What is channelopathy?

What is Channelopathy?

Channelopathies are diseases caused by dysfunctional ion channels that result in abnormal movement of electrolytes (sodium, potassium, calcium, chloride) into and/or out of cells, leading to altered electrical signaling in affected tissues. 1

Core Pathophysiology

Ion channel dysfunction disrupts normal cellular electrical activity by affecting the pore selectivity and gating mechanisms that control ion passage across cell membranes. 2 These channels contain:

• Selective pores that determine which ions can pass through
• Gates that open and close in response to voltage changes or ligand binding
• Regulatory domains that modulate channel function 2

When these channels malfunction, cells cannot maintain proper electrical signaling, predisposing tissues to abnormal excitability and symptomatic attacks. 3

Genetic Basis

Channelopathies can be either inherited or acquired:

• Inherited forms result from genetic mutations in genes encoding ion channel subunits or their regulatory proteins 1, 4
• Acquired forms develop from toxic, immune, or hormonal disturbances affecting channel function 5
• Mutations are found in 2% to 10% of sudden cardiac death victims and in 14% to 20% of young adults with unexplained sudden death 1

Affected Organ Systems

Channelopathies manifest across multiple body systems, creating diverse clinical presentations:

Cardiac Channelopathies

• Long QT syndrome (LQTS) - prolonged ventricular repolarization from potassium or sodium channel dysfunction 1, 4
• Brugada syndrome - sodium channel defects causing ventricular arrhythmias 1, 4
• Catecholaminergic polymorphic ventricular tachycardia (CPVT) 1, 4
• Short QT syndrome 1, 4

Neurologic Channelopathies

• Generalized epilepsy with febrile seizures 6
• Familial hemiplegic migraine 6
• Episodic ataxia 6
• Periodic paralysis (hyperkalemic and hypokalemic) 6, 3
• Myotonia 3, 5

Other Systems

• Respiratory: Cystic fibrosis 6
• Endocrine: Neonatal diabetes, familial hyperinsulinemic hypoglycemia 6
• Renal: Bartter syndrome, nephrogenic diabetes insipidus 6
• Gastrointestinal: Chronic intestinal pseudo-obstruction with recurrent nausea, vomiting, abdominal pain, and distension 7

Clinical Presentation Patterns

Channelopathies characteristically present with episodic or paroxysmal symptoms rather than continuous dysfunction:

• Cardiac: Syncope, seizures, unexplained accidents/drownings, sudden death 1
• Neuromuscular: Transient weakness, myotonic stiffness, paralytic attacks 3
• Neurologic: Seizures, headache, dyskinesia, ataxic episodes 3
• Gastrointestinal: Postprandial pain, chronic diarrhea, early satiety, high-volume vomiting 7

Genotype-Phenotype Relationships

A critical challenge is the incomplete penetrance and variable expressivity of channelopathy mutations. 1

• Genotype-positive/phenotype-negative (concealed channelopathy) occurs when genetic mutations are present but clinical or ECG manifestations are absent 1
• The same mutation does not necessarily predict a specific phenotype 1
• Common polymorphisms (like SCN5A-S1103Y in 10-15% of black Africans) can modify disease expression and drug responses 1

Diagnostic Implications

When sudden unexplained cardiac arrest occurs in children and young adults, obtain:

• Complete past medical and family history including syncopal episodes, seizures, unexplained accidents/drownings, or sudden death <50 years old 1
• Review of previous ECGs 1
• Unrestricted complete autopsy by a cardiovascular pathologist when resources allow 1
• Genetic analysis of preserved tissue to determine channelopathy presence 1
• Family screening revealing inherited arrhythmogenic disease in 22% to 53% of families 1

Common Clinical Pitfalls

Do not attribute chronic symptoms solely to functional disorders without considering channelopathies, especially when symptoms are severe, progressive, or associated with systemic features like family history of sudden death. 7

Recognize that certain medications can unmask or exacerbate channelopathies:

• QT-prolonging drugs in LQTS patients 1
• Drugs that exacerbate Brugada syndrome 1
• Anticholinergics, calcium channel blockers, and opioids in GI channelopathies 7

Drug-induced arrhythmias may signal underlying genetic susceptibility, with LQTS genetic testing yielding positive results in 10-15% of individuals with isolated drug-induced long QT. 1

Treatment Principles

Management should be individualized based on disease severity and phenotype, not driven by patient lifestyle preferences (e.g., athletic participation). 1

Symptomatic management must account for the underlying channelopathy to avoid medications that worsen ion channel dysfunction. 7

Refer families without identified cause of death to centers with arrhythmia expertise (Class I recommendation). 1