lqt3 midterm slides
TRANSCRIPT
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Long QT Syndrome Type 3 3
Team Members :Matthew ArgentieriMichelle HungSusan MathewSweta RoyYarden SegalDikesh Shrestha
Group 4March 22nd 2012
http://mysbfiles.stonybrook.edu/~margentieri/
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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
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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
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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.
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Prevalence
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Amin, A. Roodsari, A, and Tan, H. (2010) Cardiac sodium channelopathies. Eur J Physiol.
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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
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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
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Clinical Diagnosis
ECG
Holter monitoring
Ergometry
Family background
Genetic screening
Image:-http://www.sciencedirect.com/science/article/pii/S0735109705009162
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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
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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
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Wang, QING, ZHIZHONG Li, JIAXIANG Shen, and MARK T. Keating. "Genomic Organization of the Human SCN5A Gene Encoding the Cardiac Sodium Channel."
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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.
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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
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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
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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