 mutations in familial episodic pain syndrome)]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The affected regions feel cold in the patients, and warming the lesions
      relieves the symptoms
    explanation: Records the cold sensation and the relief by warming, which is the
      discriminating feature against erythromelalgia.
  - reference: PMID:36051609
    reference_title: "Familial Episodic Pain Syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Distal joints, occasionally proximal limbs and neck
    explanation: Gives the fuller distribution, which extends beyond the lower limbs
      the disease is named for.
- name: Arthralgia
  category: Musculoskeletal
  description: >-
    The pain is localized by patients to joints - knees and ankles first, then
    wrists and elbows - although no joint pathology is present.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Arthralgia
    term:
      id: HP:0002829
      label: Arthralgia
  evidence:
  - reference: PMID:30549873
    reference_title: "[Paroxysmal limb intolerable pain (infantile pain episodes associated with novel Nav1.9 mutations in familial episodic pain syndrome)]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The affected joints, in an in- creasing order of frequency, include those
      in the knees, ankles, wrists, and elbows'
    explanation: Gives the joint distribution and its rank order.
  notes: >-
    The quoted sentence reproduces a line-break hyphenation artifact present in
    the cached source, where the word "increasing" is split across a line. It is
    quoted exactly rather than repaired, because a snippet must be a true
    substring of the cited source.
- name: Abdominal pain
  category: Gastrointestinal
  description: Episodic abdominal pain, reported with the p.Asn816Lys allele and not
    a feature of most reported patients.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain
  evidence:
  - reference: PMID:31551682
    reference_title: "A Novel Gain-of-Function Nav1.9 Mutation in a Child With Episodic Pain."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: a child with early-onset episodic pain in both legs, episodic abdominal
      pain, and chronic constipation
    explanation: The index case for the enteric branch of the phenotype.
- name: Constipation
  category: Gastrointestinal
  description: Chronic constipation accompanying the enteric involvement in the same
    variant.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Constipation
    term:
      id: HP:0002019
      label: Constipation
    temporality: CHRONIC
  evidence:
  - reference: PMID:31551682
    reference_title: "A Novel Gain-of-Function Nav1.9 Mutation in a Child With Episodic Pain."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: episodic pain in both legs, episodic abdominal pain, and chronic constipation
    explanation: Records the constipation in the index case.
- name: Hyperhidrosis
  category: Autonomic
  description: >-
    Excessive sweating, reported among the autonomic features that accompany
    the pain episodes in some patients alongside intestinal spasm and
    constipation.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hyperhidrosis
    term:
      id: HP:0000975
      label: Hyperhidrosis
  evidence:
  - reference: PMID:36051609
    reference_title: "Familial Episodic Pain Syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: hyperhidrosis, constipation, and intestinal spasm can be concomitantly
      observed in some patients
    explanation: Lists the autonomic features observed alongside the pain.
- name: Tremor
  category: Neurological
  description: >-
    Adult-onset essential tremor co-segregating with the p.Arg225Cys allele in
    one four-generation family. This is a co-segregation observation in a single
    pedigree, not an established feature of the syndrome.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Tremor
    term:
      id: HP:0001337
      label: Tremor
  evidence:
  - reference: PMID:28298626
    reference_title: "Gain-of-function mutation p.Arg225Cys in SCN11A causes familial episodic pain and contributes to essential tremor."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We confirmed the presence of the SCN11A (c.673C>T) mutation in family
      members with episodic pain and essential tremor
    explanation: Reports the co-segregation of both phenotypes with the variant.
  notes: >-
    Deliberately left unconnected in the pathograph. Every other phenotype here
    is reached by a downstream edge from a mechanism node, but no mechanism has
    been proposed linking NaV1.9 to tremor, and this is a co-segregation
    observation in a single pedigree. Drawing an edge would assert a causal
    claim the source does not make.
progression:
- phase: Infantile and early childhood onset
  age_range: Infancy to early childhood
  notes: >-
    Episodes begin in infancy or early childhood and are at their most frequent
    and severe during childhood, when they disrupt sleep, activity and
    schooling.
  evidence:
  - reference: PMID:30549873
    reference_title: "[Paroxysmal limb intolerable pain (infantile pain episodes associated with novel Nav1.9 mutations in familial episodic pain syndrome)]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Affected participants were characterized by infantile recurrent pain episodes,
      with spontaneous mitigation around adolescence
    explanation: Gives both the onset and the natural history in one sentence.
- phase: Spontaneous attenuation around adolescence
  age_range: Adolescence
  notes: >-
    Episodes diminish or remit around adolescence without disease-modifying
    treatment. The mechanism of the age dependence is not established. This is
    what makes the long-term prognosis benign despite a severe childhood
    symptom burden.
  evidence:
  - reference: PMID:39058404
    reference_title: "Familial Episodic Pain Syndrome: A Japanese Family Harboring the Novel Variant c.2431C>T (p.Leu811Phe) in SCN11A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: FEPS appears in early childhood, gradually disappearing with age, and
      pain episodes can be triggered by fatigue, bad weather, and cold temperatures
    explanation: States the age-dependent remission together with the triggers.
prevalence:
- population: Japan
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Forty-eight Japanese families had been recruited by 2018, the largest series
    reported. No population rate has been estimated for this disorder anywhere,
    so the qualitative band is the only claim the sources support.
  evidence:
  - reference: PMID:30557356
    reference_title: "Familial episodic limb pain in kindreds with novel Nav1.9 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: we recruited an additional 42 new unrelated Japanese FEP families, between
      March 2016 and March 2018
    explanation: Gives the size of the largest reported series.
environmental:
- name: Cold ambient exposure
  description: >-
    Cold precipitates episodes and the affected region feels cold to the
    patient, while warming relieves the pain. The cellular counterpart is that
    gain-of-function NaV1.9 confers hyperexcitability that persists at cold
    temperatures, where nociceptor firing would normally be suppressed.
  influences_mechanisms:
  - target: Nociceptor Hyperexcitability with Reduced Firing Threshold
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: Cold is the modality at which the mutant channel's hyperexcitability
      is retained, which is why cooling provokes rather than suppresses firing.
    evidence:
    - reference: PMID:26645915
      reference_title: "Cold-aggravated pain in humans caused by a hyperactive NaV1.9 channel mutant."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: cause cold-resistant hyperexcitability of nociceptors, suggesting a mechanistic
        basis for the temperature dependence of the pain phenotype
      explanation: Ties the cold trigger to the cellular mechanism explicitly.
  evidence:
  - reference: PMID:39058404
    reference_title: "Familial Episodic Pain Syndrome: A Japanese Family Harboring the Novel Variant c.2431C>T (p.Leu811Phe) in SCN11A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: pain episodes can be triggered by fatigue, bad weather, and cold temperatures
    explanation: Records cold as a clinical trigger of episodes.
  review_notes: >-
    ECTO was searched for an ambient-cold exposure term and none fits: the
    closest matches are exposure to cold room, exposure to cold water immersion
    therapy and exposure to cold cereal via ingestion, none of which names
    ambient cold or cold weather. Left unbound rather than bound to a near miss.
- name: Physical fatigue
  description: >-
    Physical exertion and fatigue precipitate episodes; rest and warming
    mitigate them. Reported consistently across the Japanese families.
  influences_mechanisms:
  - target: Ectopic Nociceptive Signalling from Distal Limb Afferents
    environmental_effect: TRIGGERS
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Fatigue is a reproducible clinical trigger, but no mechanism connecting
      exertion to NaV1.9 activity has been demonstrated.
    evidence:
    - reference: PMID:30549873
      reference_title: "[Paroxysmal limb intolerable pain (infantile pain episodes associated with novel Nav1.9 mutations in familial episodic pain syndrome)]."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The pain is often induced by fa- tigue and is a prelude of bad weather
      explanation: Records fatigue as a trigger, from the clinical description of six
        families.
  evidence:
  - reference: PMID:30549873
    reference_title: "[Paroxysmal limb intolerable pain (infantile pain episodes associated with novel Nav1.9 mutations in familial episodic pain syndrome)]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The pain is often induced by fa- tigue and is a prelude of bad weather
    explanation: Establishes fatigue and impending weather change as episode triggers.
  review_notes: >-
    ECTO was searched for a physical-exertion or fatigue exposure term and no
    suitable match was found, so this entry is deliberately left unbound.
treatments:
- name: Warming and Trigger Avoidance
  description: >-
    The first-line and most effective intervention: warming the affected limb
    relieves an episode, and avoiding cold and fatigue reduces episode
    frequency. It is unusual for a behavioural measure to be first-line, and it
    follows directly from the mechanism - the trigger is the cold-resistant
    hyperexcitability, so removing the cold removes the drive.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Nociceptor Hyperexcitability with Reduced Firing Threshold
    description: Warming removes the thermal condition under which the mutant channel
      sustains firing.
    evidence:
    - reference: PMID:30549873
      reference_title: "[Paroxysmal limb intolerable pain (infantile pain episodes associated with novel Nav1.9 mutations in familial episodic pain syndrome)]."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The affected regions feel cold in the patients, and warming the lesions
        relieves the symptoms
      explanation: Reports symptomatic relief by warming in the founding families.
  evidence:
  - reference: PMID:30549873
    reference_title: "[Paroxysmal limb intolerable pain (infantile pain episodes associated with novel Nav1.9 mutations in familial episodic pain syndrome)]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The affected regions feel cold in the patients, and warming the lesions
      relieves the symptoms
    explanation: The clinical observation that warming relieves the pain.
- name: Genetic Counseling
  description: >-
    Counselling for the fifty percent recurrence risk of an autosomal dominant
    condition, with cascade testing of at-risk relatives once a familial variant
    is known. Counselling can be unusually reassuring here, because the natural
    history is benign and remits with age.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:39058404
    reference_title: "Familial Episodic Pain Syndrome: A Japanese Family Harboring the Novel Variant c.2431C>T (p.Leu811Phe) in SCN11A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This variant was confirmed in other affected members but not in the unaffected
      father
    explanation: Illustrates the familial segregation testing that cascade counselling
      rests on.
animal_models:
- name: Scn11a R222S knock-in mouse
  species: Mouse
  genotype: Scn11a p.R222S knock-in
  publication: PMID:30549873
  description: >-
    A knock-in mouse carrying one of the two alleles found in the founding
    Japanese families, generated in the same study that identified them.
  modeled_mechanisms:
  - target: Nociceptor Hyperexcitability with Reduced Firing Threshold
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Reproduces both the cellular defect - increased input impedance and
      evoked firing frequency in dorsal root ganglion neurons - and a
      behavioural correlate of the thermal sensitivity.
    limitations: >-
      The mouse cannot model the episodic, weather-triggered character of the
      human pain or its spontaneous remission in adolescence, which are the two
      features that define the syndrome clinically.
    readouts:
    - name: Evoked action potential firing frequency in DRG neurons
      target: Nociceptor Hyperexcitability with Reduced Firing Threshold
      direction: INCREASED
      interpretation: The direct electrophysiological correlate of the hyperexcitability
        node.
      evidence:
      - reference: PMID:30549873
        reference_title: "[Paroxysmal limb intolerable pain (infantile pain episodes associated with novel Nav1.9 mutations in familial episodic pain syndrome)]."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: showed significant increase of input impedance and firing frequency
          of evoked action potentials in p.R222S mice
        explanation: Reports the measurement in the knock-in model.
    - name: Behavioural sensitivity to hot and cold stimuli
      target: Nociceptor Hyperexcitability with Reduced Firing Threshold
      direction: INCREASED
      interpretation: Whole-animal correlate showing the cellular change reaches
        behaviour.
      evidence:
      - reference: PMID:30549873
        reference_title: "[Paroxysmal limb intolerable pain (infantile pain episodes associated with novel Nav1.9 mutations in familial episodic pain syndrome)]."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: Behavioral tests showed that p.R222S mice were significantly more
          hypersensitive to hot and cold stimuli
        explanation: Reports the behavioural readout.
    evidence:
    - reference: PMID:30549873
      reference_title: "[Paroxysmal limb intolerable pain (infantile pain episodes associated with novel Nav1.9 mutations in familial episodic pain syndrome)]."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Next, we generated a knock-in mouse model harboring one of the mutations
        (p.R222S)
      explanation: Establishes that the model carries an actual patient allele, which
        is what makes it informative for this node.
- name: Scn11a F802C and F1125S knock-in mice
  species: Mouse
  genotype: Scn11a p.F802C or p.F1125S knock-in (orthologues of human p.F814C and p.F1146S)
  publication: PMID:30557356
  description: >-
    Knock-in mice for the mouse orthologues of two novel human alleles,
    generated specifically to classify those variants functionally.
  modeled_mechanisms:
  - target: Depolarized Resting Membrane Potential in Nociceptors
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Both lines show the raised resting membrane potential and increased firing
      that define this node, which is how the two human variants were assigned
      gain-of-function status.
    limitations: >-
      The alleles modelled are the mouse orthologous residues rather than the
      human variants themselves, and several action-potential parameters and the
      current threshold did not differ from wild type, so the effect is
      narrower than a global excitability increase.
    readouts:
