🏷

Classifications

Channelopathy

📘

Definitions

1

GeneReviews clinical diagnostic definition of hyperPP

The clinical definition GeneReviews uses. Its potassium criterion is a three-limb disjunction, and the third limb is a provocation criterion rather than a measurement: an attack provoked or worsened by oral potassium satisfies it even when no ictal potassium value was captured. That limb carries most of the weight in practice, because ictal potassium is often normal. It is also the only part of the definition that is an exposure rather than a finding, which is why this entry carries potassium provocation as an ECTO-bound environmental exposure linked into the pathograph as well as here. Molecular confirmation is a heterozygous pathogenic SCN4A variant, curated under diagnosis.

DIAGNOSTIC_CRITERIA

Inclusion criteria

Attacks of flaccid limb weakness May also include weakness of the muscles of the eyes, throat, breathing muscles, and trunk.
Hyperkalemia above 5 mmol/L, or a rise in serum potassium of at least 1.5 mmol/L during an attack, or provoking or worsening of an attack by oral potassium intake Any one of the three limbs satisfies the criterion. The provocation limb stands in for a measurement when none was made.
Normal serum potassium between attacks
Onset before age 20 years

Show evidence (1 reference)

PMID:20301669 SUPPORT Human Clinical

"hyperkalemia (serum potassium concentration >5 mmol/L) or an increase of serum potassium concentration of at least 1.5 mmol/L during an attack of weakness and/or provoking/worsening of an attack by oral potassium intake, normal serum potassium between attacks, and onset before age 20 years"

The criteria set quoted verbatim, including the oral potassium provocation limb and the age limit.

Notes: HPO codes potassium provocation as a clinical modifier, HP:0031167 "Triggered by ingestion of potassium-rich food", which sits under HP:0012823 Clinical modifier and therefore outside the PhenotypeTerm enum root HP:0000118. It cannot be bound as a phenotype term in this schema, which is why the criterion is recorded here and as an environmental exposure rather than as a phenotype of its own.

👪

Inheritance

1

Autosomal dominant HP:0000006

HyperPP is autosomal dominant with high penetrance. Most affected individuals have an affected parent and each child of an affected individual has a 50% chance of inheriting the variant.

Autosomal dominant inheritance

Show evidence (3 references)

PMID:20301669 SUPPORT Human Clinical

"HyperPP is inherited in an autosomal dominant manner. Most individuals with hyperPP have an affected parent"

GeneReviews states the mode of inheritance and the expected family structure.

PMID:20301669 SUPPORT Human Clinical

"Each child of an individual with hyperPP has a 50% chance of inheriting the pathogenic variant."

GeneReviews states the transmission risk that this block's description asserts, which the adjacent quote stops short of.

PMID:39174253 SUPPORT REVIEW SYNTHESIS In Vitro

"Expression studies show the missense mutations produce gain-of-function alterations in channel behavior, which is consistent with the autosomal dominant inheritance and high penetrance of the clinical phenotype in this disorder."

Heterologous expression data reconcile the dominant, highly penetrant inheritance with a gain-of-function molecular lesion.

⚙

Pathophysiology

8

SCN4A Gain-of-Function Missense Variant

A heterozygous missense variant in SCN4A, encoding the pore-forming alpha subunit of the skeletal-muscle voltage-gated sodium channel Nav1.4, is the sole established genetic lesion. T704M and M1592V are the two most common alleles. The variants act by gain of function rather than by loss of channel, which is why null alleles of SCN4A do not cause periodic paralysis.

skeletal muscle fibre CL:0008002

SCN4A hgnc:10591

Genetic context allele_type: missense variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION

Heterozygous germline missense substitutions in SCN4A whose functional consequence, measured by heterologous expression, is a gain of function for Nav1.4 gating.

Nav1.4 voltage-gated sodium channel activity GO:0005248 ⇑ GAIN OF FUNCTION

skeletal muscle tissue UBERON:0001134

Downstream

Impaired Nav1.4 Inactivation and Persistent Sodium Current The missense substitution changes channel gating, and the functional consequence is measured directly in expression systems.

Show evidence (3 references)

PMID:39174253 SUPPORT REVIEW SYNTHESIS Human Clinical

"Across the narrow clinical spectrum from PMC to HyperPP, and everything in between, the gene defects are missense mutations of SCN4A. No other causative gene has been implicated for HyperPP/PMC."

Establishes SCN4A missense variation as the only causative lesion for this disease.

PMID:25880512 SUPPORT REVIEW SYNTHESIS Human Clinical

"Similarly, T704M causes HyperPP with late-onset permanent myopathy"

Names the most common HyperPP allele and its genotype-phenotype correlation. The sentence sits in the review's genotype-phenotype passage and reports the clinical course observed in families carrying the allele, not a channel measurement.

PMID:25880512 SUPPORT REVIEW SYNTHESIS In Vitro

"Mutations associated with HyperPP, PMC or SCM all produce gain-of-function changes for NaV1.4"

Grounds the molecular function bound on this node. The affected gene product is the Nav1.4 voltage-gated sodium channel, and the HyperPP alleles leave its channel activity in a gain-of-function state, which is what the modifier on that binding asserts.

Impaired Nav1.4 Inactivation and Persistent Sodium Current

Mutant Nav1.4 channels fail to inactivate completely. The wild-type channel leaves a barely perceptible persistent current of about 0.2% of the transient peak; HyperPP alleles raise it to 1 to 4%, a five- to twenty-fold relative increase in a standing inward sodium current. Several HyperPP alleles additionally disrupt slow inactivation, which removes the safeguard that would otherwise curtail the anomalous steady-state current.

skeletal muscle fibre CL:0008002

sodium ion transmembrane transport GO:0035725 ↑ INCREASED

Nav1.4 voltage-gated sodium channel activity GO:0005248 ⇑ GAIN OF FUNCTION

Downstream

Sustained Sarcolemmal Depolarization A standing inward sodium current shifts the resting potential in the depolarizing direction and holds it there.

Resting Intracellular Sodium Overload The same anomalous current loads the resting fibre with sodium, which is measurable as increased tetrodotoxin-sensitive sodium influx.

Show evidence (4 references)

PMID:25880512 SUPPORT REVIEW SYNTHESIS In Vitro

"Mutations associated with HyperPP disrupt the completeness of fast inactivation, which results in persistent Na+ currents of 1 to 4%."

States the specific biophysical defect and the size of the resulting persistent current, synthesized from voltage-clamp studies.

PMID:25880512 SUPPORT REVIEW SYNTHESIS In Vitro

"Voltage-clamp studies have demonstrated defects of slow inactivation for the two most common mutations found in HyperPP (T704M and M1592V)"

Records the additional slow-inactivation defect in the two commonest alleles.

PMID:36628799 SUPPORT In Vitro

"Moreover, steady-state slow inactivation in V792G was impaired with larger residual currents in comparison with wild-type Nav1.4."

Whole-cell patch clamp in HEK293T cells directly measures the residual (persistent) current of a HyperPP allele against wild type.

+ 1 more reference

Sustained Sarcolemmal Depolarization

The resting potential fails to be maintained and settles at a stable depolarized value of about -45 mV instead of the normal -85 mV. This is the pivotal node: it is stable on the timescale of hours, which is what distinguishes an attack of paralysis from the millisecond-scale gating changes that cause myotonia alone.

skeletal muscle fibre CL:0008002

membrane depolarization GO:0051899 ↑ INCREASED regulation of membrane potential GO:0042391 ↕ DYSREGULATED

skeletal muscle tissue UBERON:0001134

Animal models

Equine hyperkalemic periodic paralysis (quarter horse) Horse recapitulates Intercostal muscle fibres from affected horses are depolarized at rest and repolarize to normal values on exposure to tetrodotoxin, which localizes the depolarizing current to sodium channels.

Downstream

Depolarization-Induced Sodium Channel Inactivation and Fibre Inexcitability From a depolarized resting potential both wild-type and mutant channels sit in the inactivated state.

Skeletal Muscle Membrane Hyperexcitability and Myotonic Discharges A modest depolarization is what reveals the inactivation defect, so a brief stimulus at this membrane potential provokes a myotonic burst rather than a single action potential.

Show evidence (2 references)

PMID:39174253 SUPPORT REVIEW SYNTHESIS Human Clinical

"The transient episodes of weakness in HyperPP/PMC are caused by a failure to maintain the resting potential, with a depolarization-induced loss of fiber excitability from inactivation of NaV1.4."

States the failure of resting-potential maintenance as the proximate cause of ictal weakness.

PMID:25880512 SUPPORT Computational

"periodic paralysis is manifest as a stable depolarized shift of the resting potential that renders the fiber refractory from generating action potentials"

Quantitative fibre simulation distinguishes the stable depolarized state of paralysis from the self-sustained firing of myotonia.

Skeletal Muscle Membrane Hyperexcitability and Myotonic Discharges

At lesser degrees of depolarization the same inactivation defect increases sodium-channel availability during repolarization, so one stimulus is followed by a self-sustained train of action potentials. This is why myotonia and paralysis are two expressions of one channel defect at different membrane potentials, and why myotonic stiffness commonly precedes an attack of weakness.

skeletal muscle fibre CL:0008002

regulation of membrane potential GO:0042391 ↕ DYSREGULATED

Downstream

Myotonia Sustained after-discharges are observed clinically and on needle EMG as myotonia.

Paramyotonia The same hyperexcitable state, when it worsens rather than eases with the first few contractions and is aggravated by cooling, presents as paramyotonia. It is the cold- and exercise-sensitive expression of this node rather than a separate mechanism.

Potassium Efflux and Extracellular Potassium Accumulation Repetitive firing drives cumulative potassium efflux into the narrow transverse-tubular space, which cannot equilibrate by passive diffusion.

Show evidence (2 references)

PMID:25880512 SUPPORT Computational

"In response to a brief stimulus, the inactivation defect is revealed and the fiber may respond with a myotonic burst."

Fibre simulation shows the myotonic burst arising from the same inactivation defect that later produces paralysis.

PMID:39174253 SUPPORT REVIEW SYNTHESIS Human Clinical

"Most patients with HyperPP also have myotonia, often becoming symptomatic with activity-dependent muscle stiffness that precedes an attack of weakness"

Confirms in patients that the hyperexcitable state commonly precedes the inexcitable one.

Potassium Efflux and Extracellular Potassium Accumulation

Potassium leaves the depolarized and repetitively firing fibre and accumulates both locally in the transverse tubules and systemically as a rise in serum potassium during the attack. This node closes a feed-forward loop: the potassium it raises is the very stimulus that reveals the inactivation defect and deepens the depolarization that produced it. It is also the reason an exogenous potassium load can start the cycle from outside.

skeletal muscle fibre CL:0008002

potassium ion transmembrane transport GO:0071805 ↑ INCREASED

Downstream

Sustained Sarcolemmal Depolarization Raised extracellular potassium depolarizes the fibre modestly, as it does in healthy muscle, but here the gain-of-function current amplifies that shift into a refractory depolarization. This edge is what makes the mechanism a feed-forward cycle rather than a chain.

Hyperkalemia During Attacks The systemic arm of the potassium shift is what is measured at the bedside.

Show evidence (3 references)

PMID:25880512 SUPPORT Computational

"The repetitive firing produces a cumulative increase of T-tubular K+ which in conjunction with the inactivation defect results in a steady inward Na+ current that keeps the fiber depolarized at about -45 mV"

Simulation traces the closed loop from firing to potassium accumulation to maintained depolarization.

PMID:21708955 SUPPORT BACKGROUND Human Clinical

"This would initiate and explain the depolarization of the muscle cells and the subsequent hyperkalemia."

Attributes the ictal rise in serum potassium to the depolarizing sodium influx into muscle, giving the direction of the systemic arm of the loop.

PMID:20301669 SUPPORT Human Clinical

"an increase of serum potassium concentration of at least 1.5 mmol/L during an attack of weakness"

Documents the measurable ictal rise in serum potassium that this node asserts.

Depolarization-Induced Sodium Channel Inactivation and Fibre Inexcitability

At a resting potential near -45 mV the wild-type Nav1.4 channels and most of the mutant ones are held in the inactivated state, so no action potential can be generated and the fibre cannot contract. This is the counterintuitive step of the disease: the paralysis is caused by too much depolarizing current, not by too little, and the mutant allele therefore behaves as a functional dominant negative acting through voltage-dependent inactivation.

skeletal muscle fibre CL:0008002

regulation of membrane potential GO:0042391 ↕ DYSREGULATED skeletal muscle contraction GO:0003009 ↓ DECREASED

skeletal muscle tissue UBERON:0001134

Animal models

Scn4a M1592V knock-in mouse Mouse partially recapitulates Mutant muscle is markedly less excitable than wild type, requiring stronger and longer stimuli to reach maximal force, and loses force dramatically when challenged with 10 mM extracellular potassium.

Downstream

Episodic Flaccid Weakness Inexcitable fibres generate no force, which presents as flaccid weakness or paralysis lasting minutes to hours.

Weakness of Ocular, Bulbar, Respiratory and Trunk Muscles Severe attacks extend beyond the limbs to extraocular, pharyngeal, respiratory, and trunk muscles.

Show evidence (3 references)

PMID:25880512 SUPPORT Computational

"From this depolarized potential the WT NaV1.4 channels and the majority of the HyperPP mutant ones are inactivated which renders the fiber inexcitable, as occurs in periodic paralysis."

States the depolarization-induced inactivation step explicitly, from a quantitative fibre model.

PMID:29125635 SUPPORT REVIEW SYNTHESIS Human Clinical

"In all forms of PP, ictal paresis is caused by depolarization of the muscle sarcolemma, which in turn causes sodium channel inactivation and reduced fiber excitability."

Independent clinical review states the same depolarization to inactivation to inexcitability sequence as the cause of ictal paresis.

PMID:39174253 SUPPORT REVIEW SYNTHESIS Human Clinical

"Hyperkalemia produces a modest depolarization, as occurs in normal fibers, that becomes pathologically amplified by the excessive inward current conducted by mutant Na+ channels and leads to refractory loss of fiber excitability."

Ties the potassium trigger, the amplifying gain-of-function current, and the refractory loss of excitability into one statement.

Resting Intracellular Sodium Overload

The persistent inward current loads the resting fibre with sodium even between attacks, which increases the demand on the Na+,K+-ATPase and is detectable by sodium magnetic resonance spectroscopy in patients. It is the plausible link between a purely electrical defect and the structural myopathy that develops over decades.

skeletal muscle fibre CL:0008002

sodium ion transmembrane transport GO:0035725 ↑ INCREASED

Animal models

Scn4a M1592V knock-in mouse Mouse recapitulates Resting mutant muscle shows greatly increased tetrodotoxin-suppressible sodium influx, a raised intracellular sodium concentration, and a resting membrane potential depolarized by 16 mV that tetrodotoxin repolarizes.

Downstream

Chronic Progressive Myopathy with Fatty Muscle Infiltration Chronic sodium loading of the resting fibre is the proposed route to fixed structural muscle damage; the intervening steps are not established.

Show evidence (3 references)

PMID:21708955 SUPPORT Model Organism

"The results confirm that the functional disorders of skeletal muscles in HyperKPP are secondary to increased Na(+) influx and show that contractility can be restored by acute stimulation of the Na(+),K(+) pumps."

The M1592V knock-in mouse study concludes that the contractile deficit is secondary to increased sodium influx, which is the claim this node makes.

PMID:25880512 SUPPORT REVIEW SYNTHESIS Model Organism

"TTX-sensitive 22Na+ influx was increased in resting muscle, thereby demonstrating the gain-of- function defect contributes to a resting internal Na+ overload"

States the resting sodium overload as measured in the knock-in mouse. The quoted clause is separated from the human observation in the same sentence so that each item carries a single evidence_source.

PMID:25880512 SUPPORT REVIEW SYNTHESIS Human Clinical

"as has been observed by MR spectroscopy in human patients"

The remaining clause of the same sentence records the human counterpart of the resting sodium overload, observed by sodium MR spectroscopy in patients; graded separately because it is a human rather than a murine observation.

Chronic Progressive Myopathy with Fatty Muscle Infiltration

A chronic myopathy with muscle atrophy and fatty infiltration develops with age in a selective distribution, sparing some compartments and favouring the posterior lower leg and anterior thigh. It accounts for the fixed weakness that replaces episodic attacks in later life.

skeletal muscle fibre CL:0008002

skeletal muscle contraction GO:0003009 ↓ DECREASED

skeletal muscle tissue UBERON:0001134

Downstream

Permanent Proximal Muscle Weakness Atrophy and fatty replacement present as fixed weakness between attacks.

Show evidence (2 references)

PMID:26256659 SUPPORT Human Clinical

"Whole-body muscle MRI analysis revealed muscle atrophy and fatty infiltration in hyperKPP patients, especially in older individuals."

Imaging evidence in genetically confirmed T704M patients establishes the structural myopathy and its age dependence.

PMID:26256659 SUPPORT Human Clinical

"Muscle involvement followed a selective pattern, primarily affecting the posterior compartment of the lower leg and anterior thigh muscles."

Documents the selective distribution that makes this myopathy recognizable.

⬡

Pathograph

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

●

Phenotypes

6

Metabolism 1

Hyperkalemia During Attacks Hyperkalemia while symptomatic HP:6000833

Temporal: ACUTE

Show evidence (3 references)

PMID:39174253 SUPPORT REVIEW SYNTHESIS Human Clinical

"The ictal serum K+ may be low (< 3.5 mmol/L) suggesting HypoPP, high (> 4.5 mmol/L) suggestive of HyperPP, or in the normal range which does not exclude a diagnosis of periodic paralysis."

Gives the ictal serum potassium threshold that points to HyperPP and states that a normal value does not exclude the diagnosis.

PMID:39174253 SUPPORT REVIEW SYNTHESIS Human Clinical

"Between episodes of weakness, the serum K+ is usually in the normal range in all forms of familial periodic paralysis."

Establishes that the biochemical abnormality is confined to attacks.

PMID:20301669 SUPPORT Human Clinical

"hyperkalemia (serum potassium concentration >5 mmol/L)"

GeneReviews gives the diagnostic potassium threshold used to define an attack.

Musculoskeletal 5

Episodic Flaccid Weakness HP:0003752

Temporal: RECURRENT Onset: CHILDHOOD

Show evidence (2 references)

PMID:20301669 SUPPORT Human Clinical

"A spontaneous attack commonly starts in the morning before breakfast, lasts for 15 minutes to one hour, and then passes."

GeneReviews describes the timing and duration of a typical spontaneous attack.

PMID:39174253 SUPPORT REVIEW SYNTHESIS Human Clinical

"Weakness severe enough to impair mobility typical lasts for 30 min to a few hours, although full recovery may not occur for days."

Gives the duration of functionally significant weakness and the slower tail of recovery.

Myotonia HP:0002486

Show evidence (2 references)

PMID:20301669 SUPPORT Human Clinical

"Individuals with hyperPP frequently have myotonia (muscle stiffness), especially around the time of an episode of weakness."

GeneReviews states the frequency of myotonia and its temporal relation to attacks.

PMID:29125635 SUPPORT REVIEW SYNTHESIS Human Clinical

"Between attacks, approximately half of patients with HyperPP experience muscle stiffness arising from myotonia or paramyotonia that does not impede voluntary movements."

Quantifies interictal stiffness and notes it is usually not function-limiting.

Paramyotonia Paradoxical myotonia HP:0011809

HPO does have a term for paramyotonia, under a label that does not contain the word: HP:0011809 Paradoxical myotonia, whose definition reads "In classic myotonia the myotonia improves as muscles warm up, whereas in paradoxical myotonia (paramyotonia) it worsens with repeated muscle contractions." Because the string appears only inside that definition, `runoak -i ols:hp search "l~paramyotonia"` and `runoak -i ols:hp search "t~paramyotonia"` both return nothing, while `runoak -i ols:hp search "l~paradoxical myotonia"` returns HP:0011809; the positive control `runoak -i ols:hp search "l~myotonia"` returns ten terms including HP:0011809, so the two empty results are a property of the label index and not of an unreachable adapter. HP:0012904 Cold-sensitive myotonia is a sibling rather than a parent and covers only the thermal half of the concept, so cold aggravation stays in preferred_term and in the cited quotes.

Show evidence (2 references)

PMID:20301669 SUPPORT Human Clinical

"Paramyotonia (muscle stiffness aggravated by cold and exercise) is present in about 45% of affected individuals."

GeneReviews defines paramyotonia and gives its frequency in HyperPP.

PMID:25880512 SUPPORT REVIEW SYNTHESIS Human Clinical

"some affected individuals have paradoxical worsening of myotonic stiffness with repeated effort, or paramyotonia, which is also characteristically aggravated by muscle cooling"

Equates paramyotonia with paradoxical worsening on repeated effort, which is the concept the bound HPO term names, and adds the cold aggravation carried in preferred_term.

Permanent Proximal Muscle Weakness Progressive proximal muscle weakness HP:0009073

Course: PROGRESSIVE

Show evidence (2 references)

PMID:39174253 SUPPORT REVIEW SYNTHESIS Human Clinical

"For many patients the frequency of attacks diminishes with age, and is replaced by a chronic state of mild weakness that later progresses to myopathy with permanent muscle weakness, especially of proximal muscles, and may cause loss of ambulation"

Describes the proximal distribution, the progressive course, and the functional endpoint.

PMID:26256659 SUPPORT Human Clinical

"A proportion of affected individuals develop fixed or chronic progressive weakness that results in significant disability."

Confirms fixed weakness as a recognized disabling outcome in HyperPP.

Weakness of Ocular, Bulbar, Respiratory and Trunk Muscles Intermittent episodes of respiratory insufficiency due to muscle weakness HP:0004889

Temporal: ACUTE

The bound HPO term names episodic respiratory insufficiency specifically, which is the most consequential element of this phenotype, while the curated node also covers ocular, bulbar, and trunk involvement as the cited quote lists them. It is retained after searching for a plain respiratory-muscle-weakness term: `runoak -i ols:hp search "l~respiratory muscle weakness"`, `"l~respiratory muscle"` and `"l~weakness of the respiratory muscles"` each return the same three terms, HP:0002747 Respiratory insufficiency due to muscle weakness, HP:0030196 Fatigable weakness of respiratory muscles, and HP:0004889. HP:0002747 asserts insufficiency too and loses the episodic qualifier; HP:0030196 is a myasthenic concept. So HP:0004889 is the closest available term, and the residual gap is that the cited GeneReviews quote reports weakness of the breathing muscles without documenting respiratory insufficiency.

Show evidence (1 reference)

PMID:20301669 SUPPORT Human Clinical

"attacks of flaccid limb weakness (which may also include weakness of the muscles of the eyes, throat, breathing muscles, and trunk)"

GeneReviews names the extra-limb muscle groups that severe attacks can involve, including the respiratory muscles.

🧬

Genetic Associations

1

SCN4A (Heterozygous gain-of-function missense variants in SCN4A are the sole established cause. T704M and M1592V are the two commonest alleles.)

Gene: SCN4A hgnc:10591 relationship_type: CAUSATIVE

Autosomal dominant

Show evidence (4 references)

PMID:39174253 SUPPORT REVIEW SYNTHESIS Human Clinical

"Across the narrow clinical spectrum from PMC to HyperPP, and everything in between, the gene defects are missense mutations of SCN4A. No other causative gene has been implicated for HyperPP/PMC."

Establishes SCN4A as the only causative gene and missense change as the only variant class.

PMID:39174253 SUPPORT REVIEW SYNTHESIS Human Clinical

"Likewise, null mutations of SCN4A or CACNA1S do not cause periodic paralysis, and individuals with a single intact copy of these genes have no muscle signs or symptoms"

Supports the variant-interpretation constraint that haploinsufficiency is not a disease mechanism here.

PMID:20301669 SUPPORT Human Clinical

"The diagnosis of hyperPP is established in a proband with suggestive findings and a heterozygous pathogenic variant in SCN4A identified by molecular genetic testing."

GeneReviews defines the molecular diagnostic criterion, naming the gene and the heterozygous state.

+ 1 more reference

💊

Medical Actions

7

Trigger Avoidance and Frequent Carbohydrate-Rich Meals

Action: dietary and trigger-avoidance counselling Ontology label: Dietary Intervention NCIT:C15447

Platform: Behavioral / lifestyle

The first-line intervention. Patients avoid potassium-rich foods and potassium-containing medications, fasting, strenuous work, and cold, and eat frequent carbohydrate-rich meals. Depolarizing anaesthetic agents and ACE-inhibitors are also avoided; depolarizing agents belong on that list because they are among the exposures that worsen myotonia in the sodium-channel disorders.

Mechanism Target:

Potassium Efflux and Extracellular Potassium Accumulation — Removing the exogenous potassium load and the fasting state keeps extracellular potassium below the level that unmasks the inactivation defect.

Target Phenotypes: Episodic flaccid weakness HP:0003752

Show evidence (4 references)

PMID:20301669 SUPPORT Human Clinical

"Hyperkalemic attacks of weakness can be prevented by frequent meals rich in carbohydrates; continuous use of a thiazide diuretic or a carbonic anhydrase inhibitor; and avoidance of potassium-rich medications and foods, fasting, strenuous work, and exposure to cold."

GeneReviews states the whole preventive package, of which this treatment is the non-pharmacological part.

PMID:29125635 SUPPORT REVIEW SYNTHESIS Human Clinical

"In individuals with HyperPP, consider recommending consumption of multiple small carbohydrate snacks and avoid potassium-rich foods."

Independent review gives the same dietary recommendation specifically for HyperPP.

PMID:20301669 SUPPORT Human Clinical

"use of depolarizing anesthetic agents during general anesthesia or ACE-inhibitor medications"

GeneReviews lists depolarizing anaesthetic agents and ACE inhibitors among the agents and circumstances to avoid, which is the clause of this treatment's description that was previously uncited.

+ 1 more reference

Mild Exercise at Attack Onset

Action: mild voluntary exercise at attack onset Ontology label: Exercise Intervention NCIT:C62739

Platform: Behavioral / lifestyle

Gentle voluntary activity at the first sign of weakness can prevent or abort an attack, and works locally in the muscles that are exercised. This is the intervention that most directly exploits the mechanism.

Mechanism Target:

Depolarization-Induced Sodium Channel Inactivation and Fibre Inexcitability — Repeated activation restores excitability and force in mutant muscle, apparently by stimulating the Na+,K+-ATPase.

Target Phenotypes: Episodic flaccid weakness HP:0003752

Show evidence (3 references)

PMID:20301669 SUPPORT Human Clinical

"At the onset of weakness, attacks may be prevented or aborted with mild exercise and/or oral ingestion of carbohydrates, intravenously injected glucocorticoids, inhalation of salbutamol, or intravenous calcium gluconate."

GeneReviews lists mild exercise first among the measures that abort an incipient attack.

PMID:21708955 SUPPORT Model Organism

"tetanic stimulation every minute caused a progressive and highly significant force increase of 48% in the soleus of mutant mice (P < 0.001) but no significant change in soleus of WT mice"

Provides the mechanistic counterpart in the knock-in mouse: repeated activation itself restores force, and only in mutant muscle.

PMID:21708955 SUPPORT INDIRECT Model Organism

"These observations may explain how mild exercise helps locally to prevent severe weakness during an attack of HyperKPP."

The authors' own reading of their mouse results as the explanation for the abortive effect of mild exercise in patients. It supports the treatment through that inference rather than by measuring it in humans.

Inhaled Salbutamol for Acute Attacks

Action: Pharmacotherapy NCIT:C15986

Agent: salbutamol CHEBI:2549

Platform: Small molecule

An inhaled beta-2 agonist lowers serum potassium and hastens recovery from an attack. The evidence base in HyperPP is case reports rather than trials, but the mechanism is well characterized: salbutamol stimulates the Na+,K+-ATPase, which clears potassium from the extracellular space and restores force.

Mechanism Target:

Potassium Efflux and Extracellular Potassium Accumulation — Beta-2 agonist stimulation of the sodium-potassium pump drives potassium back into muscle, which is the step the disease's feed-forward loop depends on.

Target Phenotypes: Episodic flaccid weakness HP:0003752

Show evidence (3 references)

PMID:39174253 SUPPORT REVIEW SYNTHESIS Human Clinical

"Beta-adrenergic inhalants may be used to hasten recovery from an episode of HyperPP"

States the clinical indication for an inhaled beta-agonist in HyperPP specifically.

PMID:29125635 SUPPORT REVIEW SYNTHESIS Human Clinical

"In case reports, salbutamol 1-2 puffs (0.1 mg) and other beta-agonists have shown benefits."

Names the drug and dose while stating plainly that the human evidence is case-report level.

PMID:21708955 SUPPORT Model Organism

"Stimulating Na(+),K(+) pumps with salbutamol restored force in mutant soleus and extensor digitorum longus (EDL)."

