Cv 04: Long Qt Syndrome

Front 1

What are relatively common outcomes of arrhythmias?

Back 1

- Syncope
- Sudden cardiac death (SCD)
- Sudden infant death syndrome (SIDS)

Front 2

How common is Long QT Syndrome?

Back 2

1:2000 - 5000

Front 3

What genetic abnormality can lead to Long QT Syndrome?

Back 3

Mutations in ion channel genes that either cause:
- Influx of Na+/Ca2+
- Decrease K+ in cardiac cells --> shift of electrical AP and repolarization effects

Front 4

What are the criteria for diagnosis of Long QT Syndrome by gender?

Back 4

Identified by prolonged QT interval on EKG:
- >450 ms in males
- >470 ms in females

Borderline QT interval:
- 431-450 in males
- 451-470 in females

* Approx. 30-40% of LQTS carriers have a QT interval equal to that of normal individuals *

Front 5

What is the normal QT interval by gender?

Back 5

- <430 ms in males
- <450 ms in females

Front 6

What are the symptoms of Long QT Syndrome?

Back 6

- Syncope (esp. during exercise or high emotions)
- Sudden Cardiac Death
- Due to ventricular tachyarrhythmias, typically Torsades de Pointes (TdP)
- TdP may cause seizures

Front 7

What are people with Long QT Syndrome most likely to pass out? Least likely?

Back 7

- Most likely: exercise and high emotions
- Least likely: rest or sleep (although can be a trigger in certain mutations for Romano-Ward Syndrome)

Front 8

What are acquired factors that can cause QT prolongation?

Back 8

- Primary myocardial problems: MI, myocarditis, cardiomyopathy
- Electrolyte abnormalities: hypokalemia, hypomagnesemia, hypocalcemia
- Autonomic influences
- Drug effects
- Hypothermia

Front 9

What are some inherited syndromes that cause Long QT Syndrome?

Back 9

- Romano-Ward Syndrome (RWS)
- Jervell and Lange-Nielson Syndrome (JLNS)

Front 10

What happens in Romano-Ward Syndrome (RWS)? Cause?

Back 10

- Elecrophysiologic disorder that causes QT prolongation and T-wave abnormalities
- Autosomal dominant inheritance
- 10 genes associated with it including: KCNQ1, KCNH2, SCN5A

Front 11

Which genetic syndrome is associated with QT prolongation and T-wave abnormalities?

Back 11

Romano-Ward Syndrome (RWS)

Front 12

What are the most common genes that are mutated in Romano-Ward Syndrome (RWS)? How common is each one? What ions do they affect?

Back 12

- KCNQ1 (LQTS Type 1) = >60% - K+
- KCNH2 (Type 2) = 35% - K+
- SCN5A (Type 3) = <5% - Na+

Front 13

What happens in Jervell and Lange-Nielson Syndrome (JLNS)? Cause?

Back 13

- Causes QT prolongation and profound, bilateral sensorineural deafness
- Presentation: deaf child w/ syncopal episodes during periods of stress, exercise, or fright
- Increased risk of SIDS in children
- Autosomal recessive
- 2 genes associated with it: KCNQ1 and KCNE1

Front 14

Which genetic syndrome is associated with a deaf child that experiences QT prolongation causing syncopal episodes during periods of stress, exercise, or fright?

Back 14

Jervell and Lange-Nielson Syndrome (JLNS)

Front 15

What are the most common genes that are mutated in Jervell and Lange-Nielson Syndrome (JLNS)? How common is each one? What ions do they affect?

Back 15

- KCNQ1 (LQTS Type 1) = 90% - K+
- KCNE1 (LQTS Type 5) = 10% - K+

Front 16

How are the inherited forms of Long QT Syndrome inherited?

Back 16

- Romano-Ward Syndrome: Autosomal Dominant (KCNQ1 or KCNH2 or SCN5A mutations)
- Jervell and Lange-Nielson Syndrome: Autosomal Recessive (KCNQ1 or KCNE1 mutations)

Front 17

If your patient is diagnosed with Romano-Ward Syndrome (RWS), what is the chance that a 1st degree relative also has RWS?

Back 17

50% (autosomal dominant inheritance)

Front 18

What is the most common mutation (cause of >60%) that causes Romano-Ward Syndrome (RWS)?
- Incidence of cardiac event?
- Cardiac event triggers?
- Sudden cardiac death risk?

