Case report
Novel mutation in long QT syndrome in a patient with prior diagnosis of epilepsy
Nova mutação na Síndroma de QT Longo em doente com diagnóstico prévio de epilepsia
Cláudia Jorgea,
, João Silva Marquesa, João Nóbregaa, Arminda Veigaa, Maria José Correiaa, António Nunes Diogoa, Jorge Cruzb, Rita Peraltac, Gábriel Miltenberger-Miltényid
Corresponding author
a Serviço de Cardiologia I, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisboa, Portugal
b Serviço de Cirurgia Cardiotorácica, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisboa, Portugal
c Serviço de Neurologia, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisboa, Portugal
d Instituto de Medicina Molecular e Laboratório de Diagnóstico de Medicina Molecular (GenoMed), Lisboa, Portugal
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[ "paginaInicial" => "929" "paginaFinal" => "935" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Cláudia Jorge, João Silva Marques, João Nóbrega, Arminda Veiga, Maria José Correia, António Nunes Diogo, Jorge Cruz, Rita Peralta, Gábriel Miltenberger-Miltényi" "autores" => array:9 [ 0 => array:4 [ "nombre" => "Cláudia" "apellidos" => "Jorge" "email" => array:1 [ 0 => "c_jorge@sapo.pt" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">¿</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "João Silva" "apellidos" => "Marques" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "João" "apellidos" => "Nóbrega" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" 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] 8 => array:3 [ "nombre" => "Gábriel" "apellidos" => "Miltenberger-Miltényi" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Serviço de Cardiologia I, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisboa, Portugal" "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Serviço de Cirurgia Cardiotorácica, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisboa, Portugal" "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Serviço de Neurologia, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisboa, Portugal" "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Instituto de Medicina Molecular e Laboratório de Diagnóstico de Medicina Molecular (GenoMed), Lisboa, Portugal" "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "Nova mutação na Síndroma de QT Longo em doente com diagnóstico prévio de epilepsia" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 859 "Ancho" => 1500 "Tamanyo" => 411256 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">ECG trace with QTc of 482<span class="elsevierStyleHsp" style=""></span>ms.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Congenital long QT syndrome (LQTS) is an inherited arrhythmogenic disorder characterized by prolongation of the QT interval, with high risk for severe ventricular arrhythmias, especially polymorphic ventricular tachycardia (torsade de pointes). It is frequently manifested by syncope and sudden death (SD).<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> LQTS is a channelopathy caused by mutations in the genes that code for proteins in ion channels of the cardiac cell membrane.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Twelve genes linked to the condition have been identified, and there is thus considerable genotypic heterogeneity and phenotypic heterogeneity; underdiagnosis is common.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Another form of presentation is seizures, which can lead to a diagnosis of epilepsy and institution of antiepileptic therapy.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The consequences of undiagnosed LQTS can be catastrophic; if untreated, mortality is significant. Factors indicating poor prognosis include syncope in those aged under 18, female gender, corrected QT interval (QTc) ≥500<span class="elsevierStyleHsp" style=""></span>ms, and a mutation associated with type 2 LQTS.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Prevention of sudden death is based primarily on beta-blocker therapy, but may also include an implantable cardioverter-defibrillator (ICD).<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> In patients refractory to beta-blockers, persistent arrhythmias and repeated automatic shocks cause constant stress and disrupt the patient's social life.