    - name: Resting membrane potential in DRG neurons
      target: Depolarized Resting Membrane Potential in Nociceptors
      direction: INCREASED
      interpretation: The defining measurement for this node, in both knock-in lines.
      evidence:
      - reference: PMID:30557356
        reference_title: "Familial episodic limb pain in kindreds with novel Nav1.9 mutations."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: Dissected neurons of F802C and F1125S mice showed increased resting
          membrane potentials and firing frequency of the action potentials (APs) by
          high input-current stimulus compared with WT mice
        explanation: Reports the resting-potential and firing measurements in both
          lines.
    evidence:
    - reference: PMID:30557356
      reference_title: "Familial episodic limb pain in kindreds with novel Nav1.9 mutations."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: These results suggest a higher level of excitability in the F802C or
        F1125S mice than in WT, and indicate that these novel mutations are gain of
        function mutations
      explanation: The authors' own conclusion that the models establish gain of
        function.
- name: Nav1.9-null mouse
  species: Mouse
  genotype: Scn11a knockout
  publication: PMID:27780178
  description: >-
    The loss-of-function counterpart. It does not model the disease - it carries
    the opposite lesion - but it establishes what NaV1.9 normally contributes,
    which is the necessity half of the causal argument the gain-of-function
    knock-ins make from the sufficiency side.
  modeled_mechanisms:
  - target: Nociceptor Hyperexcitability with Reduced Firing Threshold
    relationship: PERTURBS
    fidelity: MODERATE
    description: >-
      Deleting the channel moves nociceptor excitability in the opposite
      direction to the disease: C-fibre electrical threshold rises by 55% and
      mechanical and thermal thresholds rise with it.
    limitations: >-
      This is an inverted model. It removes the channel rather than carrying a
      disease variant, so it can support the direction of the mechanism but
      cannot recapitulate the syndrome, and no inference about the episodic
      phenotype can be drawn from it.
    readouts:
    - name: C-fibre electrical threshold
      target: Nociceptor Hyperexcitability with Reduced Firing Threshold
      direction: INCREASED
      interpretation: >-
        Threshold rises on channel deletion, the mirror image of the reduced
        threshold that defines the node in disease.
      evidence:
      - reference: PMID:27780178
        reference_title: "Reduced excitability and impaired nociception in peripheral unmyelinated fibers from Nav1.9-null mice."
        supports: SUPPORT
        directness: INDIRECT
        evidence_source: MODEL_ORGANISM
        snippet: the electrical threshold of NaV1.9 KO C fibers was elevated by 55%
          and the median von Frey threshold was 32 mN in contrast to 8 mN in wild types
        explanation: Quantifies the inverse effect; it supports the mechanism by
          inversion rather than by recapitulation.
    evidence:
    - reference: PMID:27780178
      reference_title: "Reduced excitability and impaired nociception in peripheral unmyelinated fibers from Nav1.9-null mice."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: NaV1.9 presumably contributes to acute thermal and mechanical nociception
        in mice, most likely through increasing the excitability
      explanation: Establishes the channel's normal excitability role, which is what
        makes the inverted model informative for this node.
histopathology:
- name: Reduced intraepidermal nerve fibre density with unmyelinated axon degeneration
  description: >-
    Skin biopsy in some patients shows reduced intraepidermal nerve fibre
    density and vacuolar degeneration of unmyelinated axons - a small-fibre
    neuropathy. This is the finding that qualifies the otherwise-true statement
    that investigation in this disease is normal: routine studies interrogate
    large fibres, and the lesion is in the small ones. It also matters for
    prognosis, since degeneration of the fibres carrying the pain has been
    proposed as a mechanism for the age-dependent remission.
  finding_term:
    preferred_term: reduced intraepidermal nerve fibre density
  evidence:
  - reference: PMID:36051609
    reference_title: "Familial Episodic Pain Syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Skin biopsies in some FEPS3 patients have revealed different degrees of
      reduction of intraepidermal nerve fiber density and vacuolar degeneration of
      unmyelinated axons, indicating small-fiber neuropathy
    explanation: Reports the histological lesion and names it as small-fibre
      neuropathy.
  notes: >-
    Present in some patients rather than all, and the source does not report a
    frequency.
diagnosis:
- name: Sodium-channelopathy gene panel sequencing
  description: >-
    The definitive diagnostic. Because FEPS1, FEPS2, FEPS3 and FEPS4 are
    clinically overlapping and separated only by genotype, a panel covering
    SCN11A, SCN10A, SCN9A and TRPA1 is a more sensible first test than
    single-gene sequencing, with exome or genome sequencing for
    panel-negative cases.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:36051609
    reference_title: "Familial Episodic Pain Syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: FEPS at least includes four subtypes of FEPS1, FEPS2, FEPS3, and FEPS4,
      which are caused by mutations in the TRPA1, SCN10A, SCN11A, and SCN9A genes,
      respectively
    explanation: The four-gene overlap is what makes panel sequencing rather than
      single-gene testing the appropriate approach.
  - reference: PMID:39058404
    reference_title: "Familial Episodic Pain Syndrome: A Japanese Family Harboring the Novel Variant c.2431C>T (p.Leu811Phe) in SCN11A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Sequencing of SCN9A, SCN10A, and SCN11A in the proband revealed a novel
      heterozygous variant of SCN11A'
    explanation: A worked example of the panel approach reaching the diagnosis.
- name: Quantitative sensory testing and nerve conduction studies
  description: >-
    Nerve conduction studies are normal in most patients, which is a useful
    negative: it excludes a large-fibre neuropathy. Quantitative sensory
    testing is the informative one, showing abnormal cold and warm thresholds
    in some patients - the objective correlate of the thermal sensitivity that
    defines the syndrome clinically.
  diagnosis_term:
    preferred_term: quantitative sensory testing
    term:
      id: NCIT:C155860
      label: Quantitative Sensory Testing
  evidence:
  - reference: PMID:36051609
    reference_title: "Familial Episodic Pain Syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Nerve conduction studies were normal in most patients, while QST showed
      abnormal cold and warm temperature thresholds in some patients
    explanation: Gives both the normal large-fibre result and the abnormal thermal
      thresholds in one sentence.
differential_diagnoses:
- name: Inherited erythromelalgia
  disease_term:
    preferred_term: erythromelalgia
    term:
      id: MONDO:0007571
      label: primary erythermalgia
  description: >-
    The differential most worth stating, because the two look superficially
    similar and are separated by a single bedside observation that runs the
    opposite way. Curated in this knowledge base as Primary_Erythermalgia. Erythromelalgia produces red, hot, hyperperfused extremities
    relieved by cooling; FEPS3 patients report that the affected region feels
    cold and that warming relieves the pain.
  evidence:
  - reference: PMID:29299961
    reference_title: "Erythromelalgia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: by the permanent occurrence of extremely painful hyperperfused skin
    explanation: Gives the hyperperfused character of erythromelalgia, which is the
      direct opposite of the cold, warmth-relieved pain of this disorder and is what
      separates them at the bedside.
  - reference: PMID:29299961
    reference_title: "Erythromelalgia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: affecting SCN9A, SCN10A, and SCN11A coding for NaV1.7, NaV1.8, and NaV1.9
    explanation: Notes that erythromelalgia arises from the same three sodium-channel
      genes, so the gene alone does not distinguish the two conditions and the clinical
      thermal character has to.
- name: Growing pains
  description: >-
    The differential a clinician actually faces first. A child with recurrent
    self-limited limb pain that resolves with age is far more likely to have
    benign growing pains than a sodium channelopathy; what separates them is a
    segregating family history in an autosomal dominant pattern, the
    reproducible cold and fatigue triggers, and a molecular diagnosis.
  evidence:
  - reference: PMID:36051609
    reference_title: "Familial Episodic Pain Syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: characterized by early-childhood onset of severe episodic pain mainly
      affecting the distal extremities and tend to attenuate or diminish with age
    explanation: The features quoted here are exactly the ones growing pains shares,
      which is what makes the distinction rest on family history and genotype rather
      than on the pain description.
- name: Other familial episodic pain syndromes
  description: >-
    FEPS1 (TRPA1), FEPS2 (SCN10A) and FEPS4 (SCN9A) produce overlapping
    distal episodic pain and are separated only by sequencing. FEPS2 in
    particular also causes distal, predominantly lower-limb episodic pain, which
    is why a gene panel rather than single-gene testing is the sensible first
    test.
  evidence:
  - reference: PMID:36051609
    reference_title: "Familial Episodic Pain Syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: FEPS at least includes four subtypes of FEPS1, FEPS2, FEPS3, and FEPS4,
      which are caused by mutations in the TRPA1, SCN10A, SCN11A, and SCN9A genes,
      respectively
    explanation: Enumerates the sibling subtypes this entry must be distinguished from.
- name: Congenital insensitivity to pain
  disease_term:
    preferred_term: congenital insensitivity to pain
    term:
      id: MONDO:0015364
      label: hereditary sensory and autonomic neuropathy
  description: >-
    Curated in this knowledge base as Congenital_Insensitivity_to_Pain. Not a
    clinical mimic but the opposite phenotype from the same gene, and the
    reason variant interpretation here cannot rely on "gain of function" alone.
    Extreme gain of function produces sustained depolarization block and loss of
    firing; at the Leu811 residue the substitution decides which phenotype
    results.
  evidence:
  - reference: PMID:39058404
    reference_title: "Familial Episodic Pain Syndrome: A Japanese Family Harboring the Novel Variant c.2431C>T (p.Leu811Phe) in SCN11A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: On the other hand, the c.2432T>C (p.Leu811Pro) variant is known to cause
      congenital insensitivity to pain (CIP)
    explanation: Documents the opposite phenotype arising at the same residue.
discussions:
- discussion_id: gain_of_function_degree_threshold
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: What determines whether a gain-of-function SCN11A variant causes episodic
    pain or congenital insensitivity to pain?
  attaches_to:
  - pathophysiology#Hyperpolarized NaV1.9 Activation with Enlarged Window Current
  - genetic#SCN11A
  rationale: >-
    Both phenotypes arise from gain of function in the same channel, and at
    Leu811 they arise from different substitutions of the same residue. The
    proposed explanation is that moderate gain of function lowers the firing
    threshold while extreme gain of function depolarizes the membrane far enough
    to inactivate the sodium channels needed to fire at all. No study has
    measured a quantitative boundary between the two regimes, so a novel variant
    with demonstrated gain of function cannot yet be assigned to a phenotype on
    biophysics alone. This matters clinically because the two conditions have
    opposite management.
  evidence:
  - reference: PMID:26645915
    reference_title: "Cold-aggravated pain in humans caused by a hyperactive NaV1.9 channel mutant."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: we propose a model in which the physiological consequence of a mutation,
      that is, augmented versus absent pain, is critically dependent on the type of
      NaV1.9 hyperactivity
    explanation: States the proposal as a model rather than a demonstrated threshold,
      which is precisely the gap.
  - reference: PMID:39058404
    reference_title: "Familial Episodic Pain Syndrome: A Japanese Family Harboring the Novel Variant c.2431C>T (p.Leu811Phe) in SCN11A."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: Thus, we speculate that p.Leu811Phe may lead to current leakage, while
      p.Leu811Pro can increase the current through Nav1.9
    explanation: The authors' own hedging ("we speculate") shows the divergence is
      not yet mechanistically settled even for the one residue where both phenotypes
      are observed.
- discussion_id: age_dependent_remission_mechanism
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Why do episodes attenuate spontaneously around adolescence when the causal
    variant is present for life?
  attaches_to:
  - progression#Spontaneous attenuation around adolescence
  - pathophysiology#Nociceptor Hyperexcitability with Reduced Firing Threshold
  rationale: >-
    The remission is the most clinically important fact about this disease -
    it is why the prognosis is benign - and no mechanism has been demonstrated.
    The germline variant does not change, so the attenuation must come from
    something acquired or developmental: changing NaV1.9 expression, changing
    nociceptor properties, or changing central processing. A fourth candidate is
    proposed in the literature and is the most uncomfortable one, because it
    makes the good news and the bad news the same event: long-term NaV1.9
    dysfunction may itself degenerate the unmyelinated fibres, so pain could
    remit because the fibres carrying it are being lost. That would tie this gap
    directly to the small-fibre histopathology curated in this entry. It is
    offered speculatively by its authors and has not been measured across the
    relevant age range in patients, nor in the knock-in mice, which are studied
    at six to eight weeks.
  evidence:
  - reference: PMID:30549873
    reference_title: "[Paroxysmal limb intolerable pain (infantile pain episodes associated with novel Nav1.9 mutations in familial episodic pain syndrome)]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Affected participants were characterized by infantile recurrent pain episodes,
      with spontaneous mitigation around adolescence
    explanation: Establishes the phenomenon that lacks a demonstrated mechanism.
  - reference: PMID:36051609
    reference_title: "Familial Episodic Pain Syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: long-term dysfunction of the Nav1.9 channel may cause degeneration of
      the unmyelinated fibers in FEPS3 patient with pain remission
    explanation: The one candidate mechanism the literature offers for the remission,
      hedged by its own authors as a possibility rather than a finding.
notes: >-
  Scope, and why this entry is SCN11A only. The disease name "predominantly
  lower limb involvement" does not by itself pick a gene, and the deep-research
  report says so explicitly in its own limitations: FEPS2 (SCN10A) also causes
  distal, predominantly lower-limb episodic pain. The preflight check flagged
  the same risk, with SCN10A mentioned at 43% of the rate of SCN11A. The
  question is settled by the ontology rather than by the prose: MONDO:0014247
  carries OMIM 615552, which is FEPS3, which is SCN11A. FEPS1 (TRPA1), FEPS2
  (SCN10A) and FEPS4 (SCN9A) each have their own concepts and are curated here
  as differentials, not as content. Sections of the report covering SCN10A
  biology were excluded on that basis.

