The document summarizes Long QT Syndrome Type 3 (LQT3), a genetic condition caused by mutations in the SCN5A gene which codes for cardiac sodium channels. LQT3 causes abnormal prolongation of the QT interval on electrocardiograms. It is characterized by cardiac arrhythmias, fainting spells, and risk of sudden death. Treatment options for LQT3 include sodium channel blockers like mexiletine and flecainide, which can help shorten the QT interval. However, LQT3 tends to be less responsive to typical beta blocker therapy than other forms of Long QT Syndrome. The SCN5A gene contains over 150 known mutations that have been linked to

1. http://mysbfiles.stonybrook.edu/~margentieri/
Long QT Syndrome Type 3 3
Group 4
March 22nd 2012
Team Members :
Matthew Argentieri
Michelle Hung
Susan Mathew
Sweta Roy
Yarden Segal
Dikesh Shrestha

2. 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

3. 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

4. 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.

5. Prevalence

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

7. Occurrence of LQT3 in childhood
The QT length
prolongers as the age
increases
Graph:
solid bars :-carriers of mutant
Open bars :-non carriers
Source:- Developmental aspects of long QT syndrome type 3

8. Sign and Symptoms
Arrhythmia Clinical features:
Partial or total loss of  Long ST segments with
consciousness a late appearing T
wave
Abdominal pain and
 Has QTc >490+/- 40 ms
GI complications

9. Clinical Diagnosis
ECG
Holter monitoring
Ergometry
Family background
Genetic screening
Image:-http://www.sciencedirect.com/science/article/pii/S0735109705009162

10. 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

11. 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

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

13. 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 Brugada
syndrome.

14. 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

15. 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

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