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> In such cases, left cardiac sympathetic denervation is a last resort.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Electrical storm is a serious complication in these patients and must be rapidly recognized and treated.</p><p id="par0020" class="elsevierStylePara elsevierViewall">We present the case of a patient diagnosed with epilepsy in childhood and in whom LQTS was diagnosed only in adulthood. Subsequent investigation identified a previously undescribed mutation.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Case report</span><p id="par0025" class="elsevierStylePara elsevierViewall">A 20-year-old black woman had a history of recurrent syncope from the age of two and had been diagnosed with epilepsy. Despite medication with phenobarbital she suffered frequent syncope, sometimes accompanied by tonic seizures, sphincter incontinence and tongue biting. These events were preceded by rapid palpitations and were usually triggered by strong emotions or loud noises. There was a family history of sudden death (a paternal uncle) (<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">As syncopal episodes persisted, sometimes accompanied by seizures, she was referred to a neurologist for further investigation. The neurological examination was normal, as was the brain magnetic resonance imaging, and the intercritical electroencephalogram showed no evidence of focal slowing or epileptic activity.</p><p id="par0035" class="elsevierStylePara elsevierViewall">As no abnormalities had been identified on the initial investigation, the patient underwent video electroencephalography and provocation testing, during which she suffered a syncopal episode that was not recorded as epileptic activity on the electroencephalogram. However, the single-lead electrocardiogram (ECG) trace showed polymorphic ventricular tachycardia (torsade de pointes) that coincided with the intravenous administration of saline during provocation testing, and with the syncope (<a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a>).</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">The 12-lead ECG showed a QTc of 482<span class="elsevierStyleHsp" style=""></span>ms (<a class="elsevierStyleCrossRef" href="#fig0015">Figure 3</a>). Holter 24-hour monitoring documented frequent ventricular extrasystoles (mean of 30 per hour) and 22 pairs and 8 salvoes of ventricular tachycardia, with two episodes of torsade de pointes, of 30 and 40<span class="elsevierStyleHsp" style=""></span>s; QTc was prolonged, with a mean of 561<span class="elsevierStyleHsp" style=""></span>ms, ranging between 452 and 648<span class="elsevierStyleHsp" style=""></span>ms (<a class="elsevierStyleCrossRef" href="#fig0020">Figure 4</a>).</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">The patient was diagnosed with LQTS and transferred to the cardiology department for monitoring and treatment. Physical examination and transthoracic echocardiogram were normal. Blood samples were taken for genetic study.</p><p id="par0050" class="elsevierStylePara elsevierViewall">Therapeutic management included suspension of phenobarbital, due to its potential for QT interval prolongation, and administration of propanolol in increasing doses up to the maximum tolerated dose. Despite these measures, the patient continued to suffer syncopal episodes preceded by rapid palpitations due to polymorphic ventricular tachycardia, accompanied by mydriasis, tonic movements, urinary incontinence, noisy breathing and sweating. There were no focal neurological signs or post-seizure confusion. Given the failure of beta-blocker therapy at maximum tolerated doses, it was decided to implant an ICD in accordance with current guidelines.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> A Lumax VR<span class="elsevierStyleSup">®</span> (Biotronik<span class="elsevierStyleSup">®</span>) VVI-R device was implanted and she was discharged medicated with maximum tolerated beta-blocker therapy.