Long QT Syndrome Type 3 3

Team Members :Matthew ArgentieriMichelle HungSusan MathewSweta RoyYarden SegalDikesh Shrestha

Group 4March 22nd 2012

http://mysbfiles.stonybrook.edu/~margentieri/

Introduction

LQTS:

Romano-Ward Syndrome (RWS): autosomal dominant

Affects 1 in 7000 people in the US

Displays cardiac abnormalities

Causes 4000 deaths

Mortality rate: up to 6% by when patients turn 40

LQT3 overview

Autosomal dominant disease characterized by prolonged ventricular repolarization

Mutation in chromosome 3p21-24

3p21-24 is loci for the gene SCN5A or NaV1.5 that codes for the alpha helix of the voltage gated sodium channel

Affects inactivation gate of sodium channel

Cause to gain of function of sodium current

Jiang, Changan, Donald Atkinson, Jeffrey A. Towbin, Igor Splawski, Michael H. Lehmann, Hua Li, Katherine Timothy, R. Thomas Taggart, Peter J. Schwartz, G. Michael Vincent, Arthur J. Moss, and Mark T. Keating. "Two Long QT Syndrome Loci Map to Chromosomes 3 and 7 with Evidence for Further Heterogeneity." Nature Genetics8.2 (1994): 141-47. Print.

Prevalence

Amin, A. Roodsari, A, and Tan, H. (2010) Cardiac sodium channelopathies. Eur J Physiol.

Occurrence of LQT3 in childhood

The QT length prolongers as the age increases

Graph: solid bars :-carriers of mutantOpen bars :-non carriers

Source:- Developmental aspects of long QT syndrome type 3

Sign and Symptoms

Arrhythmia

Partial or total loss of consciousness

Abdominal pain and GI complications

Clinical features:

Long ST segments with a late appearing T wave

Has QTc >490+/- 40 ms

Clinical Diagnosis

ECG

Holter monitoring

Ergometry

Family background

Genetic screening

Image:-http://www.sciencedirect.com/science/article/pii/S0735109705009162

The SCN5A Gene

Member of the human voltage-gated sodium channel gene family

Consists of 28 exons and is 80kb long

Sodium channel are responsible for rapid influx of sodium ions

Highly expressed in cardiac muscle

Encodes a protein of 2016 amino acids

Protein Encoded by SCN5A

SCN5A codes for a very large channel protein

Contain 4 homologous domains (DI-DIV) Each domain contains 6 membrane

spanning segments (S1-S6)

LQT3 is associated with a deletion, missense and insertion mutation

Wang, QING, ZHIZHONG Li, JIAXIANG Shen, and MARK T. Keating. "Genomic Organization of the Human SCN5A Gene Encoding the Cardiac Sodium Channel."

Mutations in SCN5A Gene

More than 150 mutations have been reported in the SCN5A gene 77 mutations are known to have caused

LQT3

Other mutations are associated with Brugadasyndrome.

Treatments

Common treatments for Long QT syndrome is beta blocker therapy. However, LQT3 is less responsive toward the typical beta blocker.

Clinical treatments have been done to block the Ina in LQT3 . Sodium channel blockers such as Mexiletine Flecainide

Treatments

Mexiletine shortens QT interval by 535±32 to 445±31 ms

Both Mexiletine and Flecainide shortens the action potential duration and decreases the maximum voltage.

At an average Flecainide blood level of .11ug/ml, the QT shortens by 27.1 milliseconds when compared to placebo therapy

REFERENCES

• Baars, H. F., Smagt, J. J., & Doevendans, P. (2010). Clinical cardiogenetics. (1st ed., p. 149). Springer.• Bankston, J., & Kass, R. (2010). Molecular determinants of local anesthetic action of beta-blocking drugs: Implications

for therapeutic management of long qt syndrome variant 3. NIH Public Access• Beinart, R., Michailidis, A., Gurevitz, O., & Gilkson, M. (2009). Is flecainide dangerous in long QT-3 patients? Journal

compilation, 32, 143-145.• Brisbane, J. (2006 (Updated 2009)). Acce review summary: The long qt-syndrome (lqts). Office of Population Health

Genomics, Government of Western Australia, Department of Health.• Moss, A., Windle , J., Hall, W., Zareba, W., Robinson, J., McNitt , S., Severski, P, Rosero, S, et al. (2005). Safety and

efficacy of flecainide in subjects with long QT-3 syndrome (ΔKPQ mutation): A randomized, double-blind, placebo-controlled clinical trial. Annals of Noninvasive Electrocardiology, 10(4), 59-66.

• Ruan, Y., Liu, N., Napolitano, C., & Priori, S. (2008). Therapeutic strategies for Long-QT syndrome: Does the molecular substrate matter?. Circ Arrhythm Electrophysiol, 1, 290-297.

• Schwartz, P., Priori, S., Locati, E., Napolitano, C., Cantù, F., Towbin, J., Keating, M., & Hammoude, H, et al. (1995). Long QT syndrome patients with mutations of the

• SCN5A and HERG genes have differential responses to Na channel blockade and to increases in heart rate. Circulation, (92), 3381-3386.

• Sovari, A. (2012, January 10). Long QT syndrome. Retrieved from http://emedicine.medscape.com/article/157826-overview

• Wang , H., Zheng, Y., Yang, Z., Li , C., & Liu, Y. (2003). Effect of mexiletine on long QT syndrome model. Chinese Pharmacological Society, 4, 316-320.

• http://www.wikigenes.org/e/gene/e/6331.html