Channelopathies: An integrated⁠ review highlighting the clinical pharmacist’s role, with case report

Channelopathies: An integrated⁠ review highlighting the‍ clinical pharmacist’s role, with case report

Kalaivani. S

Group Clinical Pharmacist, Kauvery Hospital, Trichy, Tamil Nadu

Abstract

Channelopathies are rare; they are heterogeneous disorders caused by mutations in ion channels or associated proteins. Although individually uncommon, their collective prevalence is less than 5 per 10,000, with cardiac Channelopathies such as Long QT syndrome affecting about 1 in 2,000 people. These conditions involve the nervous system, heart, kidney, ⁠ bone, skeletal muscle, and pancreas, producing manifestations that range from mild to life-threatening. Current treatments are largely symptomatic, with limited options for mutation-specific therapy. Clinical pharmacists play a key role in optimizing therapy, ensuring safety, and supporting multidisciplinary care.

We described a 33-ye⁠ar-ol⁠d woman with recurrent syncope progressing to cardiac arrest, requiring prolonged resuscitation, ICU management, and AICD implantation. Genetic evaluation revealed variants of uncertain significance in FLNC and KCNQ1, genes linked to arrhythmogenic cardiomyopathy and Long QT syndrome. This case underscores the complexity of diagnosing and managing unexplained malignant arrhythmias and highlights the need for precision-guided approaches in Channelopathies.

Introduction

Channelopathies represent a heterogeneous group of disorders caused by impaired function of ion channels, which are integral components of the membranes of all cells and numerous intracellular organelles.^{(1 )}Ion channels are transmembrane proteins that enable the passive movement of ions across cell and organelle membranes, driven by electrochemical gradients. This ion flow generates electrical currents, making ion channels essential for membrane potential and various cellular functions, including signaling, neurotransmission, muscle contraction, hormone release and cell growth. They are classified based on ion type, gating mechanisms, tissue distribution and structure.⁽²⁾The human genome contains over 600 genes encoding ion channels, transporters, and related proteins that regulate key ions such as ca²⁺, K⁺, Na⁺, Cl^– and trace elements, all of which are essential for normal cellular function. The extensive presence of ion channels across tissues and their vital physiological roles mean that mutations in genes encoding ion channel subunits or their interacting proteins can lead to inherited ion channelopathies. These conditions can range from common to extremely rare and may vary severity from mild to severely disabling or even life threatening. There are two categories of channelopathies: genetic, resulting from inherited mutations, and acquired, which are triggered by factors such as drugs, toxins, and immunoglobulin that modify ion channel function.⁽³⁾

⁠Types of channelopathy:

Channelopathies are classified according to the organ systems they affect, most commonly as cardiac, skeletal muscle, or neurological channelopathies each associated with distinct ion channel gene mutations.

System Affected	Ion involved	Genes Involved	Disorder
Cardiac	Na+, K+	KCNQ1, KCNH2, SCN5A	LQTS Type 1,type 2,type 3
Cardiac	Na+	SCN5A	Brugada syndrome
Cardiac	Ca2+	RYR2, CASQ2	CPVT
Neurological	Na+	Scn1A, scn1b, scn2A	GEFS+, Dravet syndrome
Neurological	Ca2+	CACNA1A	Familial hemiplegic migraine, Episodic ataxia Type 2
Neurological	K+	KCNA1,KCNQ2,KCNQ3	Episodic ataxia Type1,Neonal seizures
Muscular	cl-	CLCN1	Myotonia congenita
Muscular	Ca2+/Na+	CACNA1S,SCN4A	Hypokalemic periodic paralysis
Pulmonary	cl-	CFTR	Cystic fibrosis
Renal	NKCC2,protein K+,CIC-Kb	SLC12A1,KCNJ1,CLCNKB,CLCNKA	Bartter Syndrome Type I,II,III,IV