</p><p id="par0055" class="elsevierStylePara elsevierViewall">The patient remained asymptomatic for a month after discharge, but two days after the onset of flu-like symptoms with fever, she had several episodes of rapid palpitations, followed by 13 appropriate shocks and six episodes of antitachycardia pacing, as shown by the ICD event record (<a class="elsevierStyleCrossRef" href="#fig0030">Figure 6</a>). Investigation of the etiology of the electrical storm ruled out hypomagnesemia, hypocalcemia, hypokalemia, suspension of current medication, and administration of drugs that prolong the QT interval.</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia><elsevierMultimedia ident="fig0030"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">Given the fever and clinical suspicion of influenza infection, the patient was screened for H1N1 virus infection, which was confirmed by polymerase chain reaction. Viral myocarditis and other possible complications were excluded. The electrical storm was ended by increasing the ventricular pacing rate, magnesium sulfate perfusion and increased propanolol dose. As her flu symptoms improved it was deemed unnecessary to begin antiviral therapy with oseltamivir, which could have further prolonged the QT interval, and she was discharged. In outpatient consultations, with the patient medicated with propanolol and alprazolam, the ICD was interrogated, and showed several isolated episodes of ventricular tachycardia with appropriate therapies. Propanolol was replaced by atenolol 200<span class="elsevierStyleHsp" style=""></span>mg/day to aid compliance with therapy.</p><p id="par0065" class="elsevierStylePara elsevierViewall">Despite beta-blocker therapy, episodes of ventricular tachycardia/fibrillation requiring cardioversion/defibrillation continued. Left cardiac sympathetic denervation was therefore performed by thoracoscopy, with removal of the lower third of the left stellate ganglion, sympathetic ablation of thoracic ganglia T2 to T5 with resection of the collateral branches. Anhidrosis of the left arm occurred, but not Horner syndrome. On the first postoperative day the atenolol dose was reduced to 100<span class="elsevierStyleHsp" style=""></span>mg/day as the patient remained in sinus rhythm, but on the fourth day there was an episode of syncopal torsade de pointes. The pacing rate was increased to 75<span class="elsevierStyleHsp" style=""></span>bpm and the patient was discharged. At three-month follow-up there had been only four episodes of unsustained polymorphic ventricular tachycardia recorded by ICD home monitoring.</p><p id="par0070" class="elsevierStylePara elsevierViewall">The genetic study revealed a heterozygous mutation, c.1817 C>T, in codon 606 of the <span class="elsevierStyleItalic">KCNH2</span> gene (<a class="elsevierStyleCrossRef" href="#fig0025">Figure 5</a>a), resulting in the replacement of serine by phenylalanine (p.S606F) in the protein coded by <span class="elsevierStyleItalic">KCNH2</span>. The affected amino acid is located at the extracellular level, between the 5th and 6th transmembrane domains of the protein. Three non-pathogenic variants, previously described, were also found in the <span class="elsevierStyleItalic">KCNH2</span> gene.</p><p id="par0075" class="elsevierStylePara elsevierViewall">Sequencing of the <span class="elsevierStyleItalic">KCNQ1</span> and <span class="elsevierStyleItalic">SCN5A</span> genes revealed no pathogenic alterations.</p><p id="par0080" class="elsevierStylePara elsevierViewall">The 606 serine residue in the KCNHR protein is highly conserved in various species (<a class="elsevierStyleCrossRef" href="#fig0025">Figure 5</a>b). Although not previously been reported in the literature, the cytosine-to-thiamine c.1817 C>T (p.S606F) mutation has been found by a research group at Oxford, UK, in a patient and his mother with “symptoms suggestive of LQTS” (Melanie Proven, personal communication).</p><p id="par0085" class="elsevierStylePara elsevierViewall">Plans are under way for clinical and genetic study of first-degree relatives, which will indicate the degree of segregation of this mutation.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Discussion</span><p id="par0090" class="elsevierStylePara elsevierViewall">The presentation of LQTS frequently makes it difficult to diagnose. Diagnosis is based on clinical history and the ECG, particularly the QTc interval.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> However, the ECG is not always reliable in this regard, since QT prolongation may not be evident in all leads or may vary between ECGs.