Long QT interval in Turner syndrome--a high prevalence of LQTS gene mutations.

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Christian Trolle

Full Text Available QT-interval prolongation of unknown aetiology is common in Turner syndrome. This study set out to explore the presence of known long QT mutations in Turner syndrome and to examine the corrected QT-interval (QTc over time and relate the findings to the Turner syndrome phenotype.Adult women with Turner syndrome (n = 88 were examined thrice and 68 age-matched healthy controls were examined once. QTc was measured by one blinded reader (intra-reader variability: 0.7%, and adjusted for influence of heart rate by Bazett's (bQTc and Hodges's formula (hQTc. The prevalence of mutations in genes related to Long QT syndrome was determined in women with Turner syndrome and a QTc >432.0 milliseconds (ms. Echocardiographic assessment of aortic valve morphology, 24-hour blood pressures and blood samples were done.The mean hQTc in women with Turner syndrome (414.0 ± 25.5 ms compared to controls (390.4 ± 17.8 ms was prolonged (p432 ms, 7 had mutations in major Long QT syndrome genes (SCN5A and KCNH2 and one in a minor Long QT syndrome gene (KCNE2.There is a high prevalence of mutations in the major LQTS genes in women with TS and prolonged QTc. It remains to be settled, whether these findings are related to the unexplained excess mortality in Turner women.NCT00624949. https://register.clinicaltrials.gov/prs/app/action/SelectProtocol/sid/S0001FLI/selectaction/View/ts/3/uid/U000099E.

A Síndrome do QT Longo Associada ao uso de Citalopram e Escitalopram / The Long QT Syndrome Associated to Citalopram and Escitalopram

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Filipe Santos Falani

2016-06-01

benefit-risk should be evaluated before use. Citalopram is the selective inhibitor of serotonin reuptake most widely prescribed in the world as escitalopram is widely used in major depressive disorder. Escitalopram is also widely prescribed because of its mild and transient side effects. The Long QT syndrome occurs because of a change in the cardiac electrical system. A duration of the QT interval greater than 450ms in men and 460ms in women should be considered anomalous, with specific etiology. However, cardiac arrhythmias occur more frequently when QT is greater than 500ms. The primary mechanism of drug-induced long QT is the inhibition of the hERG potassium channel, particularly in those patients with the polymorphic variant. Conclusion: Despite the low prevalence of QT interval prolongation induced in second-generation antidepressant users, given its wide use by the population, a greater concern for electrocardiographic monitoring is required, especially when there are risk factors or signs of overdose.

Increased vulnerability of human ventricle to re-entrant excitation in hERG-linked variant 1 short QT syndrome.

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Ismail Adeniran

2011-12-01

Full Text Available The short QT syndrome (SQTS is a genetically heterogeneous condition characterized by abbreviated QT intervals and an increased susceptibility to arrhythmia and sudden death. This simulation study identifies arrhythmogenic mechanisms in the rapid-delayed rectifier K(+ current (I(Kr-linked SQT1 variant of the SQTS. Markov chain (MC models were found to be superior to Hodgkin-Huxley (HH models in reproducing experimental data regarding effects of the N588K mutation on KCNH2-encoded hERG. These ionic channel models were then incorporated into human ventricular action potential (AP models and into 1D and 2D idealised and realistic transmural ventricular tissue simulations and into a 3D anatomical model. In single cell models, the N588K mutation abbreviated ventricular cell AP duration at 90% repolarization (APD(90 and decreased the maximal transmural voltage heterogeneity (δV during APs. This resulted in decreased transmural heterogeneity of APD(90 and of the effective refractory period (ERP: effects that are anticipated to be anti-arrhythmic rather than pro-arrhythmic. However, with consideration of transmural heterogeneity of I(Kr density in the intact tissue model based on the ten Tusscher-Noble-Noble-Panfilov ventricular model, not only did the N588K mutation lead to QT-shortening and increases in T-wave amplitude, but δV was found to be augmented in some local regions of ventricle tissue, resulting in increased tissue vulnerability for uni-directional conduction block and predisposing to formation of re-entrant excitation waves. In 2D and 3D tissue models, the N588K mutation facilitated and maintained re-entrant excitation waves due to the reduced substrate size necessary for sustaining re-entry. Thus, in SQT1 the N588K-hERG mutation facilitates initiation and maintenance of ventricular re-entry, increasing the lifespan of re-entrant spiral waves and the stability of scroll waves in 3D tissue.

In silico cardiac risk assessment in patients with long QT syndrome

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Hoefen, Ryan; Reumann, Matthias; Goldenberg, Ilan

2012-01-01

The study was designed to assess the ability of computer-simulated electrocardiography parameters to predict clinical outcomes and to risk-stratify patients with long QT syndrome type 1 (LQT1).......The study was designed to assess the ability of computer-simulated electrocardiography parameters to predict clinical outcomes and to risk-stratify patients with long QT syndrome type 1 (LQT1)....

The dark side of the QT interval. The Short QT Syndrome: pathophysiology, clinical presentation and management

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I. Comelli

2012-12-01

Full Text Available A large number of studies has been carried out to investigate the pathophysiology and the clinical implications of QT interval prolongation in the ECG over recent years (1, 2, 3, 4, 5, 6. It was only in the last decade, however, that the scientists have focused on the specular aspects of the long QT syndrome (LQTS, and it is now well established that the abnormal shortening of the QT interval is associated with meaningful clinical consequences and adverse outcomes. The aim of the present article is to summarize knowledge and existing evidence about the Short QT Syndrome (SQTS. SQTS is a rare, albeit largely underdiagnosed, genetically determined disease, which is characterized by a high tendency to develop life-threatening arrhythmias. The two clinical landmarks of SQTS are the presence of a short QT interval (i.e., less than 320 ms in a structurally normal heart. The disease is now classified as a “channellopathy”, and is principally caused by a defective functioning of both potassium and calcium ion channels. The underlying genetic anomalies cause an abnormal ripolarization and a reduced refractoriness of myocardiocites. Pharmacologic treatments are mainly tailored to slow the conduction and to prolong the refractory period of myocardiocites. The implantable cardioverter and defibrillator (ICD is currently considered the therapeutic gold standard (7.

Gene-specific paradoxical QT responses during rapid eye movement sleep in women with congenital long QT syndrome

Czech Academy of Sciences Publication Activity Database

Lanfranchi, P. A.; Ackerman, M. J.; Kára, T.; Shamsuzzaman, A. S.; Wolk, R.; Jurák, Pavel; Amin, R.; Somers, V. K.

2010-01-01

Roč. 7, č. 8 (2010), s. 1067-1074 ISSN 1547-5271 R&D Projects: GA MZd NS10098; GA MZd NS10099 Institutional research plan: CEZ:AV0Z20650511 Keywords : autonomic nervous system * heart rate * long QT syndrome * QT interval * sex * sleep Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 4.246, year: 2010

Electrophysiological mechanisms of long and short QT syndromes

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Gary Tse

2017-03-01

Full Text Available The QT interval on the human electrocardiogram is normally in the order of 450 ms, and reflects the summated durations of action potential (AP depolarization and repolarization of ventricular myocytes. Both prolongation and shortening in the QT interval have been associated with ventricular tachy-arrhythmias, which predispose affected individuals to sudden cardiac death. In this article, the molecular determinants of the AP duration and the causes of long and short QT syndromes (LQTS and SQTS are explored. This is followed by a review of the recent advances on their arrhythmogenic mechanisms involving reentry and/or triggered activity based on experiments conducted in mouse models. Established and novel clinical risk markers based on the QT interval for the prediction of arrhythmic risk and cardiovascular mortality are presented here. It is concluded by a discussion on strategies for the future rational design of anti-arrhythmic agents.

Long QT interval in Turner syndrome: a high prevalence of LQTS gene mutations

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Trolle, Christian

Objective: QT interval prolongation of unknown aetiology is common in Turner syndrome (TS). This study set out to explore the presence of known pathogenic long QT (LQT) mutations in TS and to examine the corrected QT interval (QTc) over time and relate the findings to the TS phenotype. Methods......QTc). The prevalence of mutations in genes related to Long QT syndrome (LQTS) was determined in females with TS and a QTc >432.0 milliseconds (ms). Echocardiographic assessment of aortic valve morphology, 24-hour blood pressures and blood samples were done. Results: The mean hQTc in females with TS (414.0±25.5 ms...

Long QT syndrome and torsades de pointes complicating mitral valve replacement

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Shegu Gilbert

2016-09-01

Full Text Available Severe QT interval prolongation >500 ms occurs in one quarter of cardiac surgical patients in the perioperative period while moderate prolongation occurs in most of them. Prolonged QT interval may be associated with torsades de pointes and lead to sudden cardiac death. Because of the high incidence of prolonged QT in cardiac surgery patients and its perioperative adverse outcomes, it is vital to identify it early and take necessary precautions. We report and discuss the catastrophic events and management of two patients with long QT syndrome complicating mitral valve replacement.

Anthracyclines and Acquired Long QT Syndrome. A Case Report

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Carlos Rodríguez Armada

2014-12-01

Full Text Available Acquired long QT syndrome results from secondary causes and can be caused by more than 100 non-antiarrhythmic drugs. Cardiac arrest due to Torsades de pointes induced by drugs causing prolonged QT syndrome is a rare but potentially fatal event, even in hospitals. The case of a 47-year-old patient diagnosed with non-Hodgkin lymphoma admitted to the hematology department of the Dr. Gustavo Aldereguía Lima University General Hospital in Cienfuegos is presented. The patient had been previously treated with anthracyclines and developed episodes of palpitations and syncope later. The treatment included monitoring the patient, avoiding other QT prolonging agents and administrating magnesium sulfate and potassium chloride with a proper maintenance of the fluid and acid-base balance. The presentation of this case aims at motivating interest in new reports on the subject and establishing a direct causal relationship through the evidence provided by new experiences.

Long QT syndrome genotyping by electrocardiography: fact, fiction, or something in between?

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Kanters, Jørgen K.; Graff, Claus; Andersen, Mads Peter

2006-01-01

Diagnosis of long QT syndrome (LQTS) is difficult. A prolonged QT interval is easily overlooked, and in 10% of all patients with LQTS, the QT interval is normal. Genotyping is unfortunately not able to detect all patients and healthy subjects correctly. Although QT prolongation is the most used r...... evaluation can serve as a guide for genotyping and can reduce the costs by suggesting which gene to start sequencing, but it is fiction that the ECG can replace genotyping....

The role of CAV3 in long-QT syndrome

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Hedley, Paula L; Kanters, Jørgen K.; Dembic, Maja

2013-01-01

Mutations in CAV3, coding for caveolin-3, the major constituent scaffolding protein of cardiac caveolae, have been associated with skeletal muscle disease, cardiomyopathy, and most recently long-QT syndrome (LQTS) and sudden infant death syndrome. We examined the occurrence of CAV3 mutations...

Classification of the long-QT syndrome based on discriminant analysis of T-wave morphology

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Struijk, Johannes J.; Kanters, Jørgen K.; Andersen, M P

2006-01-01

The long QT syndrome (LQTS) is a genetic disorder, typically characterized by a prolonged QT interval in the ECG due to abnormal cardiac repolarization. LQTS may lead to syncopal episodes and sudden cardiac death. Various parameters based on T-wave morphology, as well as the QT interval itself ha...