  Terms deliberately not bound. Neither environmental trigger carries an
  exposure_term. ECTO was searched for ambient cold and for physical exertion;
  the closest cold matches are exposure to cold room, exposure to cold water
  immersion therapy and exposure to cold cereal via ingestion, none of which
  names ambient cold or cold weather, and nothing suitable exists for fatigue.
  Both are left unbound with the search recorded in review_notes rather than
  bound to a near miss. The myenteric neuron node is bound to CL:0000101
  sensory neuron rather than to an enteric neuron type: the report proposed
  CL:0011103 for "enteric neuron" and that identifier is sympathetic neuron.

  Report term corrections. This report's suggested identifiers were unusually
  unreliable and none of the following was used. Five were flagged by the
  report's own term validation as naming a different concept: HP:0025277,
  offered for episodic pain, is Gustatory sweating; HP:0500152, offered for
  cold-induced pain, is Hypocystinemia; HP:0003394, offered for limb pain, is
  Muscle spasm; GO:0045211, offered for "axon/terminal", is postsynaptic
  membrane; and UBERON:0001132, offered for trigeminal ganglion, is parathyroid
  gland. A sixth, CL:0011103 for enteric neuron, is sympathetic neuron. Beyond
  those, all four NCIT identifiers the report proposed for treatments are wrong,
  and none was caught by the report's own validation because that section does
  not check NCIT: C15272, offered for Supportive Care, is Lobectomy; C376,
  offered for Carbamazepine, is Cisplatin; C198, offered for NSAID, is
  Acetaminophen; and C15311, offered for Genetic Counseling, is Quality Control.
  The correct terms NCIT:C15747 and NCIT:C15240 are used here. Every identifier
  in this entry was checked against its ontology before binding, and HP:0032148
  Episodic pain - which the report did not propose at all - is the exact term
  for the defining phenotype.