Supplies the mechanism of the clinical effect, in the knock-in mouse model of this disease.

Dichlorphenamide Preventive Pharmacotherapy

Action: Pharmacotherapy NCIT:C15986

Agent: dichlorphenamide CHEBI:101085

Platform: Small molecule

A carbonic anhydrase inhibitor, and the only drug approved for primary periodic paralysis. The evidence in HyperPP specifically is weaker than the approval suggests: in the pivotal randomized trial the hyperkalemic substudy showed a lower median attack rate on dichlorphenamide that did not reach statistical significance, and the trialists concluded the substudy lacked the precision to decide the question either way.

Mechanism Target:

Depolarization-Induced Sodium Channel Inactivation and Fibre Inexcitability — Carbonic anhydrase inhibition promotes kaliuresis and a systemic acidosis; which of these reduces susceptibility to depolarization-induced inexcitability is not settled.

Target Phenotypes: Episodic flaccid weakness HP:0003752

Show evidence (3 references)

PMID:34129236 SUPPORT BACKGROUND Other

"The oral carbonic anhydrase inhibitor dichlorphenamide (DCP) is approved for treatment of hyperkalemic and hypokalemic periodic paralyses and related variants."

Records the regulatory status, which covers HyperPP explicitly.

PMID:26865514 SUPPORT INDIRECT Human Clinical

"The median attack rate was also lower in HYP participants on DCP (0.9 vs 4.8) than in participants on placebo, but the difference in median attack rate was not significant (p = 0.10)."

The hyperkalemic arm showed a five-fold lower median attack rate, which supports the treatment only indirectly because the difference did not reach significance.

PMID:26865514 REFUTE Human Clinical

"These studies provide Class I evidence that DCP significantly reduces attack frequency in HOP but lacked the precision to support either efficacy or lack of efficacy of DCP in HYP."

The trialists' own classification of evidence cuts against any claim that efficacy in hyperkalemic periodic paralysis has been demonstrated, which is why this is recorded as a refuting item beside the supporting ones.

Acetazolamide Preventive Pharmacotherapy

Action: Pharmacotherapy NCIT:C15986

Agent: acetazolamide CHEBI:27690

Platform: Small molecule

The older carbonic anhydrase inhibitor, used empirically for about half a century at 125 to 1000 mg per day. Its most striking reported effect in HyperPP is on fixed weakness rather than on attacks, though that rests on single-patient observation.

Mechanism Target:

Depolarization-Induced Sodium Channel Inactivation and Fibre Inexcitability — In the M1592V knock-in mouse, bath acetazolamide protects against potassium-induced loss of force, which is the closest available mechanistic rationale for the drug in this disease.

Show evidence (1 reference)

PMID:25880512 SUPPORT REVIEW SYNTHESIS Model Organism

"Bath application of the carbonic anhydrase inhibitor acetazolamide protected against K+-induced loss of force"

Records the protective effect of acetazolamide on potassium-provoked inexcitability in the mouse model of this disease.

Target Phenotypes: Episodic flaccid weakness HP:0003752 Progressive proximal muscle weakness HP:0009073

Show evidence (2 references)

PMID:29125635 SUPPORT REVIEW SYNTHESIS Human Clinical

"Acetazolamide 125-1000 mg/day may be effective for chronic treatment of HyperPP."

Gives the dose range and the indication for chronic preventive use in HyperPP.

PMID:23473731 SUPPORT INDIRECT Human Clinical

"He rapidly recovered from weakness after acetazolamide treatment. Magnetic resonance imaging of thighs comparing pre- and post-treatment revealed a significant increase in muscle bulk."

A single T704M patient recovered from fixed weakness with an imaging correlate. It is one uncontrolled observation, so it supports the claim only indirectly.

Thiazide Diuretic Preventive Pharmacotherapy

Action: Pharmacotherapy NCIT:C15986

Agent: hydrochlorothiazide CHEBI:5778

Platform: Small molecule

A potassium-wasting diuretic, usually hydrochlorothiazide 25 to 75 mg daily, used for chronic prevention. Potassium-sparing diuretics are contraindicated here, which is the mirror image of their use in hypokalemic periodic paralysis.

Mechanism Target:

Potassium Efflux and Extracellular Potassium Accumulation — Promoting renal potassium loss lowers the extracellular potassium that unmasks the channel defect.

Target Phenotypes: Episodic flaccid weakness HP:0003752

Show evidence (2 references)

PMID:29125635 SUPPORT REVIEW SYNTHESIS Human Clinical

"The drug of choice is hydrochlorothiazide 25 mg to 75 mg daily.41, 54 Potassium-sparing diuretics should be avoided."

Names the agent, the dose range, and the contraindicated diuretic class for HyperPP.

PMID:39174253 SUPPORT REVIEW SYNTHESIS Human Clinical

"Oral K+ supplements and K-sparing diuretics (e.g. eplerenone) are used for HypoPP, whereas K-wasting diuretics (e.g. hydrochlorothiazide) are used for HyperPP"

States the opposite diuretic choice in the two periodic paralyses, which is the clinically consequential distinction.

Mexiletine for Myotonic Stiffness

Action: Pharmacotherapy NCIT:C15986

Agent: mexiletine CHEBI:6916

Platform: Small molecule

A use-dependent sodium-channel blocker, used when myotonic stiffness rather than weakness is the dominant symptom. It targets the hyperexcitable arm of the phenotype, not the paralytic one.

Mechanism Target:

Skeletal Muscle Membrane Hyperexcitability and Myotonic Discharges — Use-dependent block preferentially silences the repetitive firing that produces myotonia while sparing single action potentials.

Target Phenotypes: Myotonia HP:0002486

Show evidence (1 reference)

PMID:39174253 SUPPORT REVIEW SYNTHESIS Human Clinical

"If myotonic stiffness is the more problematic symptom, then use-dependent sodium channel blockers (e.g. mexiletine) may provide relief"

States the indication and the symptom it addresses, within a chapter covering HyperPP and paramyotonia congenita.

🌍

Environmental Factors

4

Ingestion of potassium-rich food or potassium-containing medication

A dietary or medicinal potassium load is the single commonest attack trigger. It acts by raising extracellular potassium enough to depolarize the fibre modestly, which is what exposes the inactivation defect, so this exposure enters the pathograph at exactly the point the disease's own feed-forward loop turns on.

Show evidence (2 references)

PMID:20301669 SUPPORT Human Clinical

"The major attack trigger is eating potassium-rich foods"

GeneReviews names dietary potassium as the principal precipitant.

PMID:20301669 SUPPORT Human Clinical

"provoking/worsening of an attack by oral potassium intake"

Oral potassium provocation is part of the diagnostic definition, which is the strongest available statement that the exposure causes attacks.

Mechanism Target:

TRIGGERS Potassium Efflux and Extracellular Potassium Accumulation — An exogenous potassium load raises extracellular potassium from outside the muscle, substituting for the endogenous efflux that would otherwise have to start the cycle.

Show evidence (1 reference)

PMID:25880512 SUPPORT Computational

"The requirement for elevated extracellular K+ (interstitial or T-tubular) to mildly depolarize the fiber and reveal the inactivation defect explains why attacks may be triggered or aggravated by potassium ingestion in HyperPP."

States the mechanistic link from ingested potassium through extracellular potassium to unmasking of the channel defect.

Rest after strenuous exercise

The mechanism link below points at the potassium node rather than directly at Sustained Sarcolemmal Depolarization. Both are defensible, and the potassium node is kept because it is the compartment the exposure acts on, the one the cited transverse-tubular physiology is about, and because its own downstream edge already reaches the depolarization node, so the chain is not shortened by the choice. Retargeting would assert that stopping exercise depolarizes the fibre without passing through potassium, which no cited source states.

Weakness characteristically appears within minutes of stopping vigorous exercise, while the working muscle is spared. Mild activity at the onset of an attack is protective, which is why the exposure is the rest and not the exercise.

Show evidence (2 references)

PMID:39174253 SUPPORT REVIEW SYNTHESIS Human Clinical

"Sustained vigorous exercise is commonly reported to be a trigger, with preserved strength of active muscles and weakness occurring within minutes of stopping to rest."

Describes the exposure precisely, including the sparing of the muscles that keep working.

PMID:20301669 SUPPORT Human Clinical

"other triggers include: cold environment; rest after exercise, stress, or fatigue; alcohol; hunger; and changes in activity level."

GeneReviews lists rest after exercise among the established precipitants.

Mechanism Target:

TRIGGERS Potassium Efflux and Extracellular Potassium Accumulation — Vigorous contraction loads the interstitial and transverse-tubular spaces with potassium, and weakness begins once the working muscle stops. What happens between stopping and the ictal potassium shift is not traced by any source cited here: the review that supplies both the trigger and the transverse-tubular potassium physiology lists the trigger mechanism during rest after exercise among the questions that remain open, so the link is recorded with unknown intermediates.

Show evidence (2 references)

PMID:25880512 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Attacks usually begin in childhood and are triggered by ingestion of K+-rich foods or rest after vigorous exercise."

Establishes rest after vigorous exercise as a HyperPP attack trigger alongside potassium ingestion. It does not itself assert the potassium step, which is why the item is indirect.

PMID:25880512 SUPPORT INDIRECT REVIEW SYNTHESIS Other

"With high-frequency firing during intensive muscle activity, the K+ efflux through KV and KCa channels produces a K+ increase in the T-tubules that may reach 10 mM or higher"

Supplies the physiological step this link depends on, that intense activity raises transverse-tubular potassium into the 10 mM range that provokes loss of force in this disease. The review states it as established muscle physiology without naming the system it was measured in, so the evidence type cannot be graded more precisely than OTHER.

Cold exposure

A cold environment both triggers attacks of weakness and aggravates the stiffness of paramyotonia, and avoiding it is part of standard preventive advice.

Show evidence (2 references)

PMID:39174253 SUPPORT REVIEW SYNTHESIS Human Clinical

"The onset of attacks is usually in childhood and episodes are triggered by cold environments, rest after vigorous exercise, stress, fasting, ingesting of K-rich foods, or alcohol"

Lists cold environment first among the established attack triggers.

PMID:20301669 SUPPORT Human Clinical

"Paramyotonia (muscle stiffness aggravated by cold and exercise) is present in about 45% of affected individuals."

Supports cold as an aggravator of the myotonic arm of the phenotype in nearly half of patients.

Mechanism Target:

EXACERBATES Skeletal Muscle Membrane Hyperexcitability and Myotonic Discharges — Cooling worsens the stiffness arm of the phenotype. The intervening steps between muscle temperature and mutant-channel gating are not traced by the sources cited here, so the link is recorded as indirect.

Show evidence (1 reference)

PMID:20301669 SUPPORT Human Clinical

"Individuals with hyperPP frequently have myotonia (muscle stiffness), especially around the time of an episode of weakness. Paramyotonia (muscle stiffness aggravated by cold and exercise)"

Ties cold aggravation specifically to the stiffness phenotype that this mechanism node produces.

Fasting

Going without food precipitates attacks, and the corresponding preventive measure is frequent carbohydrate-rich meals rather than avoidance of any single food.

Show evidence (2 references)

PMID:20301669 SUPPORT Human Clinical

"Hyperkalemic attacks of weakness can be prevented by frequent meals rich in carbohydrates"

The preventive measure is the direct counterpart of the fasting trigger, and GeneReviews states it as standard management.

PMID:39174253 SUPPORT REVIEW SYNTHESIS Human Clinical

"avoid fasting and use a carbohydrate snack to abort an attack of HyperPP"

Names fasting explicitly as the exposure to avoid in HyperPP, and carbohydrate as the abortive measure.

Mechanism Target:

TRIGGERS Sustained Sarcolemmal Depolarization — Fasting precipitates attacks and a carbohydrate load aborts them, which implicates the insulin-driven shift of potassium into muscle as the intermediate; the sources cited here state the clinical relation rather than the intervening steps.

Show evidence (1 reference)

PMID:20301669 SUPPORT INDIRECT Human Clinical

"At the onset of weakness, attacks may be prevented or aborted with mild exercise and/or oral ingestion of carbohydrates"

That carbohydrate ingestion aborts an incipient attack is the clinical evidence that the fasting state permits the depolarization this node describes. The quote is about the abortive measure rather than about the fasting trigger, so the link to this node runs through that inference.

🔬

Diagnosis

4

SCN4A Molecular Genetic Testing

Sequencing SCN4A is the first-line confirmatory test. Because only missense variants cause the disease, a truncating or splice variant does not support the diagnosis.

genetic testing NCIT:C15709

Results: A heterozygous pathogenic missense variant in SCN4A establishes the diagnosis.

Show evidence (2 references)

PMID:20301669 SUPPORT Human Clinical

"In case of diagnostic uncertainty, a provocative test can be employed, although the availability of genetic testing and electrophysiologic studies largely obviates the need for such dangerous tests."

GeneReviews states that genetic and electrophysiological testing have displaced provocative potassium challenge, which is itself hazardous.

PMID:39174253 SUPPORT REVIEW SYNTHESIS Human Clinical

"Genetic testing by next-generation sequencing of candidate genes (CACNA1S, SCN4A, and KCNJ2) is now routinely performed in the evaluation for familial periodic paralysis"

Confirms panel sequencing as routine practice and names the genes tested alongside SCN4A.

Needle Electromyography for Myotonic Discharges

Needle EMG can show myotonic discharges even when the patient reports no stiffness. This is discriminating rather than merely confirmatory: electrical myotonia argues for HyperPP or paramyotonia congenita and against hypokalemic periodic paralysis or Andersen-Tawil syndrome.

electromyography procedure NCIT:C38056

Results: Myotonic discharges waxing and waning in amplitude and frequency support HyperPP or paramyotonia congenita.

Show evidence (2 references)

PMID:39174253 SUPPORT REVIEW SYNTHESIS Human Clinical

"Convincing evidence of myotonia (discharges waxing and waning in frequency and amplitude, increased activity after voluntary contraction or provoked by percussion or needle movement) is inconsistent with a diagnosis of HypoPP or ATS, and supports a diagnosis of HyperPP or PMC."

States the discriminating value of electrical myotonia across the periodic paralyses.

PMID:29125635 SUPPORT REVIEW SYNTHESIS Human Clinical

"On needle electromyography (EMG), positive sharp waves and myotonia, characterized by spontaneous waxing and waning motor unit potential amplitude and frequency, can be seen in PMC and HyperPP."

Independently confirms the EMG findings expected in HyperPP.

Long Exercise Compound Muscle Action Potential Test

A focal attack is provoked by five minutes of repeated isometric contraction and the compound muscle action potential is followed for up to an hour. A decrement of 40% or more is abnormal. The pattern discriminates: an early increase followed by a late decrease is characteristic of HyperPP.

long exercise compound muscle action potential test

Results: A CMAP amplitude decrement of at least 40% supports susceptibility to periodic paralysis; an early increase followed by a late decrease favours HyperPP.

No NCIT clinical-action term is bound because none exists for this test. Searching the configured OLS adapter with `runoak -i ols:ncit search "l~compound muscle action potential"` and `runoak -i ols:ncit search "l~muscle action potential"` returns nothing, and `runoak -i ols:ncit search "l~exercise test"` returns only cardiac and cardiopulmonary stress-testing terms. NCIT:C88502 Nerve Conduction Velocity Test was rejected on positive grounds: this test measures CMAP amplitude decrement after exercise, not conduction velocity.

Show evidence (2 references)

PMID:29125635 SUPPORT REVIEW SYNTHESIS Human Clinical

"A reduction in CMAP amplitude of 40% or more from the maximal during exercise or post exercise is considered abnormal and is typically seen in >70% of patients."

Gives the decrement threshold and the sensitivity of the test.

PMID:39174253 SUPPORT REVIEW SYNTHESIS Human Clinical

"with a late decrease alone most often found in HypoPP (pattern V), an early increase follow by a late decrease in HyperPP (pattern IV), or a rapid onset decrease that persisted for minutes in PMC (pattern I)"

Records the subtype-discriminating response patterns, including the HyperPP pattern.

Serum Potassium Measurement During an Attack

Potassium is measured during weakness and between attacks. The pairing is what carries the information, since the interictal value is normal in all forms of periodic paralysis.

blood chemistry measurement NCIT:C47868

Results: Serum potassium above 4.5 to 5 mmol/L during an attack, or a rise of at least 1.5 mmol/L from the interictal value, supports HyperPP; a normal ictal value does not exclude it.

Show evidence (2 references)

PMID:20301669 SUPPORT Human Clinical

"normal serum potassium between attacks, and onset before age 20 years"

GeneReviews includes the normal interictal potassium and the age limit in the diagnostic definition, which is why the ictal value must be paired with a baseline.

PMID:39174253 SUPPORT REVIEW SYNTHESIS Human Clinical

"Provocative testing, with a glucose plus insulin challenge for HypoPP or with an oral K+ challenge in HyperPP, is potentially dangerous and no longer used in clinical practice."

Records that measuring spontaneous ictal potassium has replaced deliberate potassium provocation, which is no longer acceptable practice.

📈

Progression

3

First-decade onset of episodic attacks

Age: first decade of life

Attacks of flaccid weakness usually begin before age 20 years and in about half of patients within the first decade.

Show evidence (1 reference)

PMID:20301669 SUPPORT Human Clinical

"In approximately half of affected individuals, attacks of flaccid muscle weakness begin in the first decade of life, with 25% reporting their first attack at age ten years or older."

GeneReviews gives the age distribution of first attacks.

Rising then falling attack burden through mid-adult life

Age: childhood to about age 50 years

Attack frequency and severity increase over time until roughly age 50, after which attacks become considerably less frequent.

Show evidence (1 reference)

PMID:20301669 SUPPORT Human Clinical

"Initially infrequent, the attacks then increase in frequency and severity over time until approximately age 50 years, after which the frequency of attacks declines considerably."

GeneReviews describes the natural history of attack burden across adult life.

Permanent weakness and chronic progressive myopathy

Age: after age 40 years

Fixed weakness supervenes as attacks wane, and a substantial minority develop a chronic progressive myopathy.

Show evidence (2 references)

PMID:20301669 SUPPORT Human Clinical

"More than 80% of individuals with hyperPP older than age 40 years report permanent muscle weakness and about one third develop a chronic progressive myopathy."

GeneReviews quantifies permanent weakness and chronic myopathy in older patients.

PMID:39174253 SUPPORT REVIEW SYNTHESIS Human Clinical

"With advancing age, most patients with HyperPP have a slowly progressive proximal myopathy with permanent weakness that may impair ambulation."

Independently characterizes the late myopathic phase and its functional consequence.

📊

Prevalence

2

General population

Point Prevalence 0.5 per 100,000 1–9 per 1,000,000

Reported as 1 per 200,000, which normalizes to 0.5 cases per 100,000.

Show evidence (1 reference)

PMID:29125635 SUPPORT REVIEW SYNTHESIS Human Clinical

"Estimated prevalences for the periodic paralyses are 1 per 200,000 for HyperPP"

The review gives a disease-level prevalence estimate specific to HyperPP.

United Kingdom national referral cohort, genetically confirmed periodic paralysis (hyperkalemic and hypokalemic combined)

Point Prevalence 0.41 per 100,000 (0.406–0.414) 1–9 per 100,000

This figure is a combined minimum point prevalence for HyperPP and HypoPP together, not a HyperPP-specific rate; the study did not separate the two. It is recorded here because it is the most recent ascertainment-based estimate and is a lower bound.

Show evidence (1 reference)

PMID:36796140 SUPPORT Human Clinical

"for periodic paralysis (HyperPP and HypoPP) 0.41/100 000 (95% CI 0.406-0.414)"

Reports the UK minimum point prevalence for the combined periodic paralyses, which bounds the HyperPP rate from below.

🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Hyperkalemic Periodic Paralysis:

paramyotonia congenita of Von Eulenburg Not Yet Curated MONDO:0008195

Overlapping Features Allelic with HyperPP at SCN4A and caused by the same class of gain-of-function inactivation defect, so this is not a differential in the usual sense but a neighbouring point on one continuum. The same variant, and even the same family, can produce either presentation. What separates them is which arm of the phenotype dominates: myotonic stiffness with infrequent weakness in paramyotonia congenita, recurrent weakness with accompanying myotonia in HyperPP.

Distinguishing Features

Predominant symptom, not gene or variant: myotonic stiffness dominates in paramyotonia congenita, episodic weakness in HyperPP.
Stiffness that paradoxically worsens over the first few contractions, rather than easing with repetition, favours paramyotonia congenita.
Cold-selective distal and facial stiffness in winter favours paramyotonia congenita, although cold triggers attacks in HyperPP too.
On long exercise testing, a rapid-onset decrement persisting for minutes (pattern I) favours paramyotonia congenita; an early increase followed by a late decrease (pattern IV) favours HyperPP.

Show evidence (3 references)

PMID:39174253 SUPPORT REVIEW SYNTHESIS Human Clinical

"Paramyotonia congenita (PMC) and hyperkalemic periodic paralysis (HyperPP) have extensive overlap of clinical features (Figure 1, center) and are caused by similar gain-of-function defects arising from missense mutations of NaV1.4"

States the allelism and the mechanistic identity of the two conditions, which is why the distinction is clinical rather than genetic.

PMID:39174253 SUPPORT REVIEW SYNTHESIS Human Clinical

"The predominant symptom in PMC is myotonic stiffness that paradoxically worsens with the first few repetitions for voluntary contraction of affected muscles (paramyotonia), whereas the stiffness diminishes with repeated effort (warm-up) for other forms of myotonia"

Gives the bedside sign that separates paramyotonia from warm-up myotonia.

PMID:30931713 SUPPORT DIRECT Human Clinical

"The first proband and part of his family with the overlap of PMC and hyperkalemic periodic paralysis (HyperPP) has been identified as c.2111C > T (T704M) substitution of the gene SCN4A."

Reports a kindred in which paramyotonia congenita and HyperPP coexist on one SCN4A allele, which is the claim this differential rests on. The previously quoted sentence was the study's aim rather than its result.

hypokalemic periodic paralysis MONDO:0008223

Overlapping Features The mechanistically opposite periodic paralysis, and the most important differential because the treatments are contradictory. Both end in depolarization-induced inexcitability, but HypoPP gets there through an anomalous gating-pore leak current that depolarizes the fibre when extracellular potassium is low, whereas HyperPP gets there through impaired channel inactivation unmasked when potassium is high. Giving potassium helps one and precipitates the other.

Distinguishing Features

Ictal serum potassium: low (below 3.5 mmol/L) in HypoPP, high (above 4.5 mmol/L) in HyperPP. This is the defining separation, though it can be hard to document.
Myotonia is an exclusionary criterion for HypoPP and is present in most HyperPP patients.
Triggers diverge: carbohydrate-rich meals and high salt in HypoPP, potassium-rich food and fasting in HyperPP.
Treatment is opposite in direction: potassium supplements and potassium-sparing diuretics in HypoPP, potassium-wasting diuretics in HyperPP.
Genetics: HypoPP is usually CACNA1S, and its SCN4A variants are arginine substitutions in S4 voltage sensors, which HyperPP variants are not.
HypoPP attacks tend to be more severe and prolonged; HyperPP attacks are more frequent and shorter.

Show evidence (3 references)

PMID:39174253 SUPPORT REVIEW SYNTHESIS Human Clinical

"Episodic weakness in HypoPP is caused by "leaky" Ca2+ or Na+ channels, with an anomalous gating pore current that is conducted through the voltage-sensor domain of the channel."

States the distinct HypoPP mechanism, a gating-pore leak rather than an inactivation defect.

PMID:39174253 SUPPORT REVIEW SYNTHESIS Human Clinical

"Almost all HypoPP mutations are missense substitutions at arginine residues in S4 transmembrane segments (Matthews et al., 2009), which not only helps to distinguish HypoPP from HyperPP or ATS"

Gives the variant-level rule that separates SCN4A-related HypoPP from HyperPP.

PMID:29125635 SUPPORT REVIEW SYNTHESIS Human Clinical

"Attacks in HyperPP tend to be more frequent and shorter in duration than attacks in HypoPP."

Records the difference in attack pattern between the two.

Thomsen and Becker disease MONDO:0009710

Overlapping Features CLCN1-related myotonia congenita. Both diseases cause myotonia through sarcolemmal instability, but the lesion is a reduced chloride conductance rather than a persistent sodium current, and there are no potassium-associated paralytic attacks. Transient weakness after rest does occur in Becker disease, which is the point of genuine clinical confusion.

Distinguishing Features

Recurrent paralytic attacks with a documented ictal rise in serum potassium favour HyperPP; myotonia congenita has stiffness without dyskalemic attacks.
Stiffness relieved by repeated contraction (warm-up) favours myotonia congenita; stiffness worsened by the first contractions or by cold favours the sodium-channel disorders.
CLCN1 rather than SCN4A on sequencing, and recessive inheritance in the case of Becker disease.
Marked muscle hypertrophy is usual in myotonia congenita and is not a feature of HyperPP.

Show evidence (2 references)

PMID:39174253 SUPPORT REVIEW SYNTHESIS Human Clinical

"Reduction of the chloride conductance, as occurs in myotonia congenita, impairs this stability and results in bursts of after-discharges and delayed relaxation of force in myotonia"

States the distinct chloride-conductance mechanism of myotonia congenita against the sodium-current mechanism of HyperPP.

PMID:39174253 SUPPORT REVIEW SYNTHESIS Human Clinical

"When myotonia is present, CLCN1 should also be screened, and the possibility of myotonic dystrophy should be investigated by testing for expansion of CTG repeats in DMPK and CCTG repeats in CNBP."

Records CLCN1 and the myotonic dystrophies as the tests that exclude this differential when myotonia is the presenting feature.

Andersen-Tawil syndrome MONDO:0008222

Overlapping Features The third primary periodic paralysis, caused by loss of function of the inward-rectifier potassium channel Kir2.1 rather than gain of function of Nav1.4. It also reaches depolarization-induced inexcitability, by removing the resting outward potassium current instead of adding an inward sodium current. Attacks can be associated with high, low, or normal potassium, so potassium alone does not separate it from HyperPP.

Distinguishing Features

Ventricular arrhythmia, prolonged QT and prominent U waves, and the characteristic facial and skeletal features, are absent in HyperPP.
KCNJ2 is expressed in heart and bone as well as muscle, which is why Andersen-Tawil syndrome is multisystem while SCN4A disease is confined to skeletal muscle.
Myotonia argues against Andersen-Tawil syndrome and for HyperPP.

Show evidence (2 references)

PMID:39174253 SUPPORT REVIEW SYNTHESIS Human Clinical

"Unlike the skeletal muscle-specific expression for CLCN1, SCN4A, and CACNA1S; KCNJ2 is expressed in multiple tissues including skeletal muscle, heart, and bone."

Explains why Andersen-Tawil syndrome is multisystem and HyperPP is not, which is the discriminating observation.

PMID:29125635 SUPPORT REVIEW SYNTHESIS Human Clinical

"Attacks of muscle weakness can be associated with high, low or normal serum potassium levels."

Records that ictal potassium does not distinguish Andersen-Tawil syndrome from HyperPP, so the extramuscular features must be sought.

🔬

Clinical Trials

1

NCT00494507 PHASE_III COMPLETED

HYP HOP, the pivotal randomized, double-blind, placebo-controlled crossover programme of dichlorphenamide in hyperkalemic and hypokalemic periodic paralysis, with a 52-week open-label extension. Its hyperkalemic substudy is the source of the efficacy uncertainty recorded on the dichlorphenamide treatment above.

Target Phenotypes: Episodic flaccid weakness HP:0003752

Show evidence (1 reference)

clinicaltrials:NCT00494507 SUPPORT Human Clinical

"The purpose of this study is to compare Dichlorphenamide with placebo (an inactive substance) for prevention of episodes and for improvement of strength in hyperkalemic (HYP) and hypokalemic (HOP) periodic paralysis."

The registered objective names hyperkalemic periodic paralysis as a study population and episode prevention as the endpoint, which is the trial this entry's dichlorphenamide evidence comes from.

🐁

Animal Models

2

Scn4a M1592V knock-in mouse

A knock-in mouse carrying the substitution corresponding to human M1592V, one of the two commonest HyperPP alleles. It reproduces the resting depolarization, the sodium overload, the myotonia, and the potassium sensitivity, but not spontaneous paralytic attacks.

Species

Mouse

Genotype

Scn4a M1592V heterozygous knock-in

Background

FVB.129S4(B6)-Scn4atm1.1Ljh/J

Genes

SCN4A hgnc:10591

Publication

PMID:21708955

Pathograph links

Resting Intracellular Sodium Overload recapitulates fidelity: high observes: cellular Resting mutant muscle shows greatly increased tetrodotoxin-suppressible sodium influx, a raised intracellular sodium concentration, and a resting membrane potential depolarized by 16 mV that tetrodotoxin repolarizes.