Drug-Induced QT Prolongation as a Result of an Escitalopram Overdose in a Patient with Previously Undiagnosed Congenital Long QT Syndrome

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Paul Singh

2014-01-01

Full Text Available We present a case of drug-induced QT prolongation caused by an escitalopram overdose in a patient with previously undiagnosed congenital LQTS. A 15-year-old Caucasian female presented following a suicide attempt via an escitalopram overdose. The patient was found to have a prolonged QT interval with episodes of torsades de pointes. The patient was admitted to the telemetry unit and treated. Despite the resolution of the torsades de pointes, she continued to demonstrate a persistently prolonged QT interval. She was seen by the cardiology service and diagnosed with congenital long QT syndrome. This case illustrates the potential for an escitalopram overdose to cause an acute QT prolongation in a patient with congenital LQTS and suggests the importance of a screening electrocardiogram prior to the initiation of SSRIs, especially in patients at high risk for QT prolongation.

Common Variation in the NOS1AP Gene Is Associated With Drug-Induced QT Prolongation and Ventricular Arrhythmia

NARCIS (Netherlands)

Jamshidi, Yalda; Nolte, Ilja M.; Dalageorgou, Chrysoula; Zheng, Dongling; Johnson, Toby; Bastiaenen, Rachel; Ruddy, Suzanne; Talbott, Daniel; Norris, Kris J.; Snieder, Harold; George, Alfred L.; Marshall, Vanessa; Shakir, Saad; Kannankeril, Prince J.; Munroe, Patricia B.; Camm, A. John; Jeffery, Steve; Roden, Dan M.; Behr, Elijah R.

2012-01-01

Objectives This study sought to determine whether variations in NOS1AP affect drug-induced long QT syndrome (LQTS). Background Use of antiarrhythmic drugs is limited by the high incidence of serious adverse events including QT prolongation and torsades de pointes. NOS1AP gene variants play a role in

QT correction formulas and laboratory analysis on patients with metabolic syndrome and diabetes

Science.gov (United States)

Wong, Sara; Rivera, Pedro; Rodríguez, María. G.; Severeyn, Érika; Altuve, Miguel

2013-11-01

This article presents a study of ventricular repolarization in diabetic and metabolic syndrome subjects. The corrected QT interval (QTc) was estimated using four correction formulas commonly employed in the literature: Bazett, Fridericia, Framingham and Hodges. After extracting the Q, R and T waves from the electrocardiogram of 52 subjects (19 diabetic, 15 with metabolic syndrome and 18 control), using a wavelet-based approach, the RR interval and QT interval were determined. Then, QTc interval was computed using the formulas previously mentioned. Additionally, laboratory test (fasting glucose, cholesterol, triglycerides) were also evaluated. Results show that metabolic syndrome subjects have normal QTc. However, a longer QTc in this population may be a sign of future complication. The corrected QT interval by Fridericia's formula seems to be the most appropriated for metabolic syndrome subjects (low correlation coefficient between RR and QTc). Significant differences were obtained in the blood glucose and triglyceride levels, principally due to the abnormal sugar metabolization of metabolic syndrome and diabetic subjects. Further studies are focused on the acquisition of a larger database of metabolic syndrome and diabetics subjects and the repetition of this study using other populations, like high performance athletes.

Safe drug use in long QT syndrome and Brugada syndrome: comparison of website statistics

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Postema, Pieter G.; Neville, Jon; de Jong, Jonas S. S. G.; Romero, Klaus; Wilde, Arthur A. M.; Woosley, Raymond L.

2013-01-01

We sought to obtain insights into the efficacy of two websites, www.QTdrugs.org and www.BrugadaDrugs.org, that have the intention to prevent fatal arrhythmias due to unsafe drug use in Long QT syndrome and Brugada syndrome. Prospective web-use statistical analysis combined with online surveys were

Prognostic implications of mutation-specific QTc standard deviation in congenital long QT syndrome

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Mathias, Andrew; Moss, Arthur J.; Lopes, Coeli M.; Barsheshet, Alon; McNitt, Scott; Zareba, Wojciech; Robinson, Jennifer L.; Locati, Emanuela H.; Ackerman, Michael J.; Benhorin, Jesaia; Kaufman, Elizabeth S.; Platonov, Pyotr G.; Qi, Ming; Shimizu, Wataru; Towbin, Jeffrey A.; Michael Vincent, G.; Wilde, Arthur A. M.; Zhang, Li; Goldenberg, Ilan

2013-01-01

Individual corrected QT interval (QTc) may vary widely among carriers of the same long QT syndrome (LQTS) mutation. Currently, neither the mechanism nor the implications of this variable penetrance are well understood. To hypothesize that the assessment of QTc variance in patients with congenital

High prevalence of genetic variants previously associated with LQT syndrome in new exome data

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Refsgaard, Lena; Holst, Anders G; Sadjadieh, Golnaz

2012-01-01

To date, hundreds of variants in 13 genes have been associated with long QT syndrome (LQTS). The prevalence of LQTS is estimated to be between 1:2000 and 1:5000. The knowledge of genetic variation in the general population has until recently been limited, but newly published data from NHLBI GO...... variants KCNH2 P347S; SCN5A: S216L, V1951L; and CAV3 T78M in the control population (n=704) revealed prevalences comparable to those of ESP. Thus, we identified a much higher prevalence of previously LQTS-associated variants than expected in exome data from population studies. Great caution regarding...

Giant T-U waves precede torsades de pointes in long QT syndrome: a systematic electrocardiographic analysis in patients with acquired and congenital QT prolongation

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Kirchhof, Paulus; Franz, Michael R.; Bardai, Abdennasser; Wilde, Arthur M.

2009-01-01

This study sought to identify electrocardiographic (ECG) criteria that are associated with initiation of torsades de pointes (TdP) in patients with acquired (a-) and congenital (c-) long QT syndrome (LQTS). Electrocardiographic criteria used as risk predictors for TdP commonly rely on a prolonged QT

Cardiac Events During Competitive, Recreational, and Daily Activities in Children and Adolescents With Long QT Syndrome.

Science.gov (United States)

Chambers, Kristina D; Beausejour Ladouceur, Virginie; Alexander, Mark E; Hylind, Robyn J; Bevilacqua, Laura; Mah, Douglas Y; Bezzerides, Vassilios; Triedman, John K; Walsh, Edward P; Abrams, Dominic J

2017-09-21

The 2005 Bethesda Conference Guidelines advise patients with long QT syndrome against competitive sports. We assessed cardiac event rates during competitive and recreational sports, and daily activities among treated long QT syndrome patients. Long QT syndrome patients aged ≥4 years treated with anti-adrenergic therapy were included. Demographics included mechanism of presentation, corrected QT interval pretreatment, symptom history, medication compliance, and administration of QT-prolonging medications. Corrected QT interval ≥550 ms or prior cardiac arrest defined high risk. Sports were categorized by cardiovascular demand per the 2005 Bethesda Conference Guidelines. Each was classified as recreational or competitive. One hundred seventy-two patients (90; 52% female) with median age 15.2 years (interquartile range 11.4, 19.4) were included. Evaluation was performed for family history (102; 59%), incidental finding (34; 20%), and symptoms (36; 21%). Median corrected QT interval was 474 ms (interquartile range 446, 496) and 14 patients (8%) were deemed high risk. Treatment included β-blockers (171; 99%), implantable cardioverter-defibrillator (27; 16%), left cardiac sympathetic denervation (7; 4%), and pacemaker (3; 2%). Sports participation was recreational (66; 38%) or competitive (106; 62%), with 92 (53%) exercising against the Bethesda Conference Guidelines. There were no cardiac events in competitive athletes and no deaths. There were 13 cardiac events in 9 previously symptomatic patients during either recreational exercise or activities of daily life. In this cohort of appropriately managed children with long QT syndrome, cardiac event rates were low and occurred during recreational but not competitive activities. This study further supports the need for increased assessment of arrhythmia risk during exercise in this patient population. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Prognostic implications of mutation-specific QTc standard deviation in congenital long QT syndrome.

Science.gov (United States)

Mathias, Andrew; Moss, Arthur J; Lopes, Coeli M; Barsheshet, Alon; McNitt, Scott; Zareba, Wojciech; Robinson, Jennifer L; Locati, Emanuela H; Ackerman, Michael J; Benhorin, Jesaia; Kaufman, Elizabeth S; Platonov, Pyotr G; Qi, Ming; Shimizu, Wataru; Towbin, Jeffrey A; Michael Vincent, G; Wilde, Arthur A M; Zhang, Li; Goldenberg, Ilan

2013-05-01

Individual corrected QT interval (QTc) may vary widely among carriers of the same long QT syndrome (LQTS) mutation. Currently, neither the mechanism nor the implications of this variable penetrance are well understood. To hypothesize that the assessment of QTc variance in patients with congenital LQTS who carry the same mutation provides incremental prognostic information on the patient-specific QTc. The study population comprised 1206 patients with LQTS with 95 different mutations and ≥ 5 individuals who carry the same mutation. Multivariate Cox proportional hazards regression analysis was used to assess the effect of mutation-specific standard deviation of QTc (QTcSD) on the risk of cardiac events (comprising syncope, aborted cardiac arrest, and sudden cardiac death) from birth through age 40 years in the total population and by genotype. Assessment of mutation-specific QTcSD showed large differences among carriers of the same mutations (median QTcSD 45 ms). Multivariate analysis showed that each 20 ms increment in QTcSD was associated with a significant 33% (P = .002) increase in the risk of cardiac events after adjustment for the patient-specific QTc duration and the family effect on QTc. The risk associated with QTcSD was pronounced among patients with long QT syndrome type 1 (hazard ratio 1.55 per 20 ms increment; P<.001), whereas among patients with long QT syndrome type 2, the risk associated with QTcSD was not statistically significant (hazard ratio 0.99; P = .95; P value for QTcSD-by-genotype interaction = .002). Our findings suggest that mutations with a wider variation in QTc duration are associated with increased risk of cardiac events. These findings appear to be genotype-specific, with a pronounced effect among patients with the long QT syndrome type 1 genotype. Copyright © 2013. Published by Elsevier Inc.