Back 18

KCNQ1 (LQTS Type 1)
- 63% incidence of cardiac events
- Triggers: exercise, sudden emotion, swimming
- 4% risk of SCD

Front 19

What is the second most common mutation (cause of 35%) that causes Romano-Ward Syndrome (RWS)?
- Incidence of cardiac event?
- Cardiac event triggers?
- Sudden cardiac death risk?

Back 19

KCHN2 (LQTS Type 2)
- 46% incidence of cardiac events
- Triggers: exercise, emotion, postpartum, sleep
- 4% risk of SCD

Front 20

What is the third common mutation (causes <5%) that causes Romano-Ward Syndrome (RWS)?
- Incidence of cardiac event?
- Cardiac event triggers?
- Sudden cardiac death risk?

Back 20

SCN5A (LQTS Type 3)
- 18% incidence of cardiac events
- Triggers: sleep
- 4% risk of SCD

Front 21

Which mutations can predispose someone to have prolonged QT syndrome during their sleep? What syndrome does this correspond to?

Back 21

- KCHN2 = RWS
- SCN5A = RWS

Front 22

If someone has a mutation for KCNQ1, what are they at risk for?

Back 22

- Romano-Ward Syndrome (RWS)
- Jervell and Lange-Nielson Syndrome (JLNS)
- Prolongs QT interval in both
- RWS also has T-wave abnormalities
- JLNS also causes sensorineural deafness

Front 23

What indications should cause you to evaluate for Long QT Syndrome?

Back 23

- Unexplained syncope
- Onset of symptoms during childhood or adolescence
- Family history of SCD

Front 24

When should you do genetic testing for Long QT Syndrome?

Back 24

- Molecular confirmation of clinical diagnosis in symptomatic individuals
- Risk assessment of asymptomatic family members of a proband w/ arrhythmia
- Differentiation of hereditary arrhythmia from acquired arrhythmia
- Recurrence risk calculation

Front 25

What is the current genetic testing detection rate for Long QT Syndrome?

Back 25

- 75% will be positive for a mutation we know of
- 25% of families w/ a clinical diagnosis of LQTS will not have a detectable gene mutation

Front 26

If a family has a negative genetic test for LQTS, what should you tell them?

Back 26

- This does not rule out Long QT Syndrome
- Large deletions and duplications may be present in LQTS genes
- 25% of families will have a clinical diagnosis without a detectable mutation
- 5-12% of patients w/ normal sequencing of most common LQTS genes had large genomic rearrangements

Front 27

What percent of people with hereditary Long QT Syndrome will have 2 mutations?

Back 27

Up to 10%

Front 28

What are the genetic test to assess for Long QT Syndrome? Main difference?

Back 28

- Single gene analysis - assesses one gene at a time
- Arrhythmia gene panel - assesses multiple genes simultaneously

Front 29

What is done in a single gene analysis for Long QT syndrome?

Back 29

- Exon sequencing evaluates mutations in one gene
- In the event of a negative result, CGH array can assess full exon deletions or duplications

Front 30

What is done in a arrhythmia gene panel for Long QT syndrome?

Back 30

- Massive parallel sequencing (NextGeneration Sequencing) of coding exons within multiple genes simultaneously
- In the event of a negative result, CGH array can assess full exon deletions or duplications

Front 31

What is variable expressivity?

Back 31

- Extent to which genotype is phenotypically expressed (physical signs and symptoms)
- Phenotype associated w/ same genotype may vary from MILD to SEVERE within families

Front 32

What is Reduced Penetrance?

Back 32

Less than 100% of individuals with a certain genotype actually express the phenotype (ALL or NOTHING)

Front 33

What are the mechanisms of Tachycardia?

Back 33

- Re-entry
- Enhanced automaticity
- Abnormal automaticity
- Triggered activity

Front 34

What are the types of triggered activities that cause tachycardias?

Back 34

- Abnormal cellular firings which can be triggered by pacing
- Early and Delayed After-Depolarizations (EAD and DAD)

Front 35

What are early after-depolarizations (EADs) associated with?

Back 35

- Conditions that result in prolonged AP (long QT)
- Pause dependent, can be triggered by abruptly ceasing rapid pacing (resulting in a pause after)

Front 36

What are delayed after-depolarizations (DADs) associated with?

Back 36

- Excessive cytoplasmic Ca2+ and associated Ca2+ induced Ca2+ release from SR
- Tachycardia dependent can be triggered by rapid pacing

Front 37

How dose rapid pacing affect after-depolarizations?

Back 37

- EADs are triggered by ceasing rapid pacing
- DADs are triggered by rapid pacing