1. Resting state: Skeletal muscle fibres maintain a resting membrane potential of approximately −85 to −90 mV, maintained by:

   • Na+/K+ ATPase (3 Na+ out, 2 K+ in)
   • K+ leak channels (high K+ permeability at rest)
   • Cl⁻ channels (stabilise membrane potential — relevant for myotonia congenita)

2. Activation: When a motor neuron fires → acetylcholine at the NMJ → endplate potential → the membrane depolarises to threshold (~−55 mV) → voltage-gated Na+ channels (Nav1.4) open → massive Na+ influx → rapid depolarisation to ~+30 mV

3. Inactivation: Within 1-2 ms, the Nav1.4 channel inactivates — the inactivation gate (the "h-gate" or intracellular loop between domains III and IV) swings shut, stopping Na+ influx even while the channel is still in an "open" conformation. This is fast inactivation.

4. Recovery: The channel transitions from the inactivated state back to the resting (closed but activatable) state as the membrane repolarises. This recovery from inactivation allows the next action potential.

5. Repolarisation: K+ efflux through voltage-gated K+ channels restores the negative resting potential. Cl⁻ channels also help stabilise the membrane.

• Gene: SCN4A, located on chromosome 17q23 ^[1]
• Protein: Nav1.4, the α-subunit of the voltage-gated sodium channel expressed exclusively in skeletal muscle
• Structure: A single large polypeptide with 4 homologous domains (I–IV), each containing 6 transmembrane segments (S1–S6)
  • S4 segments = voltage sensors (contain positively charged arginine/lysine residues that move outward upon depolarisation → channel opening)
  • S5–S6 loop = forms the ion-selective pore
  • III–IV intracellular loop = the inactivation gate (critical for fast inactivation)

Mutations in ion channels → leaky channels → failure to maintain stable resting action potential. Minor leakage (10-15mV) → myotonia. Major leakage (20-30mV) → periodic paralysis. Paroxysmal in nature: depends on neural activation of muscles. ^[1]

This is the unifying concept for all skeletal muscle channelopathies:

PMC is caused by gain-of-function mutations in SCN4A (the gene encoding the Nav1.4 skeletal muscle sodium channel α-subunit).

• Inheritance: Autosomal dominant ^[1]
• Penetrance: High (most carriers are symptomatic, though severity varies)
• Locus: Chromosome 17q23.1-q25.3

Common Mutations

Most PMC mutations cluster in the voltage sensor (S4) of Domain IV or the III-IV intracellular linker (inactivation gate). This makes mechanistic sense — both regions are critical for fast inactivation of the sodium channel.

SCN4A mutations cause a spectrum of diseases depending on which part of the channel is affected and the degree of inactivation impairment:

^[1] Important examples: Cl⁻ channel → myotonia congenita; Na+ channel → paramyotonia congenita, hyperkalemic (K+-sensitive) periodic paralysis; Ca²+ channel → hypokalemic periodic paralysis, malignant hyperthermia.

Let's walk through the pathophysiology step by step:

Step 1 — The Mutation Creates a "Leaky" Channel

PMC mutations (e.g. T1313M, R1448C) impair the fast inactivation process of Nav1.4. Normally, after the channel opens, the inactivation gate (III-IV linker) closes within 1-2 ms to terminate Na+ influx. In PMC, this gate is sluggish or incomplete → the channel re-opens (or fails to fully close) → persistent inward Na+ current.

Step 2 — Persistent Na+ Current Causes Membrane Depolarisation

The persistent Na+ influx shifts the resting membrane potential from −85 mV towards a more positive value. The degree of depolarisation determines the clinical phenotype:

• Mild depolarisation (10-15 mV shift) → The membrane hovers near threshold → Repetitive, self-sustaining action potentials fire → MYOTONIA (the muscle contracts and cannot relax)

• Severe depolarisation (20-30 mV shift) → So many Na+ channels are driven into the inactivated state that they cannot be recruited for normal action potentials → DEPOLARISATION BLOCK → the muscle becomes electrically inexcitable → FLACCID WEAKNESS (periodic paralysis)

