sudden unexplained death in infancy and long qt syndrome. … · what is long qt syndrome? long qt...
TRANSCRIPT
Sudden unexplained death in infancy and long QT syndrome.
Jonathan Robert Skinner
Greenlane Paediatric and Congenital Cardiac Services,
Starship Children’s Hospital,
Park Road, Grafton,
Auckland New Zealand.
Dept Child Health University of Auckland,
Auckland,
New Zealand.
Tel +64 9 3074949
Fax +64 9 6310785
Email [email protected]
Abstract
After more than 30 years of research into the hypothesis that long QT syndrome (LQTS)
might be a cause of arrhythmic sudden infant death, we are now at the point where we
can state with certainty that some sudden unexplained deaths in infancy, about 10%, are
indeed due to long QT syndrome. The evidence for this lies in large population ECG
screening programmes, post-mortem molecular genetic testing of sudden infant death
victims, and some informative case reports. The cardiac sodium channel gene SCN5A
(LQTS type 3) is the most common culprit, but LQTS types 1,2, 6, 9 and 12 have also
been found. There is also new evidence that other arrhythmic syndromes sometimes
cause SUDI, in particular short QT syndrome, and catecholaminergic polymorphic
ventricular tachycardia (CPVT). These conditions are also due to disordered cardiac ion
channel function like LQTS, and are usually inherited in an autosomal dominant fashion.
There remain, however, many unanswered questions, most particularly whether all
populations are affected equally, and what should clinicians do with this knowledge?
Should newborn ECG screening become mandatory? How should we best investigate
SUDI at post mortem in order to diagnose LQTS? This review summarises the evidence
to date and addresses these questions.
Key Words
Sudden unexplained death in infancy (SUDI).
Long QT syndrome (LQTS).
Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)
SCN5A
Cardiac Channelopathy
SIDS
Sudden unexplained death in infancy (SUDI) and long QT syndrome (LQTS).
Introduction
After more than 30 years of research into the hypothesis that long QT syndrome might be
a cause of sudden infant death, we are now at the point where we can state with certainty
that some sudden unexplained deaths in infancy are indeed due to long QT syndrome.
The evidence for this lays in large population ECG screening programmes [1-3], post-
mortem molecular genetic testing of sudden infant death victims,[3-9] and some
informative case reports. There is also new evidence that other arrhythmic syndromes
sometimes cause SUDI. There remain, however, many unanswered questions, most
particularly whether all populations are affected equally, and what should we all now do
with this knowledge? Should newborn ECG screening become mandatory? How should
we best investigate SUDI at post mortem in order to diagnose LQTS?
What is long QT syndrome?
Long QT syndrome (LQTS) is one of a group of disorders of ion channels in the cardiac
cell wall. Collectively they are known as “cardiac ion channelopathies”.[10, 11] Other
examples are Brugada syndrome [12] and “CPVT”- catecholaminergic polymorphic
ventricular tachycardia.[13] These conditions are mostly inherited in an autosomal
dominant fashion, and cause sudden polymorphic ventricular tachycardia which can lead
to ventricular fibrillation and sudden cardiac death. Syncope is common in older children
and adults as a presenting feature, but is very uncommon in infancy. In general, the
younger and more severe the presentation, the more likely it is that the genetic mutation
occurred “denovo” rather than coming down the generations.
The most severe form of LQTS (Jervell and Lange-Neilsen syndrome[14]) occurs when
two potassium ion channel mutations come together, one each from the mother and
father, typically producing a child at very high risk of sudden death who is also deaf,
since the potassium ion channels are also deficient in the endolymph of the ear.
Twelve different genotypes of LQTS have thus far been identified; sodium and potassium
ion channels have been implicated in most forms.[10] The genes encode for complex
protein cell-wall channels which act as pumps to move the ions across the cell wall in a
critical time and voltage-dependant manner during the cardiac action potential. These
proteins have functional links to many other proteins, they form part of the “final
common pathway” to arrhythmogenesis in many forms of inherited heart diseases.[15,
16] It is certain that more genotypes of LQTS, and hybrid diseases will be found.
In LQTS there is prolongation of the QT interval on the surface ECG as a result of a
prolonged cardiac action potential, and longer QT interval equates to higher risk of
sudden death at all ages.[17-19] The QT interval is usually measured in leads 2 and V5,
and the QT interval is usually corrected for heart rate (“QTc”) by dividing it by the
square root of the previous R-R interval (the Bazett’s formula), though this may not be
the best way in infants.[20] The distribution of values in the normal population overlaps
with those with hereditary LQTS; typically about a third of the gene carriers will have a
QT interval in the “normal” range, depending on how that is defined. Diagnosis on the
basis of a single ECG can therefore be very difficult; individual risk is judged by the
longest value on serial ECGs.[21]
What is the population incidence of LQTS?
