Congenital long QT syndrome caused by a KCNH2 pathogenic variant exhibiting “motor seizures”: a case report and literature review

Abstract

A retrospective analysis was conducted to evaluate the clinical characteristics, diagnostic challenges, and management strategies in a child with congenital long QT syndrome (cLQTS) caused by a KCNH2 gene pathogenic variant presenting as “motor seizures”. The case involved a 10-year-old boy with a two-year history of recurrent loss of consciousness, which had worsened during the preceding week. Clinical manifestations included sudden episodes of unconsciousness, rightward strabismus of both eyes, cyanosis of the lips, guttural vocalizations, rigidity and shaking of the upper limbs, and urinary incontinence. These events typically lasted approximately two minutes, initially occurring semiannually but escalating to daily episodes over the past week, affecting both awake and sleep states. Video electroencephalography (VEEG) showed generalized slow waves and low voltage activity, while electrocardiography (ECG) demonstrated QTc prolongation, paired, and multi-source ventricular ectopy preceding torsades de pointes. Genetic testing identified a pathogenic c.1697G > A mutation in the KCNH2 gene corroborating the clinical diagnosis of cLQTS. Following confirmation, the patient was initiated on long-term oral therapy with propranolol and nicorandil. Under this regimen, the patient was seizure-free for 7-month. For patients with seizures or seizure-like episodes, such as extremity movement or rigidity, it is necessary to perform an ECG examination. Additionally, dynamic ECG and electrolyte assessments should be conducted when necessary to minimize the risk of misdiagnosis and inappropriate treatment. When VEEG shows a “slow-flat-slow” pattern, differentiation from A-S syndrome caused by malignant arrhythmias is critical. Once cLQTS is diagnosed, it is imperative to initiate prompt and aggressive treatment to mitigate the risks of syncope and sudden cardiac death.

Introduction

Congenital long QT syndrome (cLQTS) is an inherited disorder of cardiac electrophysiology characterized by prolonged QT intervals and a heightened predisposition to malignant arrhythmias, including torsades de pointes ventricular tachycardia. This condition can lead to syncope, convulsions, or, in severe cases, sudden death [1]. In some patients, particularly children, clinical presentations such as loss of consciousness, limb rigidity, hypermotor activity, or incontinence closely resemble epileptic seizures [2]. As a result, cLQTS is often misdiagnosed as epilepsy, delaying appropriate treatment and significantly increasing the risk of life-threatening events. Accurate diagnosis and early identification are, therefore, critical. This study presents the clinical data of a child with cLQTS caused by a KCNH2 pathogenic variant characterized by “motor seizures”. The features of this case were analyzed in conjunction with current literature to summarize the recent advances in understanding cLQTS, aiming to enhance clinical awareness and diagnostic precision. The report is as follows.

Case report

A 10-year-old boy presented with a 2-year history of intermittent loss of consciousness, which had worsened over the previous week. Two years earlier, he had experienced his first episode of nocturnal loss of consciousness without an identifiable cause. The event was characterized by rightward deviation of both eyes; cyanosis of the lips; guttural vocalizations; stiffness and tremors in the upper limbs; and urinary incontinence, which lasted approximately one minute before resolution. Subsequently, the patient reported transient dizziness and headache, which resolved after rest. These episodes initially occurred approximately once every 6 months. One week before admission, the frequency of episodes had increased to daily occurrences during both wakefulness and sleep. Each episode was preceded by dizziness, and the clinical manifestations were consistent with prior events. The patient denied any psychiatric symptoms or cognitive impairment between episodes. His past medical and family histories were unremarkable.

On admission, the physical examination results were unexceptional. Laboratory evaluations, including peripheral blood cells and thyroid function test results, were within normal limits. Cerebrospinal fluid analysis showed lymphocytic pleocytosis (5 × 10^6/L) with normal protein concentration. Magnetic resonance imaging of the brain, including T2/FLAIR sequences, revealed no abnormalities.

Video electroencephalogram (VEEG) monitoring recorded two clinical episodes. Each episode was preceded by a 10-s aura of headache and dizziness. The patient then exhibited loud vocalizations, random limb movements with occasional excessive motor activity, followed by limb flaccidity, rightward deviation of the eyes and head, intermittent upper limb flexion or generalized limb extension, and rapid breathing. The episodes lasted approximately 2–3 min and resolved spontaneously. Post-episode, the patient gradually regained consciousness, and he reported dizziness and headache. The background VEEG demonstrated normal activity, with a 9–10 Hz alpha rhythm observed in the bilateral occipital regions. During the interictal sleep period, 1.5–2 Hz delta waves were identified in the bilateral frontal poles, frontal regions, and midline frontal regions. The ictal VEEG revealed a distinct pattern of “generalized slow waves - low voltage - generalized slow waves - low voltage - generalized slow waves” (Fig. 1).