Genotype-Phenotype Aspects of Type 2 Long QT Syndrome

NARCIS (Netherlands)

Shimizu, Wataru; Moss, Arthur J.; Wilde, Arthur A. M.; Towbin, Jeffrey A.; Ackerman, Michael J.; January, Craig T.; Tester, David J.; Zareba, Wojciech; Robinson, Jennifer L.; Qi, Ming; Vincent, G. Michael; Kaufman, Elizabeth S.; Hofman, Nynke; Noda, Takashi; Kamakura, Shiro; Miyamoto, Yoshihiro; Shah, Samit; Amin, Vinit; Goldenberg, Ilan; Andrews, Mark L.; McNitt, Scott

2009-01-01

Objectives The purpose of this study was to investigate the effect of location, coding type, and topology of KCNH2(hERG) mutations on clinical phenotype in type 2 long QT syndrome (LQTS). Background Previous studies were limited by population size in their ability to examine phenotypic effect of

Screening of Long Q-T Syndrome in Patients with Congenital Sensorineural Hearing Loss (Jervell and Lange Neilesen Syndrome: Prevention of Fatal Events

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Farid Matin

2001-01-01

Full Text Available Objective:The idiopathic long Q-T syndrome is an infrequently occurring disorder in which affected individuals have an unusual electrocardiographic repolarization abnormality presenting as syncope or loss of consciousness related to ventricular tachycardia or fibrillation. Congenital long Q-T prolongation can be associated with congenital deafness in an autosomal recessive manner (Jervell and Lange-Nielsen syndrome. The purpose of this stuff was to screen this electrocardiographic abnormality in deaf-mute school children in our population, which has not been yet performed. Materials & Methods:  Of 1190 patients with hearing loss, 779 had congenital sensorineural deafness (CSD, aged 13±3.8 years (4-24, 63% female and 37% male. The family history of deafness was as follows: Cardiac axis deviation was found in 56 (7% patients. Electrical conduction abnormalities were found in 12 (15% patients, Wolff-Parkinson-White syndrome, sinus bradycardia, and sinus arrhythmia were found in 2 (0.25%, 4 (0.5%, and 3 (0.38% patients, respectively. The Q-T interval, and Q-Tc duration were 312.6±28.9 ms (200-500 ms, median 320 ms, and 383.6±29.3 ms (232-527 ms, median 413ms, respectively. Long Q-T syndrome was found in 4 (0.5% patients (3F and 1M. Results: Two of these 4 patients had total deafness and 2 had profound hearing loss. None of the patients with mild deafness had Q-T prolongation. Only one of these patients was symptomatic, and had been treated as a case of epilepsy for several years. Conclusion: This data supports the presence of long Q-T syndrome in patients with sensorineural hearing loss in our population, so routine electrocardiographic screening of anyone with congenital deafness is warranted to prevent subsequent associated cardiac arrhythmias and sudden cardiac death.

Flecainide provocation reveals concealed brugada syndrome in a long QT syndrome family with a novel L1786Q mutation in SCN5A

DEFF Research Database (Denmark)

Kanters, Jørgen K.; Yuan, Lei; Hedley, Paula L

2014-01-01

BACKGROUND: Mutations in SCN5A can result in both long QT type 3 (LQT3) and Brugada syndrome (BrS), and a few mutations have been found to have an overlapping phenotype. Long QT syndrome is characterized by prolonged QT interval, and a prerequisite for a BrS diagnosis is ST elevation in the right...... interval. The proband presented with an aborted cardiac arrest, and his mother died suddenly and unexpectedly at the age of 65. Flecainide treatment revealed coved ST elevation in all mutation carriers. Electrophysiological investigations of the mutant in HEK293 cells indicated a reduced peak current...

T(peak)T(end) interval in long QT syndrome

DEFF Research Database (Denmark)

Kanters, Jørgen Kim; Haarmark, Christian; Vedel-Larsen, Esben

2008-01-01

BACKGROUND: The T(peak)T(end) (T(p)T(e)) interval is believed to reflect the transmural dispersion of repolarization. Accordingly, it should be a risk factor in long QT syndrome (LQTS). The aim of the study was to determine the effect of genotype on T(p)T(e) interval and test whether it was relat...

[Long QT syndrome. History, genetics, clinical symptoms, causes and therapy].

Science.gov (United States)

Krönauer, T; Friederich, P

2015-08-01

The long QT syndrome is caused by a change in cardiac repolarization due to functional ion channel defects. A differentiation is made between a congenital (cLQTS) and an acquired (aLQTS) form of the disease. The disease results in the name-giving prolongation of the QT interval in the electrocardiogram and represents a predisposition for cardiac arrhythmia and sudden cardiac death. This article summarizes the current knowledge on the history, pathophysiology, clinical symptoms and therapy of cLQTS and aLQTS. This knowledge of pathophysiological features of the symptoms allows the underlying anesthesiological approach for individualized perioperative concepts for patients suffering from LQTS to be derived.

Clinical Aspects of Type 3 Long-QT Syndrome

DEFF Research Database (Denmark)

Wilde, Arthur A M; Moss, Arthur J; Kaufman, Elizabeth S

2016-01-01

BACKGROUND: -Risk stratification in patients with type 3 long QT syndrome (LQT3) by clinical and genetic characteristics and effectiveness of ß-blocker therapy have not been studied previously in a large LQT3 population. METHODS: -The study population included 406 LQT3 patients with 51 different......-blocker therapy reduces this risk in females, but efficacy in males could not be conclusively determined due to low number of events....

KCNE1 D85N polymorphism — a sex-specific modifier in type 1 long QT syndrome?

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Marjamaa Annukka

2011-01-01

Full Text Available Abstract Background Long QT syndrome (LQTS is an inherited ion channel disorder manifesting with prolongation of the cardiac repolarization phase and severe ventricular arrhythmias. The common KCNE1 D85N potassium channel variant prolongs QT interval by inhibiting IKs (KCNQ1 and IKr (KCNH2 currents and is therefore a suitable candidate for a modifier gene in LQTS. Methods We studied the effect of D85N on age-, sex-, and heart rate-adjusted QT-interval duration by linear regression in LQTS patients carrying the Finnish founder mutations KCNQ1 G589D (n = 492, KCNQ1 IVS7-2A>G (n = 66, KCNH2 L552S (n = 73, and KCNH2 R176W (n = 88. We also investigated the association between D85N and clinical variables reflecting the severity of the disease. Results D85N was associated with a QT prolongation by 26 ms (SE 8.6, p = 0.003 in males with KCNQ1 G589D (n = 213, but not in females with G589D (n = 279. In linear regression, the interaction between D85N genotype and sex was significant (p = 0.028. Within the KCNQ1 G589D mutation group, KCNE1 D85N carriers were more often probands of the family (p = 0.042 and were more likely to use beta blocker medication (p = 0.010 than non-carriers. The number of D85N carriers in other founder mutation groups was too small to assess its effects. Conclusions We propose that KCNE1 D85N is a sex-specific QT-interval modifier in type 1 LQTS and may also associate with increased severity of disease. Our data warrant additional studies on the role of KCNE1 D85N in other genetically homogeneous groups of LQTS patients.

Does KCNE5 play a role in long QT syndrome?

DEFF Research Database (Denmark)

Hofman-Bang, Jacob; Jespersen, Thomas; Grunnet, Morten

2004-01-01

BACKGROUND: Long QT syndrome [LQTS] is a congenital cardiac disease characterised by prolonged QTC-time, syncopes and sudden cardiac death. LQTS is caused by mutations in genes coding for ion channels involved in the action potential. KCNE5 codes for a novel beta-subunit of the ion channel conduc...

Long QT Syndrome: A Clinical Entity Resembling Epilepsy

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Mehmet Güney Şenol

2008-06-01

Full Text Available Scientific BACKGROUND: Long QT Syndrome (LQTS is a cardiac repolarization defect, characterized by lengthened QT interval in the ECG. It can cause syncope due to rapid, polimorphic ventricular tachycardia known as Torsades de Pointes (TdP or it may cause sudden cardiac death. This clinical entity is frequently mistaken for epilepsy. CASE: In this report, a 24-year old male patient with congenital LQTS is presented. The patient was originally followed-up for epilepsy. During the evaluation process his loss of consciousness attacks were linked with ventricular tachycardia -TdP- periods and thus a diagnosis of LQTS was reached. When cardiac arrest ocurred in this patient, "stellate ganglion blockage” was performed. CONCLUSION: One must bear LQTS in mind in all patients with suspicious-looking syncope attacks and it must not be forgotten that early diagnosis and timely therapy will save the life of the individual

Common variants in the hERG (KCNH2) voltage-gated potassium channel are associated with altered fasting and glucose-stimulated plasma incretin and glucagon responses

DEFF Research Database (Denmark)

Engelbrechtsen, Line; Mahendran, Yuvaraj; Jonsson, Anna

2018-01-01

BACKGROUND: Patients with long QT syndrome due to rare loss-of-function mutations in the human ether-á-go-go-related gene (hERG) have prolonged QT interval, risk of arrhythmias, increased secretion of insulin and incretins and impaired glucagon response to hypoglycemia. This is caused by a dysfun......BACKGROUND: Patients with long QT syndrome due to rare loss-of-function mutations in the human ether-á-go-go-related gene (hERG) have prolonged QT interval, risk of arrhythmias, increased secretion of insulin and incretins and impaired glucagon response to hypoglycemia. This is caused...... by a dysfunctional Kv11.1 voltage-gated potassium channel. Based on these findings in patients with rare variants in hERG, we hypothesized that common variants in hERG may also lead to alterations in glucose homeostasis. Subsequently, we aimed to evaluate the effect of two common gain-of-function variants in hERG...... in hERG on QT-interval and circulation levels of incretins, insulin and glucagon. The Danish population-based Inter99 cohort (n = 5895) was used to assess the effect of common variants on QT-interval. The Danish ADDITION-PRO cohort was used (n = 1329) to study genetic associations with levels of GLP-1...

Prevalence of long QT syndrome and other cardiac defects in deaf-mute children

International Nuclear Information System (INIS)

Niaz, A.; Rizvi, S.F.U.; Khurram, D.

2011-01-01

Background: Long QT syndrome is considered a fatal disease because of its association with ventricular arrhythmias and sudden cardiac death. Objectives of study were to determine the prevalence of long QT syndrome and other heart diseases, in deaf-mute children. Methods: A Cross-sectional descriptive study was conducted at Cholistan special education centre and Cardiology department, Sheikh Zayed hospital Rahim Yar Khan, Pakistan in September 2006. A total of 104 congenitally deaf-mute children were assessed. Height, weight and blood pressure measured, 12-lead electrocardiogram done and QTc calculated using Bazette's formula. Children with prolonged QTc underwent 24-hour ambulatory ECG recording. All were auscultated following complete protocol. A child with murmur was further evaluated with colour Doppler echocardiography. Audiometry was performed on all the children and the result interpreted according to WHO recommendations. Diagnosis of LQTS was based on Revised Schwartz criteria. Results: Out of 104 children, 62 were male with mean age 11.89 yrs. The average systolic and diastolic BP was 97/67 mmHg. Average height was 126 Cm. All children had moderate to severe bilateral sensorineural hearing loss (40-80 dB). One child had associated Patent Ductus Arteriosis. Fifteen had an innocent murmur. Prevalence of congenital heart disease was found to be 0.1/1000. Four children had QT interval more than 440 mSec, (range 0.46-0.47 mSec.). Both genders were equally affected. Three children had high probability of LQTS and one had intermediate probability. Screening of family of these 4 patients showed prolonged QT interval in the sibling of one patient. Conclusion: Our study highlights the significant prevalence of Jervell Lange-Nielsen Syndrome in Pakistani deaf-mute children, which may be associated to the high level of consanguinity in this region. Awareness of this syndrome among health care providers is needed as timely diagnosis and subsequent treatment may prevent

Síndrome de QT prolongado congénito y embarazo: reporte de dos casos Congenital long QT syndrome and pregnancy: report of two cases

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Julián M Aristizábal

2010-04-01

Full Text Available El síndrome de QT prolongado congénito, es una entidad clínica que se caracteriza por la alteración en la repolarización miocárdica dada por una prolongación significativa del intervalo QT con riesgo aumentado de síncope, taquicardia ventricular polimórfica y muerte súbita. Se produce por la alteración en la función de canales iónicos responsables del potencial de acción de las células cardíacas, como consecuencia de múltiples mutaciones, de las cuales las más frecuentes se dan en los canales de sodio y potasio. La relación con el embarazo y principalmente la presencia de eventos en el posparto, está determinada por arritmias ventriculares o episodios de muerte súbita, lo cual debe llevar a una evaluación exhaustiva de QTc prolongado y sus factores desencadenantes o enfermedades concomitantes. Se muestran los casos clínicos de dos pacientes que presentaron muerte súbita en el posparto en las cuales se diagnosticó síndrome de QT largo congénito.Congenital long QT syndrome is a clinical entity characterized by impairment of myocardial repolarization given by significant prolongation of the corrected QT interval with an increased risk of syncope, polymorphic ventricular tachycardia and sudden death. This is produced by an alteration in the function of ion channels responsible for the action potential of cardiac cells as a consequence of multiple mutations, the most common of which are in the sodium and potassium channels. The relationship with pregnancy and especially the presence of events in the postpartum period is clearly determined by the presence of ventricular arrhythmias or episodes of sudden death, that should lead to a thorough evaluation of prolonged QTc and its triggers or concomitant diseases. We present the clinical records of two patients who had sudden death during the postpartum and were diagnosed as congenital long QT Syndrome.