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,7</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">The Schwartz diagnostic score is commonly used. This includes various electrocardiographic characteristics besides QTc interval, such as T-wave morphology, evidence of bradycardia and documented torsade de pointes; clinical criteria include syncope, congenital deafness and a family history of sudden death at young ages, or of LQTS in close relatives.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Although it has high specificity, the Schwartz score has low sensitivity due to the variable penetrance of the mutations,<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> so that some carriers do not present the characteristic phenotype but may still be at risk for ventricular arrhythmias. It is therefore extremely important to perform genetic testing of patients’ families to identify other carriers.</p><p id="par0100" class="elsevierStylePara elsevierViewall">Although genetic study does not dictate diagnosis, it can identify mutations in relevant genes, detecting LQTS in individuals with a non-diagnostic QTc and influencing therapeutic decisions.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> The most common forms of LQTS are associated with mutations in genes coding for potassium channel subunits – <span class="elsevierStyleItalic">KCNQ1</span> and <span class="elsevierStyleItalic">KCNH2</span> (also known as <span class="elsevierStyleItalic">hERG</span>, <span class="elsevierStyleItalic">human ether-a-go-go</span>) – in types 1 and 2, and sodium channels (<span class="elsevierStyleItalic">SCN5A</span>), mutations in which are associated with type 3. The latter are also linked to Brugada syndrome.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">As the case reported illustrates, differential diagnosis with epilepsy can be difficult and complex. The seizures seen in LQTS are the consequence of prolonged cerebral hypoperfusion secondary to cardiac arrhythmia. However, Johnson et al. recently demonstrated that seizures are more frequent in type 2 LQTS, which may suggest that they have a common pathophysiological basis.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Epilepsy may be a part of this subtype of the syndrome, in the same way as deafness in type 1 and gastrointestinal symptoms in type 3.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> The explanation for this phenotype may be that the <span class="elsevierStyleItalic">KCNH2</span>-encoded potassium channel is also expressed in hippocampal astrocytes, which regulate extraneuronal potassium levels; perturbations in these cells may lead to epilepsy.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">There is agreement that the seizure threshold is lowered by cerebral hypoperfusion due to polymorphic ventricular tachycardia and alterations in extraneuronal potassium homeostasis in the hippocampus. It has also been speculated that seizures in LQTS are genuinely epileptic, secondary to disturbances in hippocampal KCNH2 potassium channels, causing temporal lobe epilepsy.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> This is supported by the fact that there are epileptic syndromes clearly associated with mutations in genes coding for sodium and potassium channels, including benign familial neonatal seizures related to KCNQ2 and KCNQ3 potassium channels, and febrile seizures associated with SCN1B and SCN1A sodium channels.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">It has also been suggested that epilepsy can cause malignant arrhythmias. Nashef et al. proposed that sudden unexpected death in epileptic patients may be due to central cardiorespiratory depression during a seizure, leading to ventricular arrhythmias and death.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">No epileptic activity was documented in our patient, even during episodes of arrhythmic syncope. Around 10–40% of patients with epilepsy show no epileptic activity on the EEG, and thus a normal or nonspecific EEG does not rule out a diagnosis of epilepsy.