Download The implications of genetic mutations in the sodium channel gene (SCN5A) REVIEW

Europace (2003) 5, 325–334
doi:10.1016/S1099-5129(03)00085-0
REVIEW
The implications of genetic mutations in
the sodium channel gene (SCN5A)
E. Moric1, E. Herbert1, M. Trusz-Gluza2, A. Filipecki2,
U. Mazurek1 and T. Wilczok1
1
Department of Molecular Biology, Biochemistry and Biopharmacy, Medical University of Silesia,
ul. Narcyzo´w 1, Sosnowiec, Poland; and 2I Department of Cardiology,
Medical University of Silesia, ul. Zio1owa 45/47, 40-635 Katowice, Poland
Mutations in sodium channel a-subunit gene (SCN5A)
result in multiple arrhythmic syndromes, including long
QT3 (LQT3), Brugada syndrome (BS), an inherited cardiac
conduction defect, sudden unexpected nocturnal death
syndrome (SUNDS) and sudden infant death syndrome
(SIDS), constituting a spectrum of disease entities termed
Na+ channelopathies. These diseases are allelic disorders, if
not the same disease with variable penetrance and variable
modifiers worldwide. Interestingly, death occurs during sleep
in all of these disorders, suggesting a common mechanism.
To date, mutational analyses have revealed about 103
distinct mutations in SCN5A, of which at least more than
30 mutations are associated with LQT3, whereas the rest of
the mutations are affiliated with the remaining sodium
channel disorders. The majority of these mutations are missense. However, other types such as deletions, insertions,
frameshifts, nonsense and splice-donor errors have also
been reported.
(Europace 2003; 5: 325–334)
Ó 2003 The European Society of Cardiology. Published by
Elsevier Ltd. All rights reserved.
Background
of arrhythmia in an African–American family. The
variant allele termed Y1102 is responsible for accelerating channel activation, thereby enhancing the probability of cardiac arrhythmias in persons of African descent.
Though the variant gene is not likely to cause problems
on its own as emphasized by the authors, it may be
induced or triggered by other factors to be pathogenic.
The BS is the mirror image of LQT3 and both are
known to share the same position or locus on a specific
chromosome in the diploid cells (3p24–p21). For this
reason, they are regarded as allelic diseases, differing
slightly in mutations in the amino acid sequence in the
Na+ channel of the sarcolemma (ÔchannelopathiesÕ).
The loss of function of cardiac sodium channels,
either by reducing expression levels or by increasing its
inactivation kinetics, is the main pathological origin of
the BS[6,7], whereas the mutation of LQT3 is associated
with a gain of function mechanism with a slow and
constant entry of Na+ in phase 2 (prolonged inactivated), which, in turn, increases the duration of the ST
segment leading to a prolonged QTc at the expense
The heterozygous mutations in the cardiac voltage-gated
sodium channel a-subunit gene (SCN5A) have been
implicated in rare, familial types of cardiac arrhythmogenic disorder, involving long QT syndrome variant type
3 or LQT3[1], Brugada syndrome (BS)[2,3] and progressive cardiac conduction defect (PCCD) otherwise
known as Lev–Lenegre disease syndrome[4].
Recently, Splawski et al.[5] identified a variant of the
cardiac sodium channel gene that is associated with
arrhythmia in African–Americans and linked it with risk
Manuscript submitted 4 February 2003, and accepted after revision
22 June 2003.
Correspondence: Ewa Moric, PhD, Department of Molecular
Biology, Biochemistry and Biopharmacy, Medical University of
Silesia, ul. Narcyzo´w 1, 41-200 Sosnowiec, Poland. Tel.:
+48-32-291-43-93x54; Fax: +48-32-291-74-66; E-mail: e.moric@
poczta.clinika.pl; [email protected]
1099–5129/03/000325+10 $30.00/0
Key Words: Arrhythmia, Brugada syndrome, long QT3
syndrome, SCN5A gene, sodium channel, mutation.
Ó 2003 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved.
326 E. Moric et al.
of ST, altogether resulting in late appearance of the
T wave.
Yan and Antzelevitch[8] have proposed a mechanism
for the ST segment shift and the occurrence of ventricular fibrillation in BS. The proposed mechanism per
se is consistent with observations that the characteristic
ECG pattern may be precipitated in patients with the
latent syndrome by administration of sodium channel
blocking drugs.