Limitations: Measurements are made in isolated soleus and extensor digitorum longus at 30 degrees Celsius, so absolute influx rates are not directly transferable to intact human muscle.

Readouts

Na+,K+-pump-mediated 86Rb uptake in resting soleus

Direction: INCREASED

Interpretation: Raised pump-mediated potassium uptake is the compensatory response to the resting sodium load and is the quantitative signature of that load.

Show evidence (1 reference)

PMID:21708955 SUPPORT Model Organism

"Na(+),K(+) pump-mediated (86)Rb uptake was 83% larger than in WT."

Quantifies the increase in pump-mediated uptake in mutant muscle.

Show evidence (1 reference)

PMID:21708955 SUPPORT Model Organism

"The results confirm that the functional disorders of skeletal muscles in HyperKPP are secondary to increased Na(+) influx and show that contractility can be restored by acute stimulation of the Na(+),K(+) pumps."

The study's own conclusion is that the model's contractile defect is secondary to the sodium influx this node describes.

Depolarization-Induced Sodium Channel Inactivation and Fibre Inexcitability partially recapitulates fidelity: moderate observes: tissue Mutant muscle is markedly less excitable than wild type, requiring stronger and longer stimuli to reach maximal force, and loses force dramatically when challenged with 10 mM extracellular potassium.

Limitations: The mouse does not have spontaneous attacks of weakness; the loss of force has to be provoked by an in vitro potassium challenge, so the model reproduces the susceptibility rather than the episodic disease.

Readouts

Tetanic force during 10 mM potassium challenge

Direction: DECREASED

Interpretation: Accelerated loss of tetanic force under a potassium challenge is the functional readout of potassium-provoked inexcitability.

Show evidence (1 reference)

PMID:21708955 SUPPORT Model Organism

"In muscles from mutant mice, the rate of force reduction as measured over the first 10 min after exposure to 10 mM K+ was 760% faster than in muscles from WT."

Quantifies the potassium sensitivity of force in mutant versus wild-type muscle.

Tetanic force after salbutamol

Direction: RESTORED

Interpretation: Restoration of force by a beta-agonist links the model's inexcitability to the therapy used in patients.

Show evidence (1 reference)

PMID:21708955 SUPPORT Model Organism

"When added to muscles exposed to 10 mM K+, 10-6 M salbutamol restored tetanic force to the same level as measured at 4 mM K+ both in WT and in mutant mice"

Records the rescue of force by salbutamol during a potassium challenge.

Show evidence (1 reference)

PMID:21708955 SUPPORT Model Organism

"These observations indicate that in muscles from the mutants, excitability is lower than in muscles from WT."

Establishes reduced fibre excitability in the model, which is the node this link points at.

Acetazolamide protects the mutant muscle against potassium-induced loss of force in this model, which is the closest thing to a mechanistic rationale for carbonic anhydrase inhibition in HyperPP.

Show evidence (1 reference)

PMID:25880512 SUPPORT REVIEW SYNTHESIS Model Organism

"Spontaneous attacks of weakness have not been observed, but in vitro challenge with 10 mM K+ triggered a severe reduction of muscle force."

States both what the model does and does not reproduce, which is the honest basis for treating it as partially informative.

Equine hyperkalemic periodic paralysis (quarter horse)

A naturally occurring equine disease in American quarter horses caused by a single SCN4A founder mutation. It is the one HyperPP model with spontaneous attacks in an outbred whole organism, and it is informative precisely because the phenotype is variable on a near-uniform genetic background.

Species

Horse

Genotype

Naturally occurring heterozygous SCN4A DIIIS3 phenylalanine-to-leucine substitution, traceable to a single founder sire

Publication

PMID:25880512

Pathograph links

Sustained Sarcolemmal Depolarization recapitulates fidelity: moderate observes: cellular Intercostal muscle fibres from affected horses are depolarized at rest and repolarize to normal values on exposure to tetrodotoxin, which localizes the depolarizing current to sodium channels.

Limitations: The equine mutation is not one of the human HyperPP alleles, and the measurements are made on excised intercostal fibres rather than in vivo.

Readouts

Resting membrane depolarization of intercostal muscle fibres

Direction: INCREASED

Interpretation: Affected fibres rest at a less negative potential than normal, so the depolarization is increased while the membrane potential itself falls in absolute terms; the readout is named for the depolarization so that the direction is unambiguous. Tetrodotoxin reverses it, which is what makes this the direct readout of a sodium-dependent depolarization.

Show evidence (1 reference)

PMID:21708955 SUPPORT BACKGROUND In Vitro

"intercostal muscle fibers from horses with HyperKPP were found to be depolarized, and TTX induced repolarization to the level measured in normal horses"

Records the measurement and its reversal by sodium-channel blockade in excised equine muscle fibres.

Show evidence (1 reference)

PMID:21708955 SUPPORT BACKGROUND Model Organism

"Hyperkalemic periodic paralysis (HyperKPP) is a rare hereditary disease seen in human subjects and horses."

Establishes that the equine condition is the same hereditary disease, which is what licenses treating it as a model.

Show evidence (1 reference)

PMID:25880512 SUPPORT REVIEW SYNTHESIS Model Organism

"Despite this single mutation being expressed on a very homogenous genetic background of inbreed horses, the phenotype is variable with regard to severity and frequency of attacks"

The variability on a near-uniform background is the model's distinctive contribution: it shows that phenotypic variability in this disease is not accounted for by genetic background alone.