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Differential diagnosis between LQTS and epilepsy can be challenging, but it is essential: administration of antiepileptic medication can inhibit the potassium channel subunit coded by the <span class="elsevierStyleItalic">KCNH2</span> gene and thereby increase susceptibility to polymorphic ventricular tachycardia. Several drugs have this effect, including phenobarbital, which was administered to our patient in the case presented.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">LQTS should be considered in young individuals with seizures and an EEG that does not exclude epilepsy. Studies have shown that a third of cases of treatment-resistant epilepsy may be variants of LQTS.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> This highlights the role of 24-hour Holter monitoring and video electroencephalography with ECG, which greatly improve diagnostic accuracy, particularly if the recordings include an arrhythmic event, as in the case presented.</p><p id="par0130" class="elsevierStylePara elsevierViewall">However, the clinical characteristics of syncope remain the central element in diagnosing LQTS, since the arrhythmia is triggered by physiological stress, the type of which is specific to the mutation. Type 1 is most often associated with physical exertion, particularly swimming or diving; type 2 is frequently triggered by sudden loud noises or emotional stress, as in the case described; and in type 3 events occur without emotional arousal at rest or during sleep, without waking the patient.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,8</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">Correct diagnosis and appropriate treatment can prevent the fatal events that characterize this syndrome. The incidence of SD in LQTS is 1–2% per year and 20% in the first year after diagnosis.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> Beta-blocker therapy reduces events and SD by 70%,<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> and is therefore recommended in patients with this diagnosis.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Over 10% suffer cardiac arrest and SD in spite of treatment;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> ICD implantation is mandatory in those that survive cardiac arrest.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">Arrhythmic risk differs between the three types of LQTS,<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,5</span></a> being higher in types 2 and 3, and genotype is therefore taken into consideration in indications for ICD implantation.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> The efficacy of beta-blockers also varies between the different types (lower in type 3), again highlighting the need to identify the mutation involved.</p><p id="par0145" class="elsevierStylePara elsevierViewall">In the case presented a previously undescribed mutation, p.S606F, was identified in the <span class="elsevierStyleItalic">KCNH2</span> (<span class="elsevierStyleItalic">HERG</span>) gene, associated with type 2 LQTS. The fact that this mutation codes for an amino acid in the transmembrane domain that is highly conserved across species renders it pathogenic.</p><p id="par0150" class="elsevierStylePara elsevierViewall">Left cardiac sympathetic denervation is a therapeutic option in LQTS when beta-blocker therapy fails. Reduction of the triggering effect of adrenergic stimulation and modification of the arrhythmogenic substrate (reflected in shorter QTc interval) reduce the number of cardiac events<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> at three-month follow-up. However, the patient's QTc interval of 502<span class="elsevierStyleHsp" style=""></span>ms after denervation means the prognosis is less hopeful, with a high likelihood of arrhythmias and SD, as previously suggested by the type 2 genotype and the severity of clinical symptoms before the intervention.</p><p id="par0155" class="elsevierStylePara elsevierViewall">The occurrence of an electrical storm in patients with ICDs is a serious complication. It is essential to exclude factors that prolong the QT interval. Fever, known to trigger arrhythmias in Brugada syndrome, has only occasionally been reported as prolonging QTc in patients with LQTS and only with one mutation (A558P missense mutation in <span class="elsevierStyleItalic">HERG</span>).