Mixed electrocardiographic features have been reported in a large family with SCN5A mutations showing
elevation of ST segment and prolonged QTc. In certain
cases, the production of ST-segment elevation by flecainide has raised the question whether BS and LQT3
could be two aspects of the same disease[9].
Besides the genetic similarity between BS and LQT3,
both diseases exhibit very different clinical ECG features
but show coincidences that emanate from their common
genetic root. It is not yet clear why the ECG pattern of
affected individuals with BS vary from day to day and
why most affected persons are males. Sex and hormonal
differences in ion channel distribution have been described in the heart and could cause alterations in
disease penetrance[10]. It is also not known if other
clinical conditions that cause ST or J-point elevation
(ischaemia, hypothermia, acidosis) can cause arrhythmias by mechanisms similar to BS. Future studies may
shed more light on this.
Vatta et al.[11] have reported that the clinical features
of sudden unexplained nocturnal death syndrome
(SUNDS), which is a disorder particularly found among
males in Southeast Asia, are genotypically, phenotypically and functionally identical to BS. The authors also
speculated that both SUNDS and BS could be allelic
disorders or even the same disease.
In this review, we shall focus on the SCN5A gene
mutations and summarize current information on therapeutic consequences associated with disorders of this gene.
Mutations in the SCN5A gene
Inherited mutations in SCN5A, the gene encoding the
human cardiac sodium channel, have been linked with
varied disorders of cardiac rhythm that range from
rapid, life-threatening tachyarrhythmias to bradyarrhythmias[12].
The SCN5A gene consists of 28 exons and encodes
a protein of 2016 amino acids, with a calculated molecular
mass of 227 kDa[13]. The cardiac Na+ channel a-subunit is
composed of four homologous domains, DI–DIV (Fig.
1). Each domain comprises six transmembrane segments
of which the S4 segments are believed to function as
voltage sensors. Little is known about the structure of the
C-terminus of the SCN5A gene, but disease associated
mutations within this 244 amino acid intracellular region
of the channel have recently been reported to play
a significant role in channel inactivation and stabilization
of the inactivated state[14]. SCN5A is highly expressed in
human myocardium but not in skeletal muscle, liver or
Europace, Vol. 5, October 2003
uterus. However, it has also been reported to be expressed
in the brain[15].
Mutations in the SCN5A gene have been identified in
families from all over the world. Missense mutation,
a splice-donor mutation and a frameshift mutation
in the coding region of SCN5A have been reported.
The first two are responsible for the quick recovery of
the Na+ channel from the inactivated state, and the
frameshift mutation produces lack of functioning of
the channel, which causes the heterogeneous loss of the
ÔplateauÕ, dome or phase 2, only in the right ventricular
epicardium but not in the endocardium (precisely
adjacent to leads V1–V3)[2]. Other functional consequences of missense mutation in the SCN5A include
enhancement of slower forms of inactivation[16], which is
expected to cause an activity-dependent loss of sodium
channel availability, resulting in reduced sodium current
density[17]. Shifts in the voltage dependence of activation
and inactivation have also been reported[18].
In 1995, Wang et al.[19] described deletion in nine
nucleotide bases, resulting in the loss of three amino
acids in the protein channel: lysine (K), proline (P) and
glutamine (Q). This mutation known as DKPQ is linked
with LQT3 in four different families.
Three other LQT3 mutations were reported in
asparagine, at position 1325, exchanged by serine
(N1325S), arginine at position 1644 is exchanged by
histidine (R1644H) and finally another one in the
residue 1623 (R1623Q) in the S4 segments of domains
III and IV of the Na+ channel[20]. Kambouris et al.[21]
reported that the R1623Q mutation imparts unusual
lidocaine sensitivity to the sodium channel that is
attributable to its malfunctional behaviour.
A highly conserved acidic domain in the C-terminus
appears to be a ÔhotspotÕ for LQT3 mutations. In the
C-terminus, two charge-altering LQT3 mutations
(E1784K, 1795insD) have been reported to evoke small,
sustained currents similar to DKPQ[17,22], while a third
charge deletion (D1790G) produces both a small plateau[23] and alters the voltage dependence of inactivation
in a pro-arrhythmic manner[24].