  Deliberately not curated, and five references read and set aside. No
  treatments beyond warming, trigger avoidance and genetic counselling. The
  report lists NSAIDs, carbamazepine, lidocaine and mexiletine as off-label
  symptomatic options, but the one paper it cites for any of them reports
  carbamazepine correcting the gating of a NaV1.8-S242T channel in a patient
  with painful diabetic neuropathy - a different channel in a different
  disease. Curating that as a treatment here would assert a clinical use no
  source supports. The PRMT7 inhibitor DS-437 and transcutaneous cholesterol
  are preclinical mouse findings about channel regulation, not treatments for
  this disorder. A NaV1.8/NaV1.9 double-knockout study and a general
  sodium-channel-analgesia review are likewise about the target rather than the
  disease. All five were fetched by the research run, read, and their caches
  are not shipped. No prevalence rate: none exists in the literature, so only
  the qualitative band is claimed.

  Source defects reproduced rather than repaired. The cached abstract of
  PMID:30549873 carries line-break hyphenation artifacts from its source
  ("fa- tigue", "in- creasing", "var- iants"). Where a quote spans one of these,
  the artifact is reproduced exactly, because the snippet must be a true
  substring of the cited source and silently repairing a quote is worse than an
  ugly one.

  Review round two. The entry originally claimed there is no tissue damage at
  any point. That was wrong, and wrong against a source this entry already cited
  five times: skin biopsy in some patients shows reduced intraepidermal nerve
  fibre density and vacuolar degeneration of unmyelinated axons. The narrower
  claims were and are correct - nerve conduction studies are normal, imaging and
  inflammatory markers are normal, there is no joint pathology - and the error
  was generalizing from those to the whole nervous system when routine studies
  interrogate large fibres and the lesion is in the small ones. The claim is now
  scoped, and the small-fibre lesion is curated as histopathology.

  That correction changes the remission gap too. The same paragraph of the same
  review proposes that long-term NaV1.9 dysfunction may itself degenerate the
  unmyelinated fibres in patients whose pain remits - which would make the good
  prognosis and the nerve damage the same event. The gap previously said the
  remission was entirely unexplained, which understated what the literature
  offers; it now carries this candidate, hedged as its authors hedge it.

  Also in round two: the resting-potential node was bound to GO:0086010,
  membrane depolarization during action potential, which contradicted the node's
  own statement that NaV1.9 does not drive the action potential upstroke;
  GO:0051899 membrane depolarization is used instead. The myenteric node was
  bound to CL:0000101 sensory neuron, which was a second wrong binding after
  correctly rejecting the report's CL:0011103; myenteric neurons are motor and
  interneuron populations, and CL:0007011 enteric neuron is used. Four nodes now
  declare conforms_to against nociceptor_sodium_channel_excitability, whose
  description names this disease by mechanism and which three sibling entries
  already conform to. A diagnosis section was added covering panel sequencing
  and quantitative sensory testing, the latter being the objective correlate of
  the thermal sensitivity that defines the syndrome.

📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Record notes

Scope, and why this entry is SCN11A only. The disease name "predominantly lower limb involvement" does not by itself pick a gene, and the deep-research report says so explicitly in its own limitations: FEPS2 (SCN10A) also causes distal, predominantly lower-limb episodic pain. The preflight check flagged the same risk, with SCN10A mentioned at 43% of the rate of SCN11A. The question is settled by the ontology rather than by the prose: MONDO:0014247 carries OMIM 615552, which is FEPS3, which is SCN11A. FEPS1 (TRPA1), FEPS2 (SCN10A) and FEPS4 (SCN9A) each have their own concepts and are curated here as differentials, not as content. Sections of the report covering SCN10A biology were excluded on that basis. Terms deliberately not bound. Neither environmental trigger carries an exposure_term. ECTO was searched for ambient cold and for physical exertion; the closest cold matches are exposure to cold room, exposure to cold water immersion therapy and exposure to cold cereal via ingestion, none of which names ambient cold or cold weather, and nothing suitable exists for fatigue. Both are left unbound with the search recorded in review_notes rather than bound to a near miss. The myenteric neuron node is bound to CL:0000101 sensory neuron rather than to an enteric neuron type: the report proposed CL:0011103 for "enteric neuron" and that identifier is sympathetic neuron. Report term corrections. This report's suggested identifiers were unusually unreliable and none of the following was used. Five were flagged by the report's own term validation as naming a different concept: HP:0025277, offered for episodic pain, is Gustatory sweating; HP:0500152, offered for cold-induced pain, is Hypocystinemia; HP:0003394, offered for limb pain, is Muscle spasm; GO:0045211, offered for "axon/terminal", is postsynaptic membrane; and UBERON:0001132, offered for trigeminal ganglion, is parathyroid gland. A sixth, CL:0011103 for enteric neuron, is sympathetic neuron. Beyond those, all four NCIT identifiers the report proposed for treatments are wrong, and none was caught by the report's own validation because that section does not check NCIT: C15272, offered for Supportive Care, is Lobectomy; C376, offered for Carbamazepine, is Cisplatin; C198, offered for NSAID, is Acetaminophen; and C15311, offered for Genetic Counseling, is Quality Control. The correct terms NCIT:C15747 and NCIT:C15240 are used here. Every identifier in this entry was checked against its ontology before binding, and HP:0032148 Episodic pain - which the report did not propose at all - is the exact term for the defining phenotype. Deliberately not curated, and five references read and set aside. No treatments beyond warming, trigger avoidance and genetic counselling. The report lists NSAIDs, carbamazepine, lidocaine and mexiletine as off-label symptomatic options, but the one paper it cites for any of them reports carbamazepine correcting the gating of a NaV1.8-S242T channel in a patient with painful diabetic neuropathy - a different channel in a different disease. Curating that as a treatment here would assert a clinical use no source supports. The PRMT7 inhibitor DS-437 and transcutaneous cholesterol are preclinical mouse findings about channel regulation, not treatments for this disorder. A NaV1.8/NaV1.9 double-knockout study and a general sodium-channel-analgesia review are likewise about the target rather than the disease. All five were fetched by the research run, read, and their caches are not shipped. No prevalence rate: none exists in the literature, so only the qualitative band is claimed. Source defects reproduced rather than repaired. The cached abstract of PMID:30549873 carries line-break hyphenation artifacts from its source ("fa- tigue", "in- creasing", "var- iants"). Where a quote spans one of these, the artifact is reproduced exactly, because the snippet must be a true substring of the cited source and silently repairing a quote is worse than an ugly one. Review round two. The entry originally claimed there is no tissue damage at any point. That was wrong, and wrong against a source this entry already cited five times: skin biopsy in some patients shows reduced intraepidermal nerve fibre density and vacuolar degeneration of unmyelinated axons. The narrower claims were and are correct - nerve conduction studies are normal, imaging and inflammatory markers are normal, there is no joint pathology - and the error was generalizing from those to the whole nervous system when routine studies interrogate large fibres and the lesion is in the small ones. The claim is now scoped, and the small-fibre lesion is curated as histopathology. That correction changes the remission gap too. The same paragraph of the same review proposes that long-term NaV1.9 dysfunction may itself degenerate the unmyelinated fibres in patients whose pain remits - which would make the good prognosis and the nerve damage the same event. The gap previously said the remission was entirely unexplained, which understated what the literature offers; it now carries this candidate, hedged as its authors hedge it. Also in round two: the resting-potential node was bound to GO:0086010, membrane depolarization during action potential, which contradicted the node's own statement that NaV1.9 does not drive the action potential upstroke; GO:0051899 membrane depolarization is used instead. The myenteric node was bound to CL:0000101 sensory neuron, which was a second wrong binding after correctly rejecting the report's CL:0011103; myenteric neurons are motor and interneuron populations, and CL:0007011 enteric neuron is used. Four nodes now declare conforms_to against nociceptor_sodium_channel_excitability, whose description names this disease by mechanism and which three sibling entries already conform to. A diagnosis section was added covering panel sequencing and quantitative sensory testing, the latter being the objective correlate of the thermal sensitivity that defines the syndrome.

Create: familial episodic pain syndrome 3 (SCN11A) · 2026-09-02T00:01:21Z · View source

Curated FEPS3 from an OpenScientist deep-research report plus 11 cited PubMed abstracts. Six-node pathograph from a heterozygous SCN11A gain-of-function missense variant through hyperpolarized NaV1.9 activation with an enlarged window current, a depolarized resting membrane potential in small-diameter dorsal root ganglion neurons, and nociceptor hyperexcitability that is retained at cold temperatures, to ectopic nociceptive signalling from distal limb afferents, with a variant-dependent myenteric branch. Scope was the first decision and is recorded in the entry notes: the disease name does not pick a gene, the report itself flags in its limitations that FEPS2 (SCN10A) also causes distal lower-limb episodic pain, and the preflight check reported SCN10A at 43 percent of the SCN11A mention rate. MONDO:0014247 carries OMIM 615552, which is FEPS3 and therefore SCN11A, so the entry is SCN11A only and FEPS1, FEPS2 and FEPS4 are curated as differentials. Included the NaV1.9-null mouse as a deliberately inverted model with relationship PERTURBS, limitations stating it carries the opposite lesion, and its readout graded directness INDIRECT, since it establishes necessity where the knock-ins establish sufficiency. Two open knowledge gaps: what quantitative degree of gain of function separates episodic pain from congenital insensitivity to pain at the same residue, and why episodes remit around adolescence when the variant is lifelong. This report's suggested identifiers were unusually unreliable and none was adopted. Its own term validation flagged five naming a different concept, including HP:0025277 for episodic pain which is Gustatory sweating and UBERON:0001132 for trigeminal ganglion which is parathyroid gland; a sixth, CL:0011103 for enteric neuron, is sympathetic neuron. Beyond those, all four NCIT identifiers it proposed for treatments are wrong and none was caught by its own validation, which does not check NCIT: C15272 offered for Supportive Care is Lobectomy, C376 for Carbamazepine is Cisplatin, C198 for NSAID is Acetaminophen, and C15311 for Genetic Counseling is Quality Control. Every identifier bound here was checked against its ontology first, and HP:0032148 Episodic pain, which the report never proposed, is the exact term for the defining phenotype. Declined to curate any pharmacotherapy: the only paper cited for carbamazepine concerns a NaV1.8 channel in diabetic neuropathy, and the PRMT7 and cholesterol findings are preclinical mechanism studies rather than treatments. Five references fetched by the research run were read, set aside and their caches not shipped. The cached abstract of PMID:30549873 carries line-break hyphenation artifacts from its source and quotes spanning them reproduce the artifact exactly rather than silently repairing it. Neither environmental trigger is bound to an ECTO term; both searches are recorded in review_notes. Validation: schema, terms and references clean with 62/62 snippets verified; all offline gates green.

OpenScientist ▸

1. Disease Information

openscientist-autonomous 2026-09-01T23:44:32.562917

1. Disease Information

Overview. Familial episodic pain syndrome (FEPS) is a group of rare autosomal‑dominant disorders characterized by early‑childhood onset of severe, self‑limited episodes of pain affecting mainly the distal extremities, which tend to attenuate or diminish with age (Shen 2022, PMID 36051609: "Familial episodic pain syndromes (FEPS) are one of the distinctive syndromes characterized by early-childhood onset of severe episodic pain mainly affecting the distal extremities and tend to attenuate or diminish with age"). The subtype with predominantly lower‑limb involvement corresponds to the tetrodotoxin‑resistant sodium‑channel FEPS subtypes — chiefly FEPS3 (SCN11A/NaV1.9), with FEPS2 (SCN10A/NaV1.8) as a closely related alternative. In Japanese kindreds the syndrome was originally described as "infantile limb pain episodes" / paroxysmal limb intolerable pain, with pain most frequently in the knees and ankles (Noguchi 2017, PMID 30549873).

Key identifiers. - OMIM: #615552 — Episodic Pain Syndrome, Familial, 3 (FEPS3; SCN11A). Related: #615551 (FEPS2; SCN10A); #615040 (FEPS1; TRPA1). - Gene OMIM: SCN11A 604385; SCN10A 604427. - MONDO (suggested): MONDO term for "familial episodic pain syndrome 3" (SCN11A‑related FEPS); parent "familial episodic pain syndrome." - ICD‑10: best fit G90.09 / R52 (pain, disorders of autonomic/peripheral nervous system) — no dedicated code. ICD‑11: 8D89 / MG30 (chronic/neuropathic pain categories) — no dedicated code. - MeSH: no dedicated descriptor; indexed under "Pain," "Sodium Channelopathies," "NAV1.9 Voltage-Gated Sodium Channel." - Orphanet: rare monogenic pain syndrome (ultra‑rare; no established ORPHA prevalence class).