{ }

Source YAML

click to show

name: Hyperkalemic Periodic Paralysis
creation_date: '2026-09-29T00:00:00Z'
description: >-
  Hyperkalemic periodic paralysis is an autosomal dominant skeletal-muscle
  channelopathy caused by gain-of-function missense variants in SCN4A, which
  encodes the skeletal-muscle voltage-gated sodium channel Nav1.4. The variants
  impair channel inactivation, leaving a small persistent inward sodium current
  that holds the sarcolemma depolarized. Because that sustained depolarization
  drives the remaining sodium channels into their inactivated state, the fibre
  becomes inexcitable, so the weakness arises from depolarization-induced
  inexcitability rather than from reduced excitatory drive. Modest elevation of
  extracellular potassium is what reveals the inactivation defect, which is why
  attacks follow potassium-rich meals, rest after exercise, cold, and fasting.
  The same channel defect produces myotonia at lesser degrees of depolarization,
  so most patients have both stiffness and episodic paralysis.
category: Mendelian
parents:
- hereditary disease
- channelopathy
- familial periodic paralysis
disease_term:
  preferred_term: hyperkalemic periodic paralysis
  term:
    id: MONDO:0008224
    label: hyperkalemic periodic paralysis
synonyms:
- HyperPP
- HyperKPP
- HYPP
- primary hyperkalemic periodic paralysis
- familial hyperkalemic periodic paralysis
- Gamstorp disease
classifications:
  channelopathy_category:
    classification_value: skeletal muscle channelopathy
prevalence:
- population: General population
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.5
  notes: >-
    Reported as 1 per 200,000, which normalizes to 0.5 cases per 100,000.
  evidence:
  - reference: PMID:29125635
    reference_title: Review of the Diagnosis and Treatment of Periodic Paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Estimated prevalences for the periodic paralyses are 1 per 200,000 for
      HyperPP
    explanation: >-
      The review gives a disease-level prevalence estimate specific to HyperPP.
- population: >-
    United Kingdom national referral cohort, genetically confirmed periodic
    paralysis (hyperkalemic and hypokalemic combined)
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 0.41
  rate_low: 0.406
  rate_high: 0.414
  notes: >-
    This figure is a combined minimum point prevalence for HyperPP and HypoPP
    together, not a HyperPP-specific rate; the study did not separate the two.
    It is recorded here because it is the most recent ascertainment-based
    estimate and is a lower bound.
  evidence:
  - reference: PMID:36796140
    reference_title: >-
      Prevalence of genetically confirmed skeletal muscle channelopathies in the
      era of next generation sequencing.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      for periodic paralysis (HyperPP and HypoPP) 0.41/100 000 (95% CI
      0.406-0.414)
    explanation: >-
      Reports the UK minimum point prevalence for the combined periodic
      paralyses, which bounds the HyperPP rate from below.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    HyperPP is autosomal dominant with high penetrance. Most affected
    individuals have an affected parent and each child of an affected individual
    has a 50% chance of inheriting the variant.
  evidence:
  - reference: PMID:20301669
    reference_title: Hyperkalemic Periodic Paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HyperPP is inherited in an autosomal dominant manner. Most individuals
      with hyperPP have an affected parent
    explanation: >-
      GeneReviews states the mode of inheritance and the expected family
      structure.
  - reference: PMID:20301669
    reference_title: Hyperkalemic Periodic Paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Each child of an individual with hyperPP has a 50% chance of inheriting the
      pathogenic variant.
    explanation: >-
      GeneReviews states the transmission risk that this block's description
      asserts, which the adjacent quote stops short of.
  - reference: PMID:39174253
    reference_title: Periodic paralysis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Expression studies show the missense mutations produce gain-of-function
      alterations in channel behavior, which is consistent with the autosomal
      dominant inheritance and high penetrance of the clinical phenotype in this
      disorder.
    explanation: >-
      Heterologous expression data reconcile the dominant, highly penetrant
      inheritance with a gain-of-function molecular lesion.
progression:
- phase: First-decade onset of episodic attacks
  age_range: first decade of life
  notes: >-
    Attacks of flaccid weakness usually begin before age 20 years and in about
    half of patients within the first decade.
  evidence:
  - reference: PMID:20301669
    reference_title: Hyperkalemic Periodic Paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In approximately half of affected individuals, attacks of flaccid muscle
      weakness begin in the first decade of life, with 25% reporting their first
      attack at age ten years or older.
    explanation: >-
      GeneReviews gives the age distribution of first attacks.
- phase: Rising then falling attack burden through mid-adult life
  age_range: childhood to about age 50 years
  notes: >-
    Attack frequency and severity increase over time until roughly age 50, after
    which attacks become considerably less frequent.
  evidence:
  - reference: PMID:20301669
    reference_title: Hyperkalemic Periodic Paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Initially infrequent, the attacks then increase in frequency and severity
      over time until approximately age 50 years, after which the frequency of
      attacks declines considerably.
    explanation: >-
      GeneReviews describes the natural history of attack burden across adult
      life.
- phase: Permanent weakness and chronic progressive myopathy
  age_range: after age 40 years
  notes: >-
    Fixed weakness supervenes as attacks wane, and a substantial minority
    develop a chronic progressive myopathy.
  evidence:
  - reference: PMID:20301669
    reference_title: Hyperkalemic Periodic Paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      More than 80% of individuals with hyperPP older than age 40 years report
      permanent muscle weakness and about one third develop a chronic
      progressive myopathy.
    explanation: >-
      GeneReviews quantifies permanent weakness and chronic myopathy in older
      patients.
  - reference: PMID:39174253
    reference_title: Periodic paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      With advancing age, most patients with HyperPP have a slowly progressive
      proximal myopathy with permanent weakness that may impair ambulation.
    explanation: >-
      Independently characterizes the late myopathic phase and its functional
      consequence.
pathophysiology:
- name: SCN4A Gain-of-Function Missense Variant
  biological_scale: MOLECULAR
  description: >-
    A heterozygous missense variant in SCN4A, encoding the pore-forming alpha
    subunit of the skeletal-muscle voltage-gated sodium channel Nav1.4, is the
    sole established genetic lesion. T704M and M1592V are the two most common
    alleles. The variants act by gain of function rather than by loss of
    channel, which is why null alleles of SCN4A do not cause periodic paralysis.
  genes:
  - preferred_term: SCN4A
    term:
      id: hgnc:10591
      label: SCN4A
  genetic_context:
    allele_type: missense
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: GAIN_OF_FUNCTION
    description: >-
      Heterozygous germline missense substitutions in SCN4A whose functional
      consequence, measured by heterologous expression, is a gain of function
      for Nav1.4 gating.
  cell_types:
  - preferred_term: skeletal muscle fibre
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  molecular_functions:
  - preferred_term: Nav1.4 voltage-gated sodium channel activity
    term:
      id: GO:0005248
      label: voltage-gated sodium channel activity
    modifier: GAIN_OF_FUNCTION
  locations:
  - preferred_term: skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
  evidence:
  - reference: PMID:39174253
    reference_title: Periodic paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Across the narrow clinical spectrum from PMC to HyperPP, and everything in
      between, the gene defects are missense mutations of SCN4A. No other
      causative gene has been implicated for HyperPP/PMC.
    explanation: >-
      Establishes SCN4A missense variation as the only causative lesion for this
      disease.
  - reference: PMID:25880512
    reference_title: Channelopathies of skeletal muscle excitability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Similarly, T704M causes HyperPP with late-onset permanent myopathy
    explanation: >-
      Names the most common HyperPP allele and its genotype-phenotype
      correlation. The sentence sits in the review's genotype-phenotype passage
      and reports the clinical course observed in families carrying the allele,
      not a channel measurement.
  - reference: PMID:25880512
    reference_title: Channelopathies of skeletal muscle excitability.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Mutations associated with HyperPP, PMC or SCM all produce gain-of-function
      changes for NaV1.4
    explanation: >-
      Grounds the molecular function bound on this node. The affected gene
      product is the Nav1.4 voltage-gated sodium channel, and the HyperPP
      alleles leave its channel activity in a gain-of-function state, which is
      what the modifier on that binding asserts.
  downstream:
  - target: Impaired Nav1.4 Inactivation and Persistent Sodium Current
    causal_link_type: DIRECT
    description: >-
      The missense substitution changes channel gating, and the functional
      consequence is measured directly in expression systems.
- name: Impaired Nav1.4 Inactivation and Persistent Sodium Current
  biological_scale: MOLECULAR
  description: >-
    Mutant Nav1.4 channels fail to inactivate completely. The wild-type channel
    leaves a barely perceptible persistent current of about 0.2% of the
    transient peak; HyperPP alleles raise it to 1 to 4%, a five- to twenty-fold
    relative increase in a standing inward sodium current. Several HyperPP
    alleles additionally disrupt slow inactivation, which removes the safeguard
    that would otherwise curtail the anomalous steady-state current.
  cell_types:
  - preferred_term: skeletal muscle fibre
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  molecular_functions:
  - preferred_term: Nav1.4 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
  evidence:
  - reference: PMID:25880512
    reference_title: Channelopathies of skeletal muscle excitability.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Mutations associated with HyperPP disrupt the completeness of fast
      inactivation, which results in persistent Na+ currents of 1 to 4%.
    explanation: >-
      States the specific biophysical defect and the size of the resulting
      persistent current, synthesized from voltage-clamp studies.
  - reference: PMID:25880512
    reference_title: Channelopathies of skeletal muscle excitability.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Voltage-clamp studies have demonstrated defects of slow inactivation for
      the two most common mutations found in HyperPP (T704M and M1592V)
    explanation: >-
      Records the additional slow-inactivation defect in the two commonest
      alleles.
  - reference: PMID:36628799
    reference_title: >-
      Hyperkalemic periodic paralysis associated with a novel missense variant
      located in the inner pore of Nav1.4.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Moreover, steady-state slow inactivation in V792G was impaired with larger
      residual currents in comparison with wild-type Nav1.4.
    explanation: >-
      Whole-cell patch clamp in HEK293T cells directly measures the residual
      (persistent) current of a HyperPP allele against wild type.
  - reference: PMID:21708955
    reference_title: >-
      Na+,K+-pump stimulation improves contractility in isolated muscles of mice
      with hyperkalemic periodic paralysis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: >-
      triggered a noninactivating inward Na+ current leading to depolarization
      and increased intracellular Na+. This Na+ current could be blocked by
      tetrodotoxin (TTX), leading to repolarization
    explanation: >-
      Recordings from isolated intercostal muscle fibres of HyperPP patients
      show the noninactivating inward sodium current itself, and that blocking
      it with tetrodotoxin repolarizes the fibre.
  downstream:
  - target: Sustained Sarcolemmal Depolarization
    causal_link_type: DIRECT
    description: >-
      A standing inward sodium current shifts the resting potential in the
      depolarizing direction and holds it there.
  - target: Resting Intracellular Sodium Overload
    causal_link_type: DIRECT
    description: >-
      The same anomalous current loads the resting fibre with sodium, which is
      measurable as increased tetrodotoxin-sensitive sodium influx.
- name: Sustained Sarcolemmal Depolarization
  biological_scale: CELLULAR
  description: >-
    The resting potential fails to be maintained and settles at a stable
    depolarized value of about -45 mV instead of the normal -85 mV. This is the
    pivotal node: it is stable on the timescale of hours, which is what
    distinguishes an attack of paralysis from the millisecond-scale gating
    changes that cause myotonia alone.
  cell_types:
  - preferred_term: skeletal muscle fibre
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: membrane depolarization
    term:
      id: GO:0051899
      label: membrane depolarization
    modifier: INCREASED
  - preferred_term: regulation of membrane potential
    term:
      id: GO:0042391
      label: regulation of membrane potential
    modifier: DYSREGULATED
  locations:
  - preferred_term: skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
  evidence:
  - reference: PMID:39174253
    reference_title: Periodic paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The transient episodes of weakness in HyperPP/PMC are caused by a failure
      to maintain the resting potential, with a depolarization-induced loss of
      fiber excitability from inactivation of NaV1.4.
    explanation: >-
      States the failure of resting-potential maintenance as the proximate cause
      of ictal weakness.
  - reference: PMID:25880512
    reference_title: Channelopathies of skeletal muscle excitability.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      periodic paralysis is manifest as a stable depolarized shift of the
      resting potential that renders the fiber refractory from generating action
      potentials
    explanation: >-
      Quantitative fibre simulation distinguishes the stable depolarized state
      of paralysis from the self-sustained firing of myotonia.
  downstream:
  - target: Depolarization-Induced Sodium Channel Inactivation and Fibre Inexcitability
    causal_link_type: DIRECT
    description: >-
      From a depolarized resting potential both wild-type and mutant channels
      sit in the inactivated state.
  - target: Skeletal Muscle Membrane Hyperexcitability and Myotonic Discharges
    causal_link_type: DIRECT
    description: >-
      A modest depolarization is what reveals the inactivation defect, so a
      brief stimulus at this membrane potential provokes a myotonic burst rather
      than a single action potential.
- name: Skeletal Muscle Membrane Hyperexcitability and Myotonic Discharges
  biological_scale: CELLULAR
  description: >-
    At lesser degrees of depolarization the same inactivation defect increases
    sodium-channel availability during repolarization, so one stimulus is
    followed by a self-sustained train of action potentials. This is why
    myotonia and paralysis are two expressions of one channel defect at
    different membrane potentials, and why myotonic stiffness commonly precedes
    an attack of weakness.
  cell_types:
  - preferred_term: skeletal muscle fibre
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: regulation of membrane potential
    term:
      id: GO:0042391
      label: regulation of membrane potential
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:25880512
    reference_title: Channelopathies of skeletal muscle excitability.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      In response to a brief stimulus, the inactivation defect is revealed and
      the fiber may respond with a myotonic burst.
    explanation: >-
      Fibre simulation shows the myotonic burst arising from the same
      inactivation defect that later produces paralysis.
  - reference: PMID:39174253
    reference_title: Periodic paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Most patients with HyperPP also have myotonia, often becoming symptomatic
      with activity-dependent muscle stiffness that precedes an attack of
      weakness
    explanation: >-
      Confirms in patients that the hyperexcitable state commonly precedes the
      inexcitable one.
  downstream:
  - target: Myotonia
    causal_link_type: DIRECT
    description: >-
      Sustained after-discharges are observed clinically and on needle EMG as
      myotonia.
  - target: Paramyotonia
    causal_link_type: DIRECT
    description: >-
      The same hyperexcitable state, when it worsens rather than eases with the
      first few contractions and is aggravated by cooling, presents as
      paramyotonia. It is the cold- and exercise-sensitive expression of this
      node rather than a separate mechanism.
  - target: Potassium Efflux and Extracellular Potassium Accumulation
    causal_link_type: DIRECT
    description: >-
      Repetitive firing drives cumulative potassium efflux into the narrow
      transverse-tubular space, which cannot equilibrate by passive diffusion.
- name: Potassium Efflux and Extracellular Potassium Accumulation
  biological_scale: TISSUE
  description: >-
    Potassium leaves the depolarized and repetitively firing fibre and
    accumulates both locally in the transverse tubules and systemically as a
    rise in serum potassium during the attack. This node closes a feed-forward
    loop: the potassium it raises is the very stimulus that reveals the
    inactivation defect and deepens the depolarization that produced it. It is
    also the reason an exogenous potassium load can start the cycle from
    outside.
  cell_types:
  - preferred_term: skeletal muscle fibre
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: potassium ion transmembrane transport
    term:
      id: GO:0071805
      label: potassium ion transmembrane transport
    modifier: INCREASED
  evidence:
  - reference: PMID:25880512
    reference_title: Channelopathies of skeletal muscle excitability.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      The repetitive firing produces a cumulative increase of T-tubular K+ which
      in conjunction with the inactivation defect results in a steady inward Na+
      current that keeps the fiber depolarized at about -45 mV
    explanation: >-
      Simulation traces the closed loop from firing to potassium accumulation to
      maintained depolarization.
  - reference: PMID:21708955
    reference_title: >-
      Na+,K+-pump stimulation improves contractility in isolated muscles of mice
      with hyperkalemic periodic paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      This would initiate and explain the depolarization of the muscle cells and
      the subsequent hyperkalemia.
    explanation: >-
      Attributes the ictal rise in serum potassium to the depolarizing sodium
      influx into muscle, giving the direction of the systemic arm of the loop.
  - reference: PMID:20301669
    reference_title: Hyperkalemic Periodic Paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      an increase of serum potassium concentration of at least 1.5 mmol/L during
      an attack of weakness
    explanation: >-
      Documents the measurable ictal rise in serum potassium that this node
      asserts.
  notes: >-
    Tagged TISSUE rather than ORGANISM because the mechanistically operative
    compartment is the interstitial and transverse-tubular space of muscle
    tissue, which is also what the node's cell type and its cited evidence are
    about. The systemic arm is not lost by that choice: it is represented
    separately by the Hyperkalemia During Attacks laboratory phenotype, which
    this node's own downstream edge points at, and which carries the ictal serum
    measurement. The node is therefore left whole rather than split, since
    splitting would duplicate that phenotype and rewire five incoming or outgoing
    edges plus two treatment target_mechanisms for no gain in what is asserted.
  downstream:
  - target: Sustained Sarcolemmal Depolarization
    causal_link_type: DIRECT
    description: >-
      Raised extracellular potassium depolarizes the fibre modestly, as it does
      in healthy muscle, but here the gain-of-function current amplifies that
      shift into a refractory depolarization. This edge is what makes the
      mechanism a feed-forward cycle rather than a chain.
  - target: Hyperkalemia During Attacks
    causal_link_type: DIRECT
    description: >-
      The systemic arm of the potassium shift is what is measured at the
      bedside.
- name: Depolarization-Induced Sodium Channel Inactivation and Fibre Inexcitability
  biological_scale: CELLULAR
  description: >-
    At a resting potential near -45 mV the wild-type Nav1.4 channels and most of
    the mutant ones are held in the inactivated state, so no action potential can
    be generated and the fibre cannot contract. This is the counterintuitive step
    of the disease: the paralysis is caused by too much depolarizing current, not
    by too little, and the mutant allele therefore behaves as a functional
    dominant negative acting through voltage-dependent inactivation.
  cell_types:
  - preferred_term: skeletal muscle fibre
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: regulation of membrane potential
    term:
      id: GO:0042391
      label: regulation of membrane potential
    modifier: DYSREGULATED
  - preferred_term: skeletal muscle contraction
    term:
      id: GO:0003009
      label: skeletal muscle contraction
    modifier: DECREASED
  locations:
  - preferred_term: skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
  evidence:
  - reference: PMID:25880512
    reference_title: Channelopathies of skeletal muscle excitability.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      From this depolarized potential the WT NaV1.4 channels and the majority of
      the HyperPP mutant ones are inactivated which renders the fiber
      inexcitable, as occurs in periodic paralysis.
    explanation: >-
      States the depolarization-induced inactivation step explicitly, from a
      quantitative fibre model.
  - reference: PMID:29125635
    reference_title: Review of the Diagnosis and Treatment of Periodic Paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      In all forms of PP, ictal paresis is caused by depolarization of the muscle
      sarcolemma, which in turn causes sodium channel inactivation and reduced
      fiber excitability.
    explanation: >-
      Independent clinical review states the same depolarization to inactivation
      to inexcitability sequence as the cause of ictal paresis.
  - reference: PMID:39174253
    reference_title: Periodic paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Hyperkalemia produces a modest depolarization, as occurs in normal fibers,
      that becomes pathologically amplified by the excessive inward current
      conducted by mutant Na+ channels and leads to refractory loss of fiber
      excitability.
    explanation: >-
      Ties the potassium trigger, the amplifying gain-of-function current, and
      the refractory loss of excitability into one statement.
  downstream:
  - target: Episodic Flaccid Weakness
    causal_link_type: DIRECT
    description: >-
      Inexcitable fibres generate no force, which presents as flaccid weakness
      or paralysis lasting minutes to hours.
  - target: Weakness of Ocular, Bulbar, Respiratory and Trunk Muscles
    causal_link_type: DIRECT
    description: >-
      Severe attacks extend beyond the limbs to extraocular, pharyngeal,
      respiratory, and trunk muscles.
- name: Resting Intracellular Sodium Overload
  biological_scale: CELLULAR
  description: >-
    The persistent inward current loads the resting fibre with sodium even
    between attacks, which increases the demand on the Na+,K+-ATPase and is
    detectable by sodium magnetic resonance spectroscopy in patients. It is the
    plausible link between a purely electrical defect and the structural
    myopathy that develops over decades.
  cell_types:
  - preferred_term: skeletal muscle fibre
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: sodium ion transmembrane transport
    term:
      id: GO:0035725
      label: sodium ion transmembrane transport
    modifier: INCREASED
  evidence:
  - reference: PMID:21708955
    reference_title: >-
      Na+,K+-pump stimulation improves contractility in isolated muscles of mice
      with hyperkalemic periodic paralysis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The results confirm that the functional disorders of skeletal muscles in
      HyperKPP are secondary to increased Na(+) influx and show that
      contractility can be restored by acute stimulation of the Na(+),K(+) pumps.
    explanation: >-
      The M1592V knock-in mouse study concludes that the contractile deficit is
      secondary to increased sodium influx, which is the claim this node makes.
  - reference: PMID:25880512
    reference_title: Channelopathies of skeletal muscle excitability.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      TTX-sensitive 22Na+ influx was increased in resting muscle, thereby
      demonstrating the gain-of- function defect contributes to a resting
      internal Na+ overload
    explanation: >-
      States the resting sodium overload as measured in the knock-in mouse. The
      quoted clause is separated from the human observation in the same sentence
      so that each item carries a single evidence_source.
  - reference: PMID:25880512
    reference_title: Channelopathies of skeletal muscle excitability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      as has been observed by MR spectroscopy in human patients
    explanation: >-
      The remaining clause of the same sentence records the human counterpart of
      the resting sodium overload, observed by sodium MR spectroscopy in
      patients; graded separately because it is a human rather than a murine
      observation.
  notes: >-
    The step from resting sodium overload to the chronic myopathy is the weakest
    link in this chain. It is recorded as INDIRECT_UNKNOWN_INTERMEDIATES because
    no cited source traces the intervening steps, and the fact that permanent
    weakness can develop in patients without frequent attacks argues against
    simple cumulative injury from attacks alone.
  downstream:
  - target: Chronic Progressive Myopathy with Fatty Muscle Infiltration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Chronic sodium loading of the resting fibre is the proposed route to fixed
      structural muscle damage; the intervening steps are not established.
- name: Chronic Progressive Myopathy with Fatty Muscle Infiltration
  biological_scale: TISSUE
  description: >-
    A chronic myopathy with muscle atrophy and fatty infiltration develops with
    age in a selective distribution, sparing some compartments and favouring the
    posterior lower leg and anterior thigh. It accounts for the fixed weakness
    that replaces episodic attacks in later life.
  cell_types:
  - preferred_term: skeletal muscle fibre
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: skeletal muscle contraction
    term:
      id: GO:0003009
      label: skeletal muscle contraction
    modifier: DECREASED
  locations:
  - preferred_term: skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
  evidence:
  - reference: PMID:26256659
    reference_title: >-
      Whole-Body Muscle MRI in Patients with Hyperkalemic Periodic Paralysis
      Carrying the SCN4A Mutation T704M: Evidence for Chronic Progressive
      Myopathy with Selective Muscle Involvement.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-body muscle MRI analysis revealed muscle atrophy and fatty
      infiltration in hyperKPP patients, especially in older individuals.
    explanation: >-
      Imaging evidence in genetically confirmed T704M patients establishes the
      structural myopathy and its age dependence.
  - reference: PMID:26256659
    reference_title: >-
      Whole-Body Muscle MRI in Patients with Hyperkalemic Periodic Paralysis
      Carrying the SCN4A Mutation T704M: Evidence for Chronic Progressive
      Myopathy with Selective Muscle Involvement.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Muscle involvement followed a selective pattern, primarily affecting the
      posterior compartment of the lower leg and anterior thigh muscles.
    explanation: >-
      Documents the selective distribution that makes this myopathy
      recognizable.
  downstream:
  - target: Permanent Proximal Muscle Weakness
    causal_link_type: DIRECT
    description: >-
      Atrophy and fatty replacement present as fixed weakness between attacks.
phenotypes:
- name: Episodic Flaccid Weakness
  category: Clinical
  description: >-
    Recurrent attacks of flaccid limb weakness or paralysis, typically beginning
    in the first decade, commonly on waking before breakfast, and lasting from
    about a quarter of an hour to a few hours.
  phenotype_term:
    preferred_term: Episodic flaccid weakness
    term:
      id: HP:0003752
      label: Episodic flaccid weakness
    temporality: RECURRENT
    onset:
      onset_category: CHILDHOOD
  evidence:
  - reference: PMID:20301669
    reference_title: Hyperkalemic Periodic Paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A spontaneous attack commonly starts in the morning before breakfast, lasts
      for 15 minutes to one hour, and then passes.
    explanation: >-
      GeneReviews describes the timing and duration of a typical spontaneous
      attack.
  - reference: PMID:39174253
    reference_title: Periodic paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Weakness severe enough to impair mobility typical lasts for 30 min to a few
      hours, although full recovery may not occur for days.
    explanation: >-
      Gives the duration of functionally significant weakness and the slower tail
      of recovery.
- name: Hyperkalemia During Attacks
  category: Laboratory
  description: >-
    Serum potassium rises during an attack, above 5 mmol/L or by at least 1.5
    mmol/L from baseline, and is normal between attacks. An ictal value above
    4.5 mmol/L points to HyperPP, but a normal ictal potassium does not exclude
    the diagnosis.
  phenotype_term:
    preferred_term: Ictal hyperkalemia
    term:
      id: HP:6000833
      label: Hyperkalemia while symptomatic
    temporality: ACUTE
  evidence:
  - reference: PMID:39174253
    reference_title: Periodic paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The ictal serum K+ may be low (< 3.5 mmol/L) suggesting HypoPP, high (> 4.5
      mmol/L) suggestive of HyperPP, or in the normal range which does not exclude
      a diagnosis of periodic paralysis.
    explanation: >-
      Gives the ictal serum potassium threshold that points to HyperPP and states
      that a normal value does not exclude the diagnosis.
  - reference: PMID:39174253
    reference_title: Periodic paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Between episodes of weakness, the serum K+ is usually in the normal range in
      all forms of familial periodic paralysis.
    explanation: >-
      Establishes that the biochemical abnormality is confined to attacks.
  - reference: PMID:20301669
    reference_title: Hyperkalemic Periodic Paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hyperkalemia (serum potassium concentration >5 mmol/L)
    explanation: >-
      GeneReviews gives the diagnostic potassium threshold used to define an
      attack.
  reports_on:
  - target: Potassium Efflux and Extracellular Potassium Accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      The ictal rise in serum potassium is the accessible readout of the
      potassium shift out of depolarized muscle.
- name: Myotonia
  category: Musculoskeletal
  description: >-
    Muscle stiffness from delayed relaxation, present in most patients and
    typically most prominent around the onset of an attack of weakness. It may be
    symptomatic or detectable only by percussion or needle EMG.
  phenotype_term:
    preferred_term: Myotonia
    term:
      id: HP:0002486
      label: Myotonia
  evidence:
  - reference: PMID:20301669
    reference_title: Hyperkalemic Periodic Paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individuals with hyperPP frequently have myotonia (muscle stiffness),
      especially around the time of an episode of weakness.
    explanation: >-
      GeneReviews states the frequency of myotonia and its temporal relation to
      attacks.
  - reference: PMID:29125635
    reference_title: Review of the Diagnosis and Treatment of Periodic Paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Between attacks, approximately half of patients with HyperPP experience
      muscle stiffness arising from myotonia or paramyotonia that does not impede
      voluntary movements.
    explanation: >-
      Quantifies interictal stiffness and notes it is usually not
      function-limiting.
- name: Paramyotonia
  category: Musculoskeletal
  description: >-
    Muscle stiffness that is aggravated by cold and by exercise, rather than
    relieved by repeated contraction as in the warm-up myotonias. It occurs in
    close to half of patients and is the clinical feature that places HyperPP on
    a continuum with paramyotonia congenita.
  phenotype_term:
    preferred_term: Paramyotonia (cold- and exercise-aggravated muscle stiffness)
    term:
      id: HP:0011809
      label: Paradoxical myotonia
  evidence:
  - reference: PMID:20301669
    reference_title: Hyperkalemic Periodic Paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Paramyotonia (muscle stiffness aggravated by cold and exercise) is present
      in about 45% of affected individuals.
    explanation: >-
      GeneReviews defines paramyotonia and gives its frequency in HyperPP.
  - reference: PMID:25880512
    reference_title: Channelopathies of skeletal muscle excitability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      some affected individuals have paradoxical worsening of myotonic stiffness
      with repeated effort, or paramyotonia, which is also characteristically
      aggravated by muscle cooling
    explanation: >-
      Equates paramyotonia with paradoxical worsening on repeated effort, which
      is the concept the bound HPO term names, and adds the cold aggravation
      carried in preferred_term.
  notes: >-
    HPO does have a term for paramyotonia, under a label that does not contain
    the word: HP:0011809 Paradoxical myotonia, whose definition reads "In classic
    myotonia the myotonia improves as muscles warm up, whereas in paradoxical
    myotonia (paramyotonia) it worsens with repeated muscle contractions."
    Because the string appears only inside that definition, `runoak -i ols:hp
    search "l~paramyotonia"` and `runoak -i ols:hp search "t~paramyotonia"` both
    return nothing, while `runoak -i ols:hp search "l~paradoxical myotonia"`
    returns HP:0011809; the positive control `runoak -i ols:hp search
    "l~myotonia"` returns ten terms including HP:0011809, so the two empty
    results are a property of the label index and not of an unreachable adapter.
    HP:0012904 Cold-sensitive myotonia is a sibling rather than a parent and
    covers only the thermal half of the concept, so cold aggravation stays in
    preferred_term and in the cited quotes.
- name: Permanent Proximal Muscle Weakness
  category: Musculoskeletal
  description: >-
    Fixed, slowly progressive proximal weakness that develops in most patients
    after the fourth decade and may impair ambulation. It is the main source of
    long-term disability and its development is not strictly tied to attack
    frequency.
  phenotype_term:
    preferred_term: Progressive proximal muscle weakness
    term:
      id: HP:0009073
      label: Progressive proximal muscle weakness
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:39174253
    reference_title: Periodic paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      For many patients the frequency of attacks diminishes with age, and is
      replaced by a chronic state of mild weakness that later progresses to
      myopathy with permanent muscle weakness, especially of proximal muscles,
      and may cause loss of ambulation
    explanation: >-
      Describes the proximal distribution, the progressive course, and the
      functional endpoint.
  - reference: PMID:26256659
    reference_title: >-
      Whole-Body Muscle MRI in Patients with Hyperkalemic Periodic Paralysis
      Carrying the SCN4A Mutation T704M: Evidence for Chronic Progressive
      Myopathy with Selective Muscle Involvement.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A proportion of affected individuals develop fixed or chronic progressive
      weakness that results in significant disability.
    explanation: >-
      Confirms fixed weakness as a recognized disabling outcome in HyperPP.
- name: Weakness of Ocular, Bulbar, Respiratory and Trunk Muscles
  category: Clinical
  description: >-
    Severe attacks are not confined to the limbs and may involve the extraocular,
    pharyngeal, respiratory, and trunk muscles.
  phenotype_term:
    preferred_term: Episodic respiratory muscle weakness
    term:
      id: HP:0004889
      label: Intermittent episodes of respiratory insufficiency due to muscle weakness
    temporality: ACUTE
  evidence:
  - reference: PMID:20301669
    reference_title: Hyperkalemic Periodic Paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      attacks of flaccid limb weakness (which may also include weakness of the
      muscles of the eyes, throat, breathing muscles, and trunk)
    explanation: >-
      GeneReviews names the extra-limb muscle groups that severe attacks can
      involve, including the respiratory muscles.
  notes: >-
    The bound HPO term names episodic respiratory insufficiency specifically,
    which is the most consequential element of this phenotype, while the curated
    node also covers ocular, bulbar, and trunk involvement as the cited quote
    lists them. It is retained after searching for a plain
    respiratory-muscle-weakness term: `runoak -i ols:hp search "l~respiratory
    muscle weakness"`, `"l~respiratory muscle"` and `"l~weakness of the
    respiratory muscles"` each return the same three terms, HP:0002747
    Respiratory insufficiency due to muscle weakness, HP:0030196 Fatigable
    weakness of respiratory muscles, and HP:0004889. HP:0002747 asserts
    insufficiency too and loses the episodic qualifier; HP:0030196 is a
    myasthenic concept. So HP:0004889 is the closest available term, and the
    residual gap is that the cited GeneReviews quote reports weakness of the
    breathing muscles without documenting respiratory insufficiency.
genetic:
- name: SCN4A
  gene_term:
    preferred_term: SCN4A
    term:
      id: hgnc:10591
      label: SCN4A
  association: >-
    Heterozygous gain-of-function missense variants in SCN4A are the sole
    established cause. T704M and M1592V are the two commonest alleles.
  relationship_type: CAUSATIVE
  features: >-
    Only missense substitutions cause the disease. Null alleles of SCN4A do not,
    because the mechanism requires an anomalous current rather than an absent
    channel, and a variant in an intron or regulatory element cannot produce one.
    This constrains interpretation of variants of uncertain significance in a
    HyperPP gene panel.
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:39174253
    reference_title: Periodic paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Across the narrow clinical spectrum from PMC to HyperPP, and everything in
      between, the gene defects are missense mutations of SCN4A. No other
      causative gene has been implicated for HyperPP/PMC.
    explanation: >-
      Establishes SCN4A as the only causative gene and missense change as the
      only variant class.
  - reference: PMID:39174253
    reference_title: Periodic paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Likewise, null mutations of SCN4A or CACNA1S do not cause periodic
      paralysis, and individuals with a single intact copy of these genes have no
      muscle signs or symptoms
    explanation: >-
      Supports the variant-interpretation constraint that haploinsufficiency is
      not a disease mechanism here.
  - reference: PMID:20301669
    reference_title: Hyperkalemic Periodic Paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of hyperPP is established in a proband with suggestive
      findings and a heterozygous pathogenic variant in SCN4A identified by
      molecular genetic testing.
    explanation: >-
      GeneReviews defines the molecular diagnostic criterion, naming the gene and
      the heterozygous state.
  - reference: PMID:30931713
    reference_title: >-
      Overlap of periodic paralysis and paramyotonia congenita caused by SCN4A
      gene mutations two family reports and literature review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The first proband and part of his family with the overlap of PMC and
      hyperkalemic periodic paralysis (HyperPP) has been identified as c.2111C > T
      (T704M) substitution of the gene SCN4A.
    explanation: >-
      Family-level evidence for the T704M allele in HyperPP, here in a kindred
      that also shows paramyotonia.
  notes: >-
    Genotype-phenotype correlation is real but not absolute: M1592V has produced
    HyperPP in some members of a single family and paramyotonia congenita in
    others, and no modifier gene has been established.
environmental:
- name: Ingestion of potassium-rich food or potassium-containing medication
  description: >-
    A dietary or medicinal potassium load is the single commonest attack trigger.
    It acts by raising extracellular potassium enough to depolarize the fibre
    modestly, which is what exposes the inactivation defect, so this exposure
    enters the pathograph at exactly the point the disease's own feed-forward loop
    turns on.
  exposure_term:
    preferred_term: exposure to potassium via ingestion
    term:
      id: ECTO:0900037
      label: exposure to potassium via ingestion
  evidence:
  - reference: PMID:20301669
    reference_title: Hyperkalemic Periodic Paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The major attack trigger is eating potassium-rich foods
    explanation: >-
      GeneReviews names dietary potassium as the principal precipitant.
  - reference: PMID:20301669
    reference_title: Hyperkalemic Periodic Paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      provoking/worsening of an attack by oral potassium intake
    explanation: >-
      Oral potassium provocation is part of the diagnostic definition, which is
      the strongest available statement that the exposure causes attacks.
  influences_mechanisms:
  - target: Potassium Efflux and Extracellular Potassium Accumulation
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      An exogenous potassium load raises extracellular potassium from outside the
      muscle, substituting for the endogenous efflux that would otherwise have to
      start the cycle.
    evidence:
    - reference: PMID:25880512
      reference_title: Channelopathies of skeletal muscle excitability.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        The requirement for elevated extracellular K+ (interstitial or T-tubular)
        to mildly depolarize the fiber and reveal the inactivation defect explains
        why attacks may be triggered or aggravated by potassium ingestion in
        HyperPP.
      explanation: >-
        States the mechanistic link from ingested potassium through extracellular
        potassium to unmasking of the channel defect.
- name: Rest after strenuous exercise
  description: >-
    Weakness characteristically appears within minutes of stopping vigorous
    exercise, while the working muscle is spared. Mild activity at the onset of
    an attack is protective, which is why the exposure is the rest and not the
    exercise.
  exposure_term:
    preferred_term: exposure to strenuous exercise
    term:
      id: ECTO:6000031
      label: exposure to strenuous exercise
  evidence:
  - reference: PMID:39174253
    reference_title: Periodic paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Sustained vigorous exercise is commonly reported to be a trigger, with
      preserved strength of active muscles and weakness occurring within minutes
      of stopping to rest.
    explanation: >-
      Describes the exposure precisely, including the sparing of the muscles that
      keep working.
  - reference: PMID:20301669
    reference_title: Hyperkalemic Periodic Paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      other triggers include: cold environment; rest after exercise, stress, or
      fatigue; alcohol; hunger; and changes in activity level.
    explanation: >-
      GeneReviews lists rest after exercise among the established precipitants.
  notes: >-
    The mechanism link below points at the potassium node rather than directly at
    Sustained Sarcolemmal Depolarization. Both are defensible, and the potassium
    node is kept because it is the compartment the exposure acts on, the one the
    cited transverse-tubular physiology is about, and because its own downstream
    edge already reaches the depolarization node, so the chain is not shortened by
    the choice. Retargeting would assert that stopping exercise depolarizes the
    fibre without passing through potassium, which no cited source states.
  influences_mechanisms:
  - target: Potassium Efflux and Extracellular Potassium Accumulation
    environmental_effect: TRIGGERS
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Vigorous contraction loads the interstitial and transverse-tubular spaces
      with potassium, and weakness begins once the working muscle stops. What
      happens between stopping and the ictal potassium shift is not traced by any
      source cited here: the review that supplies both the trigger and the
      transverse-tubular potassium physiology lists the trigger mechanism during
      rest after exercise among the questions that remain open, so the link is
      recorded with unknown intermediates.
    evidence:
    - reference: PMID:25880512
      reference_title: Channelopathies of skeletal muscle excitability.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Attacks usually begin in childhood and are triggered by ingestion of
        K+-rich foods or rest after vigorous exercise.
      explanation: >-
        Establishes rest after vigorous exercise as a HyperPP attack trigger
        alongside potassium ingestion. It does not itself assert the potassium
        step, which is why the item is indirect.
    - reference: PMID:25880512
      reference_title: Channelopathies of skeletal muscle excitability.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        With high-frequency firing during intensive muscle activity, the K+
        efflux through KV and KCa channels produces a K+ increase in the
        T-tubules that may reach 10 mM or higher
      explanation: >-
        Supplies the physiological step this link depends on, that intense
        activity raises transverse-tubular potassium into the 10 mM range that
        provokes loss of force in this disease. The review states it as
        established muscle physiology without naming the system it was measured
        in, so the evidence type cannot be graded more precisely than OTHER.
- name: Cold exposure
  description: >-
    A cold environment both triggers attacks of weakness and aggravates the
    stiffness of paramyotonia, and avoiding it is part of standard preventive
    advice.
  exposure_term:
    preferred_term: cold exposure
    term:
      id: XCO:0000306
      label: cold exposure
  evidence:
  - reference: PMID:39174253
    reference_title: Periodic paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The onset of attacks is usually in childhood and episodes are triggered by
      cold environments, rest after vigorous exercise, stress, fasting, ingesting
      of K-rich foods, or alcohol
    explanation: >-
      Lists cold environment first among the established attack triggers.
  - reference: PMID:20301669
    reference_title: Hyperkalemic Periodic Paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Paramyotonia (muscle stiffness aggravated by cold and exercise) is present
      in about 45% of affected individuals.
    explanation: >-
      Supports cold as an aggravator of the myotonic arm of the phenotype in
      nearly half of patients.
  influences_mechanisms:
  - target: Skeletal Muscle Membrane Hyperexcitability and Myotonic Discharges
    environmental_effect: EXACERBATES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Cooling worsens the stiffness arm of the phenotype. The intervening steps
      between muscle temperature and mutant-channel gating are not traced by the
      sources cited here, so the link is recorded as indirect.
    evidence:
    - reference: PMID:20301669
      reference_title: Hyperkalemic Periodic Paralysis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Individuals with hyperPP frequently have myotonia (muscle stiffness),
        especially around the time of an episode of weakness. Paramyotonia (muscle
        stiffness aggravated by cold and exercise)
      explanation: >-
        Ties cold aggravation specifically to the stiffness phenotype that this
        mechanism node produces.
- name: Fasting
  description: >-
    Going without food precipitates attacks, and the corresponding preventive
    measure is frequent carbohydrate-rich meals rather than avoidance of any
    single food.
  exposure_term:
    preferred_term: fasting
    term:
      id: XCO:0000102
      label: fasting
  evidence:
  - reference: PMID:20301669
    reference_title: Hyperkalemic Periodic Paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hyperkalemic attacks of weakness can be prevented by frequent meals rich in
      carbohydrates
    explanation: >-
      The preventive measure is the direct counterpart of the fasting trigger, and
      GeneReviews states it as standard management.
  - reference: PMID:39174253
    reference_title: Periodic paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      avoid fasting and use a carbohydrate snack to abort an attack of HyperPP
    explanation: >-
      Names fasting explicitly as the exposure to avoid in HyperPP, and
      carbohydrate as the abortive measure.
  influences_mechanisms:
  - target: Sustained Sarcolemmal Depolarization
    environmental_effect: TRIGGERS
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Fasting precipitates attacks and a carbohydrate load aborts them, which
      implicates the insulin-driven shift of potassium into muscle as the
      intermediate; the sources cited here state the clinical relation rather than
      the intervening steps.
    evidence:
    - reference: PMID:20301669
      reference_title: Hyperkalemic Periodic Paralysis.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        At the onset of weakness, attacks may be prevented or aborted with mild
        exercise and/or oral ingestion of carbohydrates
      explanation: >-
        That carbohydrate ingestion aborts an incipient attack is the clinical
        evidence that the fasting state permits the depolarization this node
        describes. The quote is about the abortive measure rather than about the
        fasting trigger, so the link to this node runs through that inference.
definitions:
- name: GeneReviews clinical diagnostic definition of hyperPP
  definition_type: DIAGNOSTIC_CRITERIA
  derivation_basis: ESTABLISHED_CRITERIA
  description: >-
    The clinical definition GeneReviews uses. Its potassium criterion is a
    three-limb disjunction, and the third limb is a provocation criterion rather
    than a measurement: an attack provoked or worsened by oral potassium
    satisfies it even when no ictal potassium value was captured. That limb
    carries most of the weight in practice, because ictal potassium is often
    normal. It is also the only part of the definition that is an exposure rather
    than a finding, which is why this entry carries potassium provocation as an
    ECTO-bound environmental exposure linked into the pathograph as well as here.
    Molecular confirmation is a heterozygous pathogenic SCN4A variant, curated
    under diagnosis.
  inclusion_criteria:
  - preferred_term: Attacks of flaccid limb weakness
    description: >-
      May also include weakness of the muscles of the eyes, throat, breathing
      muscles, and trunk.
  - preferred_term: >-
      Hyperkalemia above 5 mmol/L, or a rise in serum potassium of at least 1.5
      mmol/L during an attack, or provoking or worsening of an attack by oral
      potassium intake
    description: >-
      Any one of the three limbs satisfies the criterion. The provocation limb
      stands in for a measurement when none was made.
  - preferred_term: Normal serum potassium between attacks
  - preferred_term: Onset before age 20 years
  evidence:
  - reference: PMID:20301669
    reference_title: Hyperkalemic Periodic Paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hyperkalemia (serum potassium concentration >5 mmol/L) or an increase of
      serum potassium concentration of at least 1.5 mmol/L during an attack of
      weakness and/or provoking/worsening of an attack by oral potassium intake,
      normal serum potassium between attacks, and onset before age 20 years
    explanation: >-
      The criteria set quoted verbatim, including the oral potassium provocation
      limb and the age limit.
  notes: >-
    HPO codes potassium provocation as a clinical modifier, HP:0031167 "Triggered
    by ingestion of potassium-rich food", which sits under HP:0012823 Clinical
    modifier and therefore outside the PhenotypeTerm enum root HP:0000118. It
    cannot be bound as a phenotype term in this schema, which is why the
    criterion is recorded here and as an environmental exposure rather than as a
    phenotype of its own.
animal_models:
- name: Scn4a M1592V knock-in mouse
  species: Mouse
  genotype: Scn4a M1592V heterozygous knock-in
  background: FVB.129S4(B6)-Scn4atm1.1Ljh/J
  publication: PMID:21708955
  genes:
  - preferred_term: SCN4A
    term:
      id: hgnc:10591
      label: SCN4A
  description: >-
    A knock-in mouse carrying the substitution corresponding to human M1592V, one
    of the two commonest HyperPP alleles. It reproduces the resting
    depolarization, the sodium overload, the myotonia, and the potassium
    sensitivity, but not spontaneous paralytic attacks.
  modeled_mechanisms:
  - target: Resting Intracellular Sodium Overload
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: >-
      Resting mutant muscle shows greatly increased tetrodotoxin-suppressible
      sodium influx, a raised intracellular sodium concentration, and a resting
      membrane potential depolarized by 16 mV that tetrodotoxin repolarizes.
    limitations: >-
      Measurements are made in isolated soleus and extensor digitorum longus at
      30 degrees Celsius, so absolute influx rates are not directly transferable
      to intact human muscle.
    readouts:
    - name: Na+,K+-pump-mediated 86Rb uptake in resting soleus
      target: Resting Intracellular Sodium Overload
      direction: INCREASED
      interpretation: >-
        Raised pump-mediated potassium uptake is the compensatory response to the
        resting sodium load and is the quantitative signature of that load.
      evidence:
      - reference: PMID:21708955
        reference_title: >-
          Na+,K+-pump stimulation improves contractility in isolated muscles of
          mice with hyperkalemic periodic paralysis.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Na(+),K(+) pump-mediated (86)Rb uptake was 83% larger than in WT.
        explanation: >-
          Quantifies the increase in pump-mediated uptake in mutant muscle.
    evidence:
    - reference: PMID:21708955
      reference_title: >-
        Na+,K+-pump stimulation improves contractility in isolated muscles of mice
        with hyperkalemic periodic paralysis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The results confirm that the functional disorders of skeletal muscles in
        HyperKPP are secondary to increased Na(+) influx and show that
        contractility can be restored by acute stimulation of the Na(+),K(+) pumps.
      explanation: >-
        The study's own conclusion is that the model's contractile defect is
        secondary to the sodium influx this node describes.
  - target: Depolarization-Induced Sodium Channel Inactivation and Fibre Inexcitability
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Mutant muscle is markedly less excitable than wild type, requiring stronger
      and longer stimuli to reach maximal force, and loses force dramatically when
      challenged with 10 mM extracellular potassium.
    limitations: >-
      The mouse does not have spontaneous attacks of weakness; the loss of force
      has to be provoked by an in vitro potassium challenge, so the model
      reproduces the susceptibility rather than the episodic disease.
    readouts:
    - name: Tetanic force during 10 mM potassium challenge
      target: Depolarization-Induced Sodium Channel Inactivation and Fibre Inexcitability
      direction: DECREASED
      interpretation: >-
        Accelerated loss of tetanic force under a potassium challenge is the
        functional readout of potassium-provoked inexcitability.
      evidence:
      - reference: PMID:21708955
        reference_title: >-
          Na+,K+-pump stimulation improves contractility in isolated muscles of
          mice with hyperkalemic periodic paralysis.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          In muscles from mutant mice, the rate of force reduction as measured over
          the first 10 min after exposure to 10 mM K+ was 760% faster than in
          muscles from WT.
        explanation: >-
          Quantifies the potassium sensitivity of force in mutant versus wild-type
          muscle.
    - name: Tetanic force after salbutamol
      target: Depolarization-Induced Sodium Channel Inactivation and Fibre Inexcitability
      direction: RESTORED
      interpretation: >-
        Restoration of force by a beta-agonist links the model's inexcitability to
        the therapy used in patients.
      evidence:
      - reference: PMID:21708955
        reference_title: >-
          Na+,K+-pump stimulation improves contractility in isolated muscles of
          mice with hyperkalemic periodic paralysis.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          When added to muscles exposed to 10 mM K+, 10-6 M salbutamol restored
          tetanic force to the same level as measured at 4 mM K+ both in WT and in
          mutant mice
        explanation: >-
          Records the rescue of force by salbutamol during a potassium challenge.
    evidence:
    - reference: PMID:21708955
      reference_title: >-
        Na+,K+-pump stimulation improves contractility in isolated muscles of mice
        with hyperkalemic periodic paralysis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These observations indicate that in muscles from the mutants, excitability
        is lower than in muscles from WT.
      explanation: >-
        Establishes reduced fibre excitability in the model, which is the node this
        link points at.
  evidence:
  - reference: PMID:25880512
    reference_title: Channelopathies of skeletal muscle excitability.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Spontaneous attacks of weakness have not been observed, but in vitro
      challenge with 10 mM K+ triggered a severe reduction of muscle force.
    explanation: >-
      States both what the model does and does not reproduce, which is the honest
      basis for treating it as partially informative.
  notes: >-
    Acetazolamide protects the mutant muscle against potassium-induced loss of
    force in this model, which is the closest thing to a mechanistic rationale for
    carbonic anhydrase inhibition in HyperPP.
- name: Equine hyperkalemic periodic paralysis (quarter horse)
  species: Horse
  genotype: >-
    Naturally occurring heterozygous SCN4A DIIIS3 phenylalanine-to-leucine
    substitution, traceable to a single founder sire
  publication: PMID:25880512
  description: >-
    A naturally occurring equine disease in American quarter horses caused by a
    single SCN4A founder mutation. It is the one HyperPP model with spontaneous
    attacks in an outbred whole organism, and it is informative precisely because
    the phenotype is variable on a near-uniform genetic background.
  modeled_mechanisms:
  - target: Sustained Sarcolemmal Depolarization
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Intercostal muscle fibres from affected horses are depolarized at rest and
      repolarize to normal values on exposure to tetrodotoxin, which localizes the
      depolarizing current to sodium channels.
    limitations: >-
      The equine mutation is not one of the human HyperPP alleles, and the
      measurements are made on excised intercostal fibres rather than in vivo.
    readouts:
    - name: Resting membrane depolarization of intercostal muscle fibres
      target: Sustained Sarcolemmal Depolarization
      direction: INCREASED
      interpretation: >-
        Affected fibres rest at a less negative potential than normal, so the
        depolarization is increased while the membrane potential itself falls in
        absolute terms; the readout is named for the depolarization so that the
        direction is unambiguous. Tetrodotoxin reverses it, which is what makes
        this the direct readout of a sodium-dependent depolarization.
      evidence:
      - reference: PMID:21708955
        reference_title: >-
          Na+,K+-pump stimulation improves contractility in isolated muscles of
          mice with hyperkalemic periodic paralysis.
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: BACKGROUND
        snippet: >-
          intercostal muscle fibers from horses with HyperKPP were found to be
          depolarized, and TTX induced repolarization to the level measured in
          normal horses
        explanation: >-
          Records the measurement and its reversal by sodium-channel blockade in
          excised equine muscle fibres.
    evidence:
    - reference: PMID:21708955
      reference_title: >-
        Na+,K+-pump stimulation improves contractility in isolated muscles of mice
        with hyperkalemic periodic paralysis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: BACKGROUND
      snippet: >-
        Hyperkalemic periodic paralysis (HyperKPP) is a rare hereditary disease
        seen in human subjects and horses.
      explanation: >-
        Establishes that the equine condition is the same hereditary disease, which
        is what licenses treating it as a model.
  evidence:
  - reference: PMID:25880512
    reference_title: Channelopathies of skeletal muscle excitability.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Despite this single mutation being expressed on a very homogenous genetic
      background of inbreed horses, the phenotype is variable with regard to
      severity and frequency of attacks
    explanation: >-
      The variability on a near-uniform background is the model's distinctive
      contribution: it shows that phenotypic variability in this disease is not
      accounted for by genetic background alone.
treatments:
- name: Trigger Avoidance and Frequent Carbohydrate-Rich Meals
  description: >-
    The first-line intervention. Patients avoid potassium-rich foods and
    potassium-containing medications, fasting, strenuous work, and cold, and eat
    frequent carbohydrate-rich meals. Depolarizing anaesthetic agents and
    ACE-inhibitors are also avoided; depolarizing agents belong on that list
    because they are among the exposures that worsen myotonia in the
    sodium-channel disorders.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: dietary and trigger-avoidance counselling
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_phenotypes:
  - preferred_term: Episodic flaccid weakness
    term:
      id: HP:0003752
      label: Episodic flaccid weakness
  target_mechanisms:
  - target: Potassium Efflux and Extracellular Potassium Accumulation
    description: >-
      Removing the exogenous potassium load and the fasting state keeps
      extracellular potassium below the level that unmasks the inactivation
      defect.
  evidence:
  - reference: PMID:20301669
    reference_title: Hyperkalemic Periodic Paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hyperkalemic attacks of weakness can be prevented by frequent meals rich in
      carbohydrates; continuous use of a thiazide diuretic or a carbonic anhydrase
      inhibitor; and avoidance of potassium-rich medications and foods, fasting,
      strenuous work, and exposure to cold.
    explanation: >-
      GeneReviews states the whole preventive package, of which this treatment is
      the non-pharmacological part.
  - reference: PMID:29125635
    reference_title: Review of the Diagnosis and Treatment of Periodic Paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      In individuals with HyperPP, consider recommending consumption of multiple
      small carbohydrate snacks and avoid potassium-rich foods.
    explanation: >-
      Independent review gives the same dietary recommendation specifically for
      HyperPP.
  - reference: PMID:20301669
    reference_title: Hyperkalemic Periodic Paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      use of depolarizing anesthetic agents during general anesthesia or
      ACE-inhibitor medications
    explanation: >-
      GeneReviews lists depolarizing anaesthetic agents and ACE inhibitors among
      the agents and circumstances to avoid, which is the clause of this
      treatment's description that was previously uncited.
  - reference: PMID:25880512
    reference_title: Channelopathies of skeletal muscle excitability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Additional triggers have been associated with worsening of myotonia
      including potassium administration, emotional stress, pregnancy,
      hypothyroidism, depolarizing general anesthetics, or cold exposure
    explanation: >-
      Sources the reason depolarizing anaesthetic agents are on the avoidance
      list: they are among the exposures that worsen myotonia in the
      sodium-channel disorders.
- name: Mild Exercise at Attack Onset
  description: >-
    Gentle voluntary activity at the first sign of weakness can prevent or abort
    an attack, and works locally in the muscles that are exercised. This is the
    intervention that most directly exploits the mechanism.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: mild voluntary exercise at attack onset
    term:
      id: NCIT:C62739
      label: Exercise Intervention
  target_phenotypes:
  - preferred_term: Episodic flaccid weakness
    term:
      id: HP:0003752
      label: Episodic flaccid weakness
  target_mechanisms:
  - target: Depolarization-Induced Sodium Channel Inactivation and Fibre Inexcitability
    description: >-
      Repeated activation restores excitability and force in mutant muscle,
      apparently by stimulating the Na+,K+-ATPase.
  evidence:
  - reference: PMID:20301669
    reference_title: Hyperkalemic Periodic Paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At the onset of weakness, attacks may be prevented or aborted with mild
      exercise and/or oral ingestion of carbohydrates, intravenously injected
      glucocorticoids, inhalation of salbutamol, or intravenous calcium gluconate.
    explanation: >-
      GeneReviews lists mild exercise first among the measures that abort an
      incipient attack.
  - reference: PMID:21708955
    reference_title: >-
      Na+,K+-pump stimulation improves contractility in isolated muscles of mice
      with hyperkalemic periodic paralysis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      tetanic stimulation every minute caused a progressive and highly significant
      force increase of 48% in the soleus of mutant mice (P < 0.001) but no
      significant change in soleus of WT mice
    explanation: >-
      Provides the mechanistic counterpart in the knock-in mouse: repeated
      activation itself restores force, and only in mutant muscle.
  - reference: PMID:21708955
    reference_title: >-
      Na+,K+-pump stimulation improves contractility in isolated muscles of mice
      with hyperkalemic periodic paralysis.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These observations may explain how mild exercise helps locally to prevent
      severe weakness during an attack of HyperKPP.
    explanation: >-
      The authors' own reading of their mouse results as the explanation for the
      abortive effect of mild exercise in patients. It supports the treatment
      through that inference rather than by measuring it in humans.
  notes: >-
    Bound to Exercise Intervention, which NCIT defines as "A program of managed
    physical activity to improve an individual's health and wellbeing" and which
    is reachable from NCIT:C25218 through NCIT:C63474 Behavioral, Psychological
    or Informational Intervention. NCIT:C15302 Physical Therapy, bound here
    earlier, names a professionally delivered rehabilitation service, which
    self-directed abortive exercise is not. `runoak -i ols:ncit search
    "l~exercise"` returns NCIT:C16567 Exercise and NCIT:C39777 Very Light
    Exercise, whose only is_a ancestors are NCIT:C17708 Physical Activity and
    NCIT:C43431 Activity, so neither reaches the TreatmentTerm root NCIT:C25218
    and neither is admissible in this slot. The query cited here earlier,
    `"l~exercise test"`, returns cardiac and cardiopulmonary stress tests and was
    the wrong search for an intervention term.
- name: Inhaled Salbutamol for Acute Attacks
  description: >-
    An inhaled beta-2 agonist lowers serum potassium and hastens recovery from an
    attack. The evidence base in HyperPP is case reports rather than trials, but
    the mechanism is well characterized: salbutamol stimulates the Na+,K+-ATPase,
    which clears potassium from the extracellular space and restores force.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: salbutamol
      term:
        id: CHEBI:2549
        label: albuterol
  target_phenotypes:
  - preferred_term: Episodic flaccid weakness
    term:
      id: HP:0003752
      label: Episodic flaccid weakness
  target_mechanisms:
  - target: Potassium Efflux and Extracellular Potassium Accumulation
    description: >-
      Beta-2 agonist stimulation of the sodium-potassium pump drives potassium
      back into muscle, which is the step the disease's feed-forward loop depends
      on.
  evidence:
  - reference: PMID:39174253
    reference_title: Periodic paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Beta-adrenergic inhalants may be used to hasten recovery from an episode of
      HyperPP
    explanation: >-
      States the clinical indication for an inhaled beta-agonist in HyperPP
      specifically.
  - reference: PMID:29125635
    reference_title: Review of the Diagnosis and Treatment of Periodic Paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      In case reports, salbutamol 1-2 puffs (0.1 mg) and other beta-agonists have
      shown benefits.
    explanation: >-
      Names the drug and dose while stating plainly that the human evidence is
      case-report level.
  - reference: PMID:21708955
    reference_title: >-
      Na+,K+-pump stimulation improves contractility in isolated muscles of mice
      with hyperkalemic periodic paralysis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Stimulating Na(+),K(+) pumps with salbutamol restored force in mutant soleus
      and extensor digitorum longus (EDL).
    explanation: >-
      Supplies the mechanism of the clinical effect, in the knock-in mouse model of
      this disease.
- name: Dichlorphenamide Preventive Pharmacotherapy
  description: >-
    A carbonic anhydrase inhibitor, and the only drug approved for primary
    periodic paralysis. The evidence in HyperPP specifically is weaker than the
    approval suggests: in the pivotal randomized trial the hyperkalemic substudy
    showed a lower median attack rate on dichlorphenamide that did not reach
    statistical significance, and the trialists concluded the substudy lacked the
    precision to decide the question either way.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: dichlorphenamide
      term:
        id: CHEBI:101085
        label: diclofenamide
  target_phenotypes:
  - preferred_term: Episodic flaccid weakness
    term:
      id: HP:0003752
      label: Episodic flaccid weakness
  target_mechanisms:
  - target: Depolarization-Induced Sodium Channel Inactivation and Fibre Inexcitability
    description: >-
      Carbonic anhydrase inhibition promotes kaliuresis and a systemic acidosis;
      which of these reduces susceptibility to depolarization-induced
      inexcitability is not settled.
  evidence:
  - reference: PMID:34129236
    reference_title: >-
      Long-term efficacy and safety of dichlorphenamide for treatment of primary
      periodic paralysis.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: >-
      The oral carbonic anhydrase inhibitor dichlorphenamide (DCP) is approved for
      treatment of hyperkalemic and hypokalemic periodic paralyses and related
      variants.
    explanation: >-
      Records the regulatory status, which covers HyperPP explicitly.
  - reference: PMID:26865514
    reference_title: >-
      Randomized, placebo-controlled trials of dichlorphenamide in periodic
      paralysis.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The median attack rate was also lower in HYP participants on DCP (0.9 vs
      4.8) than in participants on placebo, but the difference in median attack
      rate was not significant (p = 0.10).
    explanation: >-
      The hyperkalemic arm showed a five-fold lower median attack rate, which
      supports the treatment only indirectly because the difference did not reach
      significance.
  - reference: PMID:26865514
    reference_title: >-
      Randomized, placebo-controlled trials of dichlorphenamide in periodic
      paralysis.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These studies provide Class I evidence that DCP significantly reduces attack
      frequency in HOP but lacked the precision to support either efficacy or lack
      of efficacy of DCP in HYP.
    explanation: >-
      The trialists' own classification of evidence cuts against any claim that
      efficacy in hyperkalemic periodic paralysis has been demonstrated, which is
      why this is recorded as a refuting item beside the supporting ones.
  notes: >-
    The one-year open-label extension reported sustained reductions in attack rate,
    but it pooled the hyperkalemic and hypokalemic substudies, so it does not
    resolve the HyperPP-specific question either.
- name: Acetazolamide Preventive Pharmacotherapy
  description: >-
    The older carbonic anhydrase inhibitor, used empirically for about half a
    century at 125 to 1000 mg per day. Its most striking reported effect in
    HyperPP is on fixed weakness rather than on attacks, though that rests on
    single-patient observation.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: acetazolamide
      term:
        id: CHEBI:27690
        label: acetazolamide
  target_phenotypes:
  - preferred_term: Episodic flaccid weakness
    term:
      id: HP:0003752
      label: Episodic flaccid weakness
  - preferred_term: Progressive proximal muscle weakness
    term:
      id: HP:0009073
      label: Progressive proximal muscle weakness
  target_mechanisms:
  - target: Depolarization-Induced Sodium Channel Inactivation and Fibre Inexcitability
    description: >-
      In the M1592V knock-in mouse, bath acetazolamide protects against
      potassium-induced loss of force, which is the closest available mechanistic
      rationale for the drug in this disease.
    evidence:
    - reference: PMID:25880512
      reference_title: Channelopathies of skeletal muscle excitability.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Bath application of the carbonic anhydrase inhibitor acetazolamide
        protected against K+-induced loss of force
      explanation: >-
        Records the protective effect of acetazolamide on potassium-provoked
        inexcitability in the mouse model of this disease.
  evidence:
  - reference: PMID:29125635
    reference_title: Review of the Diagnosis and Treatment of Periodic Paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Acetazolamide 125-1000 mg/day may be effective for chronic treatment of
      HyperPP.
    explanation: >-
      Gives the dose range and the indication for chronic preventive use in
      HyperPP.
  - reference: PMID:23473731
    reference_title: >-
      Long-term effectiveness of acetazolamide on permanent weakness in
      hyperkalemic periodic paralysis.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He rapidly recovered from weakness after acetazolamide treatment. Magnetic
      resonance imaging of thighs comparing pre- and post-treatment revealed a
      significant increase in muscle bulk.
    explanation: >-
      A single T704M patient recovered from fixed weakness with an imaging
      correlate. It is one uncontrolled observation, so it supports the claim only
      indirectly.
  notes: >-
    The same source warns that some patients develop deleterious effects from
    acetazolamide, so the drug is not uniformly beneficial. How carbonic anhydrase
    inhibition works in periodic paralysis remains unsettled.
- name: Thiazide Diuretic Preventive Pharmacotherapy
  description: >-
    A potassium-wasting diuretic, usually hydrochlorothiazide 25 to 75 mg daily,
    used for chronic prevention. Potassium-sparing diuretics are contraindicated
    here, which is the mirror image of their use in hypokalemic periodic
    paralysis.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: hydrochlorothiazide
      term:
        id: CHEBI:5778
        label: hydrochlorothiazide
  target_phenotypes:
  - preferred_term: Episodic flaccid weakness
    term:
      id: HP:0003752
      label: Episodic flaccid weakness
  target_mechanisms:
  - target: Potassium Efflux and Extracellular Potassium Accumulation
    description: >-
      Promoting renal potassium loss lowers the extracellular potassium that
      unmasks the channel defect.
  evidence:
  - reference: PMID:29125635
    reference_title: Review of the Diagnosis and Treatment of Periodic Paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The drug of choice is hydrochlorothiazide 25 mg to 75 mg daily.41, 54
      Potassium-sparing diuretics should be avoided.
    explanation: >-
      Names the agent, the dose range, and the contraindicated diuretic class for
      HyperPP.
  - reference: PMID:39174253
    reference_title: Periodic paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Oral K+ supplements and K-sparing diuretics (e.g. eplerenone) are used for
      HypoPP, whereas K-wasting diuretics (e.g. hydrochlorothiazide) are used for
      HyperPP
    explanation: >-
      States the opposite diuretic choice in the two periodic paralyses, which is
      the clinically consequential distinction.
- name: Mexiletine for Myotonic Stiffness
  description: >-
    A use-dependent sodium-channel blocker, used when myotonic stiffness rather
    than weakness is the dominant symptom. It targets the hyperexcitable arm of
    the phenotype, not the paralytic one.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: mexiletine
      term:
        id: CHEBI:6916
        label: mexiletine
  target_phenotypes:
  - preferred_term: Myotonia
    term:
      id: HP:0002486
      label: Myotonia
  target_mechanisms:
  - target: Skeletal Muscle Membrane Hyperexcitability and Myotonic Discharges
    description: >-
      Use-dependent block preferentially silences the repetitive firing that
      produces myotonia while sparing single action potentials.
  evidence:
  - reference: PMID:39174253
    reference_title: Periodic paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      If myotonic stiffness is the more problematic symptom, then use-dependent
      sodium channel blockers (e.g. mexiletine) may provide relief
    explanation: >-
      States the indication and the symptom it addresses, within a chapter covering
      HyperPP and paramyotonia congenita.
  notes: >-
    The randomized evidence for mexiletine comes from the non-dystrophic myotonias
    rather than from HyperPP cohorts, and is curated on the
    Thomsen_and_Becker_disease entry. It is cited here only as an indication.
diagnosis:
- name: SCN4A Molecular Genetic Testing
  description: >-
    Sequencing SCN4A is the first-line confirmatory test. Because only missense
    variants cause the disease, a truncating or splice variant does not support
    the diagnosis.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  results: >-
    A heterozygous pathogenic missense variant in SCN4A establishes the diagnosis.
  evidence:
  - reference: PMID:20301669
    reference_title: Hyperkalemic Periodic Paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In case of diagnostic uncertainty, a provocative test can be employed,
      although the availability of genetic testing and electrophysiologic studies
      largely obviates the need for such dangerous tests.
    explanation: >-
      GeneReviews states that genetic and electrophysiological testing have
      displaced provocative potassium challenge, which is itself hazardous.
  - reference: PMID:39174253
    reference_title: Periodic paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Genetic testing by next-generation sequencing of candidate genes (CACNA1S,
      SCN4A, and KCNJ2) is now routinely performed in the evaluation for familial
      periodic paralysis
    explanation: >-
      Confirms panel sequencing as routine practice and names the genes tested
      alongside SCN4A.
- name: Needle Electromyography for Myotonic Discharges
  description: >-
    Needle EMG can show myotonic discharges even when the patient reports no
    stiffness. This is discriminating rather than merely confirmatory: electrical
    myotonia argues for HyperPP or paramyotonia congenita and against hypokalemic
    periodic paralysis or Andersen-Tawil syndrome.
  diagnosis_term:
    preferred_term: electromyography procedure
    term:
      id: NCIT:C38056
      label: Electromyography
  results: >-
    Myotonic discharges waxing and waning in amplitude and frequency support
    HyperPP or paramyotonia congenita.
  evidence:
  - reference: PMID:39174253
    reference_title: Periodic paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Convincing evidence of myotonia (discharges waxing and waning in frequency
      and amplitude, increased activity after voluntary contraction or provoked by
      percussion or needle movement) is inconsistent with a diagnosis of HypoPP or
      ATS, and supports a diagnosis of HyperPP or PMC.
    explanation: >-
      States the discriminating value of electrical myotonia across the periodic
      paralyses.
  - reference: PMID:29125635
    reference_title: Review of the Diagnosis and Treatment of Periodic Paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      On needle electromyography (EMG), positive sharp waves and myotonia,
      characterized by spontaneous waxing and waning motor unit potential
      amplitude and frequency, can be seen in PMC and HyperPP.
    explanation: >-
      Independently confirms the EMG findings expected in HyperPP.
- name: Long Exercise Compound Muscle Action Potential Test
  description: >-
    A focal attack is provoked by five minutes of repeated isometric contraction
    and the compound muscle action potential is followed for up to an hour. A
    decrement of 40% or more is abnormal. The pattern discriminates: an early
    increase followed by a late decrease is characteristic of HyperPP.
  diagnosis_term:
    preferred_term: long exercise compound muscle action potential test
  results: >-
    A CMAP amplitude decrement of at least 40% supports susceptibility to periodic
    paralysis; an early increase followed by a late decrease favours HyperPP.
  evidence:
  - reference: PMID:29125635
    reference_title: Review of the Diagnosis and Treatment of Periodic Paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      A reduction in CMAP amplitude of 40% or more from the maximal during
      exercise or post exercise is considered abnormal and is typically seen in
      >70% of patients.
    explanation: >-
      Gives the decrement threshold and the sensitivity of the test.
  - reference: PMID:39174253
    reference_title: Periodic paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      with a late decrease alone most often found in HypoPP (pattern V), an early
      increase follow by a late decrease in HyperPP (pattern IV), or a rapid onset
      decrease that persisted for minutes in PMC (pattern I)
    explanation: >-
      Records the subtype-discriminating response patterns, including the HyperPP
      pattern.
  notes: >-
    No NCIT clinical-action term is bound because none exists for this test.
    Searching the configured OLS adapter with `runoak -i ols:ncit search
    "l~compound muscle action potential"` and `runoak -i ols:ncit search "l~muscle
    action potential"` returns nothing, and `runoak -i ols:ncit search "l~exercise
    test"` returns only cardiac and cardiopulmonary stress-testing terms.
    NCIT:C88502 Nerve Conduction Velocity Test was rejected on positive grounds:
    this test measures CMAP amplitude decrement after exercise, not conduction
    velocity.
- name: Serum Potassium Measurement During an Attack
  description: >-
    Potassium is measured during weakness and between attacks. The pairing is what
    carries the information, since the interictal value is normal in all forms of
    periodic paralysis.
  diagnosis_term:
    preferred_term: blood chemistry measurement
    term:
      id: NCIT:C47868
      label: Blood Chemistry Measurement
  results: >-
    Serum potassium above 4.5 to 5 mmol/L during an attack, or a rise of at least
    1.5 mmol/L from the interictal value, supports HyperPP; a normal ictal value
    does not exclude it.
  evidence:
  - reference: PMID:20301669
    reference_title: Hyperkalemic Periodic Paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      normal serum potassium between attacks, and onset before age 20 years
    explanation: >-
      GeneReviews includes the normal interictal potassium and the age limit in the
      diagnostic definition, which is why the ictal value must be paired with a
      baseline.
  - reference: PMID:39174253
    reference_title: Periodic paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Provocative testing, with a glucose plus insulin challenge for HypoPP or
      with an oral K+ challenge in HyperPP, is potentially dangerous and no longer
      used in clinical practice.
    explanation: >-
      Records that measuring spontaneous ictal potassium has replaced deliberate
      potassium provocation, which is no longer acceptable practice.
differential_diagnoses:
- name: paramyotonia congenita of Von Eulenburg
  disease_term:
    preferred_term: paramyotonia congenita of Von Eulenburg
    term:
      id: MONDO:0008195
      label: paramyotonia congenita of Von Eulenburg
  description: >-
    Allelic with HyperPP at SCN4A and caused by the same class of
    gain-of-function inactivation defect, so this is not a differential in the
    usual sense but a neighbouring point on one continuum. The same variant, and
    even the same family, can produce either presentation. What separates them is
    which arm of the phenotype dominates: myotonic stiffness with infrequent
    weakness in paramyotonia congenita, recurrent weakness with accompanying
    myotonia in HyperPP.
  distinguishing_features:
  - >-
    Predominant symptom, not gene or variant: myotonic stiffness dominates in
    paramyotonia congenita, episodic weakness in HyperPP.
  - >-
    Stiffness that paradoxically worsens over the first few contractions, rather
    than easing with repetition, favours paramyotonia congenita.
  - >-
    Cold-selective distal and facial stiffness in winter favours paramyotonia
    congenita, although cold triggers attacks in HyperPP too.
  - >-
    On long exercise testing, a rapid-onset decrement persisting for minutes
    (pattern I) favours paramyotonia congenita; an early increase followed by a
    late decrease (pattern IV) favours HyperPP.
  evidence:
  - reference: PMID:39174253
    reference_title: Periodic paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Paramyotonia congenita (PMC) and hyperkalemic periodic paralysis (HyperPP)
      have extensive overlap of clinical features (Figure 1, center) and are
      caused by similar gain-of-function defects arising from missense mutations
      of NaV1.4
    explanation: >-
      States the allelism and the mechanistic identity of the two conditions,
      which is why the distinction is clinical rather than genetic.
  - reference: PMID:39174253
    reference_title: Periodic paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The predominant symptom in PMC is myotonic stiffness that paradoxically
      worsens with the first few repetitions for voluntary contraction of
      affected muscles (paramyotonia), whereas the stiffness diminishes with
      repeated effort (warm-up) for other forms of myotonia
    explanation: >-
      Gives the bedside sign that separates paramyotonia from warm-up myotonia.
  - reference: PMID:30931713
    reference_title: >-
      Overlap of periodic paralysis and paramyotonia congenita caused by SCN4A
      gene mutations two family reports and literature review.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The first proband and part of his family with the overlap of PMC and
      hyperkalemic periodic paralysis (HyperPP) has been identified as c.2111C > T
      (T704M) substitution of the gene SCN4A.
    explanation: >-
      Reports a kindred in which paramyotonia congenita and HyperPP coexist on
      one SCN4A allele, which is the claim this differential rests on. The
      previously quoted sentence was the study's aim rather than its result.
  notes: >-
    Paramyotonia congenita has no dismech entry yet, so this differential points
    at the MONDO concept rather than at a sibling entry. Because the two are
    allelic and on one continuum, a future paramyotonia congenita entry would
    duplicate most of this entry's pathophysiology, and the lump-or-split
    decision should be made deliberately rather than by default.
- name: hypokalemic periodic paralysis
  disease_term:
    preferred_term: hypokalemic periodic paralysis
    term:
      id: MONDO:0008223
      label: hypokalemic periodic paralysis
  description: >-
    The mechanistically opposite periodic paralysis, and the most important
    differential because the treatments are contradictory. Both end in
    depolarization-induced inexcitability, but HypoPP gets there through an
    anomalous gating-pore leak current that depolarizes the fibre when
    extracellular potassium is low, whereas HyperPP gets there through impaired
    channel inactivation unmasked when potassium is high. Giving potassium helps
    one and precipitates the other.
  distinguishing_features:
  - >-
    Ictal serum potassium: low (below 3.5 mmol/L) in HypoPP, high (above 4.5
    mmol/L) in HyperPP. This is the defining separation, though it can be hard to
    document.
  - >-
    Myotonia is an exclusionary criterion for HypoPP and is present in most
    HyperPP patients.
  - >-
    Triggers diverge: carbohydrate-rich meals and high salt in HypoPP,
    potassium-rich food and fasting in HyperPP.
  - >-
    Treatment is opposite in direction: potassium supplements and
    potassium-sparing diuretics in HypoPP, potassium-wasting diuretics in
    HyperPP.
  - >-
    Genetics: HypoPP is usually CACNA1S, and its SCN4A variants are arginine
    substitutions in S4 voltage sensors, which HyperPP variants are not.
  - >-
    HypoPP attacks tend to be more severe and prolonged; HyperPP attacks are more
    frequent and shorter.
  evidence:
  - reference: PMID:39174253
    reference_title: Periodic paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Episodic weakness in HypoPP is caused by "leaky" Ca2+ or Na+ channels, with
      an anomalous gating pore current that is conducted through the
      voltage-sensor domain of the channel.
    explanation: >-
      States the distinct HypoPP mechanism, a gating-pore leak rather than an
      inactivation defect.
  - reference: PMID:39174253
    reference_title: Periodic paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Almost all HypoPP mutations are missense substitutions at arginine residues
      in S4 transmembrane segments (Matthews et al., 2009), which not only helps
      to distinguish HypoPP from HyperPP or ATS
    explanation: >-
      Gives the variant-level rule that separates SCN4A-related HypoPP from
      HyperPP.
  - reference: PMID:29125635
    reference_title: Review of the Diagnosis and Treatment of Periodic Paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Attacks in HyperPP tend to be more frequent and shorter in duration than
      attacks in HypoPP.
    explanation: >-
      Records the difference in attack pattern between the two.
- name: Thomsen and Becker disease
  disease_term:
    preferred_term: Thomsen and Becker disease
    term:
      id: MONDO:0009710
      label: Thomsen and Becker disease
  description: >-
    CLCN1-related myotonia congenita. Both diseases cause myotonia through
    sarcolemmal instability, but the lesion is a reduced chloride conductance
    rather than a persistent sodium current, and there are no potassium-associated
    paralytic attacks. Transient weakness after rest does occur in Becker disease,
    which is the point of genuine clinical confusion.
  distinguishing_features:
  - >-
    Recurrent paralytic attacks with a documented ictal rise in serum potassium
    favour HyperPP; myotonia congenita has stiffness without dyskalemic attacks.
  - >-
    Stiffness relieved by repeated contraction (warm-up) favours myotonia
    congenita; stiffness worsened by the first contractions or by cold favours the
    sodium-channel disorders.
  - >-
    CLCN1 rather than SCN4A on sequencing, and recessive inheritance in the case
    of Becker disease.
  - >-
    Marked muscle hypertrophy is usual in myotonia congenita and is not a feature
    of HyperPP.
  evidence:
  - reference: PMID:39174253
    reference_title: Periodic paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Reduction of the chloride conductance, as occurs in myotonia congenita,
      impairs this stability and results in bursts of after-discharges and delayed
      relaxation of force in myotonia
    explanation: >-
      States the distinct chloride-conductance mechanism of myotonia congenita
      against the sodium-current mechanism of HyperPP.
  - reference: PMID:39174253
    reference_title: Periodic paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      When myotonia is present, CLCN1 should also be screened, and the possibility
      of myotonic dystrophy should be investigated by testing for expansion of CTG
      repeats in DMPK and CCTG repeats in CNBP.
    explanation: >-
      Records CLCN1 and the myotonic dystrophies as the tests that exclude this
      differential when myotonia is the presenting feature.
- name: Andersen-Tawil syndrome
  disease_term:
    preferred_term: Andersen-Tawil syndrome
    term:
      id: MONDO:0008222
      label: Andersen-Tawil syndrome
  description: >-
    The third primary periodic paralysis, caused by loss of function of the
    inward-rectifier potassium channel Kir2.1 rather than gain of function of
    Nav1.4. It also reaches depolarization-induced inexcitability, by removing the
    resting outward potassium current instead of adding an inward sodium current.
    Attacks can be associated with high, low, or normal potassium, so potassium
    alone does not separate it from HyperPP.
  distinguishing_features:
  - >-
    Ventricular arrhythmia, prolonged QT and prominent U waves, and the
    characteristic facial and skeletal features, are absent in HyperPP.
  - >-
    KCNJ2 is expressed in heart and bone as well as muscle, which is why
    Andersen-Tawil syndrome is multisystem while SCN4A disease is confined to
    skeletal muscle.
  - >-
    Myotonia argues against Andersen-Tawil syndrome and for HyperPP.
  evidence:
  - reference: PMID:39174253
    reference_title: Periodic paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Unlike the skeletal muscle-specific expression for CLCN1, SCN4A, and
      CACNA1S; KCNJ2 is expressed in multiple tissues including skeletal muscle,
      heart, and bone.
    explanation: >-
      Explains why Andersen-Tawil syndrome is multisystem and HyperPP is not,
      which is the discriminating observation.
  - reference: PMID:29125635
    reference_title: Review of the Diagnosis and Treatment of Periodic Paralysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Attacks of muscle weakness can be associated with high, low or normal serum
      potassium levels.
    explanation: >-
      Records that ictal potassium does not distinguish Andersen-Tawil syndrome
      from HyperPP, so the extramuscular features must be sought.
clinical_trials:
- name: NCT00494507
  phase: PHASE_III
  status: COMPLETED
  description: >-
    HYP HOP, the pivotal randomized, double-blind, placebo-controlled crossover
    programme of dichlorphenamide in hyperkalemic and hypokalemic periodic
    paralysis, with a 52-week open-label extension. Its hyperkalemic substudy is
    the source of the efficacy uncertainty recorded on the dichlorphenamide
    treatment above.
  target_phenotypes:
  - preferred_term: Episodic flaccid weakness
    term:
      id: HP:0003752
      label: Episodic flaccid weakness
  evidence:
  - reference: clinicaltrials:NCT00494507
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The purpose of this study is to compare Dichlorphenamide with placebo (an
      inactive substance) for prevention of episodes and for improvement of
      strength in hyperkalemic (HYP) and hypokalemic (HOP) periodic paralysis.
    explanation: >-
      The registered objective names hyperkalemic periodic paralysis as a study
      population and episode prevention as the endpoint, which is the trial this
      entry's dichlorphenamide evidence comes from.
datasets: []
references:
- reference: PMID:20301669
  title: Hyperkalemic Periodic Paralysis.
  tags:
  - GeneReviews
  findings: []
- reference: PMID:39174253
  title: Periodic paralysis.
  findings: []
- reference: PMID:25880512
  title: Channelopathies of skeletal muscle excitability.
  findings: []
- reference: PMID:29125635
  title: Review of the Diagnosis and Treatment of Periodic Paralysis.
  findings: []
- reference: PMID:26865514
  title: Randomized, placebo-controlled trials of dichlorphenamide in periodic paralysis.
  findings: []
- reference: PMID:34129236
  title: Long-term efficacy and safety of dichlorphenamide for treatment of primary periodic paralysis.
  findings: []
- reference: PMID:36628799
  title: Hyperkalemic periodic paralysis associated with a novel missense variant located in the inner pore of Nav1.4.
  findings: []
- reference: PMID:21708955
  title: "Na+,K+-pump stimulation improves contractility in isolated muscles of mice with hyperkalemic periodic paralysis."
  findings: []
- reference: PMID:26256659
  title: "Whole-Body Muscle MRI in Patients with Hyperkalemic Periodic Paralysis Carrying the SCN4A Mutation T704M: Evidence for Chronic Progressive Myopathy with Selective Muscle Involvement."
  findings: []
- reference: PMID:23473731
  title: Long-term effectiveness of acetazolamide on permanent weakness in hyperkalemic periodic paralysis.
  findings: []
- reference: PMID:30931713
  title: Overlap of periodic paralysis and paramyotonia congenita caused by SCN4A gene mutations two family reports and literature review.
  findings: []
- reference: PMID:36796140
  title: Prevalence of genetically confirmed skeletal muscle channelopathies in the era of next generation sequencing.
  findings: []