Mutations in the SCN5A gene that segregated and cosegregated with PCCD in an autosomal dominant manner have been reported. In the Dutch family, frameshift
mutation co-segregated with familial non-progressive
conduction defect, while PCCD was identified in the
French family through a member with right bundle
branch block (RBBB) associated with donor splice site
mutation. Therefore, PCCD represents a third cardiac
disorder linked with SCN5A[4].
Several mutations linked to BS have been described in
SCN5A, the only gene hitherto associated with the
disorder in chromosome 3p21[25]. The theory proposed
by Yan and Antzelevitch[8] states that a decrease in the
depolarizing inward sodium current is thought to lead to
early repolarization in the right ventricular epicardium,
where the transient outward K+ current (Ito) is large.
This would cause a voltage gradient from endocardium
to epicardium, ST elevation on the ECG and susceptibility to arrhythmias caused by phase 2 reentry.
Implications of genetic mutations in SCN5A
327
Figure 1 Predicted organization of SCN5A. (A) Genomic structure of SCN5A; exons and introns are indicated by
open boxes and horizontal lines; size of each exon is given under it as bp. (B) Schematic representation of a voltagegated Na+ channel a-subunit composed of four domains (DI–DIV), each of six membrane-spanning alpha helices (S1–
S6) and beta-subunit.
Using sequencing analysis, Nissenbaum et al.[26]
reported two mutations, G35S and R104Q in two
Brugada patients and a possible R34C polymorphism
in two unrelated controls, and went further to suggest
genetic heterogeneity, as no mutations were detected in
five other patients studied.
Molecular biological analysis can document SCN5A
gene mutations in 15–25% of patients with BS.
Although the prevalence of SCN5A mutations among
BS patients is not known precisely, a study showed that
the prevalence of SCN5A defects among 84 genotyped
patients clinically affected by BS is approximately 20–
25%, representing the largest series of carriers of
SCN5A mutations reported in literature[27].
Schwartz et al.[28] described an infant who nearly died
of sudden infant death syndrome (SIDS), whose parents
had normal QT intervals and in whom the long QT
syndrome was diagnosed with identification of a spontaneous mutation of the SCN5A gene: a change of codon
941 from TCC (serine) to ACC (asparagine).
On the other hand, Tan et al.[29] studied a family who
came for medical attention when the proband, a 3-yearold girl, experienced episodes of fainting during a febrile
illness. All affected family members had a G-to-T transversion in the first nucleotide of codon 514 in exon 12 of
the SCN5A gene resulting in the replacement of glycine by
cysteine (G514C). Computational analysis predicts that
the gating defects of G514C selectively slow down
myocardial conduction, but do not provoke the rapid
cardiac arrhythmias previously associated with SCN5A
mutations.
Weiss et al.[30] described a large multigenerational
family (12 affected individuals) with an autosomal
dominant inheritance pattern characterized by incomplete penetrance that appeared to be dependent on age
and sex. Eleven of the 12 affected individuals were
males, and linkage to a locus on chromosome 3p22–25
quite distinct from SCN5A is identified, confirming
genetic heterogeneity of the disorder.
However, studies by Smits et al.[31] have shown that
the region on chromosome 3 (3p22–25) linked to BS
appears to contain no modulatory subunits of the
sodium channel, the pore-forming and modulatory
components of the transient outward current, the Ltype calcium current or ion channel components that
could represent homologues of these proteins. The
presence of conduction defects, as evidenced by a prolonged His to ventricle interval (HV) and PQ interval at
baseline, and excessive QRS interval prolongation after
Na+ channel blockade are more likely to be seen in BS
patients who are carriers of SCN5A mutation[31].
Wang et al.[32] reported a family in which the proband
had presented with first-degree atrioventricular block at
the age of 9 years, progressing to complete AV block by
the age of 20 years, and also another child in whom
second-degree AV block had been diagnosed at the age of
6 years, progressing to complete AV block by the age of 12
years. Sequencing of the coding region of SCN5A revealed
a substitution of serine for glycine (G298S) in the domain I
S5–S6 loop and asparagine for aspartic acid (D1595N)
within the S3 segment of domain IV. Both mutations are
known to impair fast inactivation but do not exhibit
sustained non-inactivating currents. The mutations also
reduce sodium current density and enhance slower
inactivation components. The summary of gene mutations associated with SCN5A gene is given in Table 1.