A recently completed study based in 18 maternity hospitals in Italy reviewed ECGs on
43,080 white infants aged 15 to 25 days old.[22] Supported by genotyping in the
majority of cases where the QT interval was prolonged, 17 infants were affected by
LQTS, demonstrating a prevalence of at least one in 2534 healthy live births. Since some
gene-carrying infants will certainly have had a shorter QT interval, a population
incidence of at least 1 in 2000 seems likely.
What triggers a syncope or cardiac arrest?
The length of the action potential, and hence the QT interval, varies over time and is
prolonged by certain physiological phenomena, including biochemical disturbance
(hyopokaleamia, hypomagnesaemia, hypocalcaemia), and hypothermia. The QT interval
is also under powerful influence from the autonomic system; [23] quiet sleep prolongs
the QT interval in normal infants for example.[24] The prolonged and disordered
repolarisation results in unstable voltage gradients across the myocardium, and a
triggered or spontaneous extrasystole can result in disorded repolarisation- this may
appear as T-Wave alternans (Fig 1), and eventually disordered depolarization. As the
origin of the ventricular tachycardia moves (rotates) around the ventricles, the direction
of depolarisation changes, giving rise to the typical “torsade de pointes” appearance to
the ECG.
It has been possible to identify genes responsible for LQTS in about 70% of familial
cases. Three genotypes, 1, 2 and 3 comprise more than 90% of these. Each genotype
tends to have a characteristic phenotype defined by the triggers which cause a cardiac
event (syncope or cardiac arrest) and the age and gender at highest risk (Table 1). Each
type also has its own characteristic T wave morphology on the ECG (e.g. high and broad
in LQT1, low and bifid in type 2, high and late onset in type 3).[25] In long QT type 1,
syncope or sudden death are classically triggered by physical exertion (especially
swimming) and those at highest risk are boys between the age of five and 15 years.[18,
19] In LQT type 2 emotional excitement or loud noise (especially noises causing waking
from sleep) are typical triggers - adult women are at highest risk.[17] With types 1 and 2
there are often several syncopal events (frequently misdiagnosed as epilepsy) prior to
sudden death. With long QT type 3, death most commonly occurs during quiet rest or
sleep, and preceding syncope is relatively uncommon i.e. the first event is often sudden
death. Young adult males are at highest risk,[17] as well, it would appear, as infants.
What are the treatments for LQTS?
Management involves removal of triggers where possible, such as swimming and
avoiding a long list of potentially dangerous medications (found at www.qtdrugs.org).
Beta blockers reduce risk of sudden death by between 50 and 75% in long QT types 1
and 2, but beneficial effect is not proven in type 3, in whom pacing to prevent nocturnal
bradycardia has a place.[17, 19, 26] Second line is left cervical sympathectomy,[27-29]
and for the highest risk cases, an intracardiac defibrillator.[29]
Studies investigating a link between SUDI and LQTS
In 1976 Maron et al performed an ECG was on 42 sets of parents with an infant with
SUDI; 11 (26%) had at least one with a prolonged QT interval.[30] A small number of
infants have been reported to have died suddenly with an ECG beforehand showing a
long QT interval or even ventricular tachycardia. For example in 1979 Southall et al
described an infant who died at 12 days with the preceding ECG showing a long heart-
rate corrected QT interval (QTc) of 630 ms, and with 2:1 atrioventricular block secondary
to the prolonged ventricular repolarisation.[31] In 1980 de Segni et al described an infant
with torsade de pointes on day one.[32] More recently, fetal echocardiography and
electrocardiography has documented intrauterine ventricular tachycardia in infants
subsequently shown to have LQTS after birth.[33-35]
Prospective evaluation of newborn ECGs
In 1986 Southall et al reported ECGs on 7254 newborn infants from two maternity
hospitals; recordings were obtained on 15 infants who subsequently died from SIDS.[2]
None showed lengthening of QT intervals and there was no difference to age, hospital,
gender, and birth weight matched controls. Weinstein et al in 1985 had similar findings
with eight infants dying from SIDS.[1]
The first positive study came from Schwarz et al in 1998.[3] The data were collected
from nine maternity units in Italy between 1976 and 1994 including 34,442 infants on
day three or four of life; 24 of these infants died of SIDS. The mean QTc of a random
sample of the non SIDS cases was 393 ms compared to 435 ms among the SIDS infants.
Only three of these infants had a value greater than 417 ms. The study was criticised
methodologically, and it was noted that the incidence of SIDS (0.7/1000) was remarkably
low for that era. A report of a further 50,000 screening ECGs taken between 15 and 25
days of age is awaited from the SUDI point of view.[22]
Molecular genetic evidence in SUDI victims
The results of four published series are summarised in table 2. LQT type 3 predominates,
but types 1,2,6, and 9 have also been implicated. The first report came from Ackerman et
al from the Mayo Clinic in 2001.[8] Ackerman since coined the now popular term
“molecular autopsy” for the molecular genetic investigation of sudden unexplained
deaths. Four of 93 cases had pathological mutations (4.3%; 95% CI 1.2-10.7%), two
within SCN5A (LQT type 3) and one within each of the potassium channel genes
associated with long QT types 1 and 2 respectively. In the same year Schwarz et al
reported a SUDI victim in whom they identified a mutation in KCNQ1 (LQT type 1).
