Congenital Long QT Syndrome

Ramachandra

A sharp brain also stops working in presence of a beauty

Tell me a story about The first documented case of Long QT syndrome was described in

Leipzig by Meissner in 1856, where a deaf girl died after her teacher yelled at her. When the parents were told about her death, they told that her older brother who also was deaf died after a terrible fright. This was several decades before the ECG was invented, but is likely the first described case of Jervell and Lange-Nielsen syndrome. In 1957, the first case documented by ECG was described by Anton Jervell and Fred Lange-Nielsen, working in Tønsberg, Norway. Italian pediatrician Cesarino Romano, in 1963 and Irish pediatrician Owen Conor Ward, in 1964 separately described the more common variant of Long QT syndrome with normal hearing, later called Romano-Ward syndrome. The establishment of the International Long-QT Syndrome Registry in 1979 allowed numerous pedigrees to be evaluated in a comprehensive manner. This helped in detecting many of the numerous genes involved.

On September 29, 2006, Konowalchuk announced his retirement after a regular examination detected Long QT Syndrome

Define

Manifested LongQTs

Positive 12 Lead ECGMan:QTc ≥ 450msWomen ≥QTc 460msScreening :QTc ≥ 470msec(M) & QTc ≥

480msec(Female)Giudicessi JR, Ackerman MJ. Determinants of incomplete penetrance and variable expressivity in heritable cardiac arrhythmia syndromes. Transl Res 2013;161:1-14 Morita H, Wu J, Zipes DP. The QT syndromes: long and short. Lancet 2008;372: 750-63

Giudicessi JR, Ackerman MJ. Determinants of incomplete penetrance and variable expressivity in heritable cardiac arrhythmia syndromes. Transl Res 2013;161:1-14 Morita H, Wu J, Zipes DP. The QT syndromes: long and short. Lancet 2008;372: 750-63

Concealed LongQTS

10%-40% of genotype-positive individuals do not display any objective

evidence of a QT abnormality

Attributes of congenital LongQT

Genetically heterogeneousHeritable Repolarisation abnormalityPhenotype of QT prolongation on 12-ECGIncreased risk of potentially life-threatening

cardiac arrhythmiasTreatable

At the molecular level

• Mutations in15 distinct genes for encoding ion channel pore-forming a-subunits and accessory β-subunits central to the electromechanical function

Inheritance-Prototypes

Autosomal dominant– Romano-Ward syndrome (RWS)

Autosomal recessive -Jervell and Lange-Nielsen syndrome (JLNS)

Phenotypes

Only cardiac: RWSCardiac and ear: JLNSMulti organ: Timothy syndrome (TS)

Key Errors: Loss or Gain

Activation and inactivation process of α/β sub units of the following channelsInward depolarizing currents(INa⁺/ICa²) -Enhance outward repolarisation currents(Ikr/Iks/Ik1) - Diminished

LongQT Projection

Major LQTS–Susceptibility Genes

KCNQ1 (LQT1) KCNH2 (LQT2)SCN5A (LQT3)

most common causes 60%-75%

KCNQ1

ADJLNS Kv7.1pore-forming α-subunitIksPhysiological QT shortening with rise in HREndocochlear K currentHeterozygous loss-of- function most prevalent LQTS subtype

KCNQ1 .....Contd

physical and emotional stressDefective IKs fails to adopt with β-adrenergic

stimulation i.e. QT prolongs in place of shortening:Fatal LongQT

About them

Minorities

• At least 10 mutations• 5% of LongQT

Multisystem Long-QT Syndrome

Ankyrin-B Anderson-Tawil Timothy syndrome Recurrent Infantile Cardiac Arrest Syndromes

Genetic Modifiers of Long QT Syndrome Disease Severity

Schwartz et al

• 2009 • Population-based ECG• Molecular screening• 44,456 Italian• Phenotypes of Congenital LQTS = 1/ 2000• Pathogenic LQTS genotype=1/80

T- morphology

Diagnosis

• Personal/family Hx• LongQTS-triggered syncope/seizure/SCD• Provoke like

accident/drownings/emotional/sleep/rest• ECG: QTc>450msec(M) & >460msec (F)

Schwartz score ≥3.5:high (P)

Bazett’s QTc =QT/√RR

Rare variants

Risk Stratification :Geno+Pheno

Mutation reports

Management

M-FACT score

External Link

http://www.youtube.com/watch?v=_QElcK_fpV8

Stop imagination....learned a lot

Have nice time