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Shawky: Sudden unexplained death in the young – a genetic approach to non-structural cardiac defects

Comment

Sudden unexplained death syndrome (SUDS) is the abrupt, unexpected natural death of an apparently healthy individual in whom no gross abnormalities could be identified post mortem. The syndrome is extremely devastating, and tragic for both the family and the community when it involves young people.

In many cases, the cause of SUDS in young people is a genetic heart disorder.1 These disorders can lead to structural abnormalities (e.g. hypertrophic cardiomyopathy and ischaemic cardiac abnormalities), which are responsible for a large majority of such deaths, or arrhythmogenic abnormalities, which account for only a small minority of all sudden death cases [e.g. long QT syndrome (LQTS), Burgada syndrome (BrS) and catecholaminergic polymorphic ventricular tachycardia (CPVT)].2

In recent years, advances in genetic research have led to the discovery of many genes that are responsible for arrhythmias and SUDS in young people.

Long QT syndrome is caused by mutations in genes encoding potassium (KCNQ1, HERG, KCNE1and KCNE2) or sodium (SCN5A) channels. These mutations cause delayed polarization of the heart following an increase in heart rate, leading to an increased risk of a torsade de pointes episode (a form of irregular heart beat which originates in the ventricles). Torsade de pointes episodes lead to heart palpitations, fainting and sudden death due to ventricular tachycardia. LQTS can be inherited in an autosomal dominant or recessive manner. The autosomal recessive forms tend to be associated with a more severe phenotype, with some variants having syndactyly or congenital neural deafness. The symptoms can also start in childhood.2

Burgada syndrome is due to mutations in SCN5A. It has an autosomal dominant pattern of transmission and causes up to 50% of all sudden deaths. It is characterized by syncopal episodes or death. It is a clinical electrocardiographic diagnosis: ST-segment elevation in precordial leads V1–V3 and QRS complex, resembling a right branch block. In many patients, the electrocardiogram changes transiently normalize, leading to underdiagnosis of the syndrome. Administration of sodium channel blockers can unmask intermittent forms.3

Catecholaminergic polymorphic ventricular tachycardia is due to a defect in calcium-handling proteins, ryanodine receptor 2 (RyR2) or calcequestrin (CASQ2). CPVT's mode of inheritance is autosomal dominant or sometimes autosomal recessive. It is characterized by episodes of syncope occurring during exercise as a result of the onset of fast ventricular tachycardia. Spontaneous recovery may occur if these arrhythmias self-terminate and sudden death occurs if ventricular tachycardia degenerates into ventricular fibrillation.4

Genetic studies in arrhythmias rely on candidate gene sequencing, which can detect a vast number of single-nucleotide polymorphisms.5

Sudden cardiac death resulting from inherited arrhythmias produces enormous stress in the family, specifically about who else is affected and who next will die. Evaluation of families requires a multidisciplinary approach, which should include cardiologists, geneticists, clinical genetic counsellors and forensic pathologists. An extended pedigree should be developed by contacting family members and screening by phenotyping and genotyping. This detailed analysis allows recognition and presymptomatic treatment of mutation carriers.6

The prognosis of patients is poor unless a cardiovascular defibrillator is implanted. Beta-blockers can be used in individuals with RyR2 mutations with no history of cardiac syncope or ventricular arrhythmia on exercise testing.

References

1. 

Vincent GM. Sudden cardiac arrest in the young due to inherited arrythmias: the importance of family care. Pacing Clin Electrophysiol 2009; 32(Suppl. 2):S19–22. http://dx.doi.org/10.1111/j.1540–8159.2009.02395.x

2. 

Morita H, Wu J, Zipes DP. The QT syndrome: long and short. Lancet 2008, 372:750–63. dx.doi.org/10.1016/S0140–6736(08)61307–0

3. 

Mokaddem A, Chattaoui R, Sidri W, et al. Brugada syndrome. Tunis Med 2001; 79: 569–73.

4. 

Wever-Pinzon OE, Myerson M, Sherrid MV. Sudden cardiac death in young competitive athletes due to genetic cardiac abnormalities. Anadolu Kardiyol Derg 2009; 9(Suppl. 2):17–23.

5. 

Koo SH, Ku CS, Chui P, Lee EJD. Unravelling the Mystery of Sudden Cardiac Death Through Genetic Approaches. Wiley & Sons; 2011.

6. 

Ingles J, Semsarian C. Sudden cardiac death in the young: a clinical genetic approach. Intern Med J 2007; 37:32–7.





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