Epidemiology of ion channelopathies

Neurological and neuromuscular channelopathies are rare genetic disorders affecting nerve and muscle excitability, with a global prevalence of ~35 per 100,000. In England, skeletal muscle channelopathies affect ~1.12 per 100,000. The most common is Myotonia congenita (0.52), followed by hyperkalemic (0.17), hypokalemic (0.13) periodic paralysis, and Andersen–Tawil syndrome (0.08 per 100000). Though uncommon, these⁠ conditions can significantly affect quality of life and are often under diagnosed due to variable symptoms.⁽⁴⁾

Cardiac channelopathies are inherited disorders of heart ion channels linked to life-threatening arrhythmias⁠. LQTS affects ~1 in 2,000–7, 000, with genotype-positive cases up to 1 in 80. Brugada Syndrome affects 3–5 per 10,000, more common in Southeast Asia (0.1–0.2 %). CPVT is rarer, at⁠ ~1 in 10,000. Early diagnosis is crucial due to the risk of sudden cardiac death. ⁽⁵⁾

Popu⁠lation-wide genome sequencing (such as in India, Europe, and the U.S.) shows that variants in ion channel genes are more common than expected based on clinical phenotypes. A study of over 1,000 healthy Indian individuals found that 26% ofknown pathogenic variants in channelopathy-related genes were unique to the Indian Population, with many people being asymptomatic carriers.⁽⁶⁾

Pathophysiology of Ion Channelopathy^{^{(1, 3)}}

Genetic Mutations in Ion Channel
↓
Altered Ion Channel Structure / Function
↓
Loss of Function or Gain of Function
↓
Abnormal Gating or Conductance
↓
Disruption of Ion Flow Across the Membrane
↓
Disruption of Cellular Excitability and Signaling
↓
Physiological Dysfunction in Affected Tissues
↓
Clinical Manifestations of Channelopathy
(e.g., Epilepsy, Ventricular Arrhythmias, etc.)

Clinical Symptoms‍ of Channelopathies^{(3, 4)}

The symptoms vary depending on the⁠ type of ion channel affected and the‍ organ system involved:

Neurological Channelopathies

Epilepsy (especially generalized epilepsy with febrile seizures plus)
Ataxia and episodic dizziness
Migraine (familial hemiplegic migraine)

Cardiac Channelopathies

Syncope and palpitations
‍Ventricular arrhythmias (e.g., torsade’s de pointes)
⁠Sudden cardiac death risk

Muscle Channelopathies

Periodic paralysis (hypokalemic or hyperkalemic)
Myotonia (delayed muscle relaxation)
Muscle stiffness and cramps

Other possible symptoms

Respiratory muscle weakness
Heat or cold sensitivity
Fatigue and exercise intolerance.

Fig (1): Clinical features of channelopathies

Diagnosis

Diagnosis of channelopathy involves a stepwise combination of clinical evaluation, family screening, ECG⁠ – based detection, and targeted genetic testing. While genetic testing can confirm the diagnosis in many cases, the absence of identifiable mutation does not rule out the disease due to variable expressivity and incomplete genetic knowledge.

Fig (2): Clinical diagnostic steps in channelopathies

Treatment of Channelopathies

1. Skeletal Muscle Channelopathies ^(7,8)

Conditions: Myotonia congenita, Paramyotonia congenita, Periodic paralyses.

Treatment⁠

Sodium channel blockers (e.g. mexiletine, carbamazepine, phenytoin, lamotrigine, ranolazine) → reduce muscle hyper excitability. Carbonic anhydrasee inhibitors (e.g., acetazolamide⁠, dichlorphe⁠namide) → especially useful in periodic paralyses.

Lifestyle modifications‍: avoid triggers (cold, high-carb meals, and rest after Ex⁠e⁠rcise).

2. Neurological Channelopathies ⁽⁹⁾

⁠Conditions: Epilepsy (SCN1A, KCNQ2 mutations), Familial hemiplegic migraine, Ataxia.

Treatment

Antiepileptic drugs (AEDs): sodium channel blockers (phenytoin, carbamazepine, lamotrigine) ⁠ depending on mutation.