[36]
In 2006 Wedekind et al from Germany reported the investigation of 41 SUDI
victims.[37] In their series they interviewed the families as well as taking ECGs from the
parents. The family histories were negative in every case, and in only two was mild QT
prolongation suspected in a family member. Although a genetic variant was found in one
case, functional evaluation of this found it to be no different from wild-type. The
maximal incidence in this series is therefore 5% but it may be 0%.
The largest series came from Norway in 2007, again with Peter Schwarz from Italy as the
senior author.[7] 201 cases diagnosed as SIDS according to the Nordic criteria underwent
molecular genetic screening of seven genes (long QT 1,2,3,5,6, 7 and 9-Caveolin).
Variants were found in 26 of the 201 cases but on the basis of the functional effect of the
variant (assessed in-vitro) 15 variants were felt to be definite pathological mutations,
such that 19 of the 201 cases were felt to be likely arrhythmic deaths secondary to LQTS
(9.5%; 95% C. I., 5.8 to 14.4%). 13 of these 19 cases (68%) had mutations in SCN5A, 2
(10%) in KCNQ1 (LQT type 1) 2 (10%) in KCNH2 (LQT type 2), 2 (10%) in caveolin
(LQT type 9) (one also had an SCN5A mutation), and one (5%) in KCNE2 (LQT type 6).
A clinical series of 52 unexpected infant deaths were investigated in France in 2009.[5]
Only 34 were eventually described as probable/definite SIDS cases; 3 of which were
definitely and 2 further probably ascribed to LQTS (9-15%). Three of the five mutations
were in SCN5A.
As new genes causing LQTS are discovered, investigation of a stored bank of DNA from
SIDS cases in the USA has shown that they are also sometimes implicated in SIDS. LQT
9 is caused by caveolin mutations[38, 39] and long QT 12 is cause by mutations in the
dystrophin gene SNTA1 (alpha-1 syntrophin).[6, 40, 41] These proteins interact with the
protein formed by SCN5A (the voltage dependant sodium channel protein- Nav1.5). 3 of
134 cases (2.2%) had a pathological mutation in caveolin,[39] and 3 of 292 (1%) had a
pathological mutation in SNTA1.[6] Interestingly all of those in SNTA1 were in black
infants (3 of 50 (6%)).
In New Zealand, a post-mortem long QT genetic diagnostic service was established in
2006 with no cost to the pathology services. All cases defined as SIDS by the forensic
pathologists over a 26 month period underwent genetic testing for long QT genes 1,2,3,5
and 6. Four of 48 cases (8.3%) had a genetic variant in SCN5A, but we are not confident
of the pathogenicity in any case. Three non-Caucasian infants had a well-known and
researched variant (R1193Q) which is rare in Caucasians, associated with an increased
risk of arrhythmia in adults, and known to have abnormal in-vitro electrophysiology, but
is found in 10% of the Han Chinese population.[42-45] The other had a novel variant for
which we await in-vitro analysis, but is predicted to be benign by in-silico (predictive
software) analysis.
SCN5A and “Cardiac sodium channel disease”
SCN5A is the gene linked to two thirds of the SIDS caused by sudden arrhythmic death.
The New Zealand experience highlights some of the significant difficulties in
understanding variants within the SCN5A gene. SCN5A has characteristics which make
interpreting genetic variants very difficult; it is large, has a high rate of spontaneous
variability (non-conservation), significant variability between populations, and a single
mutation can result in different phenotypes, even within the same family.[46, 47]
Mutations in SCN5A can result in a cardiac sodium channel (Nav1.5) which is overactive
or underactive. When overactive (failing to switch off) sodium leaks out of the cell
during repolarisation and prolongs the QT interval. When underactive, the first part of
depolarization is abnormally prolonged, leading to a risk of ventricular fibrillation
especially during sleep in young adult males. Known as Brugada syndrome,[48-51] it
has a hall-mark ECG with a right bundle-branch like pattern in the anterior V leads,
thought to be due to differential repolarisation rates in the outer and middle myocardium
of the right ventricular outflow tract. This ECG abnormality can be unmasked by giving a
sodium channel blocker such as flecainide. SCN5A mutations can also cause progressive
cardiac conduction defects and atrial fibrillation.[47]
It seems that a deformed cardiac sodium channel behaves a bit like a “sticky tap”- sodium
can either dribble across the membrane, or pour through it, depending on the
circumstances, and perhaps on age and gender, and probably on variants in the
surrounding proteins. One large kindred with an SCN5A mutant was described with
multiple sudden deaths all restricted only to young children, suggesting a developmental
influence on channel function.[52] Some families have members with long QT and some
with Brugada syndrome.