<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> In the case presented, although periods of arrhythmia were documented during the febrile phase, the QTc interval was no longer than at baseline (462<span class="elsevierStyleHsp" style=""></span>ms).</p><p id="par0160" class="elsevierStylePara elsevierViewall">At the same time, the fact that the patient presented an electrical storm when infected with the H1N1 virus raises the possibility that there is a high-risk subgroup of LQTS patients who may be vulnerable to a new arrhythmogenic mechanism specific to the newly identified mutation and H1N1 infection.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conclusion</span><p id="par0165" class="elsevierStylePara elsevierViewall">LQTS is a cause of both syncope and seizures, that makes differential diagnosis with epilepsy essential. However, current knowledge is insufficient to determine whether there is a molecular mechanism that links LQTS and epilepsy.</p><p id="par0170" class="elsevierStylePara elsevierViewall">A new mutation in the <span class="elsevierStyleItalic">KCNH2</span> gene was identified and described for the first time. This mutation appears to result in susceptibility to electrical storm in the context of fever and viral infection.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflicts of interest</span><p id="par0175" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:2 [ "identificador" => "xres175996" "titulo" => "Abstract" ] 1 => array:2 [ "identificador" => "xpalclavsec164361" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres175995" "titulo" => "Resumo" ] 3 => array:2 [ "identificador" => "xpalclavsec164362" "titulo" => "Palavras-chave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Case report" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Discussion" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Conclusion" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Conflicts of interest" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2011-04-28" "fechaAceptado" => "2011-06-28" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec164361" "palabras" => array:3 [ 0 => "Long QT syndrome" 1 => "Epilepsy" 2 => "Channelopathy" ] ] ] "pt" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palavras-chave" "identificador" => "xpalclavsec164362" "palabras" => array:3 [ 0 => "Síndroma de QT longo" 1 => "Epilepsia" 2 => "Canalopatia" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Congenital long QT syndrome (LQTS) can present as syncope or seizures, secondary to polymorphic ventricular tachycardia, mimicking a primary seizure disorder.</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">In patients treated with an implantable cardioverter-defibrillator (ICD), the recurrence of arrhythmias with subsequent frequent therapeutic shocks may cause adverse reactions, which can be psychogenic.</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">We report the case of a 22-year-old woman with syncope and seizures who was diagnosed in childhood as epileptic and in whom LQTS was diagnosed only in adulthood.</p><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Beta-blocker therapy failed and an ICD was implanted. However, as arrhythmias persisted, left cardiac sympathetic denervation was performed. After surgery, three-month follow-up showed a significant reduction in arrhythmias.</p><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">The genetic study identified a heterozygous mutation, c.1817 C>T p.S606F, on the <span class="elsevierStyleItalic">KCNH2</span> gene that has not previously been reported in the literature.</p><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">We also report the rare occurrence of an electrical storm in the course of H1N1 infection.</p><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">This case illustrates the difficulties in the diagnosis and treatment of LQTS. The possibility of a common genetic basis for arrhythmic diseases and epilepsy is discussed.</p>" ] "pt" => array:2 [ "titulo" => "Resumo" "resumen" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">A síndroma de QT longo congénita (SQTL) pode manifestar-se por síncopes ou convulsões recorrentes, no contexto de taquicardia ventricular polimórfica, podendo simular epilepsia.