Migraine: acetazolamide, ⁠flunarizine, sodium valproate, propranolol.

Emerging therapy: m⁠utation-specific/pharmacogenetic approaches (e.g., avoiding sodium channel blockers in Dravet syndrome)

3. Cardiac Channelopathies ⁽^10,11)

Conditions: Long QT syndrome (LQT), Brugada syndrome, Catecholaminergic polymorphic VT (CPVT), Andersen–Tawil syndrome.

Treatment

LQTS: β-blockers (nadolol, propranolol), ICD for high-risk cases, left cardiac sympathetic denervation (LCSD).
Brugada syndrome: ICD in symptomatic cases; quinidine may reduce arrhythmias
CPVT: β-blockers (nadolol), f⁠le⁠cainide, ICD for severe cases.
ATS: acetazolamide for periodic paralysis + a⁠ntiarrhythmics (flecainide) + ICD if high risk.

Autoimmune/Paraneoplastic Ch⁠a⁠n⁠nelopathies ⁽¹²⁾

Morvan’s syndrome, neuromyotonia, Lambert-Ea⁠ton myasthenia syndrome (LEMS)

Treatment

Imm⁠unotherapy (steroids, az⁠athioprine, cyclophosphamide, IVIG, plasma exchange). Symptomatic drugs: anticonvulsants for neuromyotonia (carbamazepine, phenytoin).

Case Presentation

A 33-year-old female with no prior comorbidities who presented with recurrent severe syncopal episodes. Initially evaluated on an outpatient basis, she was subsequently admitted due to increasing frequency of events. During hospitalization, she experienced syncope⁠ followed by cardiac arrest on 21.09.2024. Ca⁠rdiopu⁠lmon⁠ary resuscitation (CPR) was performed according to ACL⁠S protocol, and return of spontaneous⁠ circulation was achieved after 25 min. ⁠ she was intubated, mechanically ventilated, and managed in‍ the ICU.

Post–cardiac arrest echocardiography revealed severe left ventricular⁠ systolic dysfunction (LVEF ~35%). Antiarrhythmic and anticoagulant therapy was initiated. In view of cardiac⁠ arrest, suspected ventricular tachyarrhythmia, and severe LV dysfunction, she underwent implantation of an automated implantable cardioverter-defibrilla⁠tor (AICD, DDD⁠R, Boston Scientific) on 26.09.2024. After multiple weaning trials, she was extubated successfully on 27.09.2024 and gradually stabilized.

Genetic evaluation performed during hospitalization identified variants of uncertain significance (VUS) in FLNC (⁠p.Gly1115⁠Ala) and KCNQ1 (p.Ala287Thr), both heterozygous, associated with arrhythmog⁠enic cardiomyopathy and long QT syndrome, respectively. These findings supported a possible underlying cardiac channelopathy contributing to her clinical presentation.

Subsequently, the patient required readmission for further evaluation and management of recurrent syncopal events despite prior interventions. During this admission, she experienced two additional episodes of syncope with non-sust⁠ained ventricular tachycardia in the ICU. Neurology consultation⁠ was sought, and recommendations were followed. She was stabilized with beta-blockers, antiepileptic, and supportive therapy. After monitoring and clinical improvement, the patient was discharged in stable condition with an AICD in situ and appropriate follow-up advice.

She recently underwent Bilateral Cardiac Sympathetic Denervation, a surgical procedure. It is a neuromodulator intervention that targets the sympathetic nervous system’s connection to the heart. The surgery removes portions of the sympathetic nerves on both sides of the chest, specifically the lower part of the stellate ganglion and the thoracic ganglia (T1–T4). These nerves are responsible for sending excitatory, or “fight-or-flight,” signals to the heart. Interrupting these nerve signals can calm the electrical system and prevent life-threatening arrhythmias.

The procedure is typically performed using a minimally invasive video-assisted thoracoscopic surgery (VATS) approach.