Perioperative considerations in a newly described subtype of congenital long QT syndrome.

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Joseph-Reynolds, Ann; Auden, Steve; Sobczyzk, Walter

1997-05-01

An infant with a newly-described subtype of congenital long QT syndrome is presented, along with her perioperative management on three separate occasions. During each anaesthetic characteristic arrhythmias occurred. The available literature and rational approaches to these high risk patients are reviewed. 1997 Blackwell Science Ltd.

Identification of a Kir3.4 Mutation in Congenital Long QT Syndrome

DEFF Research Database (Denmark)

Yang, Yanzong; Yang, Yiqing; Liang, Bo

2010-01-01

Congenital long QT syndrome (LQTS) is a hereditary disorder that leads to sudden cardiac death secondary to fatal cardiac arrhythmias. Although many genes for LQTS have been described, the etiology remains unknown in 30%-40% of cases. In the present study, a large Chinese family (four generations...

Congenital long QT syndrome in children

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Cerović Ivana

2016-01-01

Full Text Available Long QT syndrome (LQTS is a cardiac repolarization disorder characterized by prolonged QT interval on the electrocardiogram (ECG and increased propensity to ventricular tachyarrhythmias and cardiac events. LQTS might be acquired or congenital, which presents a group of channelopathies that occur due to mutation in one of 15 so far identified genes. The most frequent types of congenital LTQS are LQT1, LQT2 and LQT3. Prolonged or delayed repolarization leads to the increase of action potential duration which predisposes early afterdepolarization, as well as the amplification of transmural dispersion of repolarization, both contributing to the development of Torsades de Pointes ventricular tachycardia. Clinical manifestations of LQTS are palpitations, syncope, aborted cardiac arrest or sudden cardiac death, but it can also be asymptomatic. Trigger factors for symptoms are specific for certain genotype. LQTS examination includes thorough clinical and family history focused on distinctive data (repeated syncopes, cases of sudden cardiac death in the family, hereditary arrhythmias, resting ECG, exercise stress testing and genetic analysis, with additional methods (serial ECG records, 24h ECG Holter, epinephrine test. Clinical LQTS diagnosis is based on Schwartz's scoring system, while the criteria for final diagnosis of LQTS depend on Schwartz's score, QT interval duration, presence of pathogenic mutation and clinical symptoms. Treatment approach begins with lifestyle modifications and β-blockers therapy, while other options include implantable cardioverter- defibrillator, permanent pacemaker or surgical sympathectomy. Sudden cardiac death is the reason of 90% of sudden deaths in young athletes, while LQTS is one of its causes. Recommendations for physical activities in children with congenital LQTS arise from the ones for adults and they presume very strict limitations. Further researches are expected to advance the understanding of genotype

Pregnancy and the risk of torsades de pointes in congenital long-QT syndrome

NARCIS (Netherlands)

Meregalli, P. G.; Westendorp, I. C. D.; Tan, H. L.; Elsman, P.; Kok, W. E. M.; Wilde, A. A. M.

2008-01-01

Patients with congenital long-QT syndrome (LQTS) are at increased risk of ventricular arrhythmias during stressful situations. Large-scale studies have pointed out that affected individuals are particularly at risk in the period following pregnancy (post-partum). This is recognised especially for

Phenotype guided characterization and molecular analysis of Indian patients with long QT syndromes

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Bijal Vyas

2016-01-01

Conclusions: This study in a cohort of Asian Indian patients highlights the mutation spectrum of common Long QT syndromes. The clinical utility for prevention of unexplained sudden cardiac deaths is an important sequel to identification of the mutation in at-risk family members.

KCNQ1 Long QT syndrome patients have hyperinsulinemia and symptomatic hypoglycemia

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Torekov, Signe S; Iepsen, Eva; Christiansen, Michael

2014-01-01

Patients with loss-of-function mutations in KCNQ1 have KCNQ1 long QT syndrome (LQTS). KCNQ1 encodes a voltage-gated K+ channel located in both cardiomyocytes and pancreatic b-cells. Inhibition of KCNQ1 in b-cells increases insulin secretion. Therefore KCNQ1 LQTS patients may exhibit increased...... min (low potassium after an oral glucose challenge, suggesting that KCNQ1...

Congenital short QT syndrome and implantable cardioverter defibrillator treatment: inherent risk for inappropriate shock delivery.

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Schimpf, Rainer; Wolpert, Christian; Bianchi, Francesca; Giustetto, Carla; Gaita, Florenzo; Bauersfeld, Urs; Borggrefe, Martin

2003-12-01

A congenital short QT interval constitutes a new primary electrical abnormality associated with syncope and/or sudden cardiac death. We report on the initial use of implantable cardioverter defibrillator (ICD) therapy in patients with inherited short QT interval and discuss sensing abnormalities and detection issues. In five consecutive patients from two unrelated European families who had structurally normal hearts, excessively shortened QT intervals, and a strong positive family history of sudden cardiac death, ICDs were placed for primary and secondary prevention. Mean QT intervals were 252 +/- 13 ms (QTc 287 +/- 13 ms). Despite normal sensing behavior during intraoperative and postoperative device testing, 3 of 5 patients experienced inappropriate shock therapies for T wave oversensing 30 +/- 26 days after implantation. Programming lower sensitivities and decay delays prevented further inappropriate discharges. The congenital short QT syndrome constitutes a new clinical entity with an increased risk for sudden cardiac death. Currently, ICD treatment is the only therapeutic option. In patients with short QT interval and implanted ICD, increased risk for inappropriate therapy is inherent due to the detection of short-coupled and prominent T waves. Careful testing of ICD function and adaptation of sensing levels and decay delays without sacrificing correct arrhythmia detection are essential.

High distress in parents whose children undergo predictive testing for long QT syndrome

NARCIS (Netherlands)

Grosfeld, FJM; Wilde, AAM; van den Bout, J; van Langen, IM; van Tintelen, JP; ten Kroode, HFJ

2005-01-01

Objectives: To assess the psychological effect of predictive testing in parents of children at risk for long QT syndrome (LQTS) in a prospective study. Methods: After their child was clinically screened by electrocardiography and blood was taken for DNA analysis, and shortly after delivery of the

QT interval prolongation associated with sibutramine treatment

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Harrison-Woolrych, Mira; Clark, David W J; Hill, Geraldine R; Rees, Mark I; Skinner, Jonathan R

2006-01-01

Aims To investigate a possible association of sibutramine with QT interval prolongation. Methods Post-marketing surveillance using prescription event monitoring in the New Zealand Intensive Medicines Monitoring Programme (IMMP) identified a case of QT prolongation and associated cardiac arrest in a patient taking sibutramine for 25 days. This patient was further investigated, including genotyping for long QT syndrome. Other IMMP case reports suggesting arrhythmias associated with sibutramine were assessed and further reports were obtained from the World Health Organisation (WHO) adverse drug reactions database. Results The index case displayed a novel mutation in a cardiac potassium channel subunit gene, KCNQ1, which is likely to prolong cardiac membrane depolarization and increase susceptibility to long QT intervals. Assessment of further IMMP reports identified five additional patients who experienced palpitations associated with syncope or presyncopal symptoms, one of whom had a QTc at the upper limit of normal. Assessment of reports from the WHO database identified three reports of QT prolongation and one fatal case of torsade de pointes in a patient also taking cisapride. Conclusions This case series suggests that sibutramine may be associated with QT prolongation and related dysrhythmias. Further studies are required, but in the meantime we would recommend that sibutramine should be avoided in patients with long QT syndrome and in patients taking other medicines that may prolong the QT interval. PMID:16542208

QT and JT dispersion and cardiac performance in children with neonatal Bartter syndrome: a pilot study.

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Hacihamdioglu, Duygu Ovunc; Fidanci, Kursat; Kilic, Ayhan; Gok, Faysal; Topaloglu, Rezan

2013-10-01

QT dispersion and JT dispersion are simple noninvasive arrhythmogenic markers that can be used to assess the homogeneity of cardiac repolarization. The aim of this study was to assess QT and JT dispersion and their relation with left ventricular systolic and diastolic functions in children with Bartter syndrome (BS). Nine neonatal patients with BS (median age 9.7 years) and 20 controls (median age 8 years) were investigated at rest. Both study and control subjects underwent electrocardiography (ECG) in which the interval between two R waves and QT intervals, corrected QT, QT dispersion, corrected QT dispersion, JT, corrected JT, JT dispersion and corrected JT dispersion were measured with 12-lead ECG. Two-dimensional, Doppler echocardiographic examinations were performed. Patients and controls did not differ for gender and for serum levels of potassium, magnesium, and calcium (p > 0.05). Both study and control subjects had normal echocardiographic examination and baseline myocardial performance indexes. The QT dispersion and JT dispersion were significantly prolonged in patients with BS compared to those of the controls {37.5 ms [interquartile range (IQR) 32.5-40] vs. 25.5 ms (IQR 20-30), respectively, p = 0.014 and 37.5 ms (IQR 27.5-40) vs. 22.5 ms (IQR 20-30), respectively, p = 0.003}. Elevated QT and JT dispersion during asymptomatic and normokalemic periods may be risk factors for the development of cardiac complications and arrhythmias in children with BS. In these patients the need for systematic cardiac screening and management protocol is extremely important for effective prevention.

Two markers in predicting the cardiovascular events in patients with polycystic ovary syndrome: increased P-wave and QT dispersion.

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Akdag, S; Cim, N; Yildizhan, R; Akyol, A; Ozturk, F; Babat, N

2015-09-01

Polycystic ovary syndrome (PCOS) is a prevalent disease with many potential long-term cardiovascular risks. P-wave dispersion (Pdis) and QT dispersion (QTdis) have been shown to be noninvasive electrocardiographic predictors for development of cardiac arrhythmias. In this study we aimed to search Pdis and QTdis parameters in patients with PCOS. The study included 82 patients with PCOS and 74 age- and sex-matched healthy controls. Baseline 12-lead electrocardiographic and transthoracic echocardiographic measurements were evaluated. P-wave maximum duration (Pmax), P-wave minimum duration (Pmin), Pdis, QT interval, heart rate-corrected QT dispersion and QTdis were calculated by two cardiologists. Patients wirh PCOS had significantly higher QT dispersion (49.5 ± 14.1 vs. 37.9 ± 12.6 ms, p PCOS patients.