Clinical features associated with
SCN5A gene
Mutations in SCN5A lead to a broad spectrum of
phenotypes, including long QT syndrome, BS, SIDS
Europace, Vol. 5, October 2003
328 E. Moric et al.
Table 1
Summary of mutations associated with the SCN5A gene
Nucleotide change
Mutation
G80A
G253A
G461A
R27H
G35S
R104Q
n.a.
K126E
E161K
Coding effect
Region
IVS5DS
A226V
I230V
R282H
V294M
G298S
n.a.
G319S
G351V
R367H
R367C
M369K
IVS7DS+4
393delF
K493
G514C
R535X
Missense
Missense
Missense
Splicing insertion
Missence
Missense
20 bp Deletion
Splice mutation
Missense
Missense
Missense
Missense
Missense
Nonsense
Missence
Missence
Missense
Missense
Missense
Splice mutation
Deletion
Deletion
Missense
Nonsense
N-term
N-term
N-term
N-term
DIS1
DI
DIS2–S3
DIS3
DIS4
DIS4
DIS5–S6
DIS5–S6
DIS5–S6
DIS5–S6
DIS5–S6
DIS5–S6
DIS5–S6
DIS5–S6
DIS5–S6
DIS5–S6
DIS6
DI–DII
DI–DII
DI–DII
T1700A
L567Q
Missense
DI–DII
C1715A
G1844A
C1852T
A2042C
C2204T
C2204A
n.a.
IVS14-1G>C
T2552C
A572D
G615E
L618F
H681P
A735V
A735E
G752R
Missense
Missense
Missense
Missense
Missense
Missense
Missense
Splice mutation
Missense
Missense
Frameshift
Missense
Missense
Missense
Missense
Missense
Missence
Missence
Missense
Missense
Missense
Missence
Missense
Missense
Missense
Missense
Frameshift
Missense
Missense
Missense
Splice mutation
Missense
Missense
Missense
Missense
Deletion
Nonsense
Missense
Missense
Missence
Frameshift
Deletion
DIIS5–S6
DI–DII
DI–DII
DI–DII
DIS1
DIS1
IVS5DS+1G>A
C677T
A688G
G845A
G880A
G892A
951X
G995A
G1100A
n.a.
n.a.
InsAAint7
1177–1179del
1479delK
G1541T
n.a.
2613delC
T2674A
T2686A
C2729T
TC2971/2AA
C2893T
G289T
G3157A
G3340A
G3575A
n.a.
C>T
C3694T+C4859T
G3708T
G3718C
T3748C
3819delG
T3887C
cGAG-G>A
C3912T
T>C
n.a.
A3974G
G>C
n.a.
4190delA
n.a.
A4372T
A1294G
4402–4406del
4498–4500
F851L
L867X
S871fs+9X
F891I
C896S
S910L
S941N
R965C
A997S
E1053K
D1114N
R1192Q
E1225K
R1232W
R1232W+T1620M
K1236N
E1240Q
F1250L
n.a.
F1293S
E1295K
T1304M
IVS22DS+2
G1319V
N1325S
A1330P
S1382I
1396
V1398X
V1405L
G1406R
R1432G
G1467fs+13X
delK1500
Europace, Vol. 5, October 2003
DIIS2
DIIIS5
DIIIS5–S6
DIIIS5–S6
DIIIS5–S6
DIIIS5–S6
DII–DIII
DII–DIII
DII–DIII
DII–DIII
DII–DIII
DIII
DIII–S1
DIIIS1–S2
DIIIS1–S2
DIIIS1–S2
DIII–S2
DIII–S2
DIIIS3–S4
DIIIS4
DIIIS4
DIIIS4–S5
DIIIS4–S5
DIIIS4–S5
DIIIS5–S6
DIIIS5–S6
DIIIS5–S6
DIIIS5–S6
DIIIS6
DIII–DIV
Phenotype
Reference
BS
BS
BS
BS
BS
BS
BS
RWS
BS
BS
BS
BS
AV block
BS
BS
BS
SUNDS/BS
BS
BS
IVF
BS
BS
ICCD
BS
BS/SIDS
IFV
RWS
aLQTS
aLQTS
BS
SUNDS/BS
BS
BS
BS
BS
BS
BS
BS
BS
BS
RWS/SIDS
RWS/BS
SIDS
BS
RWS/BS
SUNDS/BS
BS
IVF/BS
IVF/BS
BS
BS
aLQTS
BS
BS
RWS
RWS
PCCD
BS
RWS
RWS/SIDS
BS
IVF
IVF/BS
BS
BS/PCCD
BS
BS
RWS/BS/AV block
[27]
[26]
[26]
[33]
[34]
[31]
[34]
[27]
[27]
[27]
[27]
[32]
[31]
[35]
[34]
[34]
[31]
[31]
[2]
[27]
[31]
[29]
[31]
[36]
[33]
[37]
[37]
[27]
[34]
[27]
[31]
[27]
[27]
[31]
[27]
[27]
[27]
[27]
[28]
[33,35]
[16]
[35]
[33,38]
[34]
[31]