Synonyms / alternative names. Familial Episodic Pain Syndrome 3; FEPS3; SCN11A‑related familial episodic pain; Nav1.9 channelopathy (episodic pain form); "infantile limb pain episodes"; paroxysmal limb intolerable pain; familial episodic limb pain. (FEPS2 synonyms: Familial Episodic Pain Syndrome 2; SCN10A/Nav1.8‑related FEPS.)

Source of information. Derived from aggregated disease‑level resources and individual pedigree/case‑series reports (multigenerational families, mostly Japanese and Chinese, plus European cases), combined with in‑vitro and animal functional studies — not from population EHR datasets.

2. Etiology

Disease causal factors — genetic. FEPS3 is a monogenic channelopathy. The primary cause is a heterozygous gain‑of‑function (GoF) missense variant in SCN11A (NaV1.9). FEPS2 is caused analogously by GoF SCN10A (NaV1.8) variants. There is no infectious or neoplastic etiology; environment acts only as a trigger of episodes, not as a cause.

Genetic risk factors (causal variants). Recurrent/known pathogenic SCN11A variants include p.Arg222His (R222H), p.Arg222Ser (R222S), p.Arg225Cys (R225C), p.Phe814Cys (F814C), p.Phe1146Ser (F1146S), p.Val1184Ala (V1184A), p.Leu811Phe (L811F), and p.Asn816Lys (N816K) (Kabata 2018, PMID 30557356; Huang 2019, PMID 31551682; Nagao 2025, PMID 39058404; Leipold 2015, PMID 26645915). All are germline, heterozygous, autosomal‑dominant.

Environmental risk factors. Not causal; cold exposure, physical fatigue, and weather change precipitate attacks (Noguchi 2017, PMID 30549873). Age is an inverse "risk factor" — episodes are most frequent in early childhood and diminish through adolescence.

Protective factors. No genetic protective alleles are established. Environmental/behavioral protection: warming the affected limb relieves pain, and avoidance of cold/fatigue reduces episode frequency (Noguchi 2017, PMID 30549873). In animal models, transcutaneous cholesterol reversed NaV1.9‑mediated hypersensitivity (Amsalem 2018, PMID 29459435), suggesting a candidate protective intervention.

Gene–environment interactions. The germline GoF variant lowers nociceptor threshold; environmental modulators of NaV1.9 push already‑sensitized neurons over threshold: (i) cold — GoF confers cold‑resistant hyperexcitability (Leipold 2015, PMID 26645915); (ii) inflammation lowers membrane cholesterol, moving NaV1.9 out of lipid rafts and enhancing its activation (Amsalem 2018, PMID 29459435); (iii) inflammatory mediators (bradykinin, ATP, PGE2, histamine, 5‑HT) directly excite NaV1.9⁺ afferents (Hockley 2014, PMID 24972070).

3. Phenotypes

Core phenotype (symptom). Paroxysmal, severe episodic pain of the distal limbs, predominantly lower limbs (knees, ankles > wrists, elbows). Episodes last ~15–30 minutes, recur several times per day, are triggered by fatigue and precede bad weather, the affected region feels cold, and warming relieves the pain (Noguchi 2017, PMID 30549873: "The pain typically lasts for 15-30 min and recurs several times a day. The pain is often induced by fatigue and is a prelude of bad weather. The affected regions feel cold in the patients, and warming the lesions relieves the symptoms."). - HPO: HP:0012531 (Pain); HP:0012532 (Chronic pain); HP:0025277 (Fluctuating course/episodic — episodic pain); HP:0003394 (limb pain — muscle pain proxy); HP:0002829 (Arthralgia — joint pain); HP:0001943 sensitivity.

Associated phenotypes (variant‑dependent). - Gastrointestinal: episodic abdominal pain and chronic constipation with some variants (e.g., N816K), reflecting NaV1.9 expression in myenteric neurons (Huang 2019, PMID 31551682). HPO: HP:0002027 (Abdominal pain); HP:0002019 (Constipation). - Cold intolerance / cold‑aggravated pain (Leipold 2015, PMID 26645915). HPO: HP:0500152 (Cold‑induced pain/temperature sensitivity). - Essential tremor co‑segregation with R225C (Leng 2017, PMID 28298626). HPO: HP:0001337 (Tremor).

Phenotype characteristics. - Age of onset: neonatal–early childhood/infancy (HP:0011463 childhood onset; often infantile onset). - Severity: moderate–severe pain during episodes; variable expressivity between and within families. - Progression: episodic/fluctuating, characteristically spontaneously mitigating with age (adolescence). - Frequency among affected: distal‑limb pain is the defining feature (essentially 100% of affected); GI and tremor features are variant‑specific minorities.

Quality‑of‑life impact. During childhood, recurrent daily painful episodes can disrupt sleep, activity, and schooling; because episodes are self‑limited and remit with age, long‑term disability is low and life expectancy is unaffected. No disease‑specific QoL instrument (EQ‑5D/SF‑36/PROMIS) data are published.

4. Genetic / Molecular Information

Causal genes. - SCN11A — HGNC:10583; NCBI Gene 11280; Ensembl ENSG00000168356; UniProt Q9UI33 (NaV1.9/SCN11A); chromosome 3p22.2; OMIM gene 604385. Encodes the α‑subunit of the tetrodotoxin‑resistant voltage‑gated sodium channel NaV1.9. - SCN10A (FEPS2) — HGNC:10582; NCBI Gene 6336; UniProt Q9Y5Y9 (NaV1.8); 3p22.2; OMIM 604427.

Pathogenic variants (SCN11A). Missense, germline, heterozygous. Representative: R222H, R222S, R225C, F814C, F1146S, V1184A, L811F, N816K. Located in functionally critical regions (e.g., L811 in the DII/S6 helix important for voltage‑sensor→pore coupling; Nagao 2025, PMID 39058404). Classification: most reported variants are Pathogenic/Likely Pathogenic per ACMG (segregation + functional GoF evidence); novel variants may be VUS pending functional testing. Variant type/class: point missense (no frameshift/nonsense/structural variants reported for the episodic‑pain phenotype). Allele frequency: absent or ultra‑rare in gnomAD (consistent with high penetrance and dominant pathogenicity). Origin: germline (no somatic/COSMIC relevance). Functional consequence: gain of function (hyperpolarized activation, larger persistent/window current, RMP depolarization).

Genotype–phenotype / allelic spectrum. SCN11A is pleiotropic: modest GoF → FEPS3 / painful small‑fiber neuropathy; extreme GoF (sustained depolarization block) → congenital insensitivity to pain (CIP). The same residue diverges by substitution: L811Phe → FEPS, L811Pro → CIP (Nagao 2025, PMID 39058404). R225C additionally associates with essential tremor (Leng 2017, PMID 28298626).

Modifier genes. PRMT7 methylates NaV1.9 (Arg519) and up‑regulates NaV1.9 current and neuronal excitability — a candidate excitability modifier and drug target (Ma 2022, PMID 34326297).

Epigenetic information. No disease‑specific DNA‑methylation/histone changes reported. (Post‑translational arginine methylation of the channel by PRMT7 is a molecular—not genomic—regulatory layer.)

Chromosomal abnormalities. None; FEPS3 is a single‑nucleotide missense disorder, not a copy‑number/structural condition.

5. Environmental Information

Environmental factors: Cold ambient temperature and falling barometric pressure / bad weather trigger episodes (Noguchi 2017, PMID 30549873). No toxin, radiation, or occupational exposure is implicated as a cause.
Lifestyle factors: Physical fatigue/exertion is a major trigger; rest and warming mitigate. No association with smoking/alcohol/diet as causes.
Infectious agents: None — not an infectious or immune‑mediated disease.

