Update on the Diagnosis and Management of Familial Long QT Syndrome
2016; Elsevier BV; Volume: 25; Issue: 8 Linguagem: Inglês
10.1016/j.hlc.2016.01.020
ISSN1444-2892
AutoresK. Waddell-Smith, Jonathan R. Skinner,
Tópico(s)Receptor Mechanisms and Signaling
ResumoThis update was reviewed by the CSANZ Continuing Education and Recertification Committee and ratified by the CSANZ board in August 2015. Since the CSANZ 2011 guidelines, adjunctive clinical tests have proven useful in the diagnosis of LQTS and are discussed in this update. Understanding of the diagnostic and risk stratifying role of LQTS genetics is also discussed. At least 14 LQTS genes are now thought to be responsible for the disease. High-risk individuals may have multiple mutations, large gene rearrangements, C-loop mutations in KCNQ1, transmembrane mutations in KCNH2, or have certain gene modifiers present, particularly NOS1AP polymorphisms.In regards to treatment, nadolol is preferred, particularly for long QT type 2, and short acting metoprolol should not be used. Thoracoscopic left cardiac sympathectomy is valuable in those who cannot adhere to beta blocker therapy, particularly in long QT type 1. Indications for ICD therapies have been refined; and a primary indication for ICD in post-pubertal females with long QT type 2 and a very long QT interval is emerging. This update was reviewed by the CSANZ Continuing Education and Recertification Committee and ratified by the CSANZ board in August 2015. Since the CSANZ 2011 guidelines, adjunctive clinical tests have proven useful in the diagnosis of LQTS and are discussed in this update. Understanding of the diagnostic and risk stratifying role of LQTS genetics is also discussed. At least 14 LQTS genes are now thought to be responsible for the disease. High-risk individuals may have multiple mutations, large gene rearrangements, C-loop mutations in KCNQ1, transmembrane mutations in KCNH2, or have certain gene modifiers present, particularly NOS1AP polymorphisms. In regards to treatment, nadolol is preferred, particularly for long QT type 2, and short acting metoprolol should not be used. Thoracoscopic left cardiac sympathectomy is valuable in those who cannot adhere to beta blocker therapy, particularly in long QT type 1. Indications for ICD therapies have been refined; and a primary indication for ICD in post-pubertal females with long QT type 2 and a very long QT interval is emerging. •Long QT syndrome (LQTS) is a familial condition causing syncope and sudden death through polymorphic ventricular tachycardia (torsades de pointes), which can deteriorate to ventricular fibrillation, in otherwise fit and healthy young people.•Prevalence is approximately 1 in 2,500 [[1]Schwartz P.J. Stramba-Badiale M. Crotti L. Pedrazzini M. Besana A. Bosi G. et al.Prevalence of the congenital long-QT syndrome.Circulation. 2009; 120: 1761-1767Crossref PubMed Scopus (714) Google Scholar].•Clinical diagnosis is made from a combination of suspicious clinical history (sudden unheralded syncope or cardiac arrest typically associated with exercise, stress, startle or during sleep) and family history, and the 12 lead ECG.•ECG typically reveals a heart-rate corrected QT interval (QT/√R-R interval = QTc) repeatedly greater than 470ms in women and 450ms in men, in the absence of other known factors prolonging the QT interval.•High risk individuals are identified by QTc≥500ms and/or syncope in the previous two years. Boys and post pubertal females (especially in the nine post-partum months) are high risk.•Risk reduction is achieved through lifestyle modification, avoidance of QT prolonging drugs, beta blockade and less commonly with left cardiac sympathetic denervation or ICD insertion. An expanded section is included on QTc analysis, see text. Since 2011, adjunctive clinical tests have proven useful in the diagnosis of LQTS. At four minutes after cessation of an exercise test, a QTc exceeding 480ms is highly suggestive of LQTS and is reflected in the Schwarz criteria. Likewise, QTc assessment at 10 seconds after standing shows a greater prolongation in those affected by LQTS when compared with unaffected individuals. Understanding of the diagnostic and risk stratifying role of LQTS genetics is discussed. At