The SCN5A mutations found in the Norwegian study underwent in-vitro assessment, and
they behaved like long QT mutants, with over-activity of sodium current.[53] Our group
reported an infant resuscitated from ventricular fibrillation at 18 days- he collapsed
during a feed.[54] His initial ECG had a slightly prolonged QT interval, but it has
remained normal since, and aged 8 he has had no further events. He has the
aforementioned genetic variant in SCN5A (R1193Q) which has been associated with
Brugada syndrome and LQTS in other families. Yet his ECG remains normal, and even
pharmacological challenge (with a sodium channel blocker) has proven negative. While
his mother carries the gene mutation, her ECG shows slight QT prolongation only, and no
Brugada sign. There were no other sudden deaths in the family. Perhaps it is not the main
culprit after all.
This variant in SCN5A (S1103Y), occurred in one gene (heterozygous) in 120 of 1,056
healthy African Americans (11%). It was found in the homozygous state in three of 133
African American SIDS victims (2.3%), suggesting a 24-fold increase in risk for SIDS. In
vitro testing was completely normal until the intracellular pH was lowered, when it
demonstrated late-reopening such as seen with long QT type 3. This may therefore be the
perfect model of “susceptibility-to-acidosis arrhythmia”. The trigger might be a transient
upper respiratory obstruction for example, or a significant infection.
Brugada syndrome in young children most typically presents with ventricular tachycardia
induced by high fever;[48] the resultant loss of consciousness may be confused for a
febrile convulsion.[55] How many infant deaths attributed to febrile illness (such as
pneumonia), or simple overheating might thus be related to sudden arrhythmic death
through SCN5A mutations is not known, but to date it doesn’t seem to be a dominant
feature in sudden infant deaths where the autopsy is negative.
Multi-gene influence on the QT interval.
Two family members with the same mutation in an LQT gene can have impressively
different QT intervals and clinical course. From this alone it is apparent that other
“modifier” genes play a role, and variants in SCN5A have been the commonest
implicated so far. However a genome wide SNP (single nucleotide polymorphism) study
found QT intervals are influenced marginally on a population basis by a gene known as
NOS1AP. Intriguingly, a Japanese study recently showed that the homozygous form of
one of these SNPs was found more commonly in 42 SIDS victims than in 210
controls.[56]
Short QT syndrome
When the potassium channels linked to long QT types 1 and 2 are overactive, the QT
interval becomes shortened, and there is a risk of ventricular fibrillation similar to that
seen with Brugada syndrome. It is very rare, but interestingly one of the two mutants in
KCNQ1 found in the Norwegian SIDS study (I274V) had a gain-of function phenotype
typical of short QT syndrome.[57]
Other arrhythmia genes linked to SUDI.
Another cardiac ion channelopathy is “CPVT”- catecholaminergic polymorphic
ventricular tachycardia.[58] The commonest gene involved is known as the cardiac
ryanodine gene (RyR2);[59] mutations result in leak of calcium ions from the
sarcoplasmic reticulum. Ventricular tachycardia typically occurs during exercise or
excitement. CPVT is as common a cause of sudden unexpected death in teenagers and
young adults as LQTS,[60] and was also found by molecular autopsy in 2 of 134 SUDI
victims (1.5%).[4] It tends to be highly lethal, about two thirds of cases occur de novo,
and often escapes diagnosis in life because the resting ECG is normal. Management is
similar to long QT type 1.
GPD1-L (glycerol-3-phosphatase dehydrogenase like gene) has been linked to Brugada
syndrome, indirectly causing a reduced sodium channel current.[61] It was found in 2 of
221 SIDS cases (0.9%).[62]
Role of ECG screening
There is an appeal for routine infant screening for LQTS, emanating largely from a group
of Italian cardiologists.[63] There is a debate in the literature.[64, 65] The arguments for
screening are that severe cases will be detected and life-preserving therapies initiated,
that familial LQTS will be identified so other family members can also be screened, and
that the ECG is cheap and easy to perform. The arguments against are that QT
measurement on the ECG is unreliable, especially at fast heart rates in infants,[20] with
an unacceptable sensitivity and specificity for LQTS, and that the cases identified will
usually be very severe forms of long QT type 3, which do not respond well to beta
blockade (unlike types 1 and 2).
