Timothy Syndrome and Torsades De Pointes in a Newborn - Case Report

doi:10.21203/rs.3.rs-1495905/v1

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Case Report

Timothy Syndrome and Torsades De Pointes in a Newborn - Case Report

https://doi.org/10.21203/rs.3.rs-1495905/v1

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Timothy syndrome (TS) is a rare multisystem disease has a characterized association of long QT syndrome (LQTS) type-8 with the congenital cardiac and extracardiac malformations (neurological and dysmorphic facial features, syndactyly). It is caused by heterozygous mutations in the CACNA 1C gene, which participates in decoding the calcium channels. In this study, we describe a case of TS, which has systemic phenotypic characteristics associated with a long QT interval on the electrocardiogram.. The LQTS predisposes to a characteristic life-threatening ventricular arrhythmia known as Torsades de pointes or "twisting of the points". In this scenario, the authors describes the main clinical characteristics in a case of TS focusing on improve the ability of early diagnosis and better management of LTQS type-8.

Timothy syndrome

Torsade de pointes

newborn

Congenital Long QT syndrome

Long QT syndrome (LQTS) is a disorder that affects the repolarization of ion channels, characterized by QT interval prolongation and T wave abnormalities on the electrocardiogram (ECG). LQTS (congenital long QT) is an autosomal dominant or recessive disorder with an estimated prevalence of 1:2000 to 1:2500 people [1]. There is association with polymorphic ventricular tachyarrhythmias, typically Torsade de Pointes (TdP). TdP is usually self-limiting, causing a syncopal event, and is the most common symptom in individuals with LQTS. In some cases, it degenerates to ventricular fibrillation and causes cardiac arrest or sudden death. Such cardiac events typically occur during physical or emotional stress, less often during sleep, and usually without prodromes. Therefore, far, there are ten types of LQTS according to the gene that mutates [2].

The CACNA 1C gene (voltage-dependent L-type calcium channels) has been described in patients with Timothy Syndrome (TS) or LQTS type 8. This gene is essential for the process of excitability, myocyte contraction, regulation of gene expression, and by of the cardiac action potential plateau. Calcium channel dysfunction in TS is of autosomal dominant inheritance. The association of LQTS with extracardiac phenotypes such as syndactyly, facial dysmorphism, seizures, and delayed neuropsychomotor development should draw attention to TS [3]. In this study, we describe a newborn (NB) with an initial clinical picture of bradycardia who progressed to episodes of ventricular tachycardia, in which the evidence of a long QT interval, associated with syndactyly, led to a diagnostic suspicion of this syndrome.

NB, full-term, suitable for gestational age (AGA), female, born by cesarean section due to acute fetal distress and marked oligohydramnios, birth weight of 3020gr, 48 cm in length, Apgar 8/8, without prenatal complications. She evolved with respiratory distress and bradycardia, with 20 hours of life being transferred to the neonatal ICU. Physical examination showed syndactyly in the upper and lower limbs and on cardiovascular examination, the heart rhythm was irregular (Fig. 1). An ECG was performed, which showed: second degree atrioventricular block (AVB), long QT interval (660 ms), and notch T waves (or T wave alternans). On the follow-up ECG, the QT interval remained prolonged. An echocardiogram was performed, which ruled out the structural cardiac malformation, demonstrating only the presence of a patent foramen ovale (physiological for age group). Drug treatment with beta-blocker -propranolol was started (initial dose: 2mg/kg/day), however, without reduction of the QT interval. Even with the gradual adjustment of the medication up to a dose of 5mg/kg/day, the QT interval remained longer than 550 ms.

During hospitalization, he presented several episodes of low output, with periods of ventricular tachycardia: Torsades de Pointes (Fig. 2 / Video 1).

Due to the condition compatible with ST, the installation of a cardiac pacemaker was indicated and this implantation was performed at 21 days of life. After implantation of the pacemaker, there was the appearance of a voluminous chylothorax on the right. Chest drainage and antibiotic therapy were performed.

The NB maintained hemodynamic stabilization after the implantation of the pacemaker, but due to infectious complications, she died.

TS is a rare multisystem disorder associated with long QT syndrome (LQTS, TYPE 8), structural congenital heart disease, bilateral cutaneous syndactyly of the fingers and toes, dysmorphic facial features, and neurological symptoms including autism, seizures, and intellectual disability.. It is caused by heterozygous mutations in CACNA 1C, a gene that encodes a calcium channel. Cardiological changes are expressed on the electrocardiogram (ECG), characterized by QT interval prolongation.