Step 3 — Why Cold Worsens the Condition

Cold temperature has specific effects on the mutant Nav1.4 channel:

1. Slows the kinetics of fast inactivation further — the already-impaired inactivation gate becomes even more sluggish at lower temperatures
2. Slows recovery from inactivation — channels take longer to reset
3. The overall effect: at cold temperatures, more channels remain in the persistent open/re-opening state → greater persistent Na+ current → more depolarisation → worsening myotonia → if severe enough, progresses to depolarisation block (weakness)

This explains the classic clinical sequence: Cold → myotonia → if cold exposure continues → weakness.

Step 4 — Why Repeated Contraction Worsens Myotonia (Paradoxical)

In normal muscle or in myotonia congenita (Cl⁻ channelopathy), repeated contraction "warms up" the muscle because:

• Normal Cl⁻ channels help stabilise the membrane after each contraction
• Each contraction cycle allows Na+ channels to recover and re-distribute normally

In PMC, each contraction:

• Opens more mutant Na+ channels
• Each opening produces a persistent Na+ current (because inactivation is defective)
• The cumulative persistent current worsens depolarisation with each successive contraction
• → More myotonia, not less = the paradox

Step 5 — Why Hyperkalaemia Worsens the Condition

Elevated extracellular K+ → reduced K+ gradient across the membrane → membrane depolarisation (Nernst equation). In a normal person, mild hyperkalaemia is tolerable. In PMC, the already-depolarised membrane is pushed further towards the depolarisation block threshold → worsening myotonia or precipitating weakness.

Conversely, attacks ↓ by hypoK ^[1] — low extracellular K+ hyperpolarises the membrane, moving it further from threshold and partially compensating for the persistent Na+ current.

Ion Channelopathies: Mutations in ion channels → leaky channels → failure to maintain stable resting action potential ^[1]

Myotonia: delayed muscle relaxation after contraction. Causes: myotonic dystrophy, myotonia congenita, paramyotonia congenita, proximal myotonic myopathy ^[1]

This is the single most important clinical distinction between PMC and myotonia congenita:

The classic clinical vignette for PMC in an exam:

A young patient (often with a positive family history) presents with episodes of muscle stiffness affecting the face and hands, triggered by cold weather. The stiffness worsens with repeated use (paradoxical myotonia). After prolonged cold exposure, the stiffness may give way to flaccid weakness lasting minutes to hours. Between attacks, the patient is completely normal. Examination reveals percussion and grip myotonia that worsens with cold provocation. Sensory examination is normal. There are no systemic features.

These two conditions are on a spectrum of SCN4A gain-of-function disorders. Some patients cannot be cleanly classified into one or the other. Genetic testing is the definitive differentiator.

Non-dystrophic myotonic syndromes: Myotonia congenita — generalized myotonia which ↑ in cold and ↓ by warmth/exercise, minimal weakness ^[1]

Why this is different from PMC:

• The warm-up phenomenon is the cardinal distinguishing feature. In myotonia congenita, if you ask the patient to grip and release repeatedly, the stiffness improves. In PMC, it worsens (paradoxical).
• Mechanistic explanation: In myotonia congenita, the Cl⁻ channel is dysfunctional → reduced Cl⁻ conductance → membrane instability after contraction. However, with repeated contractions, the membrane gradually stabilises through compensatory K+ currents and Na+ channel inactivation (which is normal in myotonia congenita). In PMC, Na+ channel inactivation is the defect itself, so repeated contractions simply accumulate more persistent Na+ current → worsening.
• Myotonia congenita does not typically progress to flaccid weakness. PMC can.
• Cold sensitivity exists in both but is much more dramatic in PMC.