Most paediatric cardiologists in the USA do not consider such ECG screening to be a
good idea[66] and nor does this author. I believe the best way to find inherited heart
diseases is to have dedicated cardiac genetic clinics and population-based registries to
ensure thorough “cascade” family screening.[67] Still the best way to prevent SIDS is
through reducing the known risk factors. However results of the large prospective study
from Italy are awaited with interest.[22]
Summary, recommendations and future research
Molecular genetic studies and informative case reports have given us unequivocal
evidence that a minority of SUDI cases, around 10%, are due to sudden cardiac death
secondary to cardiac channelopathies. As a means of autopsy diagnosis, the molecular
autopsy is here to stay, and we are just seeing the tip of the iceberg. The prevalence in
each population will vary, and we have much to learn. Early evidence seems to suggest
African Americans may be at greater risk on the basis of heritage of variants in SCN5A.
Certainly, knowledge of the local genetic variability will be crucial in interpreting genetic
results which often turn up novel variants.
In poorer countries or areas with poorer social and medical welfare structures, one might
anticipate that arrhythmias may play less a part than in Norway, but this is yet to be
proven. On the other hand interaction with fevers and stress such as overheating, and pro-
arrhythmic biochemical disturbance such as hypokalaemia, gives a plausible mechanism
for risk of sudden death, and these may even be higher in such groups.
Thus far, the yield of family heart screening as part of the autopsy investigation has been
low, but these have not been thorough, relying at most on an ECG of the parents. Heart
screening of relatives of sudden unexplained (post-mortem negative) death victims aged
1-40 can reveal an inherited heart disease in over half, when very detailed investigations
(exercise testing, echocardiography, cardiac MRI) are performed.[68, 69] Best practice
guidelines such as those developed in Australia and New Zealand suggest this should
happen in every case over one year of age.[70, 71] Cardiomyopathies such as ARVC
(arrhythmogenic right ventricular cardiomyopathy) and hypertrophic cardiomyopathy
(HCM) can escape detection at autopsy; we don’t know yet if these cause SIDS.
Mass infant ECG screening will have little or no impact on the incidence of SIDS. It will
create a large population of worried well, and will miss many carriers of cardiac
channelopathies, but it might detect some families with LQTS and thereby potentially
save lives. National registries of inherited heart diseases, with effective family screening
programs may have a larger impact here, and population-based research is required.
In first world countries, the investigation of SUDI should include consideration of
molecular autopsy, but this should only occur as part of a multidisciplinary team
approach with expert cardiology input, effective bereavement and genetic counseling ,
and with sensitivity to cultural issues around tissue storage and genetic testing. Unlike in
sudden death over the age of one year, the diagnostic value of cardiological investigation
of first degree relatives remains to be proven.
In the mean time, according to the local demographic, the focus should still remain on
implementation of factors which have already been proven to prevent SIDS.
Acknowledgements
Jonathan Skinner receives salary support from Cure Kids New Zealand.
References
1. Weinstein, S.L. and A. Steinschneider, QTc and R-R intervals in victims of the
sudden infant death syndrome. Am J Dis Child, 1985. 139(10): p. 987-90.
2. Southall, D.P., et al., QT interval measurements before sudden infant death
syndrome. Arch Dis Child, 1986. 61(4): p. 327-33.
3. Schwartz, P.J., et al., Prolongation of the QT interval and the sudden infant death
syndrome. N Engl J Med, 1998. 338(24): p. 1709-14.
4. Tester, D.J., et al., A mechanism for sudden infant death syndrome (SIDS): stress-
induced leak via ryanodine receptors. Heart Rhythm, 2007. 4(6): p. 733-9.
5. Millat, G., et al., Contribution of long-QT syndrome genetic variants in sudden
infant death syndrome. Pediatr Cardiol, 2009. 30(4): p. 502-9.
6. Cheng, J., et al., Alpha1-syntrophin mutations identified in sudden infant death
syndrome cause an increase in late cardiac sodium current. Circ Arrhythm
Electrophysiol, 2009. 2(6): p. 667-76.
7. Arnestad, M., et al., Prevalence of long-QT syndrome gene variants in sudden
infant death syndrome. Circulation, 2007. 115(3): p. 361-7.
8. Ackerman, M.J., et al., Postmortem molecular analysis of SCN5A defects in
sudden infant death syndrome. JAMA, 2001. 286(18): p. 2264-9.
9. Ackerman, M.J., Cardiac Channel mutations in SIDS: a population-based
molecular autopsy study. Circulation, 2002. 106: p. 839.
10. Amin, A.S., H.L. Tan, and A.A. Wilde, Cardiac ion channels in health and
disease. Heart Rhythm, 2009.
11. Kaufman, E.S., Mechanisms and clinical management of inherited
channelopathies: long QT syndrome, Brugada syndrome, catecholaminergic
polymorphic ventricular tachycardia, and short QT syndrome. Heart Rhythm,
2009. 6(8 Suppl): p. S51-5.
12. Brugada, P., et al., The Brugada Syndrome. Arch Mal Coeur Vaiss, 2005. 98(2):
p. 115-22.