Fig. 1

Ictal VEEGs of the proband: (a) The proband was asleep 30-s before the episode; (b, c) The proband woke up from sleep with head discomfort, a rapid cardiac rate, and occasional ventricular ectopy; (d) The proband exhibited irregular random and non-repetitive extremity movements, with VEEG showing generalized slow waves; (e) The proband displayed quadriplegia, rightward eye deviation, right head deviation, with VEEG showing generalized voltage decrease; (f) The proband exhibited head tilting and limb straightening, with VEEG showing generalized slow waves and torsades de pointes; (g, h) The proband displayed flexion and abduction of both upper extremities, accompanied by tachypnea, with VEEG showing generalized voltage decrease, intermixed with electromyographic artifacts, and torsades de pointes; (i) VEEG showing generalized slow waves and a recovery of cardiac rate; (j) The proband showed recovery of consciousness and reported head discomfort and headache, with VEEG showing a return to normal background activity

Dynamic electrocardiography (ECG) showed a significantly prolonged QT interval, paired and multifocal ventricular premature beats, and episodes of short runs of multifocal ventricular tachycardia. During the night, when the child awoke from a dream and sat upright, the ECG captured torsades de pointes ventricular tachycardia. One week after initiating treatment, a follow-up dynamic ECG revealed an average heart rate of 63 beats/min, an average QT interval of 455 ms, and a significant shortening of the QTc interval (Fig. 2). Whole exome sequencing, performed using next-generation sequencing technology, identified a heterozygous mutation in KCNH2 (c.1697G > A, p.Cys566Tyr). According to the American College of Medical Genetics and Genomics guidelines, this variant was preliminarily classified as a likely pathogenic variant [3]. Functional analysis using REVEL, SIFT and AlphaMissense bioinformatics tools consistently predicted the mutation to be deleterious (REVEL = 0.971; PP3 strong). This variant is located within a hotspot region (PM1) and had not been previously documented in the Human Gene Mutation Database or gnomAD v2.1.1 (PM2 supporting). Additionally, an alternative variant (p.Cys566Gly) at the same amino acid residue had been previously determined as likely to be pathogenic (PM5). Genetic screening of family members was performed using Sanger sequencing, and the results revealed that both the proband and his sister carried the KCNH2: c.1697G > A variant, which was inherited from their mother (Fig. 3).

Fig. 2

24-hour dynamic ECGs of the proband: (A) ECG recording showing prolonged QTc (QTc: 545ms); (B, C, D) ECG recording during a syncopal episode, demonstrating QTc prolongation and paired/multi-source ventricular ectopy preceding the onset of torsades de pointes (Tdp); (E, F) ECG recording post-treatment showing a shortened QTc (QTc: 455ms)

Fig. 3

Pedigree of the studied family: The arrow indicates the proband. Circles and squares represent females and males, respectively. Solid symbols represent subjects with QTc prolongation. –: Wide type; m: KCNH2: c.1697G > A (p.Cys566Tyr)

After admission, the patient experienced recurrent episodes and was initially diagnosed with epilepsy and focal motor seizures; for which perampanel (PER) was prescribed. The dose of PER was 2 mg per night initially, increasing by 2 mg weekly, and the target dose was 6 mg per night. Despite treatment with PER, the patient continued to experience intermittent and recurrent episodes characterized by loss of consciousness, rightward deviation of both eyes, cyanosis of the lips, and rigidity and tremors of the upper limbs. During hospitalization, dynamic ECG monitoring recorded a clinical episode concurrent with torsades de pointes ventricular tachycardia. Consequently, the diagnosis was revised to include LQTS and ventricular tachycardia. Propranolol (10 mg, three times daily) and nicorandil (2.5 mg twice daily) were initiated to address the QT interval prolongation; thereafter, the doses of propranolol (20 mg in the morning, 20 mg in the afternoon, and 10 mg in the evening) and nicorandil (5 mg twice daily) were increased according to the ECG findings. The patient was advised to avoid nocturnal auditory stimulation. Three weeks after discharge, genetic test results were made available. Based on these findings and clinical manifestations, the diagnosis was confirmed as cLQTS. The patient continued to take propranolol (20 mg in the morning, 20 mg in the afternoon, and 10 mg in the evening) and nicorandil (5 mg twice daily); PER was gradually tapered off after 2 weeks. At the 7-month follow-up consultation, the patient remained seizure-free and without ventricular tachycardia. Although, ECG still showed a slight QT prolongation, the duration of the corrected QT was 455 ms.