Why this is different from PMC:

• DM1 is a dystrophic myotonia — there is progressive muscle wasting and weakness, which is completely different from the episodic, non-progressive nature of PMC
• The multisystem involvement is the giveaway: cataracts, cardiac conduction defects, diabetes, cognitive dysfunction — none of these occur in PMC
• DM1 weakness is distal > proximal (opposite to the periodic paralysis pattern of PMC which is proximal > distal)
• DM1 has genetic anticipation (trinucleotide repeat expansion); PMC does not (point mutation)
• DM1 can cause congenital hypotonia (congenital myotonic dystrophy, inherited from an affected mother) — this may present as a floppy infant, which is a different clinical scenario from PMC's infantile myotonia

Neuromuscular disorders including Duchenne muscular dystrophy, Becker muscular dystrophy, and myotonic dystrophy can be associated with familial dilated cardiomyopathy ^[3]

Why this is different from PMC:

• Progressive proximal weakness + systemic features → clearly dystrophic
• Myalgia is prominent (PMC myotonia is usually described as stiffness, not pain)
• No cold provocation as a trigger

Why this is different from PMC:

• The key distinction is that SCM patients do not develop episodic flaccid weakness
• Cold sensitivity is less prominent or absent in many SCM subtypes
• The paradoxical phenomenon is typically absent or less dramatic
• This is essentially the "mildest" end of the SCN4A gain-of-function spectrum: enough persistent Na+ current for myotonia, but not enough to cause depolarisation block

SCM, PMC, and HyperK PP are allelic disorders — all SCN4A mutations. They represent a clinical spectrum: SCM (myotonia only) → PMC (cold-induced paradoxical myotonia + weakness) → HyperK PP (episodic weakness ± inter-attack myotonia). Some patients have overlapping features.

Why this overlaps with and differs from PMC:

• Both are SCN4A mutations → significant clinical overlap
• HyperK PP → weakness is the dominant feature; myotonia is present between attacks but is not cold-provoked in the dramatic, paradoxical way seen in PMC
• PMC → myotonia is the dominant feature; weakness follows cold-induced myotonia
• Some patients have features of both → "PMC with periodic paralysis" or "overlap syndrome"
• Genetic testing is often needed to differentiate definitively

Why this is different from PMC:

• No myotonia — the presence of myotonia essentially rules out primary HypoK PP
• K+ is low during attacks (in PMC it is normal or mildly elevated)
• Triggered by carbohydrate load and rest after exercise, not cold
• Different channel: CACNA1S (Ca²+ channel) in most cases

This is the most important differential in the Hong Kong exam context for any episodic weakness presentation, because it is common in Asian males.

Why this is different from PMC:

• No myotonia — TPP is pure periodic paralysis
• Hypokalemia during attacks (PMC has normal/elevated K+)
• Thyrotoxic features are always present: weight loss, tremor, palpitations, heat intolerance, goitre, etc.
• Not cold-triggered — in fact, heat intolerance is a feature of thyrotoxicosis
• TPP is acquired (resolves when euthyroidism is restored); PMC is genetic (lifelong)
• TPP is a secondary form of hypoK PP; PMC is a primary channelopathy

D/dx of primary HypoK PP: TPP (check TFT) and weakness due to secondary hypoK (RFT, TTKG, normoK between attacks) ^[1]

Why this is different from PMC:

• No myotonia
• Dysmorphic features present
• Cardiac arrhythmias are a defining feature (whereas cardiac involvement in PMC is absent or minimal)
• Much rarer

• Mechanism: Autoimmune (anti-CASPR2 or anti-LGI1 antibodies) or paraneoplastic → peripheral nerve hyperexcitability
• Features: Continuous muscle fibre activity, muscle stiffness, cramps, fasciculations, pseudomyotonia (appears similar but EMG shows neuromyotonic discharges originating from peripheral nerves, not the muscle membrane itself)
• Different from PMC: Acquired (not congenital), continuous (not paroxysmal), associated with autonomic dysfunction (hyperhidrosis), no cold provocation, EMG shows characteristic high-frequency decrementing bursts

• Mechanism: Autoimmune (anti-GAD65 antibodies) → loss of GABAergic inhibition in spinal cord → continuous muscle contraction
• Features: Progressive stiffness and rigidity of axial and proximal limb muscles, exaggerated startle response, superimposed painful spasms
• Different from PMC: Acquired in adulthood, continuous (not episodic), axial predominance, anti-GAD65 positive, no myotonia on EMG, no cold provocation