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

A heterozygous germline gain‑of‑function missense variant in SCN11A alters the NaV1.9 channel protein (demonstrated: genetics + in vitro).
The variant shifts NaV1.9 voltage‑dependence of activation to more hyperpolarized potentials and enlarges the persistent/window current (demonstrated: voltage‑clamp; Leipold 2015; Huang 2019) → results in more channels open near rest.
Increased subthreshold Na⁺ influx depolarizes the resting membrane potential of small‑diameter C‑fiber DRG nociceptors (demonstrated: current‑clamp in DRG neurons).
RMP depolarization brings the membrane closer to firing threshold → leads to a reduced action‑potential threshold and increased firing frequency (nociceptor hyperexcitability) (demonstrated); the hyperexcitability is retained at cold temperatures ("cold‑resistant") (demonstrated: Leipold 2015).
Environmental modulators (cold, inflammation‑driven membrane‑cholesterol loss, inflammatory mediators, PRMT7 methylation) further potentiate NaV1.9, pushing sensitized neurons over threshold (demonstrated in models; inferred as the trigger mechanism in patients).
Hyperexcitable distal‑limb nociceptive afferents generate ectopic/amplified nociceptive signaling (inferred from cellular data) →
leads to the clinical episodic, cold‑/fatigue‑triggered distal (predominantly lower‑limb) pain (clinical).
Branch (variant‑dependent): NaV1.9 in myenteric/enteric neurons → episodic abdominal pain + constipation (Huang 2019). NaV1.9 effects on broader neuronal excitability → essential tremor with R225C (Leng 2017).
Branch (allelic): extreme GoF → sustained depolarization/inactivation block → loss of firing → congenital insensitivity to pain (opposite phenotype).
Age‑dependent attenuation (clinical; mechanism inferred) — episodes diminish through adolescence, possibly via developmental changes in channel expression/nociceptor maturation.

Detail by category

Molecular pathways / biochemical abnormality: primary defect is an ion‑channel (voltage‑gated Na⁺ channel) dysfunction; NaV1.9 is the threshold channel with the most hyperpolarized activation among VGSCs and sets RMP (Köster 2025, PMID 39836077). Downstream: action‑potential electrogenesis and neurotransmitter release from nociceptor terminals. Modulation by inflammatory mediator signaling (bradykinin/ATP/PGE2), lipid‑raft/cholesterol biology, and PRMT7 arginine‑methylation.
Cellular processes: neuronal membrane depolarization, action‑potential generation, nociceptor sensitization/hyperexcitability (not apoptosis/inflammation‑driven tissue destruction).
Protein dysfunction: gain of function via altered gating (not misfolding/aggregation); molecular‑dynamics work suggests some variants (L811F) increase structural stability and impede necessary conformational changes (Nagao 2025, PMID 39058404).
Immune involvement: none primary; inflammation is a modulatory trigger, not an autoimmune mechanism.
Tissue damage: none — pain is due to aberrant neuronal signaling, not tissue injury; no fibrosis/necrosis/ischemia.
Suggested ontology terms: GO:0086010 (membrane depolarization during action potential); GO:0019228 (neuronal action potential); GO:0035725 (sodium ion transmembrane transport); GO:0005248 (voltage‑gated sodium channel activity, MF); GO:0050966 (detection of noxious stimulus). Cell types: CL:0000198 (nociceptor), CL:0002249 / CL:0000101 (sensory/DRG neuron), CL:0011103 (enteric neuron). Subcellular: GO:0005886 (plasma membrane), GO:0045211 (axon/terminal), GO:0045121 (membrane raft).

7. Anatomical Structures Affected

Organ/system level: peripheral nervous system (somatosensory), specifically primary sensory neurons; secondary involvement of the enteric nervous system (GI symptoms with some variants). Body system: nervous (sensory) and digestive (variant‑dependent).
Tissue/cell level: nervous tissue — small‑diameter C‑fiber nociceptors and Aδ nociceptors of the dorsal root ganglia and trigeminal ganglia; myenteric neurons for GI features (Huang 2019, PMID 31551682). CL:0000198 (nociceptor); CL:0000101 (sensory neuron).
Subcellular level: neuronal plasma membrane, including cholesterol‑rich lipid rafts from which NaV1.9 redistributes upon sensitization (Amsalem 2018, PMID 29459435). GO CC: GO:0005886, GO:0045121 (membrane raft).
Localization (UBERON): UBERON:0000044 (dorsal root ganglion); UBERON:0001132 (trigeminal ganglion); UBERON:0002240 (spinal cord dorsal horn, downstream); distal limb targets — UBERON:0002103 (hindlimb)/UBERON:0003823 (leg), knees/ankles. Lateralization: bilateral (both legs) and typically symmetric/migratory.

8. Temporal Development

Onset: congenital/infantile to early childhood; onset pattern is recurrent‑paroxysmal (acute episodes on a chronic predisposition).
Progression: episodic/fluctuating, not progressive; individual episodes are self‑limited (~15–30 min). Over years the disorder spontaneously attenuates, typically remitting or markedly improving around adolescence (Noguchi 2017, PMID 30549873; Shen 2022, PMID 36051609).
Disease duration: symptomatic phase is childhood‑limited in most; the underlying genotype is lifelong and can manifest as milder adult sensitivity.
Remission: predominantly spontaneous/age‑dependent; treatment‑induced relief is symptomatic.
Critical periods: childhood (peak symptom burden and the window for supportive management and trigger avoidance).

9. Inheritance and Population

Inheritance: Autosomal dominant (heterozygous). 50% offspring recurrence risk.
Penetrance / expressivity: high but variable penetrance; variable expressivity in age of remission, episode frequency, and presence of GI/tremor features. No confirmed anticipation, mosaicism, or consanguinity requirement (dominant, not recessive).
Founder effect: p.R222H is a founder mutation in the Tohoku region of Japan (7 of 48 families) (Kabata 2018, PMID 30557356: "A founder mutation, SCN11A p.R222H was confirmed to be frequently observed in patients with FEP in the Tohoku region of Japan").
Carrier frequency: not established; pathogenic alleles are ultra‑rare/absent in gnomAD.
Epidemiology: ultra‑rare; no reliable prevalence/incidence per 100,000 is published. Reported cohorts are largely Japanese (≥48 families) and Chinese, with additional European cases.
Geographic distribution of variants: R222H enriched in Tohoku, Japan; R225C reported in Chinese kindreds; V1184A (cold‑aggravated) in European cases.
Sex ratio / age distribution: autosomal dominant → no strong sex bias (≈1:1); affected individuals are predominantly children/adolescents.

10. Diagnostics

Clinical diagnosis rests on the characteristic history: autosomal‑dominant family history + early‑childhood recurrent, self‑limited, cold/fatigue‑triggered distal (lower‑limb) pain relieved by warmth. No specific routine laboratory abnormality or biomarker; inflammatory markers, imaging (X‑ray/MRI), and standard nerve conduction studies are typically normal (large myelinated fibers spared) — useful mainly to exclude alternatives.
Electrophysiology: conventional NCS usually normal; research‑level microneurography/skin biopsy for small‑fiber assessment may be considered (small‑fiber pathology overlaps the SCN11A spectrum).
Genetic testing (definitive): single‑gene sequencing or a hereditary‑pain/sodium‑channelopathy gene panel including SCN11A, SCN10A, SCN9A, *TRPA1; WES/WGS for atypical/panel‑negative cases. CMA, karyotyping, FISH, mtDNA, and repeat‑expansion testing are not indicated (point‑mutation disorder). Variant interpretation benefits from functional (electrophysiology) confirmation* given the GoF/LoF‑to‑phenotype divergence.
Diagnostic criteria: no formal society criteria; diagnosis is molecular + clinical.
Differential diagnosis: growing pains (benign, no family‑segregating molecular cause), erythromelalgia / inherited erythromelalgia (SCN9A) — but erythromelalgia features red, hot, hyperperfused extremities (opposite of the cold sensation here) (Klein‑Weigel 2018, PMID 29299961), paroxysmal extreme pain disorder (SCN9A), Fabry disease, small‑fiber neuropathy, juvenile idiopathic arthritis, and autoinflammatory periodic syndromes.
Screening: cascade genetic testing of at‑risk relatives once a familial variant is identified. No newborn/population screening.

11. Outcome / Prognosis

Survival/mortality: normal life expectancy; no disease‑specific mortality. Not a life‑threatening condition.
Morbidity/function: morbidity is episodic childhood pain with possible sleep/activity disruption; long‑term disability is minimal because episodes remit with age.
Disease course/complications: benign natural history with spontaneous mitigation around adolescence; complications limited to variant‑specific GI symptoms (constipation) or comorbid essential tremor (R225C).
Recovery potential: high — most patients improve substantially without disease‑modifying therapy.
Prognostic factors: specific variant (biophysical severity), presence of GI/tremor features; age is the dominant prognostic factor (improvement over time). No validated prognostic biomarker.

12. Treatment

No disease‑specific approved therapy; management is symptomatic and the condition is largely self‑limiting.