least 14 LQTS genes are now thought to be responsible for the disease. High-risk individuals may have multiple mutations, large gene rearrangements, C-loop mutations in KCNQ1, transmembrane mutations in KCNH2, or have certain gene modifiers present. In regards to treatment, nadolol is preferred and short acting metoprolol should not be used. Indications for ICD therapy are refined to (1) resuscitated cardiac arrest (2) recurrent arrhythmic syncope whilst adherent to beta blockers, see text for relative indications. An emerging primary indication is post pubertal women with long QT type 2 and a QTc >550ms. The diagnosis is usually made on clinical grounds, see Table 1, [2Schwartz P.J. Moss A.J. Vincent G.M. Crampton R.S. Diagnostic criteria for the long QT syndrome. An update.Circulation. 1993; 88: 782-784Crossref PubMed Scopus (979) Google Scholar, 3Schwartz P.J. Crotti L. QTc behavior during exercise and genetic testing for the long-QT syndrome.Circulation. 2011; 124: 2181-2184Crossref PubMed Scopus (219) Google Scholar] and is suggested if the presentation is with syncope or resuscitated sudden cardiac death, particularly if associated with exercise, sudden emotional stress, loud noise, or when supine. Prodromal symptoms of pre-syncope, palpitations or a change in temperature can be experienced [[4]MacCormick J.M. Crawford J.R. Chung S.K. Shelling A.N. Evans C.A. Rees M.I. et al.Symptoms and signs associated with syncope in young people with primary cardiac arrhythmias.Heart Lung Circ. 2011; 20: 593-598Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar]. Syncope associated with swimming should be suspected to be LQTS (or CPVT; catecholaminergic polymorphic ventricular tachycardia) until proven otherwise. Misdiagnosis of LQTS as epilepsy, particularly "familial epilepsy", is common [[5]MacCormick J.M. McAlister H. Crawford J. French J.K. Crozier I. Shelling A.N. et al.Misdiagnosis of long QT syndrome as epilepsy at first presentation.Ann Emerg Med. 2009; 54: 26-32Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar]. Seizures during exertion or arousal, and during sleep, must raise the suspicion of LQTS.Table 1Diagnostic Criteria for LQTS (Schwartz Score)PointsElectrocardiographic findings#In the absence of medications or disorders known to affect these electrocardiographic features; ^QTc calculated by Bazett's formula where QTc=QT/√RR; *Mutually exclusive; @Resting heart rate below the 2nd percentile for age; $The same family member cannot be counted in A and B. Score: ≤1 point: low probability of LQTs; 1.5 to 3 points: intermediate probability of LQTS; ≥3.5 points high probability. AATc^≥480 ms3460-479 ms2450-459 ms (in males)1 BQTc^ 4th minute of recovery from exercise stress test ≥480 ms1 CTorsade de pointes*2 DT wave alternans1 ENotched T wave in 3 leads1 FLow heart rate for [email protected]0.5Clinical History ASyncope*With stress2Without stress1 BCongenital deafness0.5Family History AFamily members with definite LQTS$1 BUnexplained sudden cardiac death age 30 among immediate family members$0.5# In the absence of medications or disorders known to affect these electrocardiographic features; ^QTc calculated by Bazett's formula where QTc=QT/√RR; *Mutually exclusive; @Resting heart rate below the 2nd percentile for age; $The same family member cannot be counted in A and B.Score: ≤1 point: low probability of LQTs; 1.5 to 3 points: intermediate probability of LQTS; ≥3.5 points high probability. Open table in a new tab Differentiation from neurocardiogenic syncope is usually made on history. Neurocardiogenic syncope typically follows pain or prolonged upright posture, has a long prodrome and is associated with nausea [[6]Colman N. Bakker A. Linzer M. Reitsma J.B. Wieling W. Wilde A.A. Value of history-taking in syncope patients: in whom to suspect long QT syndrome?.Europace. 2009; 11: 937-943Crossref PubMed Scopus (62) Google Scholar]. Ambulatory event monitoring or implantable loop recorder can be valuable in detecting or excluding arrhythmia at time of syncope if other tests are inconclusive. A family history of sudden unexplained death in young people is highly suggestive [[6]Colman N. Bakker A. Linzer M. Reitsma J.B. Wieling W. Wilde A.A. Value of history-taking in syncope patients: in whom to suspect long QT syndrome?.Europace. 