• Mechanism: Hypothyroidism → slowed muscle metabolism, accumulation of glycosaminoglycans in muscle, impaired Ca²+ handling → delayed muscle relaxation (pseudomyotonia)
• Features: Generalised muscle stiffness, proximal weakness, "mounding phenomenon" (percussion causes a local mound that relaxes slowly), CK may be elevated
• Different from PMC: Acquired, associated with other hypothyroid features (weight gain, cold intolerance, constipation, dry skin, bradycardia), TFT shows elevated TSH/low fT4, "pseudomyotonia" — EMG is electrically silent during the delayed relaxation (true myotonia shows electrical activity)

Endocrine causes of myopathy include hyper/hypothyroidism, Cushing's syndrome ^[6][7]

• Mechanism: Mutation in ATP2A1 (SERCA1 — sarcoplasmic reticulum Ca²+-ATPase) → impaired Ca²+ re-uptake into SR after contraction → delayed muscle relaxation
• Features: Exercise-induced muscle stiffness (not cold-induced), especially in legs; EMG is electrically silent during the stiffness (not true myotonia)
• Different from PMC: AR inheritance, exercise-triggered (not cold), EMG silent (pseudo-myotonia), no paradoxical phenomenon

• Mechanism: Mutation in CAV3 (caveolin-3) → abnormal muscle membrane mechanics
• Features: Percussion-induced muscle mounding + rolling contractions (visible wave of contraction across muscle), muscle stiffness
• Different from PMC: The "rippling" is mechanical and electrically silent; distinct genetic basis

• Mechanism: Autoimmune (anti-AChR or anti-MuSK antibodies) → impaired neuromuscular junction transmission
• Features: Fatigable weakness — gets worse with sustained or repeated use, improves with rest (opposite to PMC where stiffness worsens with use but then weakness appears). Typically affects extraocular muscles (ptosis, diplopia), bulbar muscles (dysarthria, dysphagia), and proximal limbs
• Different from PMC: Fatigable (not myotonic), no stiffness/delayed relaxation, extraocular and bulbar involvement is common (rare in PMC), no cold sensitivity, decremental response on repetitive nerve stimulation, positive anti-AChR antibodies

GC 056 Generalised muscle weakness lecture covers classification of NMJ disorders including myasthenia gravis ^[8]

• Mechanism: Post-infectious autoimmune demyelinating polyneuropathy → ascending flaccid paralysis
• Features: Acute/subacute ascending weakness, areflexia, may have sensory symptoms, bulbar and respiratory involvement possible, albuminocytological dissociation in CSF
• Different from PMC: Monophasic (not episodic), progressive over days-weeks, sensory involvement, no myotonia, recent preceding infection, CSF protein elevation

• Muscle weakness, paralysis (proximal muscle myopathy) can result from hypokalemia from any cause ^[9]:
  • Renal losses: diuretics, renal tubular acidosis, Bartter/Gitelman syndrome, hyperaldosteronism
  • GI losses: vomiting, diarrhoea, laxative abuse
  • Transcellular shift: insulin, β2-agonists, alkalosis
• Different from PMC: No myotonia, K+ is low (and low total body K+, unlike TPP where total body K+ is normal), associated features depend on the underlying cause

These are "investigations" you perform at the bedside before ordering any tests:

Myotonia clinical tests: [grip myotonia and percussion myotonia] — features: painless, often temperature related (↑ when cold), warming-up/down phenomenon (↓ by repeated muscle contraction) ^[1][2]

Cardiac arrhythmia, particularly when K+ < 2.0 ^[9] — this severe hypoK with arrhythmia is characteristic of TPP/HypoK PP, not PMC.