QT prolongation can be assessed on the ECG and its measurement includes the QRS complex, ST segment, and T wave (ventricular depolarization and repolarization). The erroneous inclusion of the U wave when present and the noncorrection of the QT interval for HR in situations of bradycardia can falsify the prolongation of this interval. For the corrected calculation of QT for heart rate (QTc), several can be used, such as the formulas of Framingham, Fridericia, and Bazett [4, 5, 6]. In the case reported, we used the formulas of Bazett and Fredericia and both QTc values were prolonged (550ms and 520ms, respectively). In general, QTc interval values above 480ms are considered prolonged, with an indication for genetic testing for LQTS values >/= 500ms being acceptable in the absence of associated factors (such as hypocalcemia and medication use) [7, 8]. In the case reported, genetic research was not performed. Not even in the family. Although there are several formulas for calculating QTc, the diagnostic score for LQTS formulated in 1993 and updated in 2011 uses Bazett's formula to calculate this interval [9]. The criteria for LQTS are described in Table 1.

Torsade de Pointes (TsP) ventricular tachycardias are associated with LQTS. It is a ventricular rhythm with a high heart rate for ages in which the QRS complexes show variations in their morphology and/or their axis. The peaks of the QRS complexes appear to “twist” around the isoelectric line, giving rise to the denomination “torsades de pointes”. Episodes can be self-limiting, as in the present report, or progress to ventricular fibrillation with risk of cardiac arrest and sudden death.

Classical ST is caused by a repeat de novo CA V 1.2 missense mutation (G1216A transition in the 8th exon, alternative splicing of G406R CACNA 1C), causing a multisystem disorder, including arrhythmia and autism. Despite syndactyly being a common feature of the classic form of TS, OZAWA J described 2 atypical patients with severe heart defects, absence of syndactyly, and a new CACNA 1C mutation was identified [10]. This fact expands the spectrum of ST.

In relation to the ECG findings, the characteristics of ST are: 2nd degree AV block, long QT and T wave alternans (T waves with different morphologies and formats), as in the case presented.

Patients with TS are treated clinically with antiarrhythmics of the B-adrenergic blocker type, with propranolol and nadolol being more effective [11, 12] Although studies have shown a reduction in adverse cardiac events in STQL type 1, these antiarrhythmics are insufficient to prevent lethal arrhythmias in patients with TS [11, 12, 13]. Therefore, new therapies for ST are still needed. Some studies suggest that roscovitine, a cyclin-dependent kinase (CDK) inhibitor, could rescue the phenotypes in cardiomyocytes derived from human-induced pluripotent stem cells (MCs) and neurons from TS patients [10, 14, 15]. However, the mechanisms by which roscovitine restores cardiac function in CM CMS have not been fully elucidated. In the case reported, we used propranolol beta-adrenergic blockers.

In general, in LQTS, implantation of a cardioverter defibrillator is indicated in patients who survived the event of cardiac arrest, in those with syncope(s) even on a full dose of beta-adrenergic blockers, and exceptionally in those with signs of increased electrical instability ( long pauses followed by alternating T waves) and QTc interval > 550ms [13]. Left cardiac sympathetic denervation (removal of the third and fourth thoracic ganglia) by thoracotomy or thoracoscopy is an adjunctive therapy to the use of beta-blockers for the control of arrhythmic storms and repeated shock of an implantable defibrillator in LQTS [13]. However, in Jervell and Lange-Nielsen LQTS (LQT types 1 and 3 associated with deafness) and in TS, due to severity, it is recommended to associate therapy with the use of beta-adrenergic blockers such as cardioverter defibrillator and denervation.

The authors emphasize the importance of performing an electrocardiogram in the suspicion of Timothy syndrome, to aid in the diagnosis and before any procedure, in patients with the syndrome.

Ventricular arrhythmias can occur spontaneously or during anesthetic procedures, especially Torsade de Pointes (TdP). These arrhythmic events occur in up to 80% of patients, leading to death. Drug treatment and, when indicated, the insertion of an implantable cardioverter defibrillator (ICD) are imperative to avoid sudden death in these patients.

