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Genetics of congenital and
acquired long QT syndrome
By cardiovascular master members:Dr. Islam Mohammed Khedr
Dr. Wael abd el fattah
Dr. Ahmed shahin
Dr. Amr Abd El Aziz
Dr. Omar Nasser
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INTRODUCTION
The long QT syndrome (LQTS) is thephenotypic description of a group of disorderscharacterized by a prolonged QT interval inassociation with a characteristic arrhythmia,
polymorphic ventricular tachycardia. The LQTS can be inherited or acquired as an
adverse response to medication, metabolicabnormalities, or bradyarrhythmias.
Torsades de pointes (TdP) or "twisting ofpoints" is the specific type of polymorphicventricular tachycardia (VT) associated witheither form of the LQTS.
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INTRODUCTION
Modern molecular biological techniqueshave permitted the identification and
analysis of the genes responsible for
almost all patients with a congenital longQT syndrome
Hundreds of mutations in more than ten
genes have thus far been identified.
Distinct genetic types have been
designated LQT1 through LQT10 and
additional genetic types have been
identified.
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INTRODUCTION
In some patients, drug-associatedLQTS appears to represent a "forme
fruste" of congenital LQTS in which a
mutation or polymorphism in one ofthe LQTS genes is clinically
inapparent until the patient is exposed
to a particular drug or otherpredisposing factor.
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Phenotypes of congenital
LQTS Two clinical phenotypes have been
described in congenital LQTS that
vary with the type of inheritance and
the presence or absence ofsensorineural hearing loss:
1. The Romano-Ward syndrome .
2. Jervell and Lange-Nielsensyndrome.
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The Romano-Ward syndrome
Transmitted as an autosomal dominanttrait and is characterized clinically byLQTS without deafness (cardiacphenotype)
It may result from any of the underlyingmutations thus far found in LQTS orother as yet unidentified mutations.
A recessive form of the Romano-Wardsyndrome has been described in onefamily of individuals homozygous formutations in the KVLQT1 gene.
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The Jervell and Lange-Nielsen
syndrome Transmitted as an autosomal recessive
trait and is characterized clinically byLQTS and sensorineural deafness.
It has only been described withmutations in KCNQ1 (LQT1) or KCNE1(LQT5).
These encode the alpha and beta
subunits of the slowly acting componentof the outward-rectifying potassiumcurrent (IKs).
This variant has been associated with a
more malignant course.
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TYPES OF CONGENITAL LQTS
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LQT type 1
Accounts for 40 to 55 percent of cases of the LQTS. Most patients with this defect show paradoxical prolongation
of the QT interval after an infusion of epinephrine, which canalso be used to unmask latent mutation carriers.
Suppression of IKs by mutations in the KVLQT1 gene, in theabsence or presence of minK, can be correlated with and
likely underlie prolongation of human ventricular actionpotentials.
Gain-of-function mutations in KVLQT1 have been associatedwith familial atrial fibrillation and with the congenital short QTsyndrome.
Many missense mutations, and some other types of
mutations, have been identified in KVLQT1. The severity of the clinical features of LQT1 vary with the
specific mutation.
Homozygous mutations of KVLQT1 appear to cause theJervell-Lange-Nielsen syndrome.
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LQT type 2
Accounts for 35 to 45 percent of cases ofcongenital LQTS
Caused by a variety of mutations in adifferent potassium channel gene,
localized to chromosome 7 The implicated gene is called HERG (or
KCNH2), the function of which is therapidly acting component of the outward-
rectifying potassium current (ikr) Virtually all of the drugs that cause
acquired LQTS block the ikr currentmediated by HERG.
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LQT type 3
Accounts for 8 to 10 percent of cases. Caused by mutations in the sodium channel
gene (SCN5A) located on chromosome 3 atlocation 21-24; six mutations have beenassociated with LQT3.
Mutations in at least two families involve a ninebase pair deletion in a region of the sodiumchannel gene that causes impaired inactivationof the channel.
Sporadic (de novo) SCN5A mutations have alsobeen described in which neither parent hadeither the mutation or a long QT interval.
Mutations in SCN5A have been associated withsudden infant death syndrome, at least some ofwhich are sporadic.
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LQT type 4
Caused by a loss-of-function mutation of theankyrin-b (ANK2) gene on chromosome4q25-27
Ankyrin-b is a plasma membrane protein that
physically links the lipid bilayer to themembrane skeleton; it is the first proteinassociated with LQTS that is not an ionchannel or channel subunit.
Individuals with this mutation have markedsinus node dysfunction, sinus bradycardia or
junctional escape rhythm, and episodes ofatrial fibrillation.