📚

References & Deep Research

References

12

PMID:20301669

Hyperkalemic Periodic Paralysis.

No top-level findings curated for this source.

PMID:39174253

Periodic paralysis.

No top-level findings curated for this source.

PMID:25880512

Channelopathies of skeletal muscle excitability.

No top-level findings curated for this source.

PMID:29125635

Review of the Diagnosis and Treatment of Periodic Paralysis.

No top-level findings curated for this source.

PMID:26865514

Randomized, placebo-controlled trials of dichlorphenamide in periodic paralysis.

No top-level findings curated for this source.

PMID:34129236

Long-term efficacy and safety of dichlorphenamide for treatment of primary periodic paralysis.

No top-level findings curated for this source.

PMID:36628799

Hyperkalemic periodic paralysis associated with a novel missense variant located in the inner pore of Nav1.4.

No top-level findings curated for this source.

PMID:21708955

Na+,K+-pump stimulation improves contractility in isolated muscles of mice with hyperkalemic periodic paralysis.

No top-level findings curated for this source.

PMID:26256659

Whole-Body Muscle MRI in Patients with Hyperkalemic Periodic Paralysis Carrying the SCN4A Mutation T704M: Evidence for Chronic Progressive Myopathy with Selective Muscle Involvement.

No top-level findings curated for this source.

PMID:23473731

Long-term effectiveness of acetazolamide on permanent weakness in hyperkalemic periodic paralysis.

No top-level findings curated for this source.

PMID:30931713

Overlap of periodic paralysis and paramyotonia congenita caused by SCN4A gene mutations two family reports and literature review.

No top-level findings curated for this source.

PMID:36796140

Prevalence of genetically confirmed skeletal muscle channelopathies in the era of next generation sequencing.

No top-level findings curated for this source.

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)

Review round 1: paramyotonia HPO rebinding, exercise-intervention term, evidence repairs · 2026-09-30T03:23:17Z · View source

First review round on PR #13197, answering a CHANGES_REQUESTED review in one push. Six blocking findings and five suggestions. Blocking 1 - the paramyotonia binding rested on a false negative-existence note. HPO does have a term for paramyotonia, HP:0011809 Paradoxical myotonia, under a label that does not contain the word, and the previous note told the next reviewer not to look. Rebound from HP:0003552 Muscle stiffness to HP:0011809 and rewrote the note with the queries actually run: `runoak -i ols:hp search "l~paramyotonia"` -> empty, `"t~paramyotonia"` -> empty, `"l~paradoxical myotonia"` -> HP:0011809, positive control `"l~myotonia"` -> ten terms including HP:0011809. The OLS4 record for HP:0011809 carries the definition naming paramyotonia in parentheses; the local sqlite:obo:hp build carries only the shorter of its two definitions, which is why the string is not reachable by label or text search. HP:0012904 Cold-sensitive myotonia was inspected and rejected on positive grounds: it is a sibling under HP:0002486, not a parent, and covers only the thermal half of the concept. Added a PMID:25880512 quote equating paramyotonia with paradoxical worsening on repeated effort so the rebinding is cited rather than only argued. Blocking 2 - Mild Exercise at Attack Onset rebound from NCIT:C15302 Physical Therapy to NCIT:C62739 Exercise Intervention, whose is_a ancestors are NCIT:C63474 -> NCIT:C16203/NCIT:C25218, so it is admissible in a TreatmentTerm slot; it is already bound in Sarcopenia and MYH2-Related_Myopathy. `runoak -i ols:ncit search "l~exercise"` was run and its two plausible competitors checked and rejected: NCIT:C16567 Exercise and NCIT:C39777 Very Light Exercise reach only NCIT:C17708 Physical Activity and NCIT:C43431 Activity, with no NCIT:C25218 ancestor. The old note cited `"l~exercise test"`, which returns cardiopulmonary stress tests; the new note records the correct queries. Blocking 3 - two claims whose evidence did not support them. (a) Rest after strenuous exercise -> Potassium Efflux. The single PMID:21708955 quote was about exercise being protective and said nothing about potassium accumulating after exercise stops; the same paper's discussion in fact argues the protective effect "is not caused by changes in plasma K+". Replaced it with two PMID:25880512 quotes, both marked directness: INDIRECT - the HyperPP trigger sentence ("Attacks usually begin in childhood and are triggered by ingestion of K+-rich foods or rest after vigorous exercise.") and the physiology it depends on ("With high-frequency firing during intensive muscle activity, the K+ efflux ... produces a K+ increase in the T-tubules that may reach 10 mM or higher"). Care was taken not to quote the same review's superficially similar HypoPP trigger sentence, which sits in the CACNA1S section and names carbohydrate load. causal_link_type weakened from INDIRECT_KNOWN_INTERMEDIATES to INDIRECT_UNKNOWN_INTERMEDIATES, because the same review lists "the trigger mechanism during rest after exercise" among its open questions. The displaced PMID:21708955 sentence was moved to the Mild Exercise treatment, where it does support the claim, as an INDIRECT item. The target was left on the potassium node rather than retargeted to Sustained Sarcolemmal Depolarization, with the reason recorded in the exposure's notes. (b) The paramyotonia congenita differential quoted the OBJECTIVE sentence of PMID:30931713. Replaced with its RESULTS sentence naming the T704M kindred in which PMC and HyperPP coexist, which is the claim. The item was kept rather than dropped because it is the only primary family-level citation supporting a differential otherwise carried by two reviews. Blocking 4 - PMID:25880512 "Similarly, T704M causes HyperPP with late-onset permanent myopathy" regraded IN_VITRO -> HUMAN_CLINICAL. The sentence sits in the review's genotype-phenotype passage citing clinical family series, not a channel measurement. quote_role: REVIEW_SYNTHESIS retained. Blocking 5 - GeneReviews (PMID:20301669) mined further, and one rationale removed as unsourced. Added the 50% transmission-risk sentence to the inheritance block, whose description already asserted it, and the agents-to-avoid clause ("use of depolarizing anesthetic agents during general anesthesia or ACE-inhibitor medications") to the trigger-avoidance treatment, whose description already asserted it. Deleted the sentence "Respiratory involvement is the reason depolarizing anaesthetic agents are contraindicated." from the Weakness of Ocular, Bulbar, Respiratory and Trunk Muscles phenotype: no cited source says it and it is the wrong rationale. The correct one is now cited on the treatment instead, from PMID:25880512's list of exposures that worsen myotonia, which names depolarizing general anaesthetics. Blocking 6 - deep-research report committed, and its standing recorded honestly. research/Hyperkalemic_Periodic_Paralysis-deep-research-claude_code.md was generated AFTER this entry was curated, and it is NOT independent corroboration of it. The provider read the existing entry and its reference cache while writing: its own provenance note (line 520) says the quoted material is "exact-quote-verified snippets held in the dismech reference cache for this disease", line 636 quotes a dismech curation note and labels it as one, line 671 reads this entry's empty `datasets:` block, and line 1121 knows the repository's lowercase `hgnc:` convention. It cites exactly the twelve references the entry already cited and surfaced nothing new, so no content was taken from it into the entry in this round. The run logged two "Quote not found" warnings against PMID:30931713 and PMID:39174253 for a sentence beginning "Genotype-phenotype correlation is real but not absolute"; that string is this entry's own curation note being quoted back, not a source sentence, and it was not imported as evidence. Suggestions taken. The equine readout was renamed from "Resting membrane potential of intercostal muscle fibres" (direction: DECREASED, ambiguous because depolarization makes the potential less negative) to "Resting membrane depolarization of intercostal muscle fibres" with direction: INCREASED, and the interpretation now states which quantity falls. The Potassium Efflux node was retagged biological_scale: ORGANISM -> TISSUE, since the operative compartment is the interstitial and transverse-tubular space of muscle tissue, which is what its CL cell type and its cited evidence are about; it was not split, because the systemic arm is already the Hyperkalemia During Attacks laboratory phenotype that the node's own downstream edge points at, and the reasoning is recorded in the node's notes. The Fasting link's evidence item gained directness: INDIRECT, since the quote is about the abortive carbohydrate rather than the fasting trigger. Suggestion on HP:0004889 resolved by searching rather than by assertion: `runoak -i ols:hp search "l~respiratory muscle weakness"`, `"l~respiratory muscle"` and `"l~weakness of the respiratory muscles"` each return the same three terms. There is no plain respiratory-muscle-weakness term in HPO; HP:0002747 asserts insufficiency too and loses the episodic qualifier, and HP:0030196 Fatigable weakness of respiratory muscles is a myasthenic concept. HP:0004889 is retained, and its note now records the searches and the residual gap, that the cited quote reports weakness of the breathing muscles without documenting insufficiency. Suggestion on potassium provocation handled structurally. HPO codes it as the clinical modifier HP:0031167, which sits under HP:0012823 Clinical modifier and so outside the PhenotypeTerm enum root HP:0000118; it cannot be a phenotype term in this schema and no KB entry binds it. Rather than manufacture a phenotype, a `definitions:` entry was added carrying the GeneReviews clinical diagnostic definition verbatim, with the oral-potassium provocation limb as one of four inclusion criteria, and a note recording why it is not a phenotype. This is the entry's first `definitions:` block. Housekeeping. Four uncited reference-cache files left behind by the deep-research run were deleted rather than committed: three DOI records (10.1007/s00415-013-7025-9, 10.1016/j.nmd.2023.01.007, 10.1080/19336950.2019.1600967), all `content_type: unavailable` and so holding nothing quotable, and PMID_30341599.md, which is cited neither by the entry nor by the report. The DOI files are also the case-collision class of #11204. `just check-case-collisions` is clean. Validation, each run separately and read: `just validate` (0 issues, 107 snippets, 118 titles), `just count-verified-snippets` (107/107), `just validate-terms` (passed; derived the HP:0011809 label and enum rows), `just validate-disorders` (schema + terms + references all passed), `just check-duplicate-keys`, `just check-entity-refs`, `just check-causal-targets` (no new dangling), `just check-qualifier-terms`, `just check-enum-values`, `just check-environmental-evidence`, `just check-genereviews` (GeneReviews TAGGED; the StatPearls UNTAGGED_CHAPTER line is report-only and never a gap), `just check-folded-hyphens`, `just check-snippet-length`, `just check-title-snippets`, `just check-snippet-grading` (no new divergences), `just check-case-collisions`, `just validate-history-all`. `just list-disconnected-phenotypes` reports 6/6 phenotypes causally connected. No baseline file was modified.

Create: Hyperkalemic Periodic Paralysis · 2026-09-29T23:54:21Z · View source

New entry for hyperkalemic periodic paralysis (MONDO:0008224), closing issue #11700 and retiring stubs/Hyperkalemic_Periodic_Paralysis.yaml. References were derived entirely by independent PubMed search (NCBI E-utilities esearch/esummary, then `just fetch-reference` for each candidate). No deep-research report exists for this disease and none was fabricated. Twelve references are cited: eleven newly fetched (PMID:20301669 GeneReviews, PMID:39174253 and PMID:25880512 Cannon's two mechanism reviews, PMID:26865514 the HYP HOP randomized trial, PMID:34129236 its long-term extension, PMID:36628799 HEK293T patch clamp of a novel allele, PMID:21708955 the M1592V knock-in mouse, PMID:26256659 whole-body muscle MRI, PMID:23473731 acetazolamide on permanent weakness, PMID:30931713 the PMC/HyperPP overlap families, PMID:36796140 UK prevalence) plus PMID:29125635, already in references_cache from the hypokalemic periodic paralysis entry, and clinicaltrials:NCT00494507. Nothing was cited that had not been fetched and read. Mechanism. The pathograph is built around the counterintuitive step, that weakness comes from depolarization-induced inexcitability rather than from reduced excitatory drive: SCN4A gain-of-function missense variant -> impaired Nav1.4 inactivation with a persistent inward current -> sustained sarcolemmal depolarization -> depolarization-induced channel inactivation and fibre inexcitability -> episodic flaccid weakness. The potassium loop is modelled honestly as a genuine cycle rather than flattened into a chain: sustained depolarization -> membrane hyperexcitability and myotonic discharges -> potassium efflux and extracellular potassium accumulation -> back to sustained depolarization. Each of those three edges carries its own quote. A parallel branch runs from the same persistent current through resting intracellular sodium overload to the chronic progressive myopathy; that last edge is marked INDIRECT_UNKNOWN_INTERMEDIATES with a note saying why, since no cited source traces the intervening steps. Slot discipline for gain of function. The variant's consequence is recorded once, in GeneticContext.functional_impact_category on the variant node. The pathway activity state is recorded separately as molecular_functions[].modifier: GAIN_OF_FUNCTION on the Nav1.4 voltage-gated sodium channel activity descriptor, because the claim there is that the channel is operating outside its normal inactivation constraints rather than merely conducting more current than usual. The two co-occur on different nodes and make different claims. Evidence grading. Channel biophysics is graded IN_VITRO (HEK293T patch clamp, patient intercostal fibres, and expression-study syntheses), fibre simulations COMPUTATIONAL, mouse and horse work MODEL_ORGANISM, and clinical review statements HUMAN_CLINICAL with quote_role REVIEW_SYNTHESIS. quote_role BACKGROUND marks introduction sentences in the mouse paper that state human findings. No human phenotype rests on model-organism or in-vitro evidence alone. Dichlorphenamide carries a SUPPORT/REFUTE pair because the pivotal trial's hyperkalemic substudy was not significant and its authors say it lacked the precision to decide either way; recording only the FDA approval would have overstated the evidence. Modules. No conformance was declared. `just list-modules` was reviewed and four candidates were rejected on stated grounds: cardiac_ion_channel_repolarization (scoped to inherited arrhythmia in structurally normal hearts, per CLAUDE.md); nociceptor_sodium_channel_excitability (mechanistically the closest analogue -- persistent Nav current, depolarization, conduction block -- but its description scopes it to nociceptor-enriched SCN9A/SCN10A/SCN11A and hereditary pain, and every node is named "Nociceptor"); neuromuscular_transmission_failure (the endplate safety factor, not the sarcolemma); xenobiotic_cardiac_channel_perturbation and epilepsy_excitation_inhibition_imbalance (wrong tissue). The sibling Hypokalemic_Periodic_Paralysis entry declares no conforms_to either. A skeletal-muscle-excitability module covering the HyperPP/PMC/myotonia congenita cluster would be a reasonable future addition. Ontology bindings. Every CURIE was looked up in the same step it was written. hgnc:10591 SCN4A was verified in both directions (`runoak -i sqlite:obo:hgnc search "l^SCN4A"` -> hgnc:10591, and `runoak -i sqlite:obo:hgnc info hgnc:10591` -> SCN4A) and agrees with the existing binding on the hypokalemic entry. MONDO:0008224 and the four differential MONDO terms were confirmed live against ols:mondo. HP:0003752 Episodic flaccid weakness, HP:6000833 Hyperkalemia while symptomatic (whose HPO definition names this disease), HP:0009073 Progressive proximal muscle weakness and HP:0004889 were selected after OLS searches rather than reusing the coarser HP:0001324 the sibling entries use. Two negative- existence claims are recorded with the queries run: HPO has no paramyotonia term, and NCIT has no compound-muscle-action-potential or long-exercise-test term, so those bindings are a broader HP term with the specificity in preferred_term, and no term at all respectively. NCIT:C88502 Nerve Conduction Velocity Test was rejected on positive grounds (it names conduction velocity, not amplitude decrement). CHEBI:2549 albuterol was chosen over CHEBI:8746 (R)-salbutamol because the drug is racemic and "Salbutamol" is a synonym of CHEBI:2549; this matches four existing KB entries. Sibling entries read before writing: Thomsen_and_Becker_disease (which already listed MONDO:0008224 as a differential), Hypokalemic_Periodic_Paralysis, and Andersen-Tawil_Syndrome. All three are curated as reciprocal differentials here, with the clinically consequential distinctions spelled out: ictal potassium direction and opposite diuretic choice against HypoPP, chloride rather than sodium conductance and absence of dyskalemic attacks against myotonia congenita, and multisystem involvement against Andersen-Tawil. Paramyotonia congenita has no dismech entry; it is curated as a differential against MONDO:0008195 with an explicit statement that it is allelic with HyperPP at SCN4A and on one continuum, plus a note flagging that a future entry would duplicate most of this pathophysiology and the lump-or-split call should be deliberate. Validation, each run separately and all passing: just validate; just count-verified-snippets (100/100); just validate-terms; just validate-disorders (schema + terms + references, batched); just check-duplicate-keys; just check-entity-refs; just check-causal-targets; just check-qualifier-terms; just check-enum-values; just check-environmental-evidence; just check-folded-hyphens (one finding, a line-final "potassium-" in a differential feature, fixed by reflowing the line rather than by editing text); just check-snippet-length; just check-title-snippets; just check-snippet-grading; just check-reference-titles; just check-coarse-phenotypes; just check-genereviews (GeneReviews chapter present and tagged); just list-gene-term-mismatches (3 bindings, 0 findings); just list-disconnected-phenotypes (6/6 phenotypes causally connected after adding the Paramyotonia edge); just validate-history-all. No baseline file was updated. Not done: no datasets block (no disease-relevant accession was verified); no has_subtypes, because the field treats HyperPP as one entity and the PMC/normokalemic variants are neighbouring diagnoses rather than subtypes; no biochemical block, since serum potassium is modelled as a phenotype and a diagnostic test rather than as a biomarker with reference ranges.

Claude Code ▸

Hyperkalemic Periodic Paralysis (HyperPP) — Comprehensive Disease Characteristics Report

claude-haiku-4-5-20251001, claude-opus-5 17 citations 2026-09-29T20:26:26.275780

Hyperkalemic Periodic Paralysis (HyperPP) — Comprehensive Disease Characteristics Report

MONDO:0008224 · Mendelian · autosomal dominant · SCN4A skeletal-muscle sodium channelopathy Report date: 2026-09-29

Provenance note on citations. The quoted material below is drawn from two classes of source: (a) exact-quote-verified snippets held in the dismech reference cache for this disease (12 references, every quote validated as an exact substring of the cited PubMed record by linkml-reference-validator), and (b) identifier/database lookups performed during this session against OLS4, HGNC REST, NCBI E-utilities, OMIA and ICD resources. Where a fact could not be verified in this session it is marked [not verified] rather than asserted. No CURIE or accession below was written from memory.

1. Disease Definition, Nomenclature and Identifiers

Definition (MONDO:0008224, verbatim): "Hyperkalemic periodic paralysis (HyperPP) is a muscle disorder characterized by episodic attacks of muscle weakness associated with an increase in serum potassium concentration."

HyperPP is one of the primary (familial) periodic paralyses — a group of skeletal-muscle channelopathies in which episodic sarcolemmal depolarization renders muscle fibres transiently inexcitable. It is caused by gain-of-function missense variants in SCN4A, encoding the Naᵥ1.4 α-subunit, and sits on a clinical continuum with paramyotonia congenita (PMC), with which it shares both gene and mechanism.

Key identifiers (verified via OLS4 MONDO record, HGNC REST, ICD resources)

Resource	Identifier
MONDO	`MONDO:0008224` — hyperkalemic periodic paralysis
OMIM (phenotype)	`OMIM:170500` — HYPERKALEMIC PERIODIC PARALYSIS; HYPP
OMIM (gene)	`OMIM:603967` — SCN4A
Orphanet	`ORPHA:682`
MeSH	`MESH:D020513`
ICD-10-CM	`G72.3` Periodic paralysis (inclusion terms: "Hyperkalemic periodic paralysis (familial)", "Potassium sensitive periodic paralysis")
ICD-11 MMS	`8C74.11` Hyperkalaemic periodic paralysis (sibling: `8C74.10` Hypokalaemic periodic paralysis). MONDO records the ICD-11 foundation ID `1308452752`.
UMLS	`UMLS:C0238357`
MedGen	`MEDGEN:68665`
SNOMED CT	`SCTID:304737009`
DOID	`DOID:14451`
NCIT	`NCIT:C123429`
GARD	`GARD:0000195`
NANDO (Japan)	`NANDO:1200504`
OMIA (equine)	`OMIA:000785-9796` — Hyperkalemic Periodic Paralysis, HYPP in Equus caballus

Synonyms (MONDO exact synonyms, verbatim)

"familial hyperkalemic periodic paralysis"; "primary hyperkalemic periodic paralysis"; "hyperkalemic periodic paralysis, type 2"; "adynamia episodica hereditaria"; "adynamia episodica hereditaria with or without myotonia"; "Gamstorp disease"; "Gamstorp episodic adynamy"; "normokalemic periodic paralysis, potassium-sensitive"; "HYPP".

Nomenclature caution. "Normokalemic periodic paralysis, potassium-sensitive" is listed as an exact synonym of HyperPP, and the historical entity normokalemic periodic paralysis is now generally subsumed here — a nosological decision worth noting for any mapping exercise. The abbreviation HYPP is also the standard veterinary abbreviation for the equine disease and is an HGNC alias symbol for the gene itself (see §3), so the string is triply overloaded.

Classification

Nosological class: inherited skeletal-muscle channelopathy (non-dystrophic); within that, a periodic paralysis rather than a myotonia, although myotonia is present in most patients.
Mechanistic class: voltage-gated sodium channel gain-of-function disorder of excitability.
Sibling entities by gene: paramyotonia congenita (MONDO:0008195), sodium-channel myotonia, congenital myasthenic syndrome and congenital myopathy with SCN4A loss-of-function (the latter two by an opposite mechanism).
Sibling entities by syndrome: hypokalemic periodic paralysis (MONDO:0008223, CACNA1S/SCN4A), Andersen–Tawil syndrome (MONDO:0008222, KCNJ2).

2. Epidemiology

Prevalence

The most rigorous recent figure comes from the UK national referral centre for skeletal muscle channelopathies (PMID:36796140, Vivekanandam et al., Neuromuscul Disord 2023, DOI:10.1016/j.nmd.2023.01.007), which reports minimum point prevalence of genetically confirmed disease:

"We calculated a minimum point prevalence of all skeletal muscle channelopathies of 1.99/100 000 (95% CI 1.981-1.999). The minimum point prevalence of MC due to CLCN1 variants is 1.13/100 000 (95% CI 1.123-1.137), SCN4A variants which encode for PMC and SCM is 0.35/100 000 (95% CI 0.346 - 0.354) and for periodic paralysis (HyperPP and HypoPP) 0.41/100 000 (95% CI 0.406-0.414). The minimum point prevalence for ATS is 0.1/100 000 (95% CI 0.098-0.102)."

Note that this study reports HyperPP and HypoPP pooled at 0.41/100,000; it does not disaggregate them. Widely cited disaggregated estimates from secondary sources place HyperPP at approximately 0.17/100,000 (95% CI 0.13–0.20) in systematic review, 0.13/100,000 in some series, and the older textbook figure of 1:200,000 (i.e. 0.5/100,000); a Dutch study reported 0.06/100,000 (95% CI 0.03–0.12) for HyperPP and 2.38/100,000 for skeletal muscle channelopathies as a group, of which 0.69/100,000 were periodic paralyses. These disaggregated numbers were retrieved from secondary/aggregator sources in this session and the underlying primary articles were not individually verified — treat the pooled UK figure as the citable one.

The same UK paper states the direction of change explicitly:

"There has been an overall increase in point prevalence in skeletal muscle channelopathies compared to previous reports, with the biggest increase found to be in MC. This can be attributed to next generation sequencing and advances in clinical, electrophysiological and genetic characterisation of skeletal muscle channelopathies."

So published prevalence is ascertainment-limited and rising, and any figure should be read as a minimum.

Incidence

Not available. No incidence (new-cases-per-year) estimate was identified. For a fully penetrant autosomal dominant condition of this rarity, birth prevalence rather than incidence is the tractable measure, and none was found.

Sex distribution

Penetrance is described as near-complete in both sexes, but attack severity is reported to be greater in males in secondary sources; no primary sex-ratio study was verified in this session. This contrasts sharply with hypokalemic periodic paralysis, where reduced penetrance in females is well documented — a difference worth flagging as unresolved for HyperPP specifically.

Age of onset

Childhood, typically first decade:

"The onset of attacks is usually in childhood and episodes are triggered by cold environments, rest after vigorous exercise, stress, fasting, ingesting of K-rich foods, or alcohol" (PMID:39174253)

Diagnostic criteria historically required "onset before age 20 years" (PMID:20301669).

Geographic distribution, ethnicity and founder effects

No human founder effect or population-specific clustering was identified. HyperPP is reported worldwide. The striking founder effect in this disease is veterinary: equine HYPP in American Quarter Horses traces to a single founder sire (see §12).

Ancestry-specific allele frequencies

The principal human alleles are absent from population databases (see §3), so no ancestry-stratified frequency can be given.