13. Priori, S.G., et al., Clinical and molecular characterization of patients with
catecholaminergic polymorphic ventricular tachycardia. Circulation, 2002.
106(1): p. 69-74.
14. Schwartz, P.J., et al., The Jervell and Lange-Nielsen syndrome: natural history,
molecular basis, and clinical outcome. Circulation, 2006. 113(6): p. 783-90.
15. Towbin, J.A., Molecular genetic basis of sudden cardiac death. Pediatr Clin
North Am, 2004. 51(5): p. 1229-55.
16. Bowles, N.E., K.R. Bowles, and J.A. Towbin, The "final common pathway"
hypothesis and inherited cardiovascular disease. The role of cytoskeletal proteins
in dilated cardiomyopathy. Herz, 2000. 25(3): p. 168-75.
17. Sauer, A.J., et al., Long QT syndrome in adults. J Am Coll Cardiol, 2007. 49(3):
p. 329-37.
18. Hobbs, J.B., et al., Risk of aborted cardiac arrest or sudden cardiac death during
adolescence in the long-QT syndrome. JAMA, 2006. 296(10): p. 1249-54.
19. Goldenberg, I., et al., Risk factors for aborted cardiac arrest and sudden cardiac
death in children with the congenital long-QT syndrome. Circulation, 2008.
117(17): p. 2184-91.
20. Gow, R.M., et al., The measurement of the QT and QTc on the neonatal and
infant electrocardiogram: a comprehensive reliability assessment. Ann
Noninvasive Electrocardiol, 2009. 14(2): p. 165-75.
21. Goldenberg, I., et al., Corrected QT variability in serial electrocardiograms in
long QT syndrome: the importance of the maximum corrected QT for risk
stratification. J Am Coll Cardiol, 2006. 48(5): p. 1047-52.
22. Schwartz, P.J., et al., Prevalence of the congenital long-QT syndrome.
Circulation, 2009. 120(18): p. 1761-7.
23. Schwartz, P.J., Cardiac sympathetic innervation and the sudden infant death
syndrome. A possible pathogenetic link. Am J Med, 1976. 60(2): p. 167-72.
24. Haddad, G.G., et al., Effect of sleep state on the QT interval in normal infants.
Pediatr Res, 1979. 13(2): p. 139-41.
25. Zhang, L., et al., Spectrum of ST-T-wave patterns and repolarization parameters
in congenital long-QT syndrome: ECG findings identify genotypes. Circulation,
2000. 102(23): p. 2849-55.
26. Goldenberg, I., et al., Long-QT syndrome after age 40. Circulation, 2008.
117(17): p. 2192-201.
27. Schwartz, P.J., Cutting nerves and saving lives. Heart Rhythm, 2009. 6(6): p. 760-
3.
28. Collura, C.A., et al., Left cardiac sympathetic denervation for the treatment of
long QT syndrome and catecholaminergic polymorphic ventricular tachycardia
using video-assisted thoracic surgery. Heart Rhythm, 2009. 6(6): p. 752-9.
29. Eicken, A., et al., Implantable cardioverter defibrillator (ICD) in children. Int J
Cardiol, 2006. 107(1): p. 30-5.
30. Maron, B.J., et al., Potential role of QT interval prolongation in sudden infant
death syndrome. Circulation, 1976. 54(3): p. 423-30.
31. Southall, D.P., et al., Prolonged QT interval and cardiac arrhythmias in two
neonates: sudden infant death syndrome in one case. Arch Dis Child, 1979.
54(10): p. 776-9.
32. DiSegni, E., et al., Overdrive pacing in quinidine syncope and other long QT-
interval syndromes. Arch Intern Med, 1980. 140(8): p. 1036-40.
33. Tomek, V., J. Skovranek, and R.A. Gebauer, Prenatal diagnosis and management
of fetal Long QT syndrome. Pediatr Cardiol, 2009. 30(2): p. 194-6.
34. Takahashi, K., et al., Irregular peak-to-peak intervals between ascending aortic
flows during fetal ventricular tachycardia in long QT syndrome. Ultrasound
Obstet Gynecol, 2009. 33(1): p. 118-20.
35. Fujimoto, Y., et al., Prenatal diagnosis of long QT syndrome by non-invasive fetal
electrocardiography. J Obstet Gynaecol Res, 2009. 35(3): p. 555-61.
36. Schwartz, P.J., et al., Molecular diagnosis in a child with sudden infant death
syndrome. Lancet, 2001. 358(9290): p. 1342-3.
37. Wedekind, H., et al., Sudden infant death syndrome and long QT syndrome: an
epidemiological and genetic study. Int J Legal Med, 2006. 120(3): p. 129-37.
38. Vatta, M., et al., Mutant caveolin-3 induces persistent late sodium current and is
associated with long-QT syndrome. Circulation, 2006. 114(20): p. 2104-12.
