Romano-Ward Syndrome is a form of LQTS. RWS is an autosomal dominant defect that affects 1 in 7000 people in the US, as stated in a 2000 study. RWS patients shows cardiac abnormalities but normal hearing, whereas other forms of LQTS displays hearing loss as a symptom. LQT3 is under the category of Romano-Ward Syndromes. It is not specified how many people die from LQT3 every year, but LQTS is assumed to have caused 4000 deaths in the US alone. The mortality rate of LQTS reaches up to 6% by when patients turn 40.
As we said before, LQT3 is an autosomal dominant disease. It is caused by a mutation in the chromosome 3p21-24.This mutation results in the inactivation gate of the sodium channel to not work properly. It slows down the inactivation gate, so it cannot close, therefore ventricular repolarization is prolonged. This causes the sodium inward current to increase.
This figure shows chromosome 3 and the specific location of LQT3. LQT3 is genetically mapped between D3S1211 and D3S1767.This is the chromosome 3, and LQT3 is located on the p-arm.
LQT1, LQT2, and LQT3 all account for 90% for the patients who suffer from LQTS.This chart (the red box) shows that the percentage of LQT3 among those who have LQTS is between 10-15%. Although, I have read many other studies that have stated that the percentage is around 9, or a range between 7-10%. Either way, the general idea is that LQT3 is not as common as LQT1 and LQT2. In the yellow box, it shows that by the age of 40, 18% of the patients with LQT3 will have a cardiac event (which includes syncope—loss of consciousness, cardiac arrest, or even sudden death). This number is small compared to those of LQT1 and LQT2. BUT the percentage of dying during an event is 20% in LQT3 patients, which is HIGHER than those of LQT1 and LQT2, which is pointed out in the green box.Sleep and rest are triggers for LQT3, therefore the percentage of attacks happening during sleeping or resting is 39%, and 64% of those attacks can be considered as being lethal, which are shown in the blue boxes.
. (A) QT interval for carriers (solid bars) and non-carriers (open bars) in different age groups. (B) ST-segment elevation. Open bars for 0 to 1 year and solid bars for 1 to 3 years are not visible, because the values are 0.0 ± 0.0 mm. Mean ± SD. *p < 0.05.
Long QT due to gain in the inward sodium current QTc calculated using Bazette formula = QT/RR RR=interval between each QRS complex
T-wave morphology (monophasic or multiphasic) Ergometry :- the study of physical work activity, including that performed by specific muscles or muscle groups. The studies may involve testing with equipment such as stationary bicycles, treadmills, or rowing machines
The SCN5A gene stands for sodium channel, voltage-gated, type 5, alpha subunit and it is a member of the human voltage-gates sodium channel family. It consists of 28 exons and it is 80 kilobases long. Since sodium channels are responsible for the rapid influx of sodium ions that initiate and propagate action potentials in most excitable cells, the SCN5A gene is highly expressed in myocardiac muscle but shows little or no expression in skeletal muscle, liver and uterus. It encodes for a large protein of 2016 amino acids with a molecular weight of 227kDa.
The Schematic representation of LQT3 mutation in the sodium channel. As you can see the voltage-gated Na+ channel α-subunit is composed of four homologous domains (DI–DIV), each of which contains 6 putative membrane =spanning segments (S1-S6). The KPQ mutation is localized in the linker between domains III and IV of the channel protein.
Currently, there have been more than 150 mutations reported with the SCN5A gene, mostly in individuals who suffer from LQT3 and Brugada syndrome.LQT3 was localized to chromosome 3 at loci 3p21-24The LTQ type 3 syndrome is associated with a deletion mutation of 3 amino acids, lysine, proline, and glutamine and is refered to as the KPQ mutation and is located at the 1505-1507 positions. There are more mutations associated with LQT 3 in which
Common treatment toward Long QT Syndrome is usually beta blocker therapy. However LQT3 is less responsive toward it. Beta blockers inhibit normal epinephrine mediated sympathetic actions. It prevents the heart from beating fast during exercise or stressful events. Beta-blockers would seem to be a potentially harmful course of treatment because of the slowing of heart rate that accompanies reduced adrenergic input. Sodium channel blockers such as mexiletine and flecainide have been used as treatment instead.
Mexiletine has the ability to shorten the QT interval by being helping block the excess inward sodium current. It can also shorten the action potential duration in a cellular model and decrease the maximum voltage. Mexiletine shortens the QT interval by 535±32 to 445±31 ms.Flecainide is a Ic sodium channel blocker that is mostly used on patients with Brugada Syndrome. It is also used as a long term treatment for LQT3 because it shortens QT interval. Low doses of this drug can perform significant progress. At an average flecainide blood level of .11ug/ml, the QT shortens b 27.1 millisecond when compared to placebo therapy
LQT3 Midterm Slides
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
IntroductionLQTS: 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 SyndromeLoci Map to Chromosomes 3 and 7 with Evidence for FurtherHeterogeneity." Nature Genetics8.2 (1994): 141-47. Print.
The SCN5A GeneMember of the human voltage-gated sodiumchannel gene familyConsists of 28 exons and is 80kb longSodium channel are responsible for rapidinflux of sodium ionsHighly expressed in cardiac muscleEncodes a protein of 2016 amino acids
Protein Encoded by SCN5ASCN5A codes for a very large channel proteinContain 4 homologous domains (DI-DIV) Each domain contains 6 membrane spanning segments (S1-S6)LQT3 is associated with a deletion, missenseand 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 GeneMore than 150 mutations have been reported inthe SCN5A gene 77 mutations are known to have caused LQT3Other mutations are associated with Brugadasyndrome.
TreatmentsCommon treatments for Long QT syndrome isbeta blocker therapy. However, LQT3 is lessresponsive toward the typical beta blocker.Clinical treatments have been done to block theIna in LQT3 . Sodium channel blockers such as Mexiletine Flecainide
TreatmentsMexiletine shortens QT interval by 535±32 to 445±31 msBoth Mexiletine and Flecainide shortens the actionpotential duration and decreases the maximum voltage.At an average Flecainide blood level of .11ug/ml, the QTshortens by 27.1 milliseconds when compared to placebotherapy
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