[2]
[2,39]
[27]
[27]
[37]
[31]
[27]
[18]
[20]
[4]
[31]
[40]
[41]
[31]
[2]
[2,33]
[31]
[31,42]
[6,43]
[27]
[27]
Implications of genetic mutations in SCN5A
329
Table 1 Continued
Nucleotide change
Mutation
Coding effect
Region
Phenotype
Reference
L1501V
G1502S
1503
1505–1507delKPQ
R1512W
IVS2AS-24
DIII–DIV
DIII–DIV
4850–4852del
C>T
G4868A
G4868T
G4931A
C4934T
5130delG
5280delG
IVS24DS+28
D1595N
1616
1617delF
T1620M
R1623Q
R1623L
R1644H
T1645M
delG
1 bp del
Missense
Missense
Deletion
Deletion
Missense
Splice mutation
Splice mutation
Splice mutation
Missense
Deletion
Deletion
Missense
Missense
Missense
Missense
Missense
Frameshift
Frameshift
C>T
S1710L
Missense
1710
G1740R
G1743E
M1766L
I1768V
V1777M
E1784K
S1787N
D1790G
Y1795C
Y1795H
1795insD
1796insD
L1825P
R1826H
D1840G
L1921stop
A1924T
V1951L
Deletion
Missense
Missense
Missense
Missense
Missense
Missense
Missense
Missense
Missense
Missense
Insertion
Insertion
Missense
Missense
Missense
Nonsense
Missense
Missense
RWS
BS
LQT3
RWS
BS/IVF
BS
BS
BS
AV block/PCCD
LQT
RWS
IVF/BS
RWS
RWS
RWS
RWS
PCCD
AV/RBBB
IVF
BS
PCCD
Lenegre–Lev disease
BS
BS
RWS/AVblock
LQT3
RWS/AVblock
RWS/BS
RWS
RWS
LQT3/BS
LQT3/BS
RWS/IVF
RWS/BS
LQT
SIDS/LQT3
RWS
BS
BS/IVF
BS
[38]
[31]
[19]
[19,40]
[31,56]
[56]
[31]
[56]
[32]
[38]
[38]
[2,33,44]
[38,45–47]
[38]
[38,40]
[20]
[4]
[4]
[3]
[44]
[33]
[4]
[27]
[31]
[47]
[48]
[49]
[6,22,38]
[38]
[24,50,51]
[52]
[33,52]
[53,54]
[53]
[55]
[16]
[50]
[14]
[31,56]
[27]
C4501G
n.a.
4511–4520del
C5434T
C>T
IVS21+1G>A
C>T
G5218A
n.a.
G5329A
G5349A
G5360A
A5369G
C5383G
5537insTGA
5385insTAG
G5477A
A5519G
A>T
G5851T
(probably regarded as a form of LQT3), SUNDS and
isolated PCCD (Lev–Lenegre disease)[2,4,28,38]. SCN5A
mutations have been identified in the patients diagnosed
as having this disorder, thus confirming that SUNDS
and BS are the same clinical entity. SCN5A seems to
play different kinds of roles, leading in an apparent Ôsplit
personalityÕ clinically. Interestingly, death most commonly occurs during sleep in all of these disorders,
suggesting a common mechanism.
Initially, mutations of the cardiac sodium channel
gene SCN5A were identified as a cause of a rare variant
of long QT syndrome, so called LQT3. The LQT3 accounts for approximately 5–10% of the genotyped LQT
families. This is characterized by prolongation of repolarization and ventricular polymorphic tachycardia,
so called torsade de pointes, which may lead to sudden
cardiac death (SCD). Exercise-related episodes (typically
during swimming) dominate in LQT1, while rest or sleep
related events are more common in LQT3[57]. In contrast
DIII–DIV
DIII–DIV
DIVS
DIVS
DIVS3
DIVS3–S4
DIVS3–S4
DIVS4
DIVS4
DIVS4
DIVS4
DIVS5–S6
DIVS5–S6
DIVS5–S6
DIVS5–S6
DIVS6
DIVS6
C-term
DIVS6
DIVS6
DIVS6
C-term
C-term
DIVS6
C-term
C-term
C-term
C-term
C-term
to LQT1, LQT3 patients are also at risk of the onset of
cardiac events later in life.