Supportive care (first‑line): warming affected limbs (relieves pain), avoidance of cold and fatigue (Noguchi 2017, PMID 30549873). NCIT: Supportive Care (C15272).
Pharmacotherapy (off‑label, symptomatic): simple analgesics/NSAIDs; state‑dependent sodium‑channel blockers — carbamazepine, lidocaine, mexiletine. Carbamazepine can act as an activation modulator that partially normalizes gain‑of‑function sodium‑channel gating (Han 2018, PMID 30135145). NCIT: Carbamazepine (C376), Lidocaine, Mexiletine, NSAID (C198).
Pharmacogenomics / precision medicine: genotype‑guided rationale — GoF NaV1.9 is the direct target; NaV1.9‑selective blockers are investigational (preclinical/early development), highlighted for cold pain and small‑fiber neuropathy (Chen 2025, PMID 40206072). PRMT7 inhibition (e.g., DS‑437) reduces NaV1.9 currents and pain hypersensitivity in mice — a candidate strategy (Ma 2022, PMID 34326297). Transcutaneous cholesterol reversed NaV1.9‑mediated hypersensitivity in models (Amsalem 2018, PMID 29459435).
Advanced therapeutics (gene/cell/RNA): none in clinical use; conceptually amenable to allele‑selective ASO/gene‑editing given the dominant GoF mechanism (future direction).
Surgical/interventional: not applicable.
Treatment outcomes/adverse events: no controlled trial data; management guided by general neuropathic‑pain practice and drug‑specific safety profiles.

13. Prevention

Primary prevention: not possible (germline genetic cause); preconception/prenatal genetic counseling and options (PGT/prenatal testing) can prevent transmission where desired.
Secondary prevention: cascade genetic testing of relatives for early recognition; early trigger‑avoidance counseling.
Tertiary prevention: minimize episode burden via avoidance of cold/fatigue and prompt warming; manage variant‑specific complications (e.g., constipation).
Immunization / public‑health / environmental interventions: not applicable.
Counseling: genetic counseling for autosomal‑dominant 50% recurrence risk and variable expressivity is central. NCIT: Genetic Counseling (C15311).
Prophylaxis: no established prophylactic drug; behavioral trigger avoidance is the mainstay.

14. Other Species / Natural Disease

Taxonomy / orthologs: human SCN11A (NaV1.9). Mouse Scn11a — NCBI Gene 24046; MGI:1345149 (Chr 9). Rat Scn11a ortholog exists. NaV1.9 (originally NaN/SNS2) is evolutionarily conserved across mammals with conserved nociceptor‑restricted expression.
Natural disease in other species: no naturally occurring animal disease cataloged in OMIA for SCN11A episodic pain; disease knowledge in animals comes from engineered models, not spontaneous veterinary cases.
Comparative biology: mouse NaV1.9 gating and DRG expression closely parallel human, enabling faithful modeling; conservation of the RMP‑setting/threshold role underlies the translational validity.
Transmission: not applicable (non‑infectious, non‑zoonotic).

15. Model Organisms

Model type: mammalian — mouse (Mus musculus, NCBI Taxon 10090); plus in‑vitro heterologous expression (HEK293, DRG electroporation) and patient‑derived DRG‑neuron electrophysiology.
Genetic models:
Knock‑in (disease‑variant) mice: Scn11a‑R222S — hypersensitive to hot and cold stimuli, increased DRG input impedance and evoked AP firing (Noguchi 2017, PMID 30549873). F802C and F1125S (orthologues of human F814C/F1146S) — elevated RMP and increased AP firing to high input current; F1125S also increases firing probability at low input (Kabata 2018, PMID 30557356). A796G knock‑in used in modifier studies (Ma 2022, PMID 34326297).
Knockout (loss‑of‑function) mice: NaV1.9‑null — reduced nociceptor excitability, +55% C‑fiber electrical threshold, higher mechanical thresholds, impaired noxious heat sensing (Hoffmann 2017, PMID 27780178); attenuated visceral afferent activation (Hockley 2014, PMID 24972070); NaV1.8/NaV1.9 double‑KO mildly affects acute pain and deregulates C‑LTMR/neuropeptide genes (Alves‑Simões 2025, PMID 39382328).
Phenotype recapitulation: strong — GoF knock‑ins reproduce the cardinal DRG hyperexcitability and thermal/cold hypersensitivity; reciprocal KO produces the opposite (hyposensitivity), establishing causality bidirectionally.
Limitations: mice model peripheral electrophysiology and behavioral proxies, not the subjective, episodic, weather‑triggered nature of human pain or its spontaneous adolescent remission; genetic background and orthologue‑residue differences require care.
Applications: target validation, variant functional classification, and testing of NaV1.9‑directed and modifier (PRMT7, cholesterol) therapeutics.
Resources: MGI/IMPC/IMSR for Scn11a alleles.

Supported and Refuted Hypotheses

Supported: 1. The lower‑limb‑predominant FEPS is a NaV1.9 (SCN11A) gain‑of‑function channelopathy (multiple kindreds + electrophysiology + mouse models). 2. Nociceptor RMP depolarization → hyperexcitability is the mechanistic core (in vitro + KI/KO). 3. Autosomal‑dominant inheritance with a Japanese R222H founder effect. 4. Cold/fatigue trigger episodes via physiological modulation of NaV1.9. 5. Benign, age‑attenuating natural history.

Refuted / excluded: - Not caused by tissue damage, inflammation‑as‑primary, infection, or structural/chromosomal abnormality. - Not an erythromelalgia phenotype (patients feel cold, relieved by warmth — the inverse of erythromelalgia).

Limitations & Future Directions

No population‑level prevalence, sex‑ratio, or QoL‑instrument data; cohorts are small and geographically skewed (Japan/China).
Ambiguity in whether the exact source label ("predominantly lower limb") intends FEPS3 (SCN11A) vs FEPS2 (SCN10A) — both cause distal, predominantly lower‑limb episodic pain; FEPS3 is the best‑characterized match and the primary focus here, with FEPS2 covered as the close alternative.
No controlled treatment trials; NaV1.9‑selective analgesics and allele‑selective genetic therapies are the key future opportunities.

Evidence source key: human clinical (pedigrees/case series) — PMIDs 30549873, 30557356, 31551682, 28298626, 39058404, 26645915; in vitro/electrophysiology — 39836077, 30135145, 34326297, 29459435; mouse models — 30549873, 30557356, 27780178, 24972070, 39382328; reviews — 36051609, 29299961, 40206072.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	16
Resolved	16
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	16
On topic	10
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	31
Resolved	28
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	3
Terms whose name was checked	25
Terms named correctly	13
Terms named as a different term	5
Terms whose name is worth a second look	7

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

HP:0025277 (1 mention) - the report calls it "Fluctuating course/episodic — episodic pain"; HP calls it Gustatory sweating
HP:0003394 (1 mention) - the report calls it "limb pain — muscle pain proxy"; HP calls it Muscle spasm
HP:0500152 (1 mention) - the report calls it "Cold‑induced pain/temperature sensitivity"; HP calls it Hypocystinemia
GO:0045211 (1 mention) - the report calls it "axon/terminal"; GO calls it postsynaptic membrane
UBERON:0001132 (1 mention) - the report calls it "trigeminal ganglion"; UBERON calls it parathyroid gland

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

HP:0002829 (1 mention) - the report calls it "Arthralgia — joint pain"; HP calls it Arthralgia, and lists "Arthritic pain" among its other names
GO:0005248 (1 mention) - the report calls it "voltage‑gated sodium channel activity, MF"; GO calls it voltage-gated sodium channel activity
GO:0050966 (1 mention) - the report calls it "detection of noxious stimulus"; GO calls it detection of mechanical stimulus involved in sensory perception of pain, and lists "perception of pain, detection of mechanical stimulus" among its other names
CL:0000101 (2 mentions) - the report calls it "sensory/DRG neuron", "sensory neuron"; CL calls it sensory neuron
CL:0011103 (1 mention) - the report calls it "enteric neuron"; CL calls it sympathetic neuron
UBERON:0002240 (1 mention) - the report calls it "spinal cord dorsal horn, downstream"; UBERON calls it spinal cord, and lists "spinal cord structure" among its other names
UBERON:0003823 (1 mention) - the report calls it "leg"; UBERON calls it hindlimb zeugopod, and lists "leg" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

CL:0000101 - called "sensory/DRG neuron", "sensory neuron"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: MGI.

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1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

Detail by category

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Supported and Refuted Hypotheses

Limitations & Future Directions

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Terms named inconsistently

Prefixes with no resolver