The Jervell and Lange-Nielsen syndrome; atrial pacing combined with ß-blocker therapy, a favorable approach in young high-risk patients with long QT syndrome?

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Früh, Andreas; Siem, Geir; Holmström, Henrik; Døhlen, Gaute; Haugaa, Kristina H

2016-11-01

Patients with Jervell and Lange-Nielsen syndrome (JLNS) exhibit severe phenotypes that are characterized by congenital deafness, very long QT intervals, and high risk of life-threatening arrhythmias. Current treatment strategies include high doses of beta-blocker medication, left cardiac sympathetic denervation, and ICD placement, which is challenging in young children. The purpose of this study was to evaluate the safety and effect of pacing in addition to beta-blocker treatment in children with JLNS. All genetically confirmed patients with JLNS born since 1999 in Norway were included in the study. Data on history of long QT syndrome-related symptoms, QT interval, and beta-blocker and pacemaker treatment were recorded. A total of 9 patients with QT intervals ranging from 510 to 660 ms were identified. Eight patients developed long QT syndrome-related symptoms, and 1 patient died before diagnosis. The survivors received beta-blocker medication. Seven patients also received a pacemaker; 1 had a ventricular lead and 6 had atrial leads. The patient with the ventricular lead died during follow-up. The 6 patients with atrial leads survived without events at a mean follow-up of 6.9 years after pacemaker implantation. Two patients received prophylactic upgrade to a 2-chamber ICD. No arrhythmic events occurred in 6 very young JLNS patients who received atrial pacing in combination with increased doses of beta-blockers during 7-year follow-up. If confirmed in additional patients, this treatment strategy may prevent life-threatening arrhythmias in this high-risk patient group and may act as a bridge to insertion of a 2-chamber ICD when left cardiac sympathetic denervation is not available. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Prenatal diagnosis of long QT syndrome with the superior vena cava-aorta Doppler approach.

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Chabaneix, Julie; Andelfinger, Gregor; Fournier, Anne; Fouron, Jean-Claude; Raboisson, Marie-Josée

2012-10-01

We describe a fetus at 36 weeks with long QT syndrome presenting with variable types of atrioventricular blocks, ventricular premature beats, and torsades de pointes. All these diagnoses were made with the superior vena cava-aorta Doppler approach and confirmed with postnatal electrocardiography. Copyright © 2012 Mosby, Inc. All rights reserved.

Fine-mapping and initial characterization of QT interval loci in African Americans.

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Christy L Avery

Full Text Available The QT interval (QT is heritable and its prolongation is a risk factor for ventricular tachyarrhythmias and sudden death. Most genetic studies of QT have examined European ancestral populations; however, the increased genetic diversity in African Americans provides opportunities to narrow association signals and identify population-specific variants. We therefore evaluated 6,670 SNPs spanning eleven previously identified QT loci in 8,644 African American participants from two Population Architecture using Genomics and Epidemiology (PAGE studies: the Atherosclerosis Risk in Communities study and Women's Health Initiative Clinical Trial. Of the fifteen known independent QT variants at the eleven previously identified loci, six were significantly associated with QT in African American populations (P≤1.20×10(-4: ATP1B1, PLN1, KCNQ1, NDRG4, and two NOS1AP independent signals. We also identified three population-specific signals significantly associated with QT in African Americans (P≤1.37×10(-5: one at NOS1AP and two at ATP1B1. Linkage disequilibrium (LD patterns in African Americans assisted in narrowing the region likely to contain the functional variants for several loci. For example, African American LD patterns showed that 0 SNPs were in LD with NOS1AP signal rs12143842, compared with European LD patterns that indicated 87 SNPs, which spanned 114.2 Kb, were in LD with rs12143842. Finally, bioinformatic-based characterization of the nine African American signals pointed to functional candidates located exclusively within non-coding regions, including predicted binding sites for transcription factors such as TBX5, which has been implicated in cardiac structure and conductance. In this detailed evaluation of QT loci, we identified several African Americans SNPs that better define the association with QT and successfully narrowed intervals surrounding established loci. These results demonstrate that the same loci influence variation in QT

Use of mutant-specific ion channel characteristics for risk stratification of long QT syndrome patients

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Jons, Christian; O-Uchi, Jin; Moss, Arthur J

2011-01-01

Inherited long QT syndrome (LQTS) is caused by mutations in ion channels that delay cardiac repolarization, increasing the risk of sudden death from ventricular arrhythmias. Currently, the risk of sudden death in individuals with LQTS is estimated from clinical parameters such as age, gender, and...

Clinical characteristics in genetically distinct forms of the congenital long QT syndrome

International Nuclear Information System (INIS)

Kawahara, Yosuke; Sawayama, Toshitami; Samukawa, Masanobu; Nezuo, Shoso; Tanaka, Junji; Suetsuna, Ryoji; Kamiyama, Norio

1998-01-01

The clinical characteristics in genetically distinct forms of the congenital long QT syndrome (LQTs) were examined on the balance of bilateral sympathetic nerves, and ECG findings. The subjects (mean: 19.4 years old) were three genetically distinct forms of LQTs, including 3 patients in A-family (the high risk family with sudden death), 2 patients in B-family and 3 patients in C-family. All patients met the standard diagnostic criteria according to Schwartz. As the index of the balance of bilateral sympathetic nerves, the dissociation of Tl and MIBG uptake (D) was examined and the radioactivity ratio (the A/L ratio) of anteroseptal wall to posterolateral wall was calculated. The T-wave patterns of ECG and the situation at syncope were examined. In A-family, all 3 patients showed the lowered A/L ratio, D(+), and similar T-wave patterns in ECG. The syndrome developed at exercise, and their QTc extended at exercise. In B-family, all 2 patients showed normal A/L ratio and long T-wave at QT onset, and their QTc shortened at exercise. All patients had developed syncope at rest. In C-family, all 3 patients showed a little decrease of A/L ratio and similar T-wave patterns. Their QTc extended at exercise. These results suggest that the characteristics of the sympathetic nerve balance, ECG wave patterns and the syndrome may depend on each family. (K.H.)

Acquired Long QT Syndrome and Torsade de Pointes Associated with HIV Infection

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Alexander Shimabukuro-Vornhagen

2010-01-01

Full Text Available Here, we report the case of an HIV infected patient that was treated for pneumonia with a macrolid antibiotic. The patient experienced a prolongation of the already pathologic QTc interval resulting in repeated torsades de pointes necessitating CPR and implantation of an AICD. This case exemplifies that torsades de pointes due to acquired long QT syndrome is a serious and potentially fatal complication in HIV-positive patients.

A high-risk patient with long-QT syndrome with no response to cardioselective beta-blockers.

Science.gov (United States)

Toyota, Naoki; Miyazaki, Aya; Sakaguchi, Heima; Shimizu, Wataru; Ohuchi, Hideo

2015-09-01

We present a case of a high-risk 19-year-old female with long-QT syndrome (LQTS) with compound mutations. She had a history of aborted cardiac arrest and syncope and had received treatment with propranolol for 15 years. However, because she developed adult-onset asthma we tried to switch propranolol, a nonselective beta-blocker, to beta-1-cardioselective agents, bisoprolol and metoprolol. These resulted in both a markedly prolonged corrected QT interval and the development of LQTS-associated arrhythmias. Eventually, propranolol was reinitiated at a higher dose with the addition of verapamil, and she has had no further cardiac or asthmatic events for 5 years.

First International Symposium on Long QT Syndrome through the Internet, April 2004

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Sergio Dubner

2004-07-01

Full Text Available With the First Virtual Symposium on Long QT Syndrome already finished; which was held over the month of April, 2004 as an educational activity of the International Society for Holter and Noninvasive Electrocardiology (ISHNE, and completely through the Internet; we, the Presidents of the Scientific and Steering Committees, Sergio Dubner, Edgardo Schapachnik and Andrés Ricardo Pérez Riera, are wondering gladly surprised, which may have been the main causes of such a huge success as we have reached, and the enormous interest arisen. Just to have an idea of the dimension achieved, data obtained from http://www.a9.com (an Amazon.com site or with the traditional search engine Google, prove that the first reply when you request information about long QT Syndrome is the access site of the Symposium. We believe that the response to this question may be summarized in one word: REALIZATION. The best definition for success is realization. The huge motivation in each one of us made the difference. We worked with a cohesive group, like a team, aware of the unparalleled and great opportunity Prof. Arthur Moss had initially assigned to Sergio Dubner and Edgardo Schapachnik, an invitation that the latter extended to Andrés Ricardo Pérez Riera.

Glucose ingestion causes cardiac repolarization disturbances in type 1 long QT syndrome patients and healthy subjects

DEFF Research Database (Denmark)

Hyltén-Cavallius, Louise; Iepsen, Eva W; Christiansen, Michael

2017-01-01

BACKGROUND: Both hypoglycemia and severe hyperglycemia constitute known risk factors for cardiac repolarization changes potentially leading to malignant arrhythmias. Patients with loss of function mutations in KCNQ1 are characterized by long QT syndrome (LQTS) and may be at increased risk...

Interventricular dispersion in repolarization causes bifid T waves in dogs with dofetilide-induced long QT syndrome

NARCIS (Netherlands)

Meijborg, Veronique M F; Chauveau, Samuel; Janse, Michiel J; Anyukhovsky, Evgeny P; Danilo, Peter R; Rosen, Michael R; Opthof, Tobias; Coronel, Ruben

BACKGROUND: Long QT2 (LQT2) syndrome is characterized by bifid (or notched) T waves, whose mechanism is not understood. OBJECTIVE: The purpose of this study was to test whether increased interventricular dispersion of repolarization induces bifid T waves. METHODS: We simultaneously recorded surface

Interventricular dispersion in repolarization causes bifid T waves in dogs with dofetilide-induced long QT syndrome

NARCIS (Netherlands)

Meijborg, Veronique M. F.; Chauveau, Samuel; Janse, Michiel J.; Anyukhovsky, Evgeny P.; Danilo, Peter R.; Rosen, Michael R.; Opthof, Tobias; Coronel, Ruben

2015-01-01

Long QT2 (LQT2) syndrome is characterized by bifid (or notched) T waves, whose mechanism is not understood. The purpose of this study was to test whether increased interventricular dispersion of repolarization induces bifid T waves. We simultaneously recorded surface ECG and unipolar electrograms at

Prevalence and spectrum of large deletions or duplications in the major long QT syndrome-susceptibility genes and implications for long QT syndrome genetic testing.