39. Cronk, L.B., et al., Novel mechanism for sudden infant death syndrome: persistent
late sodium current secondary to mutations in caveolin-3. Heart Rhythm, 2007.
4(2): p. 161-6.
40. Wu, G., et al., alpha-1-syntrophin mutation and the long-QT syndrome: a disease
of sodium channel disruption. Circ Arrhythm Electrophysiol, 2008. 1(3): p. 193-
201.
41. Ueda, K., et al., Syntrophin mutation associated with long QT syndrome through
activation of the nNOS-SCN5A macromolecular complex. Proc Natl Acad Sci U S
A, 2008. 105(27): p. 9355-60.
42. Sun, A., et al., SCN5A R1193Q polymorphism associated with progressive
cardiac conduction defects and long QT syndrome in a Chinese family. J Med
Genet, 2008. 45(2): p. 127-8.
43. Huang, H., et al., Nav1.5/R1193Q polymorphism is associated with both long QT
and Brugada syndromes. Can J Cardiol, 2006. 22(4): p. 309-13.
44. Hwang, H.W., et al., R1193Q of SCN5A, a Brugada and long QT mutation, is a
common polymorphism in Han Chinese. J Med Genet, 2005. 42(2): p. e7; author
reply e8.
45. Wang, Q., et al., The common SCN5A mutation R1193Q causes LQTS-type
electrophysiological alterations of the cardiac sodium channel. J Med Genet,
2004. 41(5): p. e66.
46. Ruan, Y., N. Liu, and S.G. Priori, Sodium channel mutations and arrhythmias.
Nat Rev Cardiol, 2009. 6(5): p. 337-48.
47. Remme, C.A., A.A. Wilde, and C.R. Bezzina, Cardiac sodium channel overlap
syndromes: different faces of SCN5A mutations. Trends Cardiovasc Med, 2008.
18(3): p. 78-87.
48. Probst, V., et al., Clinical aspects and prognosis of Brugada syndrome in
children. Circulation, 2007. 115(15): p. 2042-8.
49. Oe, H., et al., Prevalence and clinical course of the juveniles with Brugada-type
ECG in Japanese population. Pacing Clin Electrophysiol, 2005. 28(6): p. 549-54.
50. Junttila, M.J., et al., Prevalence and prognosis of subjects with Brugada-type
ECG pattern in a young and middle-aged Finnish population. Eur Heart J, 2004.
25(10): p. 874-8.
51. Brugada, P. and J. Brugada, Right bundle branch block, persistent ST segment
elevation and sudden cardiac death: a distinct clinical and electrocardiographic
syndrome. A multicenter report. J Am Coll Cardiol, 1992. 20(6): p. 1391-6.
52. Todd, S.J., et al., Novel Brugada SCN5A mutation causing sudden death in
children. Heart Rhythm, 2005. 2(5): p. 540-3.
53. Wang, D.W., et al., Cardiac sodium channel dysfunction in sudden infant death
syndrome. Circulation, 2007. 115(3): p. 368-76.
54. Skinner, J.R., et al., Near-miss SIDS due to Brugada syndrome. Arch Dis Child,
2005. 90(5): p. 528-9.
55. Skinner, J.R., et al., Brugada syndrome masquerading as febrile seizures.
Pediatrics, 2007. 119(5): p. e1206-11.
56. Osawa, M., et al., SNP association and sequence analysis of the NOS1AP gene in
SIDS. Leg Med (Tokyo), 2009. 11 Suppl 1: p. S307-8.
57. Rhodes, T.E., et al., Cardiac potassium channel dysfunction in sudden infant
death syndrome. J Mol Cell Cardiol, 2008. 44(3): p. 571-81.
58. Francis, J., et al., Catecholaminergic polymorphic ventricular tachycardia. Heart
Rhythm, 2005. 2(5): p. 550-4.
59. Wehrens, X.H., The molecular basis of catecholaminergic polymorphic
ventricular tachycardia: what are the different hypotheses regarding
mechanisms? Heart Rhythm, 2007. 4(6): p. 794-7.
60. Tester, D.J. and M.J. Ackerman, Postmortem long QT syndrome genetic testing
for sudden unexplained death in the young. J Am Coll Cardiol, 2007. 49(2): p.
240-6.
61. Valdivia, C.R., et al., GPD1L links redox state to cardiac excitability by PKC-
dependent phosphorylation of the sodium channel SCN5A. Am J Physiol Heart
Circ Physiol, 2009. 297(4): p. H1446-52.
62. Van Norstrand, D.W., et al., Molecular and functional characterization of novel
glycerol-3-phosphate dehydrogenase 1 like gene (GPD1-L) mutations in sudden
infant death syndrome. Circulation, 2007. 116(20): p. 2253-9.
63. Quaglini, S., et al., Cost-effectiveness of neonatal ECG screening for the long QT
syndrome. Eur Heart J, 2006. 27(15): p. 1824-32.