2009; 11: 937-943Crossref PubMed Scopus (62) Google Scholar]. Studies of the three most common genotypes (Types 1, 2 and 3) have shown that the life-threatening cardiac events (syncope or sudden death) tend to occur under specific circumstances in a gene-specific manner and have characteristic T wave morphologies [[7]Schwartz P.J. Priori S.G. Spazzolini C. Moss A.J. Vincent G.M. Napolitano C. et al.Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias.Circulation. 2001; 103: 89-95Crossref PubMed Scopus (1466) Google Scholar], see Table 3. Subjects with long QT types 1 and 2 tend to have several "warning" syncopal episodes before a sudden death, whereas in long QT3 the first presentation is typically sudden death [[8]Priori S.G. Schwartz P.J. Napolitano C. Bloise R. Ronchetti E. Grillo M. et al.Risk stratification in the long-QT syndrome.N Engl J Med. 2003; 348: 1866-1874Crossref PubMed Scopus (1203) Google Scholar]. Abnormal ventricular repolarisation is demonstrated through QT prolongation or abnormal T-wave morphology on an incidental ECG or during family screening following a sudden unexplained death [9Behr E.R. Dalageorgou C. Christiansen M. Syrris P. Hughes S. Tome Esteban M.T. et al.Sudden arrhythmic death syndrome: familial evaluation identifies inheritable heart disease in the majority of families.Eur Heart J. 2008; 29: 1670-1680Crossref PubMed Scopus (333) Google Scholar, 10Tan H.L. Hofman N. van Langen I.M. van der Wal A.C. Wilde A.A. Sudden unexplained death: heritability and diagnostic yield of cardiological and genetic examination in surviving relatives.Circulation. 2005; 112: 207-213Crossref PubMed Scopus (343) Google Scholar]. QT prolongation due to drugs or biochemical imbalance (low potassium, calcium or magnesium), hypothermia and myocardial disease must be excluded. Despite the failings of the Bazett heart-rate correction formula (QT divided by square root of preceding R-R interval), it is still in popular use. The end of the QT interval is determined by extrapolating the steepest curve of the T wave down to the baseline [[11]Postema P.G. De Jong J.S. Van der Bilt I.A. Wilde A.A. Accurate electrocardiographic assessment of the QT interval: teach the tangent.Heart Rhythm. 2008; 5: 1015-1018Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar]. Take the longest measurement of lead II or V5 [[12]Monnig G. Eckardt L. Wedekind H. Haverkamp W. Gerss J. Milberg P. et al.Electrocardiographic risk stratification in families with congenital long QT syndrome.Eur Heart J. 2006; 27: 2074-2080Crossref PubMed Scopus (42) Google Scholar]. Individuals with LQTS can have a normal QTc and vice versa [13Vincent G.M. Timothy K.W. Leppert M. Keating M. The spectrum of symptoms and QT intervals in carriers of the gene for the long-QT syndrome.New England Journal of Medicine. 1992; 327: 846-852Crossref PubMed Scopus (540) Google Scholar, 14Goldenberg I. Moss A.J. Long QT syndrome.J Am Coll Cardiol. 2008; 51: 2291-2300Abstract Full Text Full Text PDF PubMed Scopus (387) Google Scholar]. Heart Rhythm Society guidelines suggest that, outside of family cascade screening, in asymptomatic individuals a QTc of ≥ 500ms on two separate ECGs is required to make the diagnosis of LQTS, but in patients with unexplained syncope, the diagnosis can be made from QTc ≥ 480 ms on repeated ECGs [[15]Priori S.G. Wilde A.A. Horie M. Cho Y. Behr E.R. Berul C. et al.HRS/EHRA/APHRS Expert Consensus Statement on the Diagnosis and Management of Patients with Inherited Primary Arrhythmia Syndromes: Document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013.Heart Rhythm. 2013; 10: 1932-1963Abstract Full Text Full Text PDF PubMed Scopus (1239) Google Scholar]. Holter recordings are of limited additional value for making the diagnosis unless torsades de pointes or T-wave alternans is documented (which is very rare), or there is a history suggesting nocturnal events. Exercise testing can be helpful. In the recovery phase following exercise, QT intervals of LQTS mutation carriers and non-carriers tend to separate more than at rest. An absolute QT interval of over 0.37 sec at a heart-rate of 100 post exercise is highly suggestive of LQTS types 1 or 2; a QT below 0.34 sec makes it unlikely [[16]Swan H. Viitasalo M. Piippo K. Laitinen P. Kontula K. Toivonen L. Sinus node function and ventricular repolarization during exercise stress test in long QT syndrome patients with KvLQT1 and HERG potassium channel defects.J Am Coll Cardiol. 