3. Genetics and Molecular Basis

Gene (verified, HGNC REST)

Field	Value
HGNC ID	`hgnc:10591`
Symbol	SCN4A
Approved name	"sodium voltage-gated channel alpha subunit 4"
Cytogenetic location	17q23.3
NCBI Gene (Entrez)	6329
Ensembl	ENSG00000007314
UniProt	P35499
RefSeq transcript	NM_000334 (curated variants below use NM_000334.4)
Alias symbols	Nav1.4, HYPP, SkM1
Previous symbol	HYKPP

SCN4A is the sole established causative gene:

"Likewise, null mutations of SCN4A or CACNA1S do not cause periodic paralysis, and individuals with a single intact copy of these genes have no muscle signs or symptoms" (PMID:39174253)

This is a mechanistically important negative statement: haploinsufficiency does not cause HyperPP. Disease requires an anomalous current, not an absent channel. The practical consequence for variant interpretation is direct — a truncating, frameshift, splice-null or whole-gene-deletion SCN4A allele found on a periodic-paralysis panel should not be reported as causative of HyperPP, however deleterious it looks by generic in silico criteria.

Inheritance

Autosomal dominant (HP:0000006), with penetrance described as near-complete. De novo occurrence is documented for the commonest allele (see ClinVar summary below).

Mode of action

Gain of function at the channel, acting as a functional dominant negative at the fibre level: the mutant channels' persistent inward current depolarizes the fibre, which then inactivates the wild-type channels too (see §6, step 6). This is why a heterozygous gain-of-function allele produces net loss of excitability.

Variant spectrum

Only missense substitutions cause HyperPP. Reported disease alleles cluster in structural elements governing fast inactivation — the DIII–DIV linker and the inner pore/S6 region — consistent with an inactivation defect:

p.Thr704Met (T704M; NM_000334.4:c.2111C>T) — the single commonest allele. ClinVar classifies it Pathogenic (2-star, multiple submitters, last evaluated 2024-09-22, 7 submissions), with no frequency in gnomAD (reported as 0.00000), described in ClinVar submission text as accounting for over 60% of pathogenic alleles in HyperPP, observed de novo in at least one individual and segregating with disease in families, with functional studies showing an effect on SCN4A function. Note that ClinVar carries RCV records linking c.2111C>T to Hyperkalemic periodic paralysis, Paramyotonia congenita, Hypokalemic periodic paralysis, "multiple conditions", "not provided" and "SCN4A-related disorder" — i.e. the same allele is submitted against contradictory phenotypes, which is a real feature of this locus and not merely database noise.
p.Met1592Val (M1592V) — the second classic allele; the basis of the knock-in mouse (§11). Clinically variable within a single family:

"Genotype-phenotype correlation is real but not absolute: M1592V has produced HyperPP in some members of a single family and paramyotonia congenita in others, and no modifier gene has been established." (dismech curation note, synthesizing PMID:30931713 and PMID:39174253)
Inner-pore variants — a novel missense variant located in the inner pore of Naᵥ1.4 has been reported to cause HyperPP (PMID:36628799), extending the spectrum beyond the classical inactivation-gate positions.
p.Asn916Ser, p.Val999Glu, p.Pro875Ser and others appear in ClinVar against the HyperPP condition term with varying classifications.

ClinVar volume (verified via NCBI E-utilities, 2026-09-29): a clinvar esearch for SCN4A[gene] AND "hyperkalemic periodic paralysis"[dis] returns Count = 2043. This is the number of SCN4A variation records touched by the HyperPP condition annotation in the aggregate — overwhelmingly VUS and benign, not 2043 pathogenic alleles. It is a useful denominator for the interpretive burden, not a count of disease alleles.

ACMG/AMP interpretation notes specific to this locus

PS3 (functional) is unusually strong here, because heterologous expression of Naᵥ1.4 gives a directly interpretable readout (persistent/non-inactivating current) and the disease mechanism is known.
PM2 (absent from controls) applies to the classical alleles (T704M has zero gnomAD frequency).
PVS1 must not be applied — loss-of-function is not the mechanism for HyperPP (PMID:39174253, above). A null allele is evidence against this diagnosis.
Phenotype-based codes are weak because of the HyperPP/PMC continuum: the same variant supports either label.

Genetic heterogeneity and diagnostic yield

A substantial minority of clinically typical patients have no identified variant — secondary sources report roughly one third of typical phenotypes negative on molecular testing, and one series found SCN4A variants in 64% of hyperKPP patients. These figures come from aggregator sources and the primary series were not verified in this session. The direction is nonetheless consistent with GeneReviews' framing that diagnosis rests on suggestive findings plus a variant:

"The diagnosis of hyperPP is established in a proband with suggestive findings and a heterozygous pathogenic variant in SCN4A identified by molecular genetic testing." (PMID:20301669)

Modifier genes

None established. The intrafamilial M1592V discordance and the equine data (§12) both argue that unidentified modifiers or non-genetic factors shape expression.

Epigenetics

No information available. No DNA-methylation, histone-modification or imprinting involvement has been reported for HyperPP, and none would be expected for a fully penetrant dominant coding-missense channelopathy.

Chromosomal abnormalities

Not applicable. HyperPP is not associated with copy-number variation, translocation or aneuploidy. Whole-gene deletion of SCN4A would produce a null allele, which does not cause this disease.

Somatic variation / mosaicism

No information available. All reported disease alleles are germline. Mosaicism has not been described.

4. Molecular Profiling, Omics and Advanced Technologies

This is the weakest-covered domain for HyperPP, and the gap is genuine rather than a search artefact.

Transcriptomics / proteomics / metabolomics / lipidomics: no disease-specific dataset identified. There is no curated geo:, dbGaP, PRIDE or MassIVE accession for HyperPP in the dismech knowledge base (datasets: is empty for this entry), and no omics study was surfaced.
Single-cell and spatial transcriptomics: no information available. This is a plausible gap to close, because the disease has selective muscle involvement (§5) that no molecular explanation currently accounts for.
CRISPR screens / functional genomics at scale: no information available. Functional work in this disease is single-variant electrophysiology, not screening.
The one quantitative human molecular measurement identified is MR spectroscopy of intracellular sodium, cited in support of resting Na⁺ overload:

"as has been observed by MR spectroscopy in human patients" (PMID:25880512)
Whole-body muscle MRI is the one imaging modality with a dedicated HyperPP study, and it is genotype-specific (T704M carriers):

"Whole-body muscle MRI analysis revealed muscle atrophy and fatty infiltration in hyperKPP patients, especially in older individuals." (PMID:26256659) "Muscle involvement followed a selective pattern, primarily affecting the posterior compartment of the lower leg and anterior thigh muscles." (PMID:26256659)

Assessment: HyperPP is mechanistically among the best-understood human diseases at the level of single-channel biophysics and among the least-characterized at the level of tissue-scale molecular phenotype. The unexplained observations — selective muscle-group involvement, progression to fixed myopathy in patients without frequent attacks, intrafamilial variability of a single allele — are precisely the questions omics and single-cell approaches are suited to, and they are unaddressed.

5. Clinical Presentation, Anatomy and Phenotype

Cardinal features

1. Episodic flaccid weakness (HP:0003752 Episodic flaccid weakness; temporality RECURRENT; onset CHILDHOOD) — the defining manifestation.

"A spontaneous attack commonly starts in the morning before breakfast, lasts for 15 minutes to one hour, and then passes." (PMID:20301669) "Weakness severe enough to impair mobility typical lasts for 30 min to a few hours, although full recovery may not occur for days." (PMID:39174253) "Attacks in HyperPP tend to be more frequent and shorter in duration than attacks in HypoPP." (PMID:29125635)

2. Ictal hyperkalemia (HP:6000833 Hyperkalemia while symptomatic; ACUTE) — a laboratory readout of the mechanism, not an upstream cause.

"hyperkalemia (serum potassium concentration >5 mmol/L)" (PMID:20301669) "an increase of serum potassium concentration of at least 1.5 mmol/L during an attack of weakness" (PMID:20301669) "The ictal serum K+ may be low (< 3.5 mmol/L) suggesting HypoPP, high (> 4.5 mmol/L) suggestive of HyperPP, or in the normal range which does not exclude a diagnosis of periodic paralysis." (PMID:39174253) "Between episodes of weakness, the serum K+ is usually in the normal range in all forms of familial periodic paralysis." (PMID:39174253)

This is the single most important clinical caveat in the disease: a normal or even low ictal potassium does not exclude HyperPP, and the name of the disease misleads at the bedside.

3. Myotonia (HP:0002486) — present in most patients, and the feature that separates HyperPP from HypoPP.

"Individuals with hyperPP frequently have myotonia (muscle stiffness), especially around the time of an episode of weakness." (PMID:20301669) "Most patients with HyperPP also have myotonia, often becoming symptomatic with activity-dependent muscle stiffness that precedes an attack of weakness" (PMID:39174253) "Between attacks, approximately half of patients with HyperPP experience muscle stiffness arising from myotonia or paramyotonia that does not impede voluntary movements." (PMID:29125635)

4. Paramyotonia — cold- and exercise-aggravated stiffness in ~45%:

"Paramyotonia (muscle stiffness aggravated by cold and exercise) is present in about 45% of affected individuals." (PMID:20301669)

Ontology gap: there is no HPO term for paramyotonia. A search of HPO (runoak -i ols:hp search "paramyotonia") returns nothing, so this phenotype can only be bound to the general HP:0003552 Muscle stiffness, losing the paradoxical-worsening distinction that is diagnostically decisive. This is a concrete HPO term-request candidate.

5. Permanent proximal weakness / fixed myopathy (HP:0009073 Progressive proximal muscle weakness; PROGRESSIVE) — the late, disabling outcome.

"For many patients the frequency of attacks diminishes with age, and is replaced by a chronic state of mild weakness that later progresses to myopathy with permanent muscle weakness, especially of proximal muscles, and may cause loss of ambulation" (PMID:39174253) "A proportion of affected individuals develop fixed or chronic progressive weakness that results in significant disability." (PMID:26256659)

6. Extra-limb muscle involvement, including respiratory (HP:0004889 Intermittent episodes of respiratory insufficiency due to muscle weakness; ACUTE):

"attacks of flaccid limb weakness (which may also include weakness of the muscles of the eyes, throat, breathing muscles, and trunk)" (PMID:20301669)

This is the feature with the greatest acute-care significance: depolarizing neuromuscular blocking agents and potassium-containing solutions are hazardous, and bulbar/respiratory involvement means an attack can be life-threatening rather than merely disabling.

Anatomical distribution, lateralization, and severity

Affected tissue: skeletal muscle only (UBERON:0001134 skeletal muscle tissue). SCN4A expression is skeletal-muscle-specific, which is precisely why HyperPP has no cardiac phenotype — in explicit contrast to Andersen–Tawil syndrome:

"Unlike the skeletal muscle-specific expression for CLCN1, SCN4A, and CACNA1S; KCNJ2 is expressed in multiple tissues including skeletal muscle, heart, and bone." (PMID:39174253)
Distribution: generalized and symmetric during attacks, with proximal predominance in the fixed weakness. Fatty infiltration is selective, "primarily affecting the posterior compartment of the lower leg and anterior thigh muscles" (PMID:26256659).
Lateralization: bilateral and symmetric. No lateralized or asymmetric presentation is described. No formal lateralization study exists — the claim rests on clinical description.
Severity/course: attacks are episodic (HP:0003752) and the fixed weakness is progressive; the two have an inverse temporal relationship, with attack frequency falling as fixed weakness rises (PMID:39174253).
Non-muscle systems: none involved. No cardiac, renal, endocrine, skeletal, dysmorphic, cognitive, ocular-structural or dermatological features. The ictal hyperkalemia is of muscle origin and is not a primary renal or adrenal disturbance — an important negative when the differential includes adrenal insufficiency or renal tubular disease.

Triggers (clinically actionable)

"The major attack trigger is eating potassium-rich foods" and "provoking/worsening of an attack by oral potassium intake" (PMID:20301669) "other triggers include: cold environment; rest after exercise, stress, or fatigue; alcohol; hunger; and changes in activity level." (PMID:20301669) "Sustained vigorous exercise is commonly reported to be a trigger, with preserved strength of active muscles and weakness occurring within minutes of stopping to rest." (PMID:39174253)

The exercise trigger has a diagnostic signature worth emphasizing: weakness appears on stopping, not during, exertion, and the actively worked muscles are spared.

6. Pathophysiology and Mechanism

6.1 The causal chain

A heterozygous missense variant in SCN4A (most often p.Thr704Met, or p.Met1592Val) alters a residue in the fast-inactivation machinery of the Naᵥ1.4 α-subunit — leads to an impaired fast-inactivation gate in the mutant channel population. (Demonstrated: heterologous expression and ClinVar functional data; PMID:36628799 extends the spectrum to inner-pore residues.)
The inactivation defect results in a persistent, non-inactivating inward Na⁺ current through the mutant channels at potentials where wild-type channels are silent. (Demonstrated in vitro.)
That persistent depolarizing current leads to sustained sarcolemmal depolarization — the resting potential settles at about −45 mV instead of −85 mV, and is stable on a timescale of hours. (Demonstrated; PMID:25880512: "periodic paralysis is manifest as a stable depolarized shift of the resting potential that renders the fiber refractory from generating action potentials".) This is the pivotal node — every downstream branch departs from here.
Branch A (hyperexcitability). From the mildly depolarized state, a brief stimulus results in membrane hyperexcitability with myotonic after-discharges — (PMID:25880512: "In response to a brief stimulus, the inactivation defect is revealed and the fiber may respond with a myotonic burst.") — which leads to the clinical myotonia and paramyotonia.
Branch A continues, and closes a loop. The repetitive firing results in K⁺ efflux and accumulation of K⁺ in the T-tubular and interstitial space, which leads back to further depolarization at step 3. (Demonstrated; PMID:25880512: "The repetitive firing produces a cumulative increase of T-tubular K+ which in conjunction with the inactivation defect results in a steady inward Na+ current that keeps the fiber depolarized at about -45 mV".) This feed-forward loop, not a linear cascade, is what makes the disease episodic and self-amplifying — and the same K⁺ efflux leads to the measurable ictal hyperkalemia, which is therefore a consequence of the muscle lesion, not its cause. (PMID:21708955: "This would initiate and explain the depolarization of the muscle cells and the subsequent hyperkalemia.")
Branch B (the paralysis, and the counterintuitive step). Once depolarization is sustained, voltage-dependent inactivation silences both the wild-type and most of the mutant channels — resulting in fibre inexcitability and flaccid weakness. (Demonstrated; PMID:25880512: "From this depolarized potential the WT NaV1.4 channels and the majority of the HyperPP mutant ones are inactivated which renders the fiber inexcitable, as occurs in periodic paralysis."; PMID:29125635: "In all forms of PP, ictal paresis is caused by depolarization of the muscle sarcolemma, which in turn causes sodium channel inactivation and reduced fiber excitability.") The paralysis is caused by too much depolarizing current, not too little — the gain-of-function allele behaves as a functional dominant negative acting through voltage-dependent inactivation. This leads to the clinical episodic flaccid weakness, and to weakness of ocular, bulbar, respiratory and trunk muscles.
Branch C (the chronic arm). The persistent Na⁺ leak at rest results in resting intracellular Na⁺ overload, with compensatory Na⁺/K⁺-pump upregulation. (Demonstrated; PMID:25880512: "TTX-sensitive 22Na+ influx was increased in resting muscle, thereby demonstrating the gain-of- function defect contributes to a resting internal Na+ overload"; PMID:21708955: "The results confirm that the functional disorders of skeletal muscles in HyperKPP are secondary to increased Na(+) influx and show that contractility can be restored by acute stimulation of the Na(+),K(+) pumps.")
Resting Na⁺ overload is inferred to lead to chronic progressive myopathy with fatty muscle infiltration — by unknown intermediates. (Inferred, not demonstrated. This is the weakest link in the chain: no cited source traces the intervening steps, and the fact that permanent weakness can develop in patients without frequent attacks argues against simple cumulative injury from attacks alone.) This leads to permanent proximal muscle weakness. (The endpoint itself is demonstrated: PMID:26256659.)

6.2 Where the mechanism amplifies the modest into the pathological

The single clearest statement of why a physiological stimulus becomes a paralysing one:

"Hyperkalemia produces a modest depolarization, as occurs in normal fibers, that becomes pathologically amplified by the excessive inward current conducted by mutant Na+ channels and leads to refractory loss of fiber excitability." (PMID:39174253)

Normal fibres depolarize slightly with a potassium load and recover. In HyperPP that same small depolarization is the trigger that unmasks the inactivation defect, and the fibre enters the feed-forward loop of step 5.

6.3 How each trigger enters the chain

Trigger	Entry point	Predicate	Directness
Potassium-rich food / K⁺ medication (`ECTO:0900037`)	K⁺ efflux & extracellular accumulation (step 5)	TRIGGERS	DIRECT — "The requirement for elevated extracellular K+ (interstitial or T-tubular) to mildly depolarize the fiber and reveal the inactivation defect explains why attacks may be triggered or aggravated by potassium ingestion in HyperPP." (PMID:25880512)
Rest after strenuous exercise (`ECTO:6000031`)	K⁺ efflux & accumulation (step 5)	TRIGGERS	INDIRECT, known intermediates — exercise-induced K⁺ release, unopposed once pumping activity falls at rest
Cold exposure (`XCO:0000306`)	Membrane hyperexcitability (step 4)	EXACERBATES	INDIRECT, unknown intermediates
Fasting (`XCO:0000102`)	Sustained depolarization (step 3)	TRIGGERS	INDIRECT, unknown intermediates — the unstated intermediate is loss of the insulin-driven K⁺ shift into muscle; the therapeutic corollary is that carbohydrate aborts attacks

The fasting/carbohydrate relationship is where mechanism and treatment meet most tidily:

"Hyperkalemic attacks of weakness can be prevented by frequent meals rich in carbohydrates" (PMID:20301669) "avoid fasting and use a carbohydrate snack to abort an attack of HyperPP" (PMID:39174253)

6.4 Subcellular localization and molecular components

Naᵥ1.4 (UniProt P35499) localizes to the sarcolemma (GO:0042383) and, critically, the T-tubule (GO:0030315) — the compartment whose restricted volume allows K⁺ to accumulate to depolarizing concentrations during repetitive firing (step 5). The T-tubule is therefore not incidental anatomy but a necessary part of the mechanism: a diffusionally restricted space is what converts K⁺ efflux into a positive-feedback signal.
Molecular function: voltage-gated sodium channel activity (GO:0005248), gain of function.
Processes: regulation of membrane potential (GO:0042391, dysregulated); sodium ion transmembrane transport (GO:0035725, increased); potassium ion transmembrane transport (GO:0071805, increased); skeletal muscle contraction (GO:0003009, decreased).
Compensatory effector: the Na⁺/K⁺-ATPase, whose stimulation reverses the functional defect (PMID:21708955) — the mechanistic basis of β₂-agonist rescue (§8).

6.5 Processes and mechanisms explicitly not involved

Immune/inflammatory mechanisms: not involved. HyperPP is not autoimmune and has no inflammatory infiltrate; this distinguishes it from immune-mediated myositis, which is a separate entity in the same species (cf. OMIA:002141-9796).
Infectious agents: not applicable.
Microbiome: no information available; no plausible role.
Neoplastic transformation: not applicable.
Fibrosis as the primary lesion: the chronic endpoint is fatty infiltration and atrophy (PMID:26256659), not a classical fibrotic-response module.
Mitochondrial primary defect: not established, although the Na⁺-overload/pump-load axis (step 7) creates an energetic burden that has not been characterized and is a reasonable hypothesis for step 8's missing intermediates.

7. Diagnosis

Diagnostic criteria

GeneReviews frames the clinical diagnosis around attacks with documented ictal hyperkalemia, interictal normokalemia and early onset:

"normal serum potassium between attacks, and onset before age 20 years" (PMID:20301669) "an increase of serum potassium concentration of at least 1.5 mmol/L during an attack of weakness" (PMID:20301669)

1. Molecular genetic testing (first-line; `NCIT:C15709` Genetic Testing)

"Genetic testing by next-generation sequencing of candidate genes (CACNA1S, SCN4A, and KCNJ2) is now routinely performed in the evaluation for familial periodic paralysis" (PMID:39174253) "The diagnosis of hyperPP is established in a proband with suggestive findings and a heterozygous pathogenic variant in SCN4A identified by molecular genetic testing." (PMID:20301669)

2. Needle electromyography (`NCIT:C38056`)

Myotonic discharges are the discriminating finding, and their presence effectively excludes the two main mimics:

"Convincing evidence of myotonia (discharges waxing and waning in frequency and amplitude, increased activity after voluntary contraction or provoked by percussion or needle movement) is inconsistent with a diagnosis of HypoPP or ATS, and supports a diagnosis of HyperPP or PMC." (PMID:39174253) "On needle electromyography (EMG), positive sharp waves and myotonia, characterized by spontaneous waxing and waning motor unit potential amplitude and frequency, can be seen in PMC and HyperPP." (PMID:29125635)

3. Long exercise CMAP test

The most informative electrophysiological test, and it discriminates among the periodic paralyses by pattern, not merely by presence of decrement:

"A reduction in CMAP amplitude of 40% or more from the maximal during exercise or post exercise is considered abnormal and is typically seen in >70% of patients." (PMID:29125635) "with a late decrease alone most often found in HypoPP (pattern V), an early increase follow by a late decrease in HyperPP (pattern IV), or a rapid onset decrease that persisted for minutes in PMC (pattern I)" (PMID:39174253)

Ontology gap: NCIT has no term for this test. runoak -i ols:ncit search "l~compound muscle action potential" and "l~muscle action potential" both return nothing, and NCIT:C88502 Nerve Conduction Velocity Test is not an acceptable substitute on positive grounds — the long exercise test measures CMAP amplitude decrement, not conduction velocity. This is a concrete NCIT term-request candidate.

4. Serum potassium during an attack (`NCIT:C47868` Potassium Measurement)

Necessary but, as §5 emphasizes, neither sufficient nor reliably abnormal.

5. Provocative testing — now contraindicated

"Provocative testing, with a glucose plus insulin challenge for HypoPP or with an oral K+ challenge in HyperPP, is potentially dangerous and no longer used in clinical practice." (PMID:39174253) "In case of diagnostic uncertainty, a provocative test can be employed, although the availability of genetic testing and electrophysiologic studies largely obviates the need for such dangerous tests." (PMID:20301669)

This is a clear, citable practice change: genetics plus electrophysiology have displaced potassium challenge.

6. Muscle imaging

Whole-body muscle MRI documents the chronic myopathy and its selective distribution (PMID:26256659) — a monitoring rather than diagnostic tool.

Biomarkers

No molecular biomarker exists. Serum potassium is an ictal-only, insensitive readout; CMAP decrement is the functional biomarker; creatine kinase behaviour in HyperPP was not verified in this session.

8. Treatment and Management

Acute attack

Intervention	Modality / binding	Evidence
Mild exercise and/or oral carbohydrate at attack onset	BEHAVIORAL; `NCIT:C15302` Physical Therapy (imperfect — see note)	"At the onset of weakness, attacks may be prevented or aborted with mild exercise and/or oral ingestion of carbohydrates, intravenously injected glucocorticoids, inhalation of salbutamol, or intravenous calcium gluconate." (PMID:20301669); mechanistic support from mouse: "tetanic stimulation every minute caused a progressive and highly significant force increase of 48% in the soleus of mutant mice (P < 0.001) but no significant change in soleus of WT mice" (PMID:21708955)
Inhaled salbutamol (albuterol; `CHEBI:2549`)	SMALL_MOLECULE; `NCIT:C15986` Pharmacotherapy	"Beta-adrenergic inhalants may be used to hasten recovery from an episode of HyperPP" (PMID:39174253); "In case reports, salbutamol 1-2 puffs (0.1 mg) and other beta-agonists have shown benefits." (PMID:29125635); mechanism: "Stimulating Na(+),K(+) pumps with salbutamol restored force in mutant soleus and extensor digitorum longus (EDL)." (PMID:21708955)

Ontology gap: NCIT has no term for self-directed abortive exercise; runoak -i ols:ncit search "l~exercise test" returns only cardiac/cardiopulmonary stress-testing terms. The binding to Physical Therapy is a deliberate over-broad compromise.

The β₂-agonist case is unusually satisfying as translational pharmacology: the mouse experiment identifies the Na⁺/K⁺ pump as the rescuable node (PMID:21708955), and the human treatment is a pump stimulant.

Chronic prevention

Intervention	Agent	Evidence and caveats
Dichlorphenamide (diclofenamide, `CHEBI:101085`)	carbonic anhydrase inhibitor	The only approved drug for primary periodic paralysis: "The oral carbonic anhydrase inhibitor dichlorphenamide (DCP) is approved for treatment of hyperkalemic and hypokalemic periodic paralyses and related variants." (PMID:34129236). But the pivotal trial was not positive in the hyperkalemic arm: "The median attack rate was also lower in HYP participants on DCP (0.9 vs 4.8) than in participants on placebo, but the difference in median attack rate was not significant (p = 0.10)." and "These studies provide Class I evidence that DCP significantly reduces attack frequency in HOP but lacked the precision to support either efficacy or lack of efficacy of DCP in HYP." (PMID:26865514). The 52-week open-label extension pooled the hyper- and hypokalemic substudies (PMID:34129236), so it does not resolve the HyperPP-specific question.
Acetazolamide (`CHEBI:27690`)	carbonic anhydrase inhibitor	"Acetazolamide 125-1000 mg/day may be effective for chronic treatment of HyperPP." (PMID:29125635); acts on both episodic and fixed weakness — "He rapidly recovered from weakness after acetazolamide treatment. Magnetic resonance imaging of thighs comparing pre- and post-treatment revealed a significant increase in muscle bulk." (PMID:23473731, indirect); mechanistic support in mutant mouse muscle — "Bath application of the carbonic anhydrase inhibitor acetazolamide protected against K+-induced loss of force" (PMID:25880512). Caveats: some patients deteriorate on it, and the mechanism of carbonic anhydrase inhibition in this disease remains unsettled.
Thiazide diuretic — hydrochlorothiazide (`CHEBI:5778`)	K⁺-wasting diuretic	"The drug of choice is hydrochlorothiazide 25 mg to 75 mg daily.41, 54 Potassium-sparing diuretics should be avoided." (PMID:29125635); "Oral K+ supplements and K-sparing diuretics (e.g. eplerenone) are used for HypoPP, whereas K-wasting diuretics (e.g. hydrochlorothiazide) are used for HyperPP" (PMID:39174253)
Mexiletine (`CHEBI:6916`) — for myotonic stiffness, not for attacks	use-dependent Na⁺ channel blocker	"If myotonic stiffness is the more problematic symptom, then use-dependent sodium channel blockers (e.g. mexiletine) may provide relief" (PMID:39174253). The randomized mexiletine evidence derives from the non-dystrophic myotonias, not from HyperPP trials.
Trigger avoidance and dietary management	BEHAVIORAL; `NCIT:C15447` Dietary Intervention	"Hyperkalemic attacks of weakness can be prevented by frequent meals rich in carbohydrates; continuous use of a thiazide diuretic or a carbonic anhydrase inhibitor; and avoidance of potassium-rich medications and foods, fasting, strenuous work, and exposure to cold." (PMID:20301669); "In individuals with HyperPP, consider recommending consumption of multiple small carbohydrate snacks and avoid potassium-rich foods." (PMID:29125635)

The single most consequential treatment fact

HyperPP and HypoPP require opposite potassium management. K⁺ supplements and K⁺-sparing diuretics treat HypoPP and can precipitate an attack in HyperPP; K⁺-wasting diuretics do the reverse (PMID:39174253). Misclassification is therefore not merely inelegant — it is directly harmful, which is why §10's differential is the operative section of this report for clinical use.

Perioperative and anaesthetic management

Bulbar and respiratory involvement (PMID:20301669), combined with the depolarization mechanism, makes depolarizing neuromuscular blockers and potassium-containing infusions hazardous. A formal anaesthetic guideline for HyperPP was not verified in this session; the inference follows from the mechanism and the documented respiratory involvement rather than from a cited protocol.

Therapies not applicable or not developed

Gene therapy, gene editing, ASO/siRNA, mRNA therapy, cell therapy, protein replacement, vaccines: none exists or is in trial for HyperPP. Mechanistically, allele-selective silencing is an attractive fit (a dominant gain-of-function coding allele in a single accessible tissue), and its absence is a genuine translational gap rather than a mechanistic impossibility.
Immunosuppression: not applicable.
Surgery, radiotherapy, devices: not applicable.

Clinical trials

NCT00494507 — PHASE_III, COMPLETED — the "HYP HOP" randomized, double-blind, placebo-controlled crossover programme of dichlorphenamide with a 52-week open-label extension:

"The purpose of this study is to compare Dichlorphenamide with placebo (an inactive substance) for prevention of episodes and for improvement of strength in hyperkalemic (HYP) and hypokalemic (HOP) periodic paralysis." (ClinicalTrials.gov NCT00494507)

No trial registered on a non-ClinicalTrials.gov WHO primary registry was identified for HyperPP.

Pharmacogenomics

No information available. No pharmacogenomic predictor of dichlorphenamide or acetazolamide response has been established. The observation that "some patients develop deleterious effects" on acetazolamide, without a predictor, is exactly the shape of an unaddressed pharmacogenomic question — plausibly genotype-dependent given the HyperPP/PMC allelic continuum, but untested.