Why ECG matters: Although PMC is a skeletal muscle Na+ channelopathy (SCN4A, not cardiac SCN5A), ECG is still important because:

1. Electrolyte disturbances during attacks can cause arrhythmia
2. Must exclude Andersen-Tawil syndrome (KCNJ2), which has periodic paralysis + cardiac arrhythmia (prolonged QT, prominent U waves, bidirectional VT)
3. Must exclude myotonic dystrophy, which has cardiac conduction defects

Genetic testing: Identification of a gene mutation is diagnostic. Only ~50% positive for known mutation → negative genetic test has limited diagnostic value ^[13] — while this quote refers to LQTS, the principle applies to all channelopathies: a negative genetic test does not exclude the diagnosis if the clinical phenotype is characteristic.

The cooling EMG protocol is the most informative electrophysiological test for PMC. Here's what each finding means:

1. Increased myotonic discharges after cooling = The mutant Na+ channels have worsened inactivation kinetics in the cold → more persistent Na+ current → more membrane instability → more repetitive firing → more myotonic discharges. This proves that the myotonia is temperature-dependent, which is the hallmark of PMC.

2. Decreased CMAP amplitude after cooling = Prolonged cold has pushed many Na+ channels into a permanently inactivated state (depolarisation block) → fewer channels available to generate action potentials → the summed electrical output of the motor unit (CMAP) decreases → this is the electrophysiological equivalent of clinical weakness. The greater the CMAP decrement, the more severe the depolarisation block.

3. Recovery of CMAP after rewarming = As the muscle warms up, the channel kinetics improve → channels recover from inactivation → CMAP normalises → this correlates with the clinical recovery of strength after rewarming.

These are the first-line interventions and should be implemented in every patient regardless of disease severity. Many patients with mild PMC can be managed with these alone.

Acute attacks of PMC (typically cold-induced myotonia progressing to flaccid weakness) are usually self-limiting and resolve with rewarming. However, severe attacks may require monitoring.

This is a critical safety issue that must be communicated to anaesthetists before any surgical procedure.

Malignant hyperthermia: RYR1 or DHP mutation → unregulated Ca²+ influx from SR → sustained muscle contraction → ↑↑metabolism → metabolic acidosis, rhabdomyolysis, hyperthermia. Triggered by anaesthetic agents (e.g., halothane, isoflurane) ^[1]. This is a different condition from PMC.

• During the transition from myotonia → weakness, there is a window where the patient's legs may suddenly "give way"
• If walking or on stairs when weakness strikes, the patient can fall and sustain injuries (fractures, head trauma)
• Pathophysiological basis: The shift from mild depolarisation (myotonia, where muscles are stiff but contracted) to severe depolarisation (depolarisation block, where muscles are flaccid) can occur relatively abruptly, especially with sudden cold exposure

• During severe attacks, serum K+ may be mildly elevated (due to K+ efflux from depolarised muscle cells)
• Cardiac arrhythmia, particularly when K+ < 2.0 ^[9] — this applies to hypoK states; for PMC, the concern is the opposite direction. Mild hyperK can cause:
  • Peaked T waves
  • Bradycardia
  • Very rarely, more serious arrhythmias
• However, clinically significant cardiac arrhythmia from PMC attacks is extremely rare because:
  • The hyperK is usually mild and transient
  • The cardiac Na+ channel (SCN5A, Nav1.5) is a different isoform from the skeletal muscle channel (SCN4A, Nav1.4) — PMC mutations affect Nav1.4, not Nav1.5, so the heart's electrical system is not directly affected by the genetic defect
  • Cardiac monitoring is recommended during severe attacks out of caution, not because arrhythmia is expected

• Usually spares respiratory and bulbar muscles ^[1] — this is true for most attacks
• However, in extremely severe attacks (very rare), diaphragmatic and intercostal weakness could theoretically impair ventilation
• This is far more of a concern in hyperkalemic periodic paralysis (where attacks can be more severe) than in PMC
• Practical point: if a PMC patient presents with respiratory difficulty during an attack, it is more likely due to cold-induced bronchospasm or an intercurrent illness than the PMC itself

Malignant hyperthermia: RYR1 or DHP mutation → unregulated Ca²+ influx from SR → sustained muscle contraction → ↑↑ metabolism → metabolic acidosis, rhabdomyolysis, hyperthermia. Triggered by anaesthetic agents (e.g., halothane, isoflurane) ^[1]