1999; 34: 823-829Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar]. QTc prolongation at four mins post exercise >480ms gains 1 Schwartz score point [17Chattha IS, Sy RW, Yee R, Gula LJ, Skanes AC, Klein GJ, et al. Utility of the recovery electrocardiogram after exercise: a novel indicator for the diagnosis and genotyping of long QT syndrome? Heart Rhythm. 7:906–11.Google Scholar, 18Sy R.W. van der Werf C. Chattha I.S. Chockalingam P. Adler A. Healey J.S. et al.Derivation and validation of a simple exercise-based algorithm for prediction of genetic testing in relatives of LQTS probands.Circulation. 2011; 124: 2187-2194Crossref PubMed Scopus (141) Google Scholar]. Normative values for children are available [[19]Berger W.R. Gow R.M. Kamberi S. Cheung M. Smith K.R. Davis A.M. The QT and corrected QT interval in recovery after exercise in children.Circ Arrhythm Electrophysiol. 2011; 4: 448-455Crossref PubMed Scopus (18) Google Scholar]. Examination of QT interval in the moments after standing can indicate LQTS carriage [[20]Viskin S. Postema P.G. Bhuiyan Z.A. Rosso R. Kalman J.M. Vohra J.K. et al.The response of the QT interval to the brief tachycardia provoked by standing: a bedside test for diagnosing long QT syndrome.J Am Coll Cardiol. 2010; 55: 1955-1961Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar]. With the patient supine and 12-lead ECG monitoring, the patient briskly stands and within 10 secs, heart rate increases (i.e. RR interval decreases). In those affected by LQTS, the QT interval reduces much less than the RR interval (there is less than a 20ms change in absolute QT). Therefore, at maximal QT stretch (where the end of the T-wave is closest to the next P-wave (i.e. the RR has shortened without the QTc adapting and shortening)) the QTc increases by 89±47ms and ventricular ectopic beats or T-wave alternans may be seen. In comparison, in those without LQTS, QTc increases by 50±30ms (P<0.001) [[20]Viskin S. Postema P.G. Bhuiyan Z.A. Rosso R. Kalman J.M. Vohra J.K. et al.The response of the QT interval to the brief tachycardia provoked by standing: a bedside test for diagnosing long QT syndrome.J Am Coll Cardiol. 2010; 55: 1955-1961Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar]. This is a relatively new test requiring validation in other cohorts, and there is a paucity of normative data, especially in children, so while it may add value, it is prudent to be cautious in interpreting these results. A detailed family history looks for a history of syncope or sudden unexplained death at a young age in a close relative. Directed questioning is essential, with a family tree being drawn. Consider unexpected drowning in a strong swimmer, or road traffic accidents on a straight road. Document age and mode of death or syncope in all close relatives. Familial epilepsy and sudden infant death are suspicious. Any sudden unexpected natural death with a negative post-mortem should trigger a family investigation for LQTS and other channelopathies. Once the diagnosis is suspected, ECGs should be obtained on all first-degree relatives. QTc values of ≥440ms are treated as suspicious and values below 410ms are uncommon in gene carriers. Up to one third of asymptomatic gene mutation carriers have QTc values within the normal range [[21]Priori S.G. Schwartz P.J. Napolitano C. Bloise R. Ronchetti E. Grillo M. et al.Risk stratification in the long QT syndrome.The New England Journal of Medicine. 