Long-QT syndrome and channelopathies — formative SAQs

SAQ 1 (10 marks)

A nine-year-old girl is brought to the emergency department after collapsing during a school swimming carnival. She was pulled from the pool unconscious, had brief jerking movements of her limbs, and recovered fully within two minutes. Her mother, who has had "fainting spells" all her life, wonders if this was a seizure. The triage label reads "vasovagal or seizure — query epilepsy." The registrar has ordered a CT head and an EEG. Her twelve-lead ECG shows a QTc of 520 milliseconds. [1] [2]

1. Give the immediate diagnostic and initial management steps for this child, explaining the significance of the QTc and the errors the triage team is making. (4) [1] [3]
2. Describe the investigation strategy that confirms the diagnosis and identifies the genotype, and explain why the genotype matters for management. (3) [1] [3]
3. Outline the definitive management, including the first-line therapy, its expected efficacy, and the circumstances that would prompt escalation. (3) [4] [5]

Model answer — SAQ 1

(1) Immediate diagnostic and management steps (4). This is a high-probability presentation of long-QT syndrome: syncope during exertion (swimming), seizure-like movements during cerebral hypoxia from a transient arrhythmia, a maternal history of "fainting," and a QTc of 520 milliseconds which is diagnostic of LQTS regardless of symptoms. The team's errors are triaging this as a neurological event (CT, EEG) rather than a cardiac one, and not recognising that exercise-related syncope with a prolonged QTc is arrhythmic until proven otherwise. The immediate steps are to admit the child for cardiac monitoring, stop any QT-prolonging medications, maintain electrolytes (particularly potassium above 4.0 mmol/L), and refer urgently to the inherited cardiac conditions service. The child must not return to swimming or competitive sport until assessed. The maternal history of fainting warrants investigation for familial LQTS with cascade screening. [1] [3]

(2) Investigation strategy and genotype (3). The diagnosis is confirmed by the Schwartz diagnostic score, which integrates the QTc (520 ms scores 3 points), the syncopal event triggered by exertion (2 points), and the family history (at least 0.5 points), giving a score well above the high-probability threshold of four. Genetic testing for the three major genes (KCNQ1, KCNH2, SCN5A) should be requested through the inherited cardiac conditions service; the yield is approximately seventy to seventy-five per cent for these three genes. The genotype matters because it determines the trigger profile, the response to beta-blockers, and the threshold for aggressive therapy: LQT1 (KCNQ1, the likely genotype given the swimming trigger) is well-protected by beta-blockers, LQT2 has intermediate response, and LQT3 responds poorly and may need mexiletine or an ICD at a lower threshold. Echocardiography excludes structural heart disease, and an exercise test may be useful to assess QT adaptation if the resting QTc is borderline. [1] [3]

(3) Definitive management (3). The first-line therapy is a beta-blocker — nadolol (0.5–2 mg/kg/day) is the preferred agent in children because of its long half-life and tolerability. Beta-blockers reduce arrhythmic events by approximately two-thirds across the LQTS cohort, though efficacy is genotype-dependent (best in LQT1, worst in LQT3). Lifestyle modification is universal: restriction from competitive and exertional sports, avoidance of QT-prolonging medications for life, and aggressive correction of electrolyte disturbance during intercurrent illness. Escalation to left cardiac sympathetic denervation (LCSD) is warranted for breakthrough events on maximally tolerated beta-blockers — LCSD reduces events by over ninety per cent and is the preferred intermediate step in children before an implantable cardioverter defibrillator. An ICD is reserved for the highest-risk patients: survivors of aborted cardiac arrest, those with recurrent syncope despite beta-blockers and LCSD, or very high-risk genotypes such as LQT3 with QTc above 500 milliseconds. [4] [5]

SAQ 2 (10 marks)

A twelve-year-old boy presents after three episodes of syncope during physical education class. His resting twelve-lead ECG is normal with a QTc of 410 milliseconds, and his echocardiogram shows a structurally normal heart. During an exercise stress test, his heart rate reaches 160 beats per minute and the ECG shows bursts of bidirectional ventricular tachycardia that resolve when he stops exercising. His father died suddenly at age thirty-two during an argument. [2] [6]

1. Give the diagnosis, explain the pathophysiology, and explain why the resting ECG is normal. (3) [2] [3]
2. Outline the pharmacological and non-pharmacological management, including the role of exercise testing in follow-up. (4) [3] [6]
3. Describe the implications for the family, including the screening of relatives and the genetic counselling. (3) [2] [3]

Model answer — SAQ 2

(1) Diagnosis and pathophysiology (3). The diagnosis is catecholaminergic polymorphic ventricular tachycardia (CPVT), a calcium-handling disorder characterised by a structurally normal heart, a normal resting electrocardiogram, and bidirectional or polymorphic ventricular tachycardia provoked by exercise or emotional stress. The pathophysiology is a mutation in the cardiac ryanodine receptor (RYR2 in approximately sixty to seventy per cent of cases) that causes excessive calcium leak from the sarcoplasmic reticulum during diastole, particularly under adrenergic stimulation. The calcium overload produces delayed afterdepolarisations that trigger the characteristic bidirectional VT during exertion. The resting ECG is normal because the calcium leak is adrenergine-dependent — at rest, with low catecholamine levels, the sarcoplasmic reticulum handles calcium normally and the ECG is unremarkable. The father's sudden death during emotional stress is consistent with an undiagnosed inherited arrhythmia syndrome. [2] [3]

(2) Management (4). The first-line therapy is a beta-blocker, with nadolol the preferred agent, to suppress the adrenergic-driven calcium leak and the resulting delayed afterdepolarisations. Flecainide is added as an adjunct for patients with breakthrough ventricular ectopy on beta-blockers, because it directly reduces the ryanodine-receptor calcium leak in addition to its sodium-channel-blocking effects. Lifestyle modification — restriction from competitive and high-intensity sport — is universal. For patients with recurrent events despite maximal pharmacological therapy, left cardiac sympathetic denervation reduces the cardiac sympathetic input and is an effective adjunct, and an implantable cardioverter defibrillator is considered for the highest-risk patients, particularly those with a history of aborted cardiac arrest or syncope despite optimal medical therapy. Exercise testing is the key follow-up tool: it is used to assess the adequacy of beta-blockade by demonstrating suppression of ventricular ectopy at peak exertion, and breakthrough ectopy on exercise testing despite therapy is an indication to intensify treatment. [3] [6]

(3) Family implications (3). CPVT is inherited in an autosomal dominant pattern (RYR2) in most cases, so every first-degree relative — parents, siblings, and the patient's future children — is at risk and requires screening. Screening combines a resting ECG (which is expected to be normal in CPVT), an exercise stress test (which is the key diagnostic test, because it provokes the arrhythmia in affected individuals), and genetic testing for the RYR2 mutation once it is identified in the proband. Genetic counselling is essential: the result enables predictive testing of relatives, which distinguishes affected from unaffected family members and guides who needs treatment. The psychological burden of the diagnosis — the knowledge of a life-threatening, heritable condition and the impact on siblings and parents — must be addressed with appropriate psychosocial support. Structured transition to adult inherited cardiac conditions care is planned for adolescence. [2] [3]