Literature review

A systematic search of PubMed (including MEDLINE) was conducted for human studies published in English up to December 20, 2024, using the keywords “[long QT syndrome] AND [epilepsy].” Relevant reference lists were also reviewed for additional articles. Summarize the demographic data, family history, age at seizure onset, classification of seizure, antiseizure medicines, auxiliary examinations (including electroencephalograms, CT/MRI scans, ECGs, and genetic testing), as well as the outcomes reported in the literature.

Our literature review identified 23 cases of cLQTS presenting as epilepsy [2, 4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19]. Analysis of these cases, including the present one, revealed that 10 patients (41.7%) were male. The median diagnostic delay was 7 years (range: 3–14 years), with the longest delay spanning 31 years. Ten patients (43.5%) had a family history of epilepsy, cardiac arrhythmia, or sudden unexpected death in epilepsy (SUDEP). Four patients (17.4%) reported experiencing an aura, including palpitations and dizziness, before their episodes. The predominant seizure type was generalized tonic-clonic seizures (GTCS). Eighteen patients (78.3%) received treatment with antiseizure medications (ASMs). Electroencephalogram (EEG) data were available for 15 cases (65.2%), six of which exhibited mild to moderate abnormalities. These abnormalities included mainly non-specific unilateral 4–7 Hz theta activity, followed by regional sharp waves and/or spikes, and occasionally focal 2–3 Hz delta activity. However, most reports did not document synchronous EEG changes during episodes. Of the 73.9% of patients who underwent genetic testing, 43.5% were identified as having KCNH2 variants; 13% had KCNQ2 variants; another 13% exhibited SCN5A variants; and 4.4% presented with normal genes. ECGs revealed torsades de pointes in conjunction with QT prolongation in seven patients (30.4%). During follow-up, three patients (13%) experienced SUDEP. Most patients remained seizure-free after discontinuing their antiepileptic medications and initiating treatment with β-blockers, along with the implantation of a cardioverter-defibrillator. The clinical features of these patients are summarized in Table 1.

Table 1 Clinical features of patients with congenital long QT syndrome masquerading as epilepsy

Our literature review also identified 145 cases of cLQTS co-occurring with epilepsy [20,21,22,23,24,25,26,27,28,29]. Analysis of these cases revealed that 117 patients (80.7%) had a family history of epilepsy, cardiac arrhythmia, or SUDEP. The predominant seizure types observed were focal epilepsy and GTCS. ASM data were available for 31 cases (21.4%), with patients receiving one or two types of medication. Interictal EEG data were accessible for 29 cases (20%), which included focal regional sharp waves and/or spikes. Only, one patient recorded an ictal EEG, characterized by low-wave sharp waves and spikes intermixed with electromyographic artifacts. ECG demonstrated QT prolongation in all patients. Genetic testing revealed pathogenic variants in KCNQ1, KCNH2, and SCN5A, with KCNH2 pathogenic variants being the most prevalent. Follow-up data were available for 37 cases (25.5%); among these, SUDEP occurred in 29 patients (20%). Detailed clinical characteristics of the patients are provided in Table 2.

Table 2 Clinical features of patients with congenital long QT syndrome comorbiding with epilepsy

Compared to the previously published literature, this patient presented with a relatively younger age of onset, prodromal symptoms such as dizziness and headache before the episodes, and synchronous EEG findings during the episodes that demonstrated a distinct “slow-flat-slow” pattern. Concurrently, synchronous ECG recordings revealed torsades de pointes ventricular tachycardia. Genetic testing results identified a missense mutation in KCNH2. Based on the clinical presentation, EEG findings during episodes (slow-flat-slow), and changes in the synchronous ECG, this patient was diagnosed with Adams-Stokes syndrome triggered by arrhythmia due to cLQTS.

Discussion

LQTS is a complex cardiac disorder characterized by prolonged QT intervals, which predispose individuals to severe arrhythmias and sudden cardiac death [30]. Due to the clinical similarity between syncope episodes and epileptic seizures, patients often present with sudden loss of consciousness and limb convulsions. Moreover, ECG evaluations are frequently delayed, resulting in the critical diagnostic feature of QT interval prolongation being overlooked. As a result, LQTS is often misdiagnosed as epilepsy in clinical practice. A study reported that 83.3% of patients with LQTS were initially misdiagnosed with epilepsy during their first medical consultation [31]. This high rate of misdiagnosis is primarily attributed to an incomplete assessment of the patient’s medical history and symptoms; insufficient utilization of genetic testing; and inadequate attention to family history. These factors contribute significantly to diagnostic errors [32]. Misdiagnosis not only delays appropriate treatment but may also expose patients to unnecessary medication side effects. When LQTS is suspected, dynamic ECG monitoring should be prioritized to detect transient changes in electrical activity before and after an episode. In this case, the child was monitored during one episode while awake and another episode during sleep. Both episodes were characterized by stereotyped, transient, and brief manifestations involving shouting and excessive limb movements. VEEG revealed brain wave changes, leading to an initial diagnosis of epilepsy with motor seizures.

However, after one week of treatment with perampanel, the frequency of episodes remained unchanged. At this point, dynamic ECG monitoring demonstrated prolonged QT intervals and frequent ventricular tachycardia. Additionally, ECG recordings during the episodes captured torsades de pointes ventricular tachycardia. Based on these findings, the VEEG was reanalyzed, revealing a significant increase in cardiac rate preceding the onset of limb movements. When torsades de pointes ventricular tachycardia occurred, the capacity of cardiac effective ejection was decreased, subsequently lowering the cerebral blood flow and leading to hypoxemia. The VEEG initially showed generalized slow wave activity, and then evolved into generalized low voltage activity. As the cardiac rate gradually returned to normal toward the end of the episodes, cerebral blood flow and oxygenation were gradually increased, and the VEEG changed from generalized slow waves to normal brain activity, revealing a characteristic “slow-flat-slow” pattern. Given that the changes in cardiac rate occurred before the brain discharges, the ineffectiveness of antiepileptic drug treatment, and the similarity between torsades de pointes ventricular tachycardia waveforms recorded during the dynamic ECG monitoring and the VEEG findings, it was reasonable to infer that these episodes were caused by malignant arrhythmias associated with LQTS, leading to Adams-Stokes syndrome. Following treatment with medication to shorten the QT interval, perampanel was gradually discontinued. Over the seven-month follow-up period, the patient remained seizure-free.

LQTS can be categorized as either acquired (aLQTS) or cLQTS based on etiology. aLQTS is primarily associated with medications that prolong the QT interval, electrolyte imbalances (such as hypokalemia and hypomagnesemia), or cardiomyopathy. In this case, no significant abnormalities were found in the patient’s electrolyte profile, including hypokalemia, hypomagnesemia, gastrointestinal bleeding, or arrhythmia. Additionally, no history of myocarditis, amiodarone use, or other QT-prolonging drugs were evident. Therefore, acquired LQTS was excluded as a potential diagnosis. Congenital LQTS, on the other hand, is predominantly linked to genetic alterations. Among these, mutations in genes such as KCNQ1, KCNH2, and SCN5A are the most common pathogenic factors [33]. The KCNH2 gene encodes the ERG1 potassium voltage-gated channels, which are widely expressed in the brain and contribute to neuronal firing patterns regulation. A blockade of ERG potassium voltage-gated channels increases potassium concentrations extraneuronally, and such changes are epileptogenic [34]. The KCNH2 gene mutations also impair the normal function of cardiac ion channels, resulting in abnormal myocardial electrical activity. cLQTS and epilepsy can co-exist in a single patient. Studies have demonstrated that 28.6–30.8% of patients with cLQTS also have epilepsy [24, 26], Furthermore, research on sudden death in patients with epilepsy indicates that 18–25% of these individuals have genetic mutations associated with cLQTS [25, 28]. A heterozygous variation at the c.1697G > A locus of the KCNH2 gene was identified in the proband’s family. This gene is highly expressed during adolescence, which may explain the significant increase in seizure frequency observed in children during this developmental stage. The proband’s sister also carried the same genetic mutation and exhibited a prolonged QT interval on ECG. Both the proband and his sister are currently being treated with drugs to shorten their QT interval. The identified mutation follows an autosomal dominant inheritance pattern and was inherited from their mother, who does not presently have any cardiac symptoms. Her lack of symptoms may be attributed to incomplete gene expression.

This study has certain limitations. The results may be difficult to apply to other patients, especially patient populations with different pathological or physiological conditions, thus limiting the generalizability of its clinical application. The limitations of a single case may be addressed through the followings: first, by describing each step and method of the study in as much detail as possible, so that other researchers can reproduce the study, and at the same time disclose all data and analysis processes to enhance the transparency of the results; and second, by systematically reviewing and comparing other similar cases.

In conclusion, for patients presenting with seizures or seizure-like episodes accompanied by excessive movement or rigidity, the presence of a “slow-flat-slow” feature on EEG necessitates differentiation from Adams-Stokes syndrome caused by malignant arrhythmias. Once cLQTS syndrome is diagnosed, the prompt initiation of active treatment is essential to prevent syncope and sudden death.