2003; 348: 1866-1874Crossref PubMed Scopus (0) Google Scholar]. Therefore, examining T-wave morphology, reviewing QT interval behaviour after exercise testing and performing genetic testing are important adjuvants. The length of the QT interval is linked to the risk of syncope and sudden death, but all gene carriers are at an increased risk, and have 50% chance of passing on the mutation to each of their children. LQTS is caused by mutations in any of 15 LQTS genes (Table 2), with the number of genes expected to keep rising with further studies. The most common pattern of inheritance is autosomal dominant (sometimes called Romano-Ward syndrome) which is caused by a single mutation in any of these genes. Each child of an affected parent has a 50% chance of inheriting a disease-causing gene mutation.Table 2Long QT genesClinical nameChromosomal locusGene nameCurrent AffectedProportion of mutationsLQT111p15.5KCNQ1 (KVLQT1)K+ (IKs)38%LQT27q35-36HERG (KCNH2)K+ (IKr)42%LQT33p21-24SCN5ANa+ (INA)12%LQT44q25-27Ankyrin BNa+ (INA)1%LQT521q22.1-22.2KCNE1 (minK)K+ (IKs)5%LQT621q22.1-22.2KCNE2 (MiRP1)K+ (IKr)1%LQT7 (Anderson)17q23KCNJ2K+ (Kir2.1)<0.1%LQT8 (Timothy)12p13.3CACNA1C*Calcium channel, voltage-dependent, L type, alpha 1C subunit. LQT7-Anderson syndrome is a rare neurological disorder characterised by periodic paralysis, skeletal developmental abnormalities, and QT prolongation. LQT8-Timothy syndrome is a rare condition characterised by syndactyly, facial dysmorphism, autism and severe LQTS. Two further LQT types are referenced in the text; due to mutations in Calmodulin and Triadin.Ca++(ICa-L)<0.1%LQT93p25CAV3 (Caveolin)Na+ (INA)<0.1%LQT1011q23.3SCN4BNa+ (INA)<0.1%LQT117q21-q22AKAP9 (A -anchor protein 9)K+ (IKs)<0.1%LQT1220q11.2SNTA1 (alpha-1 syntrophin)Na+ (INA)<0.1%LQT1311q24.3KCNJ5K+ (Kir)<0.1%^ From Modell, 2006 [63]Modell S.M. Lehmann M.H. The long QT syndrome family of cardiac ion channelopathies: a HuGE review.Genet Med. 2006; 8: 143-155Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar.* Calcium channel, voltage-dependent, L type, alpha 1C subunit.LQT7-Anderson syndrome is a rare neurological disorder characterised by periodic paralysis, skeletal developmental abnormalities, and QT prolongation.LQT8-Timothy syndrome is a rare condition characterised by syndactyly, facial dysmorphism, autism and severe LQTS.Two further LQT types are referenced in the text; due to mutations in Calmodulin and Triadin. Open table in a new tab ^ From Modell, 2006 [63]Modell S.M. Lehmann M.H. The long QT syndrome family of cardiac ion channelopathies: a HuGE review.Genet Med. 2006; 8: 143-155Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar. The most common genotypes are types 1 and 2; next in frequency are types 3 and 5 [[22]Earle N. Crawford J. Smith W. Hayes I. Shelling A. Hood M. et al.Community detection of long QT syndrome with a clinical registry: an alternative to ECG screening programs?.Heart Rhythm. 2013; 10: 233-238Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar]. In each, a dysfunctional cardiac ion-channel results in prolongation and/or distortion of the cardiac action potential, and thus the QT interval and T wave. Many of the hundreds of mutations found to date are unique to a family or very rare; and detail about pathogenicity may be lacking. About a quarter of families with LQTS do not yet have a recognised genetic locus. Test yield and interpretation are best when clinical phenotype is well established in the proband. Two recently described new syndromes seem at this stage to be very severe and affect only young children, the so-called triadin-knock out syndrome with recessive inheritance, and Calmodulin related disease [23Altmann H.M. Tester D.J. Will M.L. Middha S. Evans J.M. Eckloff B.W. et al.Homozygous/Compound Heterozygous Triadin Mutations Associated With Autosomal-Recessive Long-QT Syndrome and Pediatric Sudden Cardiac Arrest: Elucidation of the Triadin Knockout Syndrome.Circulation. 2015; 131: 2051-2060Crossref PubMed Scopus (76) Google Scholar, 24Crotti L. Johnson C.N. Graf E. De Ferrari G.M. Cuneo B.F. Ovadia M. et al.Calmodulin mutations associated with recurrent cardiac arrest in infants.Circulation. 