Funding None

Compliance with Ethical Standarts

Conflict of Interest The authors declare that they have no conflicts of interest.

Ethical Approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed Consent Written consent form for publication of the details and images of the case was obtained from the parent of the patient.

Schwartz PJ, Stramba-Badiale M, Crotti L, Pedrazzini M, Besana A, Bosi G, Gabbarini F, Goulene K, Insolia R, Mannarino S, Mosca F, Nespoli L, Rimini A, Rosati E, Salice P, Spazzolini C. Prevalence of the congenital long -QT syndrome. Circulation. 2009; 120:1761–1767.
Nogueira RB, Rebello ES, Rebello AP, Sotomaior VS, Raskin S. Síndrome do QT Longo. Estud Biol. 2010;32 (76–81):105–110.
Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R, et al. Ca (V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia autismo. Cell. 2004; 119:19–31.
Sagie A, Larson MG, Goldberg RJ et al. An improved method for adjusting the QT interval for heart rate (the Framingham Heart Study). Am J Cardiol. 1992;70:797–801.
Fridericia, LS. Die Systolendauer im Elekrokardiogramm bei normalen Menschen und bei Herzkranken. Acta Med. Scand. 1920; 53: 469–486
Bazett, JC. An analysis of time relations of electrocardiograms. Heart 1920; 7,353–367.
Queres JFM, Brandão LF, Matoso LB, Lucas E. O que o clínico deve saber. In: Mallet AR, Muxfeldt ES. Eletrocardiograma: da graduação à prática clínica. Rio de Janeiro: Thieme Revinter Publicações; 2019.
Sociedade Brasileira de Cardiologia. III Diretriz sobre análise e emissão de laudos eletrocardiográficos. Arq Bras Cardiol 2016; 106 (4 supl1); 1–23.
Schwartz P, Crotti L. QTc Behavior During Exercise and Genetic Testing for the Long-QT Syndrome. Circulation. 2011; 124: 2181–2184.
Ozawa J, Ohno S, Saito H, Saitoh A, Matsuura H, Horie M. A novel CACNA1Cmutation identified in a patient with Timothy syndrome without syndactyly exerts both marked loss- and gain-of-function effects. Heart Rhythm Case Rep. 2018;4(7):273–277
Bauer R, Timothy KW, Golden A. Update on the Molecular Genetics of Timothy Syndrome. Front Pediatr 2021;17 (9):668546.
Skinner JR, Winbo A, Abrams D, Vohra J, Wilde AA. Channelopathies that lead to sudden cardiac death: clinical and genetic aspects. Heart Lung Circ 2019; 28: 22–30.
Schwartz PJ, Crotti L, Insolia R. Long-QT syndrome: from genetics to management. Circ Arrhythm Electrophysiol 2012;5(4):868 – 77. Erratum in: Circ Arrhythm Electrophysiol 2012;5(6):e119-20.
Song L, Park SE, Isseroff Y, Morikawa K, Yazawa M. Inhibition of CDK5 Alleviates the Cardiac Phenotypes in Timothy Syndrome. Stem Cell Reports 2017;9(1):50–57.
Yazawa M, Hsueh B, Jia X, Pasca AM, Bernstein JA, Hallmayer J, Dolmetsch RE. Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome. Nature 2011;471(7337):230–4.

Table 1 Clinical diagnosis of long QT syndrome (scoring system)

ECG and clinical characteristics

Findings

Points

ECG QTc values*

* QTc calculated by Bazett's formula

>/= 480 m

460−479 ms

450−459 ms

≥ 480 ms at the 4^th min recovery from exercise stress test

ECG T wave features, Torsades de Pointes and HR #

# in the absence of medications or disorders known to affect these ECG findings

Torsade de Pointes

T-wave alternans

Notched T-wave in 3 leads

Low HR for age

0.5

Clinical history

Syncope with stress

Syncope with no stress

Family history

Family member(s) with definitive LQTS

Unexplained sudden cardiac death aged < 30 years in the immediate family

0.5

Total score: ≤1.0 point = low probability of SQTL 1.5–3.0 points = intermediate probability of SQT ≥ 3.5 points = high probability of SQTL .

Adapted from Schwartz & Crotti (2011)

No competing interests reported.

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Timothy Syndrome and Torsades De Pointes in a Newborn - Case Report

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