BS also is a familial disease which is often characterized by syncope or SCD as the only symptom among
its patients. In some cases, sudden death is the first
symptom of the disease. Monitoring of BS patients has
shown the polymorphic ventricular tachycardias (VTs)
as the underlying cause[58]. VT usually begins with a
short coupling interval and self-terminating episodes
typically result in recurrent episodes of syncope. About
80% of victims of cardiac arrest associated with BS had
experienced a syncopal event[59]. Clinical reports signify
that sudden death in patients with BS occurs mostly
during sleep, especially late at night. Fever has been
reported as a possible risk factor for cardiac arrest. The
mean age at which symptoms first appear in affected
individuals is the third to fourth decade of life. However, symptomatic twins at 1 year of age have been
reported[60,61].
Europace, Vol. 5, October 2003
330 E. Moric et al.
BS may occur with a peculiar high prevalence in the
Far East countries where it is suspected to constitute
a major cause of sudden death among young individuals
and the cause of SUNDS[11]. The clinical features and
electrocardiographic findings of SUNDS, a disorder
found in Southeast Asia, particularly Thailand, Japan,
Philippines and Cambodia[11], are similar to those of BS.
The sex-related difference in the phenotypic expression
of BS is more pronounced than that in any other autosomally transmitted arrhythmic syndrome. Although the
genotype is transmitted in equal proportion to males
and females, the manifestation of the clinical syndrome
is observed 10 times more often in males than in
females. This low penetrance of the disease in females
led to the Southeast Asian custom of men dressing in
women’s clothes at bedtime to fool the Ôevil spiritsÕ that
were presumed to target males in their sleep. The basis
for this disparity between the sexes has long defied
explanation[62–65].
More recently, Tan et al.[29] demonstrated that
mutations in SCN5A cause complete AV block in some
patients, resulting in bradycardia-induced symptoms,
which suggest that cardiac conduction system abnormalities may exist in some cases. Patients with typical
isolated cardiac conduction defect (ICCD) do not show
ECG characteristics of BS and also do not respond
positively to flecainide challenge used as a provocative
test.
Expression studies revealed the existence of silent
mutated channels but normal intracellular trafficking.
Kyndt et al.[42] have raised the possibility that the
consequence of the same SCN5A mutation may be
individual-specific or, precisely, branch-specific. The
authors also reported that the same SCN5A mutation
can lead to two different ECG phenotypes and,
thereafter, to different syndromes and, most importantly,
different risks, i.e. tachyarrhythmia or inversely extreme
bradycardia, depending on the family collateral branch.
Sex differences may be related to genetic factors
influencing phenotype. Thus, it is conceivable that sex
can influence the phenotype via the effects of sex
hormones on repolarizing potassium currents. This
hypothesis still requires further evaluation[42].
ECG findings
LQT3
Moss[66] showed that the ECG manifestations of LQTS
were determined by the mutated gene. The ECG of
LQT3 is associated with unusually increased duration of
the ST segment leading to a prolonged QTc at the
expense of ST, altogether with the late appearance of the
T wave. Zhang et al.[67] identified in patients with LQT3
late-onset peaked/biphasic T wave and asymmetric
peaked T wave. However, rate-corrected QT interval
duration did not differ among LQT1, LQT2 and LQT3
patients[68] and overlap existed among the repolarization
patterns of LQT1, LQT2 and LQT3, and one-third of
Europace, Vol. 5, October 2003
LQT3 gene carriers had repolarization similar to those
of LQT1 gene carriers. LQT3 patients tend to shorten
QT intervals during exercise induced tachycardia and to
have significant QT prolongation at long cycle lengths.
