Muscle channelopathies and periodic paralysis
- Mechanism
Faulty ion channels in muscle cause attacks of paralysis tied to potassium, stiffness that eases with movement, or a deadly reaction to anaesthesia.
What it is
Inherited channelopathies of skeletal muscle alter excitability rather than structure. Hypokalaemic periodic paralysis (CACNA1S or SCN4A) causes attacks of flaccid weakness after carbohydrate-rich meals or rest after exercise, with low potassium; a thyrotoxic form occurs in young men, especially of Asian descent. Hyperkalaemic periodic paralysis (SCN4A) gives short attacks with high or normal potassium. Myotonia congenita (CLCN1, chloride channel) causes stiffness that improves with repetition, while paramyotonia congenita (SCN4A) worsens with cold and repetition. Malignant hyperthermia, caused mostly by RYR1 variants, is a hypermetabolic crisis triggered by volatile anaesthetics and succinylcholine.
Structure
- Biopsy is often normal between attacks.
- Permanent weakness later in periodic paralysis: vacuolar myopathy and tubular aggregates.
- Malignant hyperthermia susceptibility: may show cores (central core disease) or be normal.
Step by step
- Muscle excitability depends on sodium, potassium, chloride and calcium channels and the ryanodine receptor.
- Gain-of-function sodium channel variants keep the membrane depolarized and inexcitable (paralysis) or repetitively firing (myotonia).
- Loss of chloride conductance makes the membrane hyperexcitable: myotonia.
- Gating-pore currents in CACNA1S or SCN4A variants depolarize fibres when potassium is low.
- In malignant hyperthermia, triggering drugs open mutant RYR1, releasing calcium uncontrollably: sustained contraction, heat and acidosis.
Muscle channelopathies
| Disorder | Gene | Trigger | Key features |
|---|---|---|---|
| Hypokalaemic periodic paralysis | CACNA1S, SCN4A | Carbohydrate meal, rest after exercise | Low potassium, attacks lasting hours |
| Hyperkalaemic periodic paralysis | SCN4A | Rest after exercise, potassium | Short attacks, high or normal potassium |
| Myotonia congenita | CLCN1 | Rest | Stiffness easing with repetition |
| Paramyotonia congenita | SCN4A | Cold, repetition | Stiffness worsening with repetition |
| Malignant hyperthermia | RYR1, CACNA1S | Volatile anaesthetics, succinylcholine | Rigidity, hyperthermia, acidosis, high CO2 |
Clinical notes
- Sudden flaccid weakness on waking after a carbohydrate-rich evening meal with low potassium: think of hypokalaemic periodic paralysis and check thyroid function.
- Malignant hyperthermia is an anaesthetic emergency; family members of patients are tested or avoid triggering agents.
- Beware: neuroleptic malignant syndrome resembles malignant hyperthermia but follows antipsychotics.
Test yourself
Think of the answer, then tap the question to see it.
Which gene is most often mutated in malignant hyperthermia?
RYR1, the skeletal muscle ryanodine receptor.
Which drugs trigger malignant hyperthermia?
Volatile inhalational anaesthetics and succinylcholine.
What channel is defective in myotonia congenita?
The skeletal muscle chloride channel CLCN1.
What endocrine disease can cause periodic paralysis with low potassium?
Hyperthyroidism (thyrotoxic periodic paralysis).
Elsewhere in DurgiPedia
Connections
Educational content on the mechanisms of disease; not a diagnostic or treatment guide and no substitute for a health professional's advice. No doses are given.
Sources: Hypokalemic periodic paralysis: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2025); Malignant hyperthermia: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2025).
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Representative model, for educational purposes only.