</p><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Nos doentes tratados com cardioversor-desfibrilhador implantável (CDI) a recorrência de arritmias com consequente terapêutica com choques frequentes pode conduzir a reacções adversas, nomeadamente psicogénicas.</p><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Apresentamos o caso de uma doente de 22 anos com síncopes e crises convulsivas, cujo diagnóstico era desde a infância de epilepsia, e em quem a SQTL foi diagnosticada apenas em idade adulta. Por falência da terapêutica beta-bloqueante implantou CDI, e por persistência de arritmias foi submetida a simpaticectomia cardíaca esquerda. O <span class="elsevierStyleItalic">follow-up</span> pós-cirurgia aos 3 meses mostrou redução significativa do número de arritmias.</p><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">O estudo genético identificou uma mutação patogénica no gene <span class="elsevierStyleItalic">KCNH2</span> (SQTL tipo 2), em heterozigotia, a mutação c.1817<span class="elsevierStyleHsp" style=""></span>C >T p.S606F, ainda não descrita na literatura. Relatamos também a rara ocorrência de tempestade arrítmica no contexto de infecção a H1N1.</p><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">O caso clínico ilustra as dificuldades quer do diagnóstico quer do tratamento da SQTL. É discutida a possibilidade duma base genética partilhada entre a doença disrítmica e neurológica.</p>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara">Please cite this article as: Jorge, C. Nova mutação na Síndroma de QT Longo em doente com diagnóstico prévio de epilepsia. doi 10.1016/j.repc.2011.10.003.</p>" ] ] "multimedia" => array:6 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1118 "Ancho" => 2500 "Tamanyo" => 108893 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Genealogical tree. III-1: index case. II-3: sudden death.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1064 "Ancho" => 1500 "Tamanyo" => 365220 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Polymorphic ventricular tachycardia recorded on single-lead ECG during video EEG.</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 859 "Ancho" => 1500 "Tamanyo" => 411256 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">ECG trace with QTc of 482<span class="elsevierStyleHsp" style=""></span>ms.</p>" ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1028 "Ancho" => 1500 "Tamanyo" => 534743 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Polymorphic ventricular tachycardia (torsade de pointes) recorded on Holter 24-hour monitoring.</p>" ] ] 4 => array:7 [ "identificador" => "fig0025" "etiqueta" => "Figure 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 1285 "Ancho" => 2528 "Tamanyo" => 342224 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">(a) Heterozygous c.1817 C>T p.S606F mutation (arrow) in the <span class="elsevierStyleItalic">KCNH2</span> gene. The upper line is the sequence from a normal control. (b) Homology of amino acid sequences in different species as tested by the NCBI HomoloGene program (<span class="elsevierStyleInterRef" href="http://www.ncbi.nlm.nih.gov/homologene">http://www.ncbi.nlm.nih.gov/homologene</span>). Codon p.S606 is homologous in all these species.</p>" ] ] 5 => array:7 [ "identificador" => "fig0030" "etiqueta" => "Figure 6" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr6.jpeg" "Alto" => 1660 "Ancho" => 2500 "Tamanyo" => 530752 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">ICD record showing several episodes of ventricular fibrillation and 19 appropriate therapies (13 shocks and six episodes of antitachycardia pacing); electrogram showing ventricular fibrillation with successful defibrillation after a 40-J shock.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:17 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Long QT syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "I. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 October | 36 | 29 | 65 |
| 2024 September | 55 | 29 | 84 |
| 2024 August | 157 | 59 | 216 |
| 2024 July | 57 | 42 | 99 |
| 2024 June | 55 | 29 | 84 |
| 2024 May | 49 | 30 | 79 |
| 2024 April | 47 | 38 | 85 |
| 2024 March | 47 | 31 | 78 |
| 2024 February | 42 | 29 | 71 |
| 2024 January | 46 | 32 | 78 |
| 2023 December | 47 | 32 | 79 |