2013; 127: 1009-1017Crossref PubMed Scopus (259) Google Scholar]. Determination of genotype can be useful to confirm diagnosis, allow genetic screening of potentially affected family members and tailor therapy. Certain mutations can identify individuals at higher risk, and due to genotype-phenotype correlation (see Table 3), gene (and even mutation)-specific risk avoidance and therapy can be instituted after genotyping has been performed.Table 3Phenotypic characteristics of LQT types 1,2 and 3LQT typeT-wave morphologyEvents triggered by exercise (%)Events triggered by excitement (%)Events during rest or sleep (%)Reduction of risk of SCD by beta blockersGroup most severely affectedPercentage of LQT gene positive SUDI cases*SUDI, sudden unexplained death in infancy.1Broad based6226375%Boys aged 5-1510%2Low voltage, double bump13432950%Adult women10%3Late onset high amplitude131939No established benefitAdult male and infants68%* SUDI, sudden unexplained death in infancy. Open table in a new tab Approximately 5% of families have two mutations, and family members with both mutations tend to be more severely affected. The presence of two mutations on opposite chromosomes in either the LQT1 or LQT5 gene results in a severe autosomal recessive form of LQTS with associated sensorineural deafness, (Jervell and Lange-Nielsen syndrome) [[25]Schwartz P.J. Spazzolini C. Crotti L. Bathen J. Amlie J.P. Timothy K. et al.The Jervell and Lange-Nielsen syndrome: natural history, molecular basis, and clinical outcome.Circulation. 2006; 113: 783-790Crossref PubMed Scopus (306) Google Scholar] low gastric acid secretion and iron deficiency anaemia are also features of this rare condition [[26]Winbo A. Sandstrom O. Palmqvist R. Rydberg A. Iron-deficiency anaemia, gastric hyperplasia, and elevated gastrin levels due to potassium channel dysfunction in the Jervell and Lange-Nielsen Syndrome.Cardiol Young. 2013; 23: 325-334Crossref PubMed Scopus (17) Google Scholar]. Secondary testing for deletions and duplications of exons should be considered in the group of patients who are definitely and severely affected by LQTS yet standard genetic testing was uninformative. Deletions and duplications have been identified in 5-15% of such individuals [27Eddy C.A. MacCormick J.M. Chung S.K. Crawford J.R. Love D.R. Rees M.I. et al.Identification of large gene deletions and duplications in KCNQ1 and KCNH2 in patients with long QT syndrome.Heart Rhythm. 2008; 5: 1275-1281Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 28Tester D.J. Benton A.J. Train L. Deal B. Baudhuin L.M. Ackerman M.J. Prevalence and spectrum of large deletions or duplications in the major long QT syndrome-susceptibility genes and implications for long QT syndrome genetic testing.Am J Cardiol. 2010; 106: 1124-1128Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar]. Patients with missense mutations in the cytoplasmic loops of KCNQ1 are at the highest risk of cardiac events (regardless of other risk factors), generally triggered by exercise. However, their risk is also most significantly reduced by the use of beta blockers, so this therapy is particularly important here [[29]Barsheshet A, Goldenberg I, J OU, Moss AJ, Jons C, Shimizu W, et al. Mutations in cytoplasmic loops of the KCNQ1 channel and the risk of life-threatening events: implications for mutation-specific response to beta-blocker therapy in type 1 long-QT syndrome. Circulation. 2012;125:1988–96.Google Scholar]. Mutations in the cardiac sodium channel gene SCN5A, cause long QT type 3 if the cardiac sodium channel (Nav1.5) is overactive (leaking sodium and prolonging the action potential), and cause Brugada syndrome if it is underactive [[30]Abriel H. Cardiac sodium channel Na(v)1.5 and interacting proteins: Physiology and pathophysiology.J Mol Cell Cardiol. 2009; PubMed Google Scholar]. Both clinical conditions tend to cause nocturnal sudden death as their first symptom, and families exist where both of these conditions are present in different family members, with the same genetic mutation. Among LQTS related sudden unexpected death in infancy and 1-40 year olds, SCN5A mutations are the most common [[31]Wang D. Shah K.R. Um S.Y. Eng L.S. Zhou B. Lin Y. et al.Cardiac channelopathy testing in 274 ethnically diverse sudden unexplained deaths.Forensic Sci Int. 2014; 237: 90-99Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar]. Modifiers of gene expression have been identified and show promise as potential tools to assess risk. They include untranslated regions which modify the RNA binding site in LQT1 [[32]Amin A.S. Giudicessi J.R. Tijsen A.J. Spanjaart A.M. Reckman Y.J. Klemens C.A. et al.Variants in the 3′ untranslated region of the KCNQ1-encoded Kv7.1 potassium channel modify disease severity in patients with type 1 long QT syndrome in an allele-specific manner.Eur Heart J. 2012; 33: 714-723Crossref PubMed Scopus (119) Google Scholar] and minor changes (single nucleotide polymorphisms) in NOS1AP, a gene linked to QT prolongation in the general population [[33]Earle N. Yeo Han D. Pilbrow A. Crawford J. Smith W. Shelling A.N. et al.Single nucleotide polymorphisms in arrhythmia genes modify the risk of cardiac events and sudden death in long QT syndrome.Heart Rhythm. 