Discussion

This‍ case highlights the complexity of diagnosing and managing recurrent unexplained syncope and arrhythmias in young individual’s without‍ structural heart disease or comorbidities. The index patient presented with recurrent syncope culminating in⁠ cardiac arrest and required prolonged resuscitation, mechanical ventilation, and subsequent AICD⁠ implantation for secondary⁠ prevention of sudden cardiac death.

Genetic testing revealed variants of uncertain significance in FLNC and KCNQ1. The⁠ FLNC gene encodes filamin C, a cytoskeletal protein critical for cardio myocyte structural⁠ integrity, with pathogenic variants linked to arrhy⁠thmogenic cardiomyopathy, restrictive cardiomyopathy, and ventricular arrhythmias. The KCNQ1 gene encodes a potassium channel α-subunit involved in cardiac repolarization; and⁠ variants are classically associated with long QT syndrome type⁠ 1 and familial atrial fibrillation. Although both detected variants were classified as VUS, their presence⁠ in the setting of recurrent malignant arrhythmias supports a possible pathogenic role, either independently or in combination, through impaired ion channel function and arrhythmogenic remodeling.

Clinical pharmacist roles in treatment of channelopathy⁠

The clinical pharmacist plays a vital role in management in channelopathies.

1. Optimizing⁠ Drug⁠ Therapy

Select appropriate pharmacological agents based on type of channelopathy and system affected (e.g., mexiletine in skeletal muscle, β-blockers in cardiac,

AEDs in neurological).

Adjust doses considering pharmacokinetics and comorbidities (renal/hepatic impairment, drug–drug interactions).
Recommend alternatives when first-line agents are contraindicated (e.g., avoiding sodium channel blockers in Dravert⁠ syndrome).

2. Patient Counseling & Education

Educate patients on trigger avoidance (e.g., high-carb meals in‍ periodic paralysis, fever in Brugada).
Counsel on adherence to β-blockers, antiarrhythmi⁠c⁠s, or antiepileptic’s, as non-compliance can be life threatening.
Provide information on possible adverse drug effects (e.g., β-blockers → bradycardia)

3. Monitoring⁠ & Safety

Monitor treatment efficacy: muscle strength (skeletal),‍ seizure frequency (neurological), ECG/QTc intervals (cardiac).
Detect adverse events early: arrhythmias, electrolyte‌ disturbances, drug⁠-‍induced myopathy.
Ensure regular therapeutic drug monitoring (TDM)⁠ when available (e.g.., phenytoin, carbamazepine).

⁠4. Inter-professional Collaboration

Work closely with ne⁠urologis⁠ts, cardiologists, and endocrinologists to tailor therapy.
Participate in genotype-guide⁠d therapy discussions as channelopathies often have mutation-specific drug responses.
Support implementation of clinical guidelines (e.g., HRS/EHRA for cardiac channelopathies).

5. Pharmacogenomics & Precision Medicine

Interpret genetic test results in collaboration with specialists to guide therapy (e.g.., avoiding sodium channel blockers in SCN1A epilepsy).
Recommend mutation-sensitive treatments (e.g.., flec⁠ain⁠ide in CPVT, acetazolamide in hypo⁠kal⁠emic periodic paralysis).

6. Emergency & Supportive Care

Assist in acute management (e.g., IV potassium for thyrotoxic periodic paralysis, IV antiarrhythmi⁠c⁠s for cardiacarrhythmias).
Educate patient⁠s/families on emergency preparedness‍ (AED availability, action⁠ plan for seizures/arrhythmias).

Conclusion

Channelopathies, though rare, require genotype-guided strategies beyond symptomatic care. Advances in precision medicine andd genetic-based therapies offer hope⁠ for improved management. The reported case of⁠ recurrent malignant arrhythmias with FLNC and KCNQ1 varian⁠ts illustrates the diagnostic and therapeutic challenges. Healthcare professionals must increase awareness of precision medicine, embrace teamwork, and include clinical pharmacists in multidisciplinary teams to improve therapeutic outcomes and enhance patient quality of life.

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Channelopathies: An integrated⁠ review highlighting the clinical pharmacist’s role, with case report