Science.gov (United States)

Tester, David J; Benton, Amber J; Train, Laura; Deal, Barbara; Baudhuin, Linnea M; Ackerman, Michael J

2010-10-15

Long QT syndrome (LQTS) is a cardiac channelopathy associated with syncope, seizures, and sudden death. Approximately 75% of LQTS is due to mutations in genes encoding for 3 cardiac ion channel α-subunits (LQT1 to LQT3). However, traditional mutational analyses have limited detection capabilities for atypical mutations such as large gene rearrangements. We set out to determine the prevalence and spectrum of large deletions/duplications in the major LQTS-susceptibility genes in unrelated patients who were mutation negative after point mutation analysis of LQT1- to LQT12-susceptibility genes. Forty-two unrelated, clinically strong LQTS patients were analyzed using multiplex ligation-dependent probe amplification, a quantitative fluorescent technique for detecting multiple exon deletions and duplications. The SALSA multiplex ligation-dependent probe amplification LQTS kit from MRC-Holland was used to analyze the 3 major LQTS-associated genes, KCNQ1, KCNH2, and SCN5A, and the 2 minor genes, KCNE1 and KCNE2. Overall, 2 gene rearrangements were found in 2 of 42 unrelated patients (4.8%, confidence interval 1.7 to 11). A deletion of KCNQ1 exon 3 was identified in a 10-year-old Caucasian boy with a corrected QT duration of 660 ms, a personal history of exercise-induced syncope, and a family history of syncope. A deletion of KCNQ1 exon 7 was identified in a 17-year-old Caucasian girl with a corrected QT duration of 480 ms, a personal history of exercise-induced syncope, and a family history of sudden cardiac death. In conclusion, because nearly 5% of patients with genetically elusive LQTS had large genomic rearrangements involving the canonical LQTS-susceptibility genes, reflex genetic testing to investigate genomic rearrangements may be of clinical value. Copyright © 2010 Elsevier Inc. All rights reserved.

Multiple independent genetic factors at NOS1AP modulate the QT interval in a multi-ethnic population.

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Dan E Arking

Full Text Available Extremes of electrocardiographic QT interval are associated with increased risk for sudden cardiac death (SCD; thus, identification and characterization of genetic variants that modulate QT interval may elucidate the underlying etiology of SCD. Previous studies have revealed an association between a common genetic variant in NOS1AP and QT interval in populations of European ancestry, but this finding has not been extended to other ethnic populations. We sought to characterize the effects of NOS1AP genetic variants on QT interval in the multi-ethnic population-based Dallas Heart Study (DHS, n = 3,072. The SNP most strongly associated with QT interval in previous samples of European ancestry, rs16847548, was the most strongly associated in White (P = 0.005 and Black (P = 3.6 x 10(-5 participants, with the same direction of effect in Hispanics (P = 0.17, and further showed a significant SNP x sex-interaction (P = 0.03. A second SNP, rs16856785, uncorrelated with rs16847548, was also associated with QT interval in Blacks (P = 0.01, with qualitatively similar results in Whites and Hispanics. In a previously genotyped cohort of 14,107 White individuals drawn from the combined Atherosclerotic Risk in Communities (ARIC and Cardiovascular Health Study (CHS cohorts, we validated both the second locus at rs16856785 (P = 7.63 x 10(-8, as well as the sex-interaction with rs16847548 (P = 8.68 x 10(-6. These data extend the association of genetic variants in NOS1AP with QT interval to a Black population, with similar trends, though not statistically significant at P<0.05, in Hispanics. In addition, we identify a strong sex-interaction and the presence of a second independent site within NOS1AP associated with the QT interval. These results highlight the consistent and complex role of NOS1AP genetic variants in modulating QT interval.

Landiolol suppression of electrical storm of torsades de pointes in patients with congenital long-QT syndrome type 2 and myocardial ischemia

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Ryota Kitajima, MD

2017-10-01

Full Text Available A 76-year-old man who had been diagnosed with long-QT syndrome type 2 had frequent syncopal attacks. The electrocardiogram was monitored, and frequent torsades de pointes (TdP was detected despite administration of conventional medications: oral propranolol, verapamil, intravenous magnesium sulfate, verapamil, and lidocaine. In contrast, 2 μg/kg/min landiolol could completely suppress TdP. Subsequently, an implantable cardioverter defibrillator was placed, and he was diagnosed with silent myocardial ischemia using myocardial perfusion scintigraphy and coronary angiography. This is the first case report wherein landiolol effectively suppressed TdP due to long-QT syndrome with silent myocardial ischemia.

Functional assessment of compound mutations in the KCNQ1 and KCNH2 genes associated with long QT syndrome

DEFF Research Database (Denmark)

Grunnet, Morten; Behr, Elijah Raphael; Calloe, Kirstine

2005-01-01

BACKGROUND: Long QT syndrome (LQTS) is a cardiovascular disorder characterized by prolonged QTc time, syncope, or sudden death caused by torsades de pointes and ventricular fibrillation. We investigated the clinical and electrophysiologic phenotype of individual mutations and the compound mutations...

The Importance of the Family History in Caring for Families With Long QT Syndrome and Dilated Cardiomyopathy

NARCIS (Netherlands)

Ruiter, J.S.; Berkenbosch-Nieuwhof, K.; van den Berg, M.P.; van Dijk, R.; Middel, B.; van Tintelen, J.P.

In potentially inherited cardiac diseases, the family history is of great importance. We looked at the way cardiologists take a family history in patients with idiopathic dilated cardiomyopathy (DCM) or long QT syndrome (LQTS) and whether this led to screening of relatives or other follow-up. We

[Long QT syndrome and polymorphic ventricular tachycardia due to hypopituitarism. Report of one case].

Science.gov (United States)

García-Castro, José Miguel; García-Martín, Antonia; Guirao-Arrabal, Emilio; Carrillo-Alascio, Pedro Luis

2017-07-01

Symptoms of hypopituitarism are usually chronic and nonspecific, but rarely the disease can have acute and life threatening manifestations. We report a 53 years old female with a pituitary adenoma that was admitted to our hospital because of syncope. The electrocardiogram showed sinus bradycardia with a prolonged QT interval. Frequent runs of non-sustained polymorphic ventricular tachycardia were noted on telemetry. The patient had a history of severe acute headaches in the previous days and laboratory tests revealed severe secondary hypothyroidism, adrenal insufficiency and a decrease in pituitary hormones. A magnetic resonance imaging of the head showed changes in the size and contrast enhancement of the adenoma. A diagnosis of hypopituitarism secondary to pituitary apoplexy was made and treatment with hydrocortisone and, subsequently, levothyroxine was started. Hormonal disorders such as hypothyroidism, adrenal insufficiency or hypopituitarism should be considered as unusual causes for reversible cardiomyopathy, long QT syndrome and ventricular arrhythmias.

Dandy-Walker variant in Coffin-Siris syndrome.

Science.gov (United States)

Imai, T; Hattori, H; Miyazaki, M; Higuchi, Y; Adachi, S; Nakahata, T

2001-04-22

We describe a five-month-old male infant with Coffin-Siris syndrome, the so-called Dandy-Walker variant (hypoplasia of the cerebellar vermis with cystic dilatation of the fourth ventricle, but without enlargement of the posterior fossa), and partial agenesis of the corpus callosum. Dandy-Walker malformation and mega cisterna magna, but not Dandy-Walker variant, have been reported in Coffin-Siris syndrome. The presence of Dandy-Walker variant in the infant we described confirms that the full continuum of the Dandy-Walker complex can occur in Coffin-Siris syndrome. The yet unidentified gene(s) for the syndrome may be related to the development of the hindbrain. Copyright 2001 Wiley-Liss, Inc.

Computational Analysis of the Mode of Action of Disopyramide and Quinidine on hERG-Linked Short QT Syndrome in Human Ventricles

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Dominic G. Whittaker

2017-10-01

Full Text Available The short QT syndrome (SQTS is a rare cardiac disorder associated with arrhythmias and sudden death. Gain-of-function mutations to potassium channels mediating the rapid delayed rectifier current, IKr, underlie SQTS variant 1 (SQT1, in which treatment with Na+ and K+ channel blocking class Ia anti-arrhythmic agents has demonstrated some efficacy. This study used computational modeling to gain mechanistic insights into the actions of two such drugs, disopyramide and quinidine, in the setting of SQT1. The O'Hara-Rudy (ORd human ventricle model was modified to incorporate a Markov chain formulation of IKr describing wild type (WT and SQT1 mutant conditions. Effects of multi-channel block by disopyramide and quinidine, including binding kinetics and altered potency of IKr/hERG channel block in SQT1 and state-dependent block of sodium channels, were simulated on action potential and multicellular tissue models. A one-dimensional (1D transmural ventricular strand model was used to assess prolongation of the QT interval, effective refractory period (ERP, and re-entry wavelength (WL by both drugs. Dynamics of re-entrant excitation waves were investigated using a 3D human left ventricular wedge model. In the setting of SQT1, disopyramide, and quinidine both produced a dose-dependent prolongation in (i the QT interval, which was primarily due to IKr block, and (ii the ERP, which was mediated by a synergistic combination of IKr and INa block. Over the same range of concentrations quinidine was more effective in restoring the QT interval, due to more potent block of IKr. Both drugs demonstrated an anti-arrhythmic increase in the WL of re-entrant circuits. In the 3D wedge, disopyramide and quinidine at clinically-relevant concentrations decreased the dominant frequency of re-entrant excitations and exhibited anti-fibrillatory effects; preventing formation of multiple, chaotic wavelets which developed in SQT1, and could terminate arrhythmias. This

Acquired long QT syndrome and Torsades de Poin

Directory of Open Access Journals (Sweden)

Ahmet Seyfeddin Gurbuz

2016-09-01

Full Text Available Acetylcholinesterase inhibitors are group of drugs commonly used in Alzheimer disease and have beneficial effects on treatment. Although they have many known side effects, cardiovascular side effects are rarely seen. We present a 84 year old female who was admitted to emergency service due to repetitive syncope episodes while taking donepezil. Her electrocardiogram showed QT prolongation and on follow-up a Torsades de Pointes episode occurred. Patient was discharged with normal corrected QT time after removal of donepezil.

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

NARCIS (Netherlands)