The cellular mechanism for QT prolongation in most
LQT3 is believed to be persistent Na+ current during
the action potential plateau attributable to the defects in
Na+ channel fast inactivation (gain of function) that
delay repolarization. LQT3 patients have a further
prolongation of the QT interval at night and are
particularly likely to die while at rest or in their sleep,
and during their first arrhythmic episode. The administration of sodium channel blockers such as mexiletine
shortens the QT interval in these patients and may
prevent the arrhythmias. Most notable for LQT3
patients is the long isoelectric segment followed by
a normal T-wave duration with a relatively sharp
deflection (present in 82% of LQT3 patients with
a typical ST–T wave pattern).
BS
The electrocardiographic feature of BS is ST-segment
elevation in the right precordial leads which is dynamic
and often concealed. Three types of ECG abnormalities
are recognized[58]. Type 1 is characterized by a prominent
coved ST-segment elevation displaying J-wave amplitude or ST-segment elevation 2 mm or 0.2 mV at its
peak followed by a negative T wave. Type 2 has a high
take-off ST-segment elevation and wave amplitude (2
mm) gives rise to a gradually descending ST-segment
elevation, followed by a positive or biphasic T wave.
This results in a saddle back configuration. Type 3 is
a right precordial ST-segment elevation of 1 mm of
saddle back type, coved type, or both. The absence of S
waves in the left lateral leads precludes the true presence
of RBBB.
No reciprocal ST-segment depression is noted in most
cases. In selected subjects alternative higher intercostals
space V1 to V3 lead ECG could be helpful in detecting
BS patients. The PR interval is often increased due to
the presence of HV prolongation and other conduction
disorders such as left anterior hemiblock and RBBB are
present. About 10% of BS patients have concomitant
atrial fibrillation. Preliminary evidence suggested the
existence of a variant of BS associated with ST elevation
in the inferior leads. Intermittent nature of ECG
findings can make diagnosis of BS difficult. Sodium
channel blocking agents such as ajmaline, procainamide,
flecainide and propafenone can provoke or accentuate
the ST changes and are used in diagnostic tests. SUNDS
shares the same ECG pattern as BS.
Smits et al.[31] tested a genotype–phenotype relationship in BS patients and showed that the presence of
conduction defects (prolonged HV and PQ) at baseline
and excessive QRS interval prolongation after sodium
channel blockers are more likely found in BS patients
who are carriers of an SCN5A mutation.
It is well known that ST segment varies day by day,
and so may be an inadequate indicator of BS. In order
Implications of genetic mutations in SCN5A
to distinguish the normal ST-segment elevation observed
in athletes from that of BS, the magnitude of the ST
elevation and the QRS duration may be useful.
Therefore, not only ST elevation, but also the S wave
width should be measured to detect high-risk patients.
PCCD
PCCD is characterized by progressive slowing of cardiac
conduction velocity through the His–Purkinje system
with right or left bundle branch block and widening of
QRS complexes. Relatively little information is available
concerning the spectrum of genetic defects, the clinical
manifestations and the genetic epidemiology of PCCD.
Presently, it is not possible to delineate fully the picture
of this form of cardiac sodium channel disorder.
Risk stratification
The genetic defects on the cardiac sodium channel gene
linked with the LQT3 are associated with higher risk of
SCD[57]. Cardiac arrhythmias are significantly more
frequent among patients with LQT1 and LQT2, while
lethal events are more frequent in those with LQT3[68].
The higher lethal nature of cardiac events in patients
with mutations at the LQT3 locus may contribute to
a potential under-representation of such patients among
patients with a diagnosis of LQTS. Risk stratification is
mainly based on history of syncope, torsade de pointes
or cardiac arrest[69]. The duration of the corrected QT
interval or macroscopic T wave alternans are weaker
predictors of SCD.
The risk stratification in BS is still undefined[35,70]. The
mortality in symptomatic patients averages 10% per
year. Asymptomatic patients appear to have a better
prognosis. It is not known how to identify those
individuals who at the moment are asymptomatic but
may become symptomatic in the future. Ikeda et al.[71]
assessed various noninvasive markers in identifying
patients at risk in BS. There was no relationship
between the magnitude of J-point elevation at rest and
life-threatening events. However, it has been shown that
detection of late potentials was a useful stratifier
predicting life-threatening arrhythmic events.
Ventricular arrhythmia inducibility in BS patients, at
variance with healthy controls, is high (50–80%) but
does not correlate with clinical presentation[72]. Results
are deeply influenced by the protocol used[73]. In
Consensus Report the Study Group on the Molecular
Basis of Arrhythmias of the European Society of
Cardiology experts in this field suggested a protocol
using two stimulation sites using at least three cycle
lengths 1–3 extrastimuli and a minimal coupling interval
of 200 ms[58].