Sudden death occurs after physical exertionor emotional stress.
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LQT type 5
Results from a mutation in the mink(KCNE1) gene on chromosome21q22.1-22.2.
This protein, when combined with theproduct of the kvlqt1 gene, forms theslowly acting component of theoutward-rectifying potassium current.
Homozygous mutations in kcne1 havebeen reported to cause the jervell-lange-nielsen syndrome
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LQT type 6
Is the result of a mutation in the mink relatedpeptide 1 (mirp1 or KCNE2) gene onchromosome 21q22.1-22.2
This small membrane peptide is thought toassemble with herg to alter its function, affecting
ikr. Three missense mutations associated with lqts
and ventricular fibrillation have been identified inmirp1; mutants form channels that open slowlyand close rapidly, decreasing the potassium
current. One polymorphism in mirp1, which is present in
approximately 1.6 percent of the generalpopulation, can be clinically silent but appears topredispose to drug-induced LQTS at therapeutic
levels of sulfamethoxazole
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LQT type 7
results from a mutation in the KCNJ2 gene onchromosome 17 that encodes Kir2.1, the inwardrectifier potassium channel expressed in cardiacand skeletal muscle
The mutation appears to prolong the terminal
phase of the myocardial action potential and, inthe presence of low extracellular potassium, caninduce Na-Ca exchanger-dependent delayedafterpotentials
Affected patients with this rare autosomal
dominant disorder, called Andersen syndrome orAndersen-Tawil syndrome, can develop periodicparalysis, skeletal developmental abnormalities,and long QT syndrome with ventriculararrhythmias that are exacerbated by
hypokalemia
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LQT type 8
Results from a mutation in CACNA1C, thegene encoding the l-type calcium channel(cav 1.2).
The mutation, which leads to an increase in
calcium current, underlies timothy syndrome,a multisystem disorder with major phenotypicabnormalities including syndactyly,dysmorphic features, cognitive deficits,
autism and arrhythmias The disorder is rare, with case reports
including 17 children.
Severe qt prolongation is a common feature
(qtc >650 msec), and malignant arrhythmiashave been documented in 12 of the 17 cases.
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CLINICAL FEATURES
LQT1, LQT2, and LQT3 account for over 90 percent of cases of congenitalLQTS
In addition to their genetic differences, there are certain clinical differences thatmay suggest one of these disorders:
Triggers of arrhythmia vary with the LQTS type.
In a review of 670 symptomatic patients, events triggered by exercise were
much more common in lqt1(62 versus 13 percent in types 2 and 3), whileevents occurring at rest or during sleep were most often seen in lqt3 (36 versus13 versus 29 percent).
The sensitivity of patients with lqt1 to exercise may be related to exaggeratedprolongation of the qt interval during and after exercise (compared to lqt2 andlqt3), primarily due to increased transmural dispersion of repolarization
Events before age 10 are common only in lqt1 (40 versus 16 and 2 percent)
Beta blockers are most likely to prevent events in lqt1. This was illustrated in anobservational study of 670 patients of known genotype .Patients with LQT1were highly likely to be free from recurrence and had a very low SCD rate (81and 4 percent, respectively) with beta blocker therapy; these events were morecommon with beta blockers in patients with LQT2 (59 and 4 percent) and LQT3(50 and 17 percent). (
Mexiletine is highly likely to shorten the qt interval in lqt3 with little or no effect intypes 1 and 2
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Diagnosis & management
In patients with a confirmed or suspectedclinical diagnosis of LQTS, genetic diagnosiscould have important implications for bothmanagement decisions and family members.
In a patient with the diagnosis established byclinical criteria, identification of a specificgenotype may result in modifications intreatment. Strenuous exercise should be
limited, while beta blockers may be beneficialin LQT1. In comparison, beta blockers areless likely to be effective in LQT3, whilemexiletine may be beneficial since it shortensthe QT interval
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Diagnosis & management
In a patient with borderline clinicalcriteria for LQTS, identification of aspecific mutation can confirm thediagnosis. However, the diagnosis isnot excluded by failure to identify aknown mutation.
Genetic testing can confirm or exclude
the diagnosis in an asymptomaticrelative of a patient with LQTS and aknown mutation.
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MUTATIONS IN ACQUIRED
LQTS Long QT syndrome can also be an
acquired disorder, most often due to
drugs.
Virtually all of the drugs that produceLQTS act by blocking the IKr current
mediated by the potassium channel
encoded by the HERG gene.As noted before, mutations in HERG
are responsible for LQT2.
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THANK YOU