D.E. Arking (Dan); S.L. Pulit (Sara); L. Crotti (Lia); P. van der Harst (Pim); P. Munroe (Patricia); T.T. Koopmann (Tamara); N. Sotoodehnia (Nona); E. Rossin (Elizabeth); M. Morley (Michael); X. Wang (Xinchen); A.D. Johnson (Andrew); A. Lundby (Alicia); D.F. Gudbjartsson (Daniel); P.A. Noseworthy (Peter); M. Eijgelsheim (Mark); Y. Bradford (Yuki); K.V. Tarasov (Kirill); M. Dörr (Marcus); M. Müller-Nurasyid (Martina); A.M. Lahtinen (Annukka); I.M. Nolte (Ilja); G.D. Smith; J.C. Bis (Joshua); A.J. Isaacs (Aaron); S.J. Newhouse (Stephen); D.S. Evans (Daniel); W.S. Post (Wendy S.); D. Waggott (Daryl); L.-P. Lyytikäinen (Leo-Pekka); A.A. Hicks (Andrew); L. Eisele (Lewin); D. Ellinghaus (David); C. Hayward (Caroline); P. Navarro (Pau); S. Ulivi (Shelia); T. Tanaka (Toshiko); D.J. Tester (David); S. Chatel (Stéphanie); S. Gustafsson (Stefan); M. Kumari (Meena); R. Morris (Richard); A.T. Naluai (Asa); S. Padmanabhan (Sandosh); A. Kluttig (Alexander); B. Strohmer (Bernhard); A.G. Panayiotou (Andrie); M. Torres (Maria); M. Knoflach (Michael); J.A. Hubacek (Jaroslav A.); K. Slowikowski (Kamil); S. Raychaudhuri (Soumya); R.D. Kumar (Runjun); T.B. Harris (Tamara); L.J. Launer (Lenore); A.R. Shuldiner (Alan); A. Alonso (Alvaro); J.S. Bader (Joel); G.B. Ehret (Georg); H. Huang (Hailiang); W.H.L. Kao (Wen); J.B. Strait (James); P.W. Macfarlane (Peter); M.J. Brown (Morris); M. Caulfield (Mark); N.J. Samani (Nilesh); F. Kronenberg (Florian); J. Willeit (Johann); J.G. Smith (J. Gustav); K.H. Greiser (Karin Halina); H.M. Zu Schwabedissen (Henriette Meyer); K. Werdan (Karl); C. Carella (Cintia); L. Zelante (Leopoldo); S.R. Heckbert (Susan); B.M. Psaty (Bruce); J.I. Rotter (Jerome); I. Kolcic (Ivana); O. Polasek (Ozren); A.F. Wright (Alan); M. Griffin (Maura); M.J. Daly (Mark); D.O. Arnar (David); H. Hólm (Hilma); U. Thorsteinsdottir (Unnur); J.C. Denny (Joshua); D.M. Roden (Dan); R.L. Zuvich (Rebecca); V. Emilsson (Valur); A.S. Plump (Andrew); M.G. Larson (Martin); C.J. O'Donnell (Christopher); X. Yin (Xiaoyan); M. Bobbo (Marco); P. d' Adamo (Pio); A. Iorio (Annamaria); G. Sinagra (Gianfranco); A. Carracedo (Angel); S.R. Cummings (Steven); M.A. Nalls (Michael); A. Jula (Antti); K.K. Kontula (Kimmo); A. Marjamaa (Annukka); L. Oikarinen (Lasse); M. Perola (Markus); K. Porthan (Kimmo); R. Erbel (Raimund); P. Hoffmann (Per); K.-H. Jöckel (Karl-Heinz); H. Kälsch (Hagen); M.M. Nöthen (Markus); M. den Hoed (Marcel); R.J.F. Loos (Ruth); D.S. Thelle (Dag); C. Gieger (Christian); T. Meitinger (Thomas); S. Perz (Siegfried); A. Peters (Annette); H. Prucha (Hanna); M.F. Sinner (Moritz); M. Waldenberger (Melanie); R.A. de Boer (Rudolf); L. Franke (Lude); P.A. van der Vleuten (Pieter); B.M. Beckmann (Britt); E. Martens (Eimo); A. Bardai (Abdennasser); N. Hofman (Nynke); A.A.M. Wilde (Arthur); E.R. Behr (Elijah ); C. Dalageorgou (Chrysoula); J.R. Giudicessi (John); A. Medeiros-Domingo (Argelia); J. Barc (Julien); F. Kyndt (Florence); V. Probst (Vincent); A. Ghidoni (Alice); R. Insolia (Roberto); R.M. Hamilton (Robert); S.W. Scherer (Stephen); J. Brandimarto (Jeffrey); K. Margulies (Kenneth); C.E. Moravec (Christine); F. Del Greco M (Fabiola); C. Fuchsberger (Christian); J.R. O'Connell (Jeffery); W.K. Lee (Wai); G.C.M. Watt (Graham); H. Campbell (Harry); S.H. Wild (Sarah); N.E. El Mokhtari (Nour); N. Frey (Norbert); F.W. Asselbergs (Folkert); I.M. Leach (Irene Mateo); G. Navis (Gerjan); M.P. van den Berg (Maarten); D.J. van Veldhuisen (Dirk); M. Kellis (Manolis); B.P. Krijthe (Bouwe); O.H. Franco (Oscar); A. Hofman (Albert); J.A. Kors (Jan); A.G. Uitterlinden (André); J.C.M. Witteman (Jacqueline); L. Kedenko (Lyudmyla); C. Lamina (Claudia); B.A. Oostra (Ben); G.R. Abecasis (Gonçalo); E. Lakatta (Edward); A. Mulas (Antonella); M. Orrù (Marco); D. Schlessinger (David); M. Uda (Manuela); M.R.P. Markus (Marcello R. P.); U. Völker (Uwe); H. Snieder (Harold); T.D. Spector (Timothy); J. Ärnlöv (Johan); L. Lind (Lars); J. Sundstrom (Johan); A.C. Syvanen; M. Kivimaki (Mika); M. Kähönen (Mika); K. Mononen (Kari); O. Raitakari (Olli); J. Viikari (Jorma); V. Adamkova (Vera); S. Kiechl (Stefan); M.-J. Brion (Maria); A.N. Nicolaides (Andrew); B. Paulweber (Bernhard); J. Haerting (Johannes); A. Dominiczak (Anna); F. Nyberg (Fredrik); P.H. Whincup (Peter); A. Hingorani (Aroon); J.-J. Schott (Jean-Jacques); C.R. Bezzina (Connie); E. Ingelsson (Erik); L. Ferrucci (Luigi); P. Gasparini (Paolo); J.F. Wilson (James); I. Rudan (Igor); A. Franke (Andre); T.W. Mühleisen (Thomas); P.P. Pramstaller (Peter Paul); T. Lehtimäki (Terho); A.D. Paterson (Andrew); A. Parsa (Afshin); Y. Liu (YongMei); C.M. van Duijn (Cornelia); D.S. Siscovick (David); V. Gudnason (Vilmundur); Y. Jamshidi (Yalda); V. Salomaa (Veikko); S.B. Felix (Stephan); S. Sanna (Serena); M.D. Ritchie (Marylyn); B.H.Ch. Stricker (Bruno); J-A. Zwart (John-Anker); L.A. Boyer (Laurie); T.P. Cappola (Thomas); J.V. Olsen (Jesper); P. Lage (Pedro); P.J. Schwartz (Peter); S. Kääb (Stefan); A. Chakravarti (Aravinda); M. Ackerman (Margaret); A. Pfeufer (Arne); P.I.W. de Bakker (Paul); C. Newton-Cheh (Christopher)

2014-01-01

textabstractThe QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

DEFF Research Database (Denmark)

Arking, Dan E; Pulit, Sara L; Crotti, Lia

2014-01-01

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Usi...

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

NARCIS (Netherlands)

Arking, Dan E.; Pulit, Sara L.; Crotti, Lia; van der Harst, Pim; Munroe, Patricia B.; Koopmann, Tamara T.; Sotoodehnia, Nona; Rossin, Elizabeth J.; Morley, Michael; Wang, Xinchen; Johnson, Andrew D.; Lundby, Alicia; Gudbjartsson, Daníel F.; Noseworthy, Peter A.; Eijgelsheim, Mark; Bradford, Yuki; Tarasov, Kirill V.; Dörr, Marcus; Müller-Nurasyid, Martina; Lahtinen, Annukka M.; Nolte, Ilja M.; Smith, Albert Vernon; Bis, Joshua C.; Isaacs, Aaron; Newhouse, Stephen J.; Evans, Daniel S.; Post, Wendy S.; Waggott, Daryl; Lyytikäinen, Leo-Pekka; Hicks, Andrew A.; Eisele, Lewin; Ellinghaus, David; Hayward, Caroline; Navarro, Pau; Ulivi, Sheila; Tanaka, Toshiko; Tester, David J.; Chatel, Stéphanie; Gustafsson, Stefan; Kumari, Meena; Morris, Richard W.; Naluai, Åsa T.; Padmanabhan, Sandosh; Kluttig, Alexander; Strohmer, Bernhard; Panayiotou, Andrie G.; Torres, Maria; Knoflach, Michael; Hubacek, Jaroslav A.; Slowikowski, Kamil; Raychaudhuri, Soumya; Kumar, Runjun D.; Harris, Tamara B.; Launer, Lenore J.; Shuldiner, Alan R.; Alonso, Alvaro; Bader, Joel S.; Ehret, Georg; Huang, Hailiang; Kao, W. H. Linda; Strait, James B.; Macfarlane, Peter W.; Brown, Morris; Caulfield, Mark J.; Samani, Nilesh J.; Kronenberg, Florian; Willeit, Johann; Smith, J. Gustav; Greiser, Karin H.; Meyer zu Schwabedissen, Henriette; Werdan, Karl; Carella, Massimo; Zelante, Leopoldo; Heckbert, Susan R.; Psaty, Bruce M.; Rotter, Jerome I.; Kolcic, Ivana; Polašek, Ozren; Wright, Alan F.; Griffin, Maura; Daly, Mark J.; Arnar, David O.; Hólm, Hilma; Thorsteinsdottir, Unnur; Denny, Joshua C.; Roden, Dan M.; Zuvich, Rebecca L.; Emilsson, Valur; Plump, Andrew S.; Larson, Martin G.; O'Donnell, Christopher J.; Yin, Xiaoyan; Bobbo, Marco; D'Adamo, Adamo P.; Iorio, Annamaria; Sinagra, Gianfranco; Carracedo, Angel; Cummings, Steven R.; Nalls, Michael A.; Jula, Antti; Kontula, Kimmo K.; Marjamaa, Annukka; Oikarinen, Lasse; Perola, Markus; Porthan, Kimmo; Erbel, Raimund; Hoffmann, Per; Jöckel, Karl-Heinz; Kälsch, Hagen; Nöthen, Markus M.; den Hoed, Marcel; Loos, Ruth J. F.; Thelle, Dag S.; Gieger, Christian; Meitinger, Thomas; Perz, Siegfried; Peters, Annette; Prucha, Hanna; Sinner, Moritz F.; Waldenberger, Melanie; de Boer, Rudolf A.; Franke, Lude; van der Vleuten, Pieter A.; Beckmann, Britt Maria; Martens, Eimo; Bardai, Abdennasser; Hofman, Nynke; Wilde, Arthur A. M.; Behr, Elijah R.; Dalageorgou, Chrysoula; Giudicessi, John R.; Medeiros-Domingo, Argelia; Barc, Julien; Kyndt, Florence; Probst, Vincent; Ghidoni, Alice; Insolia, Roberto; Hamilton, Robert M.; Scherer, Stephen W.; Brandimarto, Jeffrey; Margulies, Kenneth; Moravec, Christine E.; del Greco M, Fabiola; Fuchsberger, Christian; O'Connell, Jeffrey R.; Lee, Wai K.; Watt, Graham C. M.; Campbell, Harry; Wild, Sarah H.; El Mokhtari, Nour E.; Frey, Norbert; Asselbergs, Folkert W.; Mateo Leach, Irene; Navis, Gerjan; van den Berg, Maarten P.; van Veldhuisen, Dirk J.; Kellis, Manolis; Krijthe, Bouwe P.; Franco, Oscar H.; Hofman, Albert; Kors, Jan A.; Uitterlinden, André G.; Witteman, Jacqueline C. M.; Kedenko, Lyudmyla; Lamina, Claudia; Oostra, Ben A.; Abecasis, Gonçalo R.; Lakatta, Edward G.; Mulas, Antonella; Orrú, Marco; Schlessinger, David; Uda, Manuela; Markus, Marcello R. P.; Völker, Uwe; Snieder, Harold; Spector, Timothy D.; Ärnlöv, Johan; Lind, Lars; Sundström, Johan; Syvänen, Ann-Christine; Kivimaki, Mika; Kähönen, Mika; Mononen, Nina; Raitakari, Olli T.; Viikari, Jorma S.; Adamkova, Vera; Kiechl, Stefan; Brion, Maria; Nicolaides, Andrew N.; Paulweber, Bernhard; Haerting, Johannes; Dominiczak, Anna F.; Nyberg, Fredrik; Whincup, Peter H.; Hingorani, Aroon D.; Schott, Jean-Jacques; Bezzina, Connie R.; Ingelsson, Erik; Ferrucci, Luigi; Gasparini, Paolo; Wilson, James F.; Rudan, Igor; Franke, Andre; Mühleisen, Thomas W.; Pramstaller, Peter P.; Lehtimäki, Terho J.; Paterson, Andrew D.; Parsa, Afshin; Liu, Yongmei; van Duijn, Cornelia M.; Siscovick, David S.; Gudnason, Vilmundur; Jamshidi, Yalda; Salomaa, Veikko; Felix, Stephan B.; Sanna, Serena; Ritchie, Marylyn D.; Stricker, Bruno H.; Stefansson, Kari; Boyer, Laurie A.; Cappola, Thomas P.; Olsen, Jesper V.; Lage, Kasper; Schwartz, Peter J.; Kääb, Stefan; Chakravarti, Aravinda; Ackerman, Michael J.; Pfeufer, Arne; de Bakker, Paul I. W.; Newton-Cheh, Christopher

