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)

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)

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

1. 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.)
2. 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.)
3. 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.
4. 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.
5. 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.")
6. 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.
7. 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.")
8. 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

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

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

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

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:

1. 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.
2. 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.
3. 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.
4. No mortality or survival data, despite documented respiratory muscle involvement.
5. 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.
6. 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.
7. 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.
8. 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.
9. Diagnostic yield is incomplete: a substantial minority of typical patients are genetically unsolved, implying either non-coding SCN4A variation or an unidentified locus.
10. 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.
11. Pharmacogenomics of carbonic anhydrase inhibitor response — some patients deteriorate on acetazolamide with no predictor.
12. 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

GO — molecular function, process, cellular component

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

1. 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.
2. 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

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