2014; 11: 76-82Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar]. The main value of genetic testing lies in family screening. Following the identification of a proband with unequivocal LQTS, molecular diagnosis is then sought through screening the known LQTS genes in the affected individual. Once the disease causing mutation is identified, screening for this specific mutation in the family is relatively quick and inexpensive. Careful counselling prior to testing is essential (particularly if the individual is clinically unaffected). Negative aspects of a positive genetic diagnosis include potential insurance, employment and psychological problems. Input from a cardiac-genetic counsellor is beneficial, [[34]Ingles J. Yeates L. Semsarian C. The emerging role of the cardiac genetic counselor.Heart Rhythm. 2011; 8: 1958-1962Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar] especially when the genetics of LQTS is outside the clinicians' usual scope of practice [[35]Tester D.J. Ackerman M.J. Genetic testing for potentially lethal, highly treatable inherited cardiomyopathies/channelopathies in clinical practice.Circulation. 2011; 123: 1021-1037Crossref PubMed Scopus (158) Google Scholar]. Interpretation of genetic results is best performed with input from molecular and clinical genetics. Genetic screening for LQTS as part of a molecular autopsy in autopsy-negative young sudden death can reveal a diagnosis in 15-20% of cases [31Wang D. Shah K.R. Um S.Y. Eng L.S. Zhou B. Lin Y. et al.Cardiac channelopathy testing in 274 ethnically diverse sudden unexplained deaths.Forensic Sci Int. 2014; 237: 90-99Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 36Skinner J.R. Crawford J. Smith W. Aitken A. Heaven D. Evans C.A. et al.Prospective, population-based long QT molecular autopsy study of postmortem negative sudden death in 1 to 40 year olds.Heart Rhythm. 2011; 8: 412-419Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar]. All gene carriers must avoid medications which prolong the QT interval, can cause torsade de pointes or lower serum potassium or magnesium levels. A constantly updated list is available at www.crediblemeds.org. Herbal remedies and some dietary treatments also represent a risk [[37]Nazeri A. Massumi A. Wilson J.M. Frank C.M. Bensler M. Cheng J. et al.Arrhythmogenicity of weight-loss supplements marketed on the Internet.Heart Rhythm. 2009; 6: 658-662Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar]. Secondary triggers such as hypokalaemia and medications are especially common in adults [[38]Sakaguchi T. Shimizu W. Itoh H. Noda T. Miyamoto Y. Nagaoka I. et al.Age- and genotype-specific triggers for life-threatening arrhythmia in the genotyped long QT syndrome.J Cardiovasc Electrophysiol. 2008; 19: 794-799Crossref PubMed Scopus (28) Google Scholar]. With all forms of LQTS, where there is a long QT interval (and not necessarily just gene carriage), a degree of caution with sporting activity is recommended. There is increasing evidence that the risk is low if patients adhere to beta blocker therapy [[39]Johnson J.N. Ackerman M.J. Return to play? Athletes with congenital long QT syndrome.Br J Sports Med. 2013; 47: 28-33Crossref PubMed Scopus (104) Google Scholar]. With LQT1, and subjects with a history of exercise induced syncope, swimming and diving are generally contraindicated. However, many patients choose to continue with swimming, and these are sometimes managed by the use of an advisory defibrillator with a supervisor at the pool-side, and adjuvant cardiac sympathectomy may be used. Exercise precautions are more imperative with LQT1, or in those who have already experienced events during exercise, than in LQT2 and 3. Such individuals should generally be advised away from becoming professional at
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