2014-01-01

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using

Long QT in children with congenital deafness: a brief report

Directory of Open Access Journals (Sweden)

Naseraldin Akbari Asbagh

2013-08-01

Full Text Available Background: Long QT syndromes (LQT are genetic abnormalities of ventricular repo-larization, with an estimated incidence of about one per 10000 births. It is characterized by prolongation of the QT interval in electrocardiogram (EKG and associated with a high risk for syncope and sudden death in patients. Type of this syndrome is association with congenital deafness. Our objective was to evaluate QT interval in children with congenital deafness.Methods: For 219 patients referred to Imam Khomeini Hospital audiometric clinic in 2011, questionnaire were completed. A total of 23 congenitally deaf children were incl-uded. All patients’ examinations were done by a pediatric cardiologist. Electrocardio-gram is conducted in all children (23 patients with sever and deep congenital deafness. Then the QT interval was measured based on Bazett’s formula. Echocardiography was also performed in these children to assess left ventricular function and the presence of mitral valve prolapse.Results: The overall patients were two hundred and nineteen children. A total of twenty three congenitally deaf children were included and electrocardiogram was obtained. Three children had obviously prolonged QTc (0.48±0.02 second. The median age of them was 6.1±5 year, the median weight was 18±11.3 kilogram and the median of QT interval was 0.48±0.02 second.Conclusion: The QT interval obtained 0.48±0.02 second. In the present study we found prolonged QT in congenital deafness, thus we recommend to evaluate the electrocardio-gram of children with congenital deafness.

Determinants of torsades de pointes in older patients with drug-associated long QT syndrome: a case-control study.

Science.gov (United States)

Goutelle, Sylvain; Sidolle, Elodie; Ducher, Michel; Caron, Jacques; Timour, Quadiri; Nony, Patrice; Gouraud, Aurore

2014-08-01

Many elderly patients are routinely exposed to drugs that may prolong the cardiac QT interval and cause Torsades de pointes (TdP). However, predictors of TdP in patients with drug-associated long QT syndrome (LQTS) are not fully understood, especially in the geriatric population. The objective of this study was to identify risk factors of TdP in elderly patients with drug-associated LQTS. In this retrospective, case-control study, documented reports of drug-associated LQTS plus TdP (n = 125) and LQTS without TdP (n = 81) in patients ≥65 years of age were retrieved from the French Pharmacovigilance Database over a 10-year period. Available clinical, biological, and drug therapy data were compared in the two groups and logistic regression was performed to identify significant predictors of TdP. The uncorrected QT interval was significantly longer in patients with TdP than in patients without TdP (577 ± 79 vs. 519 ± 68 ms; p = 0.0001). The number of drugs with a known risk of TdP administered to each patient was not a predictor of arrhythmia, nor was female gender. Logistic regression analysis identified the uncorrected QT interval as the only significant predictor of TdP. The receiver operating characteristic curve analysis was characterized by an area under the curve of 0.77 (95 % confidence interval 0.64-0.88) and a QT cutoff of 550 ms. The uncorrected QT interval was significantly associated with the probability of TdP in elderly patients with acquired, drug-associated LQTS.

Diagnostic criteria for congenital long QT syndrome in the era of molecular genetics: Do we need a scoring system?

NARCIS (Netherlands)

Hofman, Nynke; Wilde, Arthur A.M.; Kääb, Stefan; Van Langen, Irene M.; Tanck, Michael W.T.; Mannens, Marcel M.A.M.; Hinterseer, Martin; Beckmann, Britt-Maria; Tan, Hanno L.

2007-01-01

Aims: Previously published diagnostic systems, based on ECG analysis and clinical parameters (Schwartz criteria and Keating criteria), have been used to estimate the probability of inherited long QT syndrome (LQTS). Nowadays, a certain diagnosis can often be made by DNA testing. We aimed to

Low-Pass Filtering Approach via Empirical Mode Decomposition Improves Short-Scale Entropy-Based Complexity Estimation of QT Interval Variability in Long QT Syndrome Type 1 Patients

Directory of Open Access Journals (Sweden)

Vlasta Bari

2014-09-01

Full Text Available Entropy-based complexity of cardiovascular variability at short time scales is largely dependent on the noise and/or action of neural circuits operating at high frequencies. This study proposes a technique for canceling fast variations from cardiovascular variability, thus limiting the effect of these overwhelming influences on entropy-based complexity. The low-pass filtering approach is based on the computation of the fastest intrinsic mode function via empirical mode decomposition (EMD and its subtraction from the original variability. Sample entropy was exploited to estimate complexity. The procedure was applied to heart period (HP and QT (interval from Q-wave onset to T-wave end variability derived from 24-hour Holter recordings in 14 non-mutation carriers (NMCs and 34 mutation carriers (MCs subdivided into 11 asymptomatic MCs (AMCs and 23 symptomatic MCs (SMCs. All individuals belonged to the same family developing long QT syndrome type 1 (LQT1 via KCNQ1-A341V mutation. We found that complexity indexes computed over EMD-filtered QT variability differentiated AMCs from NMCs and detected the effect of beta-blocker therapy, while complexity indexes calculated over EMD-filtered HP variability separated AMCs from SMCs. The EMD-based filtering method enhanced features of the cardiovascular control that otherwise would have remained hidden by the dominant presence of noise and/or fast physiological variations, thus improving classification in LQT1.

ADULT VARIANT BARTTER’S SYNDROME- A CASE REPORT

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Ishwar Sidappa Hasabi

2017-02-01

Full Text Available BACKGROUND Bartter syndrome is a group of channelopathies with different genetic origins and molecular pathophysiologies, but sharing common feature of decreased tubular transport of sodium chloride in thick ascending loop of Henle (TAL, 1 although more common in antenatal group. Classic adult variant of Bartter syndrome is a rare entity. We hereby present a rare adult variant of classic Bartter syndrome.

Increases of QT dispersion, corrected QT dispersion and QT interval in young healthy individuals during Ramadan fasting

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Moradmand S

2003-06-01

Full Text Available Ramadan fasting is one of the most important religious duties of Muslims, that its effect on the heart has not been determined yet. Our objective was to evaluate the effect of Ramadan fasting on ventricular repolarization as assessed by QT interval, corrected QT interval, QT dispersion or corrected QT dispersion. Sixthy healthy subjects aged 20 to 35 years were dispersion included in this study. QT interval, corrected QT interval (QTc QT dispersion QTc dispersion, RR interval and QRS axis were measured in 12-lead surface electrocardiogram, once during fasting (10 to 11.5 hours of absolute fasting from food and liquid and another time, 15 tp 60 minutes after eating food at sunset, All of the subjects had been fasting 11 to 12 hours each day at least for 25 days during Ramadan. The study was performed at Amir Alam hospital in the year 2000. Maximal QT interval, mean QT interval and RR-interval, were longer during fasting (P<0.05, and both QT dispersion and QTc dispersion were increased (P<0.05. (QT dispersion: mean ±SD= 57.2±20.1 ms during fasting Vs 41.6±15.1 ms after meal, QTc dispersion=75.4±24.6 ms during fasting Vs 64.1±22.8 ms after meal. But mean QTc interval maximal QTc interval and QRS axis showed no significant difference. Prolongation of QT interval and RR interval during fasting, instead of no significant changes in corrected QT interval may primarily suggest that prolongation of RR-interval causes QTc interval not to have significant difference. But increases of QT dispersion and corrected QT dispersion (QTc dispersion during fasting -that are more reliable indicators of ventricular repolarization-support the idea that ventricular repolarization may be changed during Ramadan fasting. QT dispersion in cardiac patients is showed to increase from normal values of 30-40 to 64-138 ms, but in our study their increases did not reach critical value.

Association of functional genetic variants of A-kinase anchoring protein 10 with QT interval length in full-term Polish newborns.

Science.gov (United States)

Łoniewska, Beata; Kaczmarczyk, Mariusz; Clark, Jeremy Simon; Gorący, Iwona; Horodnicka-Józwa, Anita; Ciechanowicz, Andrzej

2015-03-16

A-Kinase Anchoring Proteins (AKAPs) coordinate the specificity of protein kinase A signaling by localizing the kinase to subcellular sites. The 1936G (V646) AKAP10 allele has been associated in adults with low cholinergic/vagus nerve sensitivity, shortened PR intervals in ECG recording and in newborns with increased blood pressure and higher cholesterol cord blood concentration. The aim of the study was to answer the question of whether 1936A > G AKAP10 polymorphism is associated with the newborn electrocardiographic variables. Electrocardiograms were recorded from 114 consecutive healthy Polish newborns (55 females, 59 males), born after 37 gestational weeks to healthy women with uncomplicated pregnancies. All recordings were made between 3(rd) and 7(th) day of life to avoid QT variability. The heart rate per minute and duration of PR, QRS, RR and QT intervals were usually measured. The ECGs were evaluated independently by three observers. At birth, cord blood of neonates was obtained for isolation of genomic DNA. The distribution of anthropometric and electrocardiographic variables in our cohort approached normality (skewness G variant and QTc interval in Polish newborns.

Can parents adjust to the idea that their child is at risk for a sudden death?: Psychological impact of risk for Long QT Syndrome

NARCIS (Netherlands)

Hendriks, Karin S. W. H.; Grosfeld, F. J. M.; van Tintelen, J. P.; van Langen, I. M.; Wilde, A. A. M.; van den Bout, J.; ten Kroode, H. F. J.

2005-01-01

Can a parent adjust to the idea that its child is at risk for a sudden death? This question is raised by a diagnostic procedure in which children were tested for an inherited Long QT Syndrome (LQTS). This potentially life-threatening but treatable cardiac arrhythmia syndrome may cause sudden death,

Can parents adjust to the idea that their child is at risk for a sudden death? : Psychological impact of risk for Long QT Syndrome

NARCIS (Netherlands)

Hendriks, Karin S. W. H.; Grosfeld, FJM; van Tintelen, JP; van Langen, IM; Wilde, AAM; van den Bout, J; ten Kroode, HFJ

2005-01-01

Can a parent adjust to the idea that its child is at risk for a sudden death? This question is raised by a diagnostic procedure in which children were tested for an inherited Long QT Syndrome (LQTS). This potentially life-threatening but treatable cardiac arrhythmia syndrome may cause sudden death,

Het lange-QT-tijdsyndroom bij kinderen

NARCIS (Netherlands)

Ten Harkel, A.D.J