Data reported by Brugada et al.[74] have shown a low
positive predictive value of PES (13%) but a good
predictive value of PES in asymptomatic non-inducible
individuals (99%). In contrast to this study, Priori
331
et al.[35] reported a low positive (50%) and negative
(46%) predictive value. PES results have been reported
at mid-term observation to have poor correlation with
the incidence of arrhythmic events. However, this does
not exclude the possibility of correlation with long-term
follow-up[75]. Before drawing any conclusion on the
value of PES in BS, data on a large population of
patients studied with the same protocol and with a longer
follow-up are required. It seems that asymptomatic
patients with Brugada ECG pattern and negative family
history are not candidates for PES.
Priori et al.[59] evaluated the natural history of BS in
a large cohort of 200 patients including the largest
worldwide population of genotyped individuals. Highrisk patients (10%) presented a baseline ST-segment
elevation and had history of syncope. Forty-four percent
of them had cardiac arrest. Patients with intermediate
risk (41%) had spontaneous ST-segment elevation 2
mm without history of syncope and presented a strong
trend toward an increased risk that fails to reach
statistical significance. Lastly, patients with a negative
phenotype (silent mutation carriers) or who have
a diagnostic ECG only after provocative test were at
lower risk of cardiac events. No study has shown the
impact of genetic analysis on risk stratification of the
syndrome.
Splawski et al.[5] recently identified a common SCN5A
variant in Africans and African–Americans, which
causes a small but inherent and chronic risk of acquired
arrhythmia. The identification of the variant allele
known as Y1102 causes a subtle increase in the risk of
life-threatening arrhythmias and prevention could be
facilitated through rapid identifications of individuals at
risk. However, most of these individuals will never have
an arrhythmia because the effect of Y1102 is subtle[5].
Management
Knowledge about the mutations causing LQT syndrome
has initiated research on the therapies targeted at the
mutant ion channels. Adjustment of lifestyle is of vital
importance in the prevention of SCD in all categories of
patients with LQT (symptomatic, asymptomatic and
silent carriers of the genetic defect)[59]. However, while
this is extremely important for LQT1 patients, some
degree of flexibility for non-competitive physical activity
may not have to be withheld, except for persons who
have already experienced episodes during exercise[68]. All
patients must avoid the use of drugs that prolong QT.
The percentage of patients who were free of recurrence with beta-blocker therapy was higher and the
death rate lower among LQT1 patients (81% and 4%,
respectively) than among LQT3 (50% and 17%, respectively) patients[68]. LQT3 patients are at higher risk
at longer cycle lengths. Therefore, they may benefit more
from pacemaker implantation, which allows the safe use
of beta-blockers[68,76]. In addition, selective left cardiac
sympathetic denervation, which does not reduce heart
rate, may be more effective in LQT3 symptomatic
Europace, Vol. 5, October 2003
332 E. Moric et al.
patients with recurrences on beta-blockers. Implanted cardioverter defibrillator (ICD) implantation is
recommended in survivors of cardiac arrest. The use of
beta-blockers should be continued along with the
implantation of an ICD.
The sodium channel blockers flecainide and mexiletine have been reported beneficial in the LQT3[77]. The
extent to which these agents may be effective in preventing SCD is not yet known. At present, these drugs
may be considered only as adjuncts to the standard
therapy.
BS survivors of cardiac arrest and patients with a
history of syncope, VT or a family history of juvenile
SCD should receive an ICD[69]. Management of asymptomatic patients is still undetermined and debated. Silent
mutation carriers and patients who have BS ECG pattern only after provocative test should be reassured[27]
and educated about symptoms and the need for reevaluation. Sodium channel blocking agents and tricyclic
antidepressants should be avoided[78]. Caution should be
exercised when using alpha-agonists or neostigmine[79].
Antiarrhythmic agents such as beta-blockers and amiodarone are ineffective. Some investigators advocate
quinidine[80].
In summary, it should be noted that SUNDS, BS,
SIDS, LQT3 and conduction system diseases are allelic
disorders, if not the same disease with variable penetrance and variable modifiers worldwide. Subclinical
mutations associated with the SCN5A gene may predispose the subset of individuals to life-threatening
arrhythmias in the course of drug therapy.
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