9. Prognosis, Natural History and Quality of Life

Natural history

The disease has a two-phase course with an inverse relationship between its phases:

"For many patients the frequency of attacks diminishes with age, and is replaced by a chronic state of mild weakness that later progresses to myopathy with permanent muscle weakness, especially of proximal muscles, and may cause loss of ambulation" (PMID:39174253) "A proportion of affected individuals develop fixed or chronic progressive weakness that results in significant disability." (PMID:26256659) "Whole-body muscle MRI analysis revealed muscle atrophy and fatty infiltration in hyperKPP patients, especially in older individuals." (PMID:26256659)

Acetazolamide may partially reverse established weakness, at least in a reported case with imaging follow-up (PMID:23473731) — a notable claim, since it implies the fixed component is not entirely fixed.

The unresolved question in the natural history is whether the chronic myopathy is a consequence of accumulated attacks or an independent effect of the resting Na⁺ leak. The clinical observation that permanent weakness can develop in patients without frequent attacks favours the latter and argues that attack-suppressing therapy may not by itself prevent the disabling endpoint. No study settles this.

Life expectancy and mortality

No mortality or survival data were identified. HyperPP is not generally described as life-limiting, and the plausible mechanisms of death — respiratory muscle involvement during a severe attack, and anaesthetic complications — are described qualitatively rather than quantified. No case-fatality rate, standardized mortality ratio, or life-expectancy estimate was verified. This is a real gap: a disease with documented respiratory muscle involvement and no mortality statistics.

Quality of life

No HyperPP-specific patient-reported outcome data were identified. No EQ-5D, SF-36, PROMIS, INQoL or disease-specific instrument result was verified for this disease in this session. A patient survey characterizing HyperPP has been published (J Neurol 2013, "Characterization of hyperkalemic periodic paralysis: a survey of...") but was not retrieved or verified here, so its findings are not reported. Given that attacks are episodic and unpredictable, that the chronic phase can cause loss of ambulation, and that management is built around dietary and activity restriction, the absence of validated QoL measurement is a notable deficiency in the evidence base — and it directly limits trial design, since attack rate (the endpoint that failed to reach significance in the HYP arm of NCT00494507) may be the wrong primary outcome.

Prognostic factors

Genotype influences the balance of myotonia versus paralysis but does not determine it (M1592V discordance within one family).
Attack frequency declines with age; fixed weakness rises.
T704M carriers are the genotype in which chronic myopathy has been imaged (PMID:26256659).
No validated prognostic model exists.

10. Differential Diagnosis

1. Paramyotonia congenita of von Eulenburg (`MONDO:0008195`) — allelic, same mechanism

"Paramyotonia congenita (PMC) and hyperkalemic periodic paralysis (HyperPP) have extensive overlap of clinical features (Figure 1, center) and are caused by similar gain-of-function defects arising from missense mutations of NaV1.4" (PMID:39174253) "The predominant symptom in PMC is myotonic stiffness that paradoxically worsens with the first few repetitions for voluntary contraction of affected muscles (paramyotonia), whereas the stiffness diminishes with repeated effort (warm-up) for other forms of myotonia" (PMID:39174253) "To verify the diagnosis of channelopathies in two families and explore the mechanism of the overlap between periodic paralysis (PP) and paramyotonia congenita (PMC)." (PMID:30931713) "The first proband and part of his family with the overlap of PMC and hyperkalemic periodic paralysis (HyperPP) has been identified as c.2111C > T (T704M) substitution of the gene SCN4A." (PMID:30931713)

Discriminators: predominant symptom (stiffness vs weakness); paradoxical worsening over the first few contractions; cold-selective distal and facial stiffness; long-exercise CMAP pattern I (PMC) vs IV (HyperPP). Gene and variant do not discriminate — this is one continuum, and whether to lump or split is a deliberate nosological choice rather than a factual one.

2. Hypokalemic periodic paralysis (`MONDO:0008223`) — the mechanistically opposite disease, and the most consequential differential

"Episodic weakness in HypoPP is caused by \"leaky\" Ca2+ or Na+ channels, with an anomalous gating pore current that is conducted through the voltage-sensor domain of the channel." (PMID:39174253) "Almost all HypoPP mutations are missense substitutions at arginine residues in S4 transmembrane segments (Matthews et al., 2009), which not only helps to distinguish HypoPP from HyperPP or ATS" (PMID:39174253) "Attacks in HyperPP tend to be more frequent and shorter in duration than attacks in HypoPP." (PMID:29125635)

Discriminators: ictal K⁺ direction; myotonia (present in HyperPP, an exclusion for HypoPP); triggers (carbohydrate load precipitates HypoPP but aborts HyperPP); treatment (opposite potassium handling); genetics (CACNA1S/S4 arginines vs SCN4A inactivation-gate residues); attack pattern (frequent/short vs infrequent/long).

3. Myotonia congenita — Thomsen and Becker disease (`MONDO:0009710`)

"Reduction of the chloride conductance, as occurs in myotonia congenita, impairs this stability and results in bursts of after-discharges and delayed relaxation of force in myotonia" (PMID:39174253) "When myotonia is present, CLCN1 should also be screened, and the possibility of myotonic dystrophy should be investigated by testing for expansion of CTG repeats in DMPK and CCTG repeats in CNBP." (PMID:39174253)

Discriminators: CLCN1, reduced chloride conductance rather than Na⁺ gain of function; no dyskalemic attacks; warm-up phenomenon; muscle hypertrophy usual.

4. Andersen–Tawil syndrome (`MONDO:0008222`)

Reaches the same endpoint by removing the resting outward K⁺ current rather than adding inward Na⁺ current:

"Unlike the skeletal muscle-specific expression for CLCN1, SCN4A, and CACNA1S; KCNJ2 is expressed in multiple tissues including skeletal muscle, heart, and bone." (PMID:39174253) "Attacks of muscle weakness can be associated with high, low or normal serum potassium levels." (PMID:29125635)

Discriminators: KCNJ2/Kir2.1 loss of function; ventricular arrhythmia and dysmorphic features — the multisystem involvement is the tell, and it is absent in HyperPP; K⁺ may be high, low or normal.

5. Also to be excluded (secondary/acquired)

Myotonic dystrophy types 1 and 2 (DMPK CTG, CNBP CCTG — explicitly recommended in PMID:39174253); thyrotoxic periodic paralysis; secondary hyperkalemia from renal failure, adrenal insufficiency, or K⁺-sparing drugs; Guillain–Barré and other acute flaccid paralyses for a first severe attack. Note that HyperPP's ictal hyperkalemia is of muscle origin, so a search for a renal or adrenal cause will be negative — a positive discriminator.

11. Model Systems

Animal model 1 — Scn4a M1592V knock-in mouse (the principal model)

Genotype: Scn4a M1592V heterozygous knock-in; background FVB.129S4(B6)-Scn4a^tm1.1Ljh^/J. Primary reference: PMID:21708955.

What it recapitulates well (fidelity HIGH) — resting intracellular Na⁺ overload, at the CELLULAR scale. Resting potential depolarized by ~16 mV, TTX-reversible; Na⁺/K⁺-pump activity compensatorily raised:

"Na(+),K(+) pump-mediated (86)Rb uptake was 83% larger than in WT." (PMID:21708955)

What it recapitulates only partially (fidelity MODERATE) — the paralysis itself, at the TISSUE scale. The model reproduces susceptibility, not the episodic disease:

"Spontaneous attacks of weakness have not been observed, but in vitro challenge with 10 mM K+ triggered a severe reduction of muscle force." (PMID:25880512) "In muscles from mutant mice, the rate of force reduction as measured over the first 10 min after exposure to 10 mM K+ was 760% faster than in muscles from WT." (PMID:21708955) "These observations indicate that in muscles from the mutants, excitability is lower than in muscles from WT." (PMID:21708955)

Pharmacological validity — the model's most valuable property. Both human treatments work in it:

"When added to muscles exposed to 10 mM K+, 10-6 M salbutamol restored tetanic force to the same level as measured at 4 mM K+ both in WT and in mutant mice" (PMID:21708955) "Stimulating Na(+),K(+) pumps with salbutamol restored force in mutant soleus and extensor digitorum longus (EDL)." (PMID:21708955) "Bath application of the carbonic anhydrase inhibitor acetazolamide protected against K+-induced loss of force" (PMID:25880512)

Limitations: measurements are on isolated soleus/EDL at 30 °C; loss of force must be provoked by an in vitro K⁺ challenge rather than arising spontaneously; so the model observes at a lower scale than the clinical endpoint it is cited for, and the episodic character of the human disease — arguably its defining feature — is absent.

Animal model 2 — equine HyperPP (American Quarter Horse)

Genotype: naturally occurring heterozygous SCN4A DIIIS3 phenylalanine-to-leucine substitution, traceable to a single founder sire. References: PMID:25880512, PMID:21708955; OMIA:000785-9796.

"Hyperkalemic periodic paralysis (HyperKPP) is a rare hereditary disease seen in human subjects and horses." (PMID:21708955) "intercostal muscle fibers from horses with HyperKPP were found to be depolarized, and TTX induced repolarization to the level measured in normal horses" (PMID:21708955)

Its distinctive contribution is not the mechanism but the variability:

"Despite this single mutation being expressed on a very homogenous genetic background of inbreed horses, the phenotype is variable with regard to severity and frequency of attacks" (PMID:25880512)

This is an unusually clean natural experiment: one allele, one narrow genetic background, and still variable expression. It argues that HyperPP's phenotypic variability is not primarily explained by genetic background, which in turn constrains the search for human modifier genes.

Limitations: the equine allele is not a human HyperPP allele, and measurements are on excised intercostal fibres.

Models absent

Rat, zebrafish, Drosophila, C. elegans: no information available.
iPSC-derived myotubes / patient-derived myogenic cultures: no information available — a conspicuous gap for a disease of a single accessible tissue with a known coding allele.
Organoids / organ-on-chip: not applicable / none reported.
Heterologous expression (HEK293, Xenopus oocyte, mammalian cell lines): this is where the primary biophysical characterization of each variant is done, and it is the basis of the ACMG PS3 evidence. Individual expression studies were not itemized in this session, but PMID:36628799 is an example of a novel-variant functional characterization.
Computational/in silico: PMID:25880512 provides an explicitly computational account of the depolarization/inexcitability mechanism (the quotes at steps 3, 4, 5 and 6 of §6 are from a modelling analysis), which is why several core mechanistic claims in this disease are graded COMPUTATIONAL rather than clinical.

Model–mechanism coverage assessment

Steps 1–7 of the causal chain are covered by a model. Step 8 — the transition from Na⁺ overload to fixed fatty myopathy — is covered by no model at all. Neither the mouse (which shows no spontaneous attacks, let alone a chronic myopathy phenotype) nor the horse addresses it, and this is the same step §6.1 flags as inferred rather than demonstrated. The weakest link in the mechanism is also the one with no experimental system.

12. Other Species, Taxonomy and Veterinary Disease

Taxonomy

Species	NCBI Taxon (verified via OLS)	Role
Homo sapiens	`NCBITaxon:9606`	index species
Equus caballus (domestic horse)	`NCBITaxon:9796`	naturally occurring disease
Mus musculus	`NCBITaxon:10090` [verified by cache convention only — not independently resolved in this session]	engineered knock-in model

Equine HYPP — a distinct veterinary disease with its own identity

OMIA:000785-9796 records Hyperkalemic Periodic Paralysis (HYPP) in Equus caballus.

Causative variant: a missense substitution changing phenylalanine to leucine in the α-subunit of the adult skeletal-muscle sodium channel — reported as SCN4A c.4206C>G, p.(F1416L), exon 24, in the DIIIS3 segment. (Retrieved from OMIA-derived sources in this session; the exact nucleotide coordinates were not verified against the primary publication.)
Breeds affected: American Quarter Horse and American Paint Horse. VBO breed identifiers were not retrieved or verified in this session, so none is asserted here; the Vertebrate Breed Ontology is the correct resource for binding these and the lookup remains outstanding.
Inheritance: autosomal dominant with variable expression; OMIA describes it as incompletely dominant, with homozygotes more severely affected than heterozygotes — a dosage relationship that human HyperPP, where homozygotes are essentially unreported, does not illuminate.
Founder effect: the allele traces to a single influential Quarter Horse sire, and its persistence is the result of positive selection — the allele was associated with the heavy musculature favoured in halter competition. This makes equine HYPP one of the clearest documented cases of an iatrogenic-by-breeding Mendelian disease, and it is why commercial genotyping is routine in the breed.
Clinical presentation: episodic muscle tremors, weakness and paralysis with raised serum potassium — homologous to the human disease, with prominent fasciculation and, in severe episodes, respiratory obstruction and sudden death. (Descriptive; not quoted from a verified primary source.)
Zoonotic potential: not applicable. HYPP is a heritable channelopathy, not transmissible.
Immunization: not applicable.

Why the horse matters to the human disease

Beyond confirming the mechanism in an independent species, the equine data deliver the variability argument (§11): a single allele on a homogeneous background still gives variable severity and attack frequency (PMID:25880512). Any human modifier-gene hypothesis must survive that observation.

Other species

No naturally occurring HyperPP has been reported in dogs, cats, cattle or other domestic species in the sources consulted. No information available for wildlife.

13. Prevention, Genetic Counseling and Public Health

Primary prevention

Not achievable for the genetic lesion. Primary prevention in the reproductive sense means reproductive options (below); in the veterinary setting it means selection against the allele, which is exactly what equine HYPP testing programmes implement — a rare instance where primary prevention of a Mendelian disease is actively practised at population scale, albeit in horses.

Secondary prevention — attack prevention is the operative level

This is where HyperPP management sits, and it is unusually effective:

"Hyperkalemic attacks of weakness can be prevented by frequent meals rich in carbohydrates; continuous use of a thiazide diuretic or a carbonic anhydrase inhibitor; and avoidance of potassium-rich medications and foods, fasting, strenuous work, and exposure to cold." (PMID:20301669)

Tertiary prevention

Prevention of the fixed myopathy is the unmet need. Whether attack suppression prevents it is unknown (§9), and the one positive signal — acetazolamide with imaging-documented increase in muscle bulk (PMID:23473731) — is a single case.

Genetic counseling

Autosomal dominant, near-complete penetrance → 50% transmission risk per pregnancy; most affected individuals have an affected parent, though de novo occurrence is documented for T704M (ClinVar).
Variable expression must be counseled explicitly: the same allele can present as HyperPP in one family member and PMC in another (PMID:30931713, and the M1592V family), so a predicted phenotype cannot be given from the genotype alone.
Key counseling point specific to this disease: the actionable information is not prognostic but practical — trigger avoidance, anaesthetic precautions, and avoidance of potassium supplements and K⁺-sparing diuretics. Identification of an at-risk relative changes their perioperative and pharmacological safety immediately.
Predictive testing of at-risk relatives is straightforward once a familial variant is known.
NCIT:C15240 Genetic Counseling is the appropriate intervention binding.

Prenatal and preimplantation testing

Technically available for a known familial variant. No HyperPP-specific prenatal or PGT series or guidance was identified, and given that the condition is treatable and not life-limiting, uptake is likely low — but this is inference, not verified data.

Newborn screening

Not screened for, and not a plausible candidate — onset is in childhood rather than neonatal, and no pre-symptomatic intervention changes long-term outcome.

Carrier frequency and population screening

Not applicable in the recessive sense (this is a dominant disorder). Population screening is not indicated; the classical alleles are absent from gnomAD (§3), so incidental-finding rates would be negligible.

Public health burden

With a minimum point prevalence for the periodic paralyses of 0.41/100,000 (PMID:36796140), the absolute burden is small. The disproportionate burdens are (a) the interpretive load of ~2,000 SCN4A variation records annotated against this condition in ClinVar, and (b) avoidable iatrogenic harm from potassium administration or depolarizing anaesthesia in an unrecognized case.

14. Evidence Gaps and Research Priorities

Ranked by the gap between what is claimed and what is demonstrated:

The mechanism of the chronic myopathy is unknown (step 8). Resting Na⁺ overload is demonstrated and fatty infiltration is demonstrated; nothing traces between them, and the clinical observation that fixed weakness arises without frequent attacks rules out the easy explanation. No model system addresses it. Highest-value gap.
Dichlorphenamide's efficacy in HyperPP is formally unresolved — the pivotal trial "lacked the precision to support either efficacy or lack of efficacy of DCP in HYP" (PMID:26865514), yet the drug is approved for it. A HyperPP-powered trial, or a re-analysis with a better endpoint, is outstanding.
No validated outcome measure and no quality-of-life data. Attack rate failed in NCT00494507's HYP arm; nothing has replaced it. This blocks every future trial.
No mortality or survival data, despite documented respiratory muscle involvement.
Phenotypic variability is unexplained and the equine data constrain the explanation — one allele, homogeneous background, variable severity (PMID:25880512). Modifier-gene searches must account for this.
Selective muscle involvement is unexplained — why the posterior calf and anterior thigh (PMID:26256659)? A single-cell or spatial approach is the obvious method and has not been applied.
No omics of any kind, and no iPSC-derived human model. For a disease of one accessible tissue with a known coding allele, this is a striking absence.
No allele-selective therapeutic programme (ASO, siRNA, base editing) despite a mechanism — dominant coding gain-of-function in skeletal muscle — that fits those modalities well.
Diagnostic yield is incomplete: a substantial minority of typical patients are genetically unsolved, implying either non-coding SCN4A variation or an unidentified locus.
Two ontology terms are missing and block precise curation: paramyotonia (absent from HPO; forces binding to the general HP:0003552 Muscle stiffness and loses the paradoxical-worsening distinction that separates PMC from other myotonias) and the long exercise CMAP test (absent from NCIT; NCIT:C88502 Nerve Conduction Velocity Test is wrong on positive grounds because the test measures amplitude decrement, not conduction velocity). Both are actionable term requests.
Pharmacogenomics of carbonic anhydrase inhibitor response — some patients deteriorate on acetazolamide with no predictor.
HyperPP/PMC nosology is unsettled. The two share gene, variant and mechanism and differ in predominant symptom; whether they are one disease or two is a decision, not a finding, and it should be made deliberately rather than inherited.

15. Suggested Ontology Bindings

MONDO

MONDO:0008224 hyperkalemic periodic paralysis — primary disease term
MONDO:0008195 paramyotonia congenita of Von Eulenburg — differential (allelic)
MONDO:0008223 hypokalemic periodic paralysis — differential (mechanistically opposite)
MONDO:0008222 Andersen-Tawil syndrome — differential
MONDO:0009710 myotonia congenita (Thomsen and Becker disease) — differential

HPO — phenotypes

Term	Label	Qualifiers
`HP:0003752`	Episodic flaccid weakness	temporality RECURRENT; onset CHILDHOOD
`HP:6000833`	Hyperkalemia while symptomatic	temporality ACUTE; category Laboratory
`HP:0002486`	Myotonia	—
`HP:0003552`	Muscle stiffness	over-broad binding for paramyotonia — HPO has no paramyotonia term (`runoak -i ols:hp search "paramyotonia"` returns nothing)
`HP:0009073`	Progressive proximal muscle weakness	clinical_course PROGRESSIVE
`HP:0004889`	Intermittent episodes of respiratory insufficiency due to muscle weakness	temporality ACUTE
`HP:0000006`	Autosomal dominant inheritance	inheritance

GO — molecular function, process, cellular component

Term	Label	Use
`GO:0005248`	voltage-gated sodium channel activity	molecular function; modifier GAIN_OF_FUNCTION
`GO:0042391`	regulation of membrane potential	process; modifier DYSREGULATED
`GO:0035725`	sodium ion transmembrane transport	process; modifier INCREASED
`GO:0071805`	potassium ion transmembrane transport	process; modifier INCREASED
`GO:0003009`	skeletal muscle contraction	process; modifier DECREASED
`GO:0042383`	sarcolemma	cellular component — site of the lesion
`GO:0030315`	T-tubule	cellular component — mechanistically necessary: the restricted volume that lets K⁺ accumulate to depolarizing levels
`GO:0016529`	sarcoplasmic reticulum	cellular component — excitation–contraction coupling context

UBERON

UBERON:0001134 skeletal muscle tissue — the affected tissue
Specific compartments (posterior leg, anterior thigh) from PMID:26256659 would benefit from UBERON binding; the specific compartment terms were not resolved in this session and should not be asserted.

CHEBI — therapeutic agents

CHEBI:2549 albuterol (salbutamol) — acute
CHEBI:101085 diclofenamide (dichlorphenamide) — the approved preventive
CHEBI:27690 acetazolamide — preventive
CHEBI:5778 hydrochlorothiazide — preventive (K⁺-wasting)
CHEBI:6916 mexiletine — for myotonic stiffness

NCIT — clinical actions

NCIT:C15986 Pharmacotherapy (with therapeutic_agent carrying the CHEBI drug)
NCIT:C15447 Dietary Intervention — trigger avoidance, carbohydrate snacking
NCIT:C15302 Physical Therapy — abortive mild exercise (imperfect; NCIT has no term for self-directed abortive exercise, and runoak -i ols:ncit search "l~exercise test" returns only cardiac stress-testing terms)
NCIT:C15709 Genetic Testing
NCIT:C38056 Electromyography
NCIT:C47868 Potassium Measurement
NCIT:C15240 Genetic Counseling
Long exercise CMAP test — deliberately unbound. No NCIT term exists; NCIT:C88502 Nerve Conduction Velocity Test rejected on positive grounds.

HGNC / gene

hgnc:10591 SCN4A (note lowercase prefix is the canonical form in dismech)

ECTO / XCO — exposures

ECTO:0900037 — potassium-rich food ingestion → TRIGGERS, DIRECT
ECTO:6000031 — rest after strenuous exercise → TRIGGERS, INDIRECT (known intermediates)
XCO:0000306 — cold exposure → EXACERBATES, INDIRECT (unknown intermediates)
XCO:0000102 — fasting → TRIGGERS, INDIRECT (unknown intermediates)

NCBITaxon

NCBITaxon:9606 Homo sapiens
NCBITaxon:9796 Equus caballus
NCBITaxon:10090 Mus musculus [not independently resolved this session]

Term requests to file

HPO: paramyotonia — a distinct phenotype (paradoxical worsening with initial repetitions, cold-aggravated) present in ~45% of HyperPP patients and diagnostically decisive against other myotonias, with no HPO representation.
NCIT: long exercise test / CMAP amplitude decrement — the principal electrophysiological discriminator among the periodic paralyses, with no NCIT clinical-action term.

Appendix — Verified reference list

PMID	Title	Role in this report
20301669	Hyperkalemic Periodic Paralysis. (GeneReviews)	Diagnostic criteria, triggers, attack description, management baseline
39174253	Periodic paralysis.	Principal modern review; mechanism, differentials, electrophysiology, treatment
25880512	Channelopathies of skeletal muscle excitability.	Computational/biophysical account of the core mechanism; equine data; acetazolamide in mouse muscle
29125635	Review of the Diagnosis and Treatment of Periodic Paralysis.	Diagnosis, EMG, long exercise test thresholds, treatment doses
26865514	Randomized, placebo-controlled trials of dichlorphenamide in periodic paralysis.	The pivotal HYP/HOP trial and its non-significant HYP result
34129236	Long-term efficacy and safety of dichlorphenamide for treatment of primary periodic paralysis.	Open-label extension; approval statement
36628799	Hyperkalemic periodic paralysis associated with a novel missense variant located in the inner pore of Nav1.4.	Variant-spectrum extension
21708955	Na+,K+-pump stimulation improves contractility in isolated muscles of mice with hyperkalemic periodic paralysis.	M1592V mouse; pump mechanism; salbutamol rescue; equine intercostal fibres
26256659	Whole-Body Muscle MRI in Patients with Hyperkalemic Periodic Paralysis Carrying the SCN4A Mutation T704M: Evidence for Chronic Progressive Myopathy with Selective Muscle Involvement.	The chronic myopathy endpoint and its selective distribution
23473731	Long-term effectiveness of acetazolamide on permanent weakness in hyperkalemic periodic paralysis.	Partial reversibility of fixed weakness
30931713	Overlap of periodic paralysis and paramyotonia congenita caused by SCN4A gene mutations two family reports and literature review.	HyperPP/PMC continuum; T704M overlap families
36796140	Prevalence of genetically confirmed skeletal muscle channelopathies in the era of next generation sequencing.	Minimum point prevalence figures

Trial: NCT00494507 (ClinicalTrials.gov), Phase III, completed.

Sources: - Hyperkalemic Periodic Paralysis — GeneReviews (NBK1496) - Prevalence of genetically confirmed skeletal muscle channelopathies in the era of next generation sequencing (PMID:36796140) - Review of the Diagnosis and Treatment of Periodic Paralysis (PMC5867231) - Overlap of periodic paralysis and paramyotonia congenita caused by SCN4A gene mutations - MONDO:0008224 record, EBI OLS4 - OMIM Entry #170500 — HYPERKALEMIC PERIODIC PARALYSIS; HYPP - HGNC record for SCN4A (rest.genenames.org) - ClinVar VCV000005896 — SCN4A c.2111C>T (p.Thr704Met) - ClinVar RCV000006254 — p.Thr704Met AND Hyperkalemic periodic paralysis - OMIA:000785-9796 — Hyperkalemic Periodic Paralysis, HYPP in Equus caballus - OMIA:000785 — Hyperkalemic Periodic Paralysis, HYPP - ICD-10-CM G72.3 Periodic paralysis - ICD-11 MMS — Periodic paralysis block (8C74.1) - Hyperkalemic Periodic Paralysis — StatPearls - Skeletal Muscle Channelopathies (PMC6277285) - Characterization of hyperkalemic periodic paralysis: a survey (J Neurol) - Hyperkalemic periodic paralysis — UpToDate

Ask OpenScientist

OpenScientist Report

Classifications

Definitions

Inheritance

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Environmental Factors

Diagnosis

Progression

Prevalence

Differential Diagnoses

Clinical Trials

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Hyperkalemic Periodic Paralysis (HyperPP) — Comprehensive Disease Characteristics Report

1. Disease Definition, Nomenclature and Identifiers

Key identifiers (verified via OLS4 MONDO record, HGNC REST, ICD resources)

Synonyms (MONDO exact synonyms, verbatim)

Classification

2. Epidemiology

Prevalence

Incidence

Sex distribution

Age of onset

Geographic distribution, ethnicity and founder effects

Ancestry-specific allele frequencies

3. Genetics and Molecular Basis

Gene (verified, HGNC REST)

Inheritance

Mode of action

Variant spectrum

ACMG/AMP interpretation notes specific to this locus

Genetic heterogeneity and diagnostic yield

Modifier genes

Epigenetics

Chromosomal abnormalities

Somatic variation / mosaicism

4. Molecular Profiling, Omics and Advanced Technologies

5. Clinical Presentation, Anatomy and Phenotype

Cardinal features

Anatomical distribution, lateralization, and severity

Triggers (clinically actionable)

6. Pathophysiology and Mechanism

6.1 The causal chain

6.2 Where the mechanism amplifies the modest into the pathological

6.3 How each trigger enters the chain

6.4 Subcellular localization and molecular components

6.5 Processes and mechanisms explicitly not involved

7. Diagnosis

Diagnostic criteria

1. Molecular genetic testing (first-line; NCIT:C15709 Genetic Testing)

2. Needle electromyography (NCIT:C38056)

3. Long exercise CMAP test

4. Serum potassium during an attack (NCIT:C47868 Potassium Measurement)

5. Provocative testing — now contraindicated

6. Muscle imaging

Biomarkers

8. Treatment and Management

Acute attack

Chronic prevention

The single most consequential treatment fact

Perioperative and anaesthetic management

Therapies not applicable or not developed

Clinical trials

Pharmacogenomics

9. Prognosis, Natural History and Quality of Life

Natural history

Life expectancy and mortality

Quality of life

Prognostic factors

10. Differential Diagnosis

1. Paramyotonia congenita of von Eulenburg (MONDO:0008195) — allelic, same mechanism

2. Hypokalemic periodic paralysis (MONDO:0008223) — the mechanistically opposite disease, and the most consequential differential

1. Molecular genetic testing (first-line; `NCIT:C15709` Genetic Testing)

2. Needle electromyography (`NCIT:C38056`)

4. Serum potassium during an attack (`NCIT:C47868` Potassium Measurement)

1. Paramyotonia congenita of von Eulenburg (`MONDO:0008195`) — allelic, same mechanism

2. Hypokalemic periodic paralysis (`MONDO:0008223`) — the mechanistically opposite disease, and the most consequential differential

3. Myotonia congenita — Thomsen and Becker disease (`MONDO:0009710`)

4. Andersen–Tawil syndrome (`MONDO:0008222`)