64. Schwartz, P.J., Pro: Newborn ECG screening to prevent sudden cardiac death.
Heart Rhythm, 2006. 3(11): p. 1353-5.
65. van Langen, I.M. and A.A. Wilde, Con: Newborn screening to prevent sudden
cardiac death? Heart Rhythm, 2006. 3(11): p. 1356-9.
66. Chang, R.K., S. Rodriguez, and M.Z. Gurvitz, Electrocardiogram screening of
infants for long QT syndrome: survey of pediatric cardiologists in North America.
J Electrocardiol. 43(1): p. 4-7.
67. Gimeno, J.R., et al., Penetrance and risk profile in inherited cardiac diseases
studied in a dedicated screening clinic. Am J Cardiol, 2009. 104(3): p. 406-10.
68. Tan, H.L., et al., Sudden unexplained death: heritability and diagnostic yield of
cardiological and genetic examination in surviving relatives. Circulation, 2005.
112(2): p. 207-13.
69. Behr, E.R., et al., Sudden arrhythmic death syndrome: familial evaluation
identifies inheritable heart disease in the majority of families. Eur Heart J, 2008.
29(13): p. 1670-80.
70. TRAGADY. Post-mortem in Sudden Unexpected Death in the Young: Guidelines
on Autopsy Practise. 2007; Available from:
http://www.cidg.org/webcontent/LinkClick.aspx?fileticket=DO9YIQWqegI%3d
&tabid=161.
71. Skinner, J.R., J.A. Duflou, and C. Semsarian, Reducing sudden death in young
people in Australia and New Zealand: the TRAGADY initiative. Med J Aust,
2008. 189(10): p. 539-40.
72. Modell, S.M. and M.H. Lehmann, The long QT syndrome family of cardiac ion
channelopathies: a HuGE review. Genet Med, 2006. 8(3): p. 143-55.
Figure 1
Diagram of the cardiac action potential, highlighting the phase of the potential influenced
by the commoner genes linked to LQTS. Caveolin (LQT9) also influences INa.
Figure 2
6 lead electrocardiogram showing gross QT prolongation and T-wave alternans in an
infant with Jervell and Lange-Neilsen syndrome detected because of neonatal
bradycardia. Best seen in lead I, III, and avL, the T waves are alternately upright and
inverted. This tends to immediately precede collapse with torsade de pointes. It is also
seen well in the rhythm strip at the bottom.
Figure 3
Torsade de pointes (TdP). Two lead rhythm strip. Beats labeled with an “N” are normal
sinus beats, V, ventricular beats. A four beat run of ventricular tachycardia is followed by
the onset of TdP.
Table
Long QT genes, and other cardiac channelopathies linked to SUDI.
Clinical name Chromosomal locus Gene name Current Affected
Among LQTS
families^
Among SUDI gene
positive deaths*
LQT1 11p15.5 KCNQ1 (KVLQT1) K+ (IKs) 38% 10%
LQT2 7q35-36 HERG (KCNH2) K+ (IKr) 42% 10%
LQT3 3p21-24 SCN5A Na+ (INA) 12% 68%
LQT4 4q25-27 Ankyrin B Na+ (INA) 1% None so far
LQT5 21q22.1-22.2 KCNE1 (minK) K+ (IKs) 5% None so far
LQT6 21q22.1-22.2 KCNE2 (MiRP1) K+ (IKr) 1% 5%
LQT7 (Anderson) 17q23 KCNJ2 K+ (Kir2.1) <0.1% None so far
LQT8 (Timothy) 12p13.3 CACNA1C^ Ca++(ICa-L) <0.1% None so far
LQT9 3p25 CAV3 (Caveolin) Na+ (INA) <0.1% 10%**
LQT10 11q23.3 SCN4B Na+ (INA) <0.1% None so far
LQT11 7q21-q22 AKAP9 (A -anchor protein 9) K+ (IKs) <0.1% None so far
LQT12 20q11.2 SNTA1 (alpha-1 syntrophin) Na+ (INA) <0.1% Implicated^^
CPVT 1q42-1q43 RYR2 (cardiac ryanodine) 1.5%***
- 1q23.3 NOS1AP (nitric oxide synthase)
SUNDS/Brugada GPD1-L Na+ (INA) 0.9%^^^
^ Proportion of mutations (Modell, 2006)[72]
* From Norwegian series of 19 mutation positive infants among 201 SUDI victims.
**In a US series of 134 SIDS, 3 had caveolin mutations, all among black infants (3 of 50 black infants; 6%).
^^Among 292 US SIDS cases 3 pathogenic mutations were found (1%).- a similar proportion to KCNQ1 and HERG in the Norwegian study
^Calcium channel, voltage-dependent, L type, alpha 1C subunit
***ref Tester et al [4]
SUNDS: Sudden unexpected nocturnal death syndrome