| 2023 November | 54 | 33 | 87 |
| 2023 October | 49 | 25 | 74 |
| 2023 September | 46 | 26 | 72 |
| 2023 August | 48 | 30 | 78 |
| 2023 July | 42 | 19 | 61 |
| 2023 June | 43 | 17 | 60 |
| 2023 May | 73 | 44 | 117 |
| 2023 April | 47 | 4 | 51 |
| 2023 March | 50 | 22 | 72 |
| 2023 February | 57 | 26 | 83 |
| 2023 January | 48 | 15 | 63 |
| 2022 December | 73 | 19 | 92 |
| 2022 November | 80 | 31 | 111 |
| 2022 October | 48 | 21 | 69 |
| 2022 September | 52 | 34 | 86 |
| 2022 August | 52 | 38 | 90 |
| 2022 July | 50 | 35 | 85 |
| 2022 June | 44 | 26 | 70 |
| 2022 May | 60 | 42 | 102 |
| 2022 April | 48 | 32 | 80 |
| 2022 March | 73 | 42 | 115 |
| 2022 February | 53 | 20 | 73 |
| 2022 January | 70 | 24 | 94 |
| 2021 December | 84 | 37 | 121 |
| 2021 November | 47 | 47 | 94 |
| 2021 October | 81 | 54 | 135 |
| 2021 September | 40 | 32 | 72 |
| 2021 August | 50 | 41 | 91 |
| 2021 July | 76 | 36 | 112 |
| 2021 June | 42 | 27 | 69 |
| 2021 May | 67 | 46 | 113 |
| 2021 April | 97 | 46 | 143 |
| 2021 March | 80 | 16 | 96 |
| 2021 February | 143 | 19 | 162 |
| 2021 January | 47 | 16 | 63 |
| 2020 December | 48 | 11 | 59 |
| 2020 November | 65 | 17 | 82 |
| 2020 October | 43 | 12 | 55 |
| 2020 September | 79 | 8 | 87 |
| 2020 August | 46 | 12 | 58 |
| 2020 July | 63 | 7 | 70 |
| 2020 June | 52 | 6 | 58 |
| 2020 May | 60 | 10 | 70 |
| 2020 April | 53 | 11 | 64 |
| 2020 March | 56 | 15 | 71 |
| 2020 February | 147 | 16 | 163 |
| 2020 January | 34 | 9 | 43 |
| 2019 December | 58 | 5 | 63 |
| 2019 November | 29 | 6 | 35 |
| 2019 October | 61 | 7 | 68 |
| 2019 September | 84 | 15 | 99 |
| 2019 August | 17 | 3 | 20 |
| 2019 July | 64 | 18 | 82 |
| 2019 June | 43 | 11 | 54 |
| 2019 May | 43 | 24 | 67 |
| 2019 April | 33 | 24 | 57 |
| 2019 March | 98 | 19 | 117 |
| 2019 February | 103 | 28 | 131 |
| 2019 January | 65 | 10 | 75 |
| 2018 December | 69 | 14 | 83 |
| 2018 November | 129 | 8 | 137 |
| 2018 October | 171 | 23 | 194 |
| 2018 September | 118 | 17 | 135 |
| 2018 August | 32 | 11 | 43 |
| 2018 July | 21 | 8 | 29 |
| 2018 June | 55 | 8 | 63 |
| 2018 May | 51 | 7 | 58 |
| 2018 April | 63 | 4 | 67 |
| 2018 March | 95 | 7 | 102 |
| 2018 February | 84 | 2 | 86 |
| 2018 January | 64 | 6 | 70 |
| 2017 December | 97 | 7 | 104 |
| 2017 November | 68 | 7 | 75 |
| 2017 October | 46 | 9 | 55 |
| 2017 September | 42 | 12 | 54 |
| 2017 August | 59 | 10 | 69 |
| 2017 July | 40 | 13 | 53 |
| 2017 June | 54 | 12 | 66 |
| 2017 May | 43 | 7 | 50 |
| 2017 April | 47 | 3 | 50 |
| 2017 March | 90 | 20 | 110 |
| 2017 February | 76 | 5 | 81 |
| 2017 January | 48 | 3 | 51 |
| 2016 December | 60 | 15 | 75 |
| 2016 November | 60 | 10 | 70 |
| 2016 October | 75 | 9 | 84 |
| 2016 September | 58 | 10 | 68 |
| 2016 August | 27 | 4 | 31 |
| 2016 July | 31 | 6 | 37 |
| 2016 June | 10 | 3 | 13 |
| 2016 May | 18 | 2 | 20 |
| 2016 April | 79 | 2 | 81 |
| 2016 March | 97 | 18 | 115 |
| 2016 February | 114 | 33 | 147 |
| 2016 January | 92 | 19 | 111 |
| 2015 December | 96 | 19 | 115 |
| 2015 November | 107 | 19 | 126 |
| 2015 October | 113 | 16 | 129 |
| 2015 September | 93 | 12 | 105 |
| 2015 August | 97 | 9 | 106 |
| 2015 July | 163 | 9 | 172 |
| 2015 June | 92 | 4 | 96 |
| 2015 May | 96 | 7 | 103 |
| 2015 April | 92 | 11 | 103 |
| 2015 March | 106 | 7 | 113 |
| 2015 February | 158 | 7 | 165 |
| 2015 January | 101 | 7 | 108 |
| 2014 December | 86 | 8 | 94 |
| 2014 November | 83 | 8 | 91 |
| 2014 October | 119 | 13 | 132 |
| 2014 September | 111 | 11 | 122 |
| 2014 August | 99 | 11 | 110 |
| 2014 July | 90 | 12 | 102 |
| 2014 June | 85 | 12 | 97 |
| 2014 May | 102 | 20 | 122 |
| 2014 April | 83 | 9 | 92 |
| 2014 March | 98 | 18 | 116 |
| 2014 February | 118 | 14 | 132 |
| 2014 January | 121 | 19 | 140 |
| 2013 December | 95 | 21 | 116 |
| 2013 November | 96 | 19 | 115 |
| 2013 October | 114 | 19 | 133 |
| 2013 September | 91 | 32 | 123 |
| 2013 August | 85 | 21 | 106 |
| 2013 July | 111 | 23 | 134 |
| 2013 June | 89 | 15 | 104 |
| 2013 May | 87 | 11 | 98 |
| 2013 April | 98 | 32 | 130 |
| 2013 March | 95 | 20 | 115 |
| 2013 February | 88 | 24 | 112 |
| 2013 January | 346 | 21 | 367 |
| 2012 December | 93 | 21 | 114 |
| 2012 November | 116 | 22 | 138 |
| 2012 October | 43 | 15 | 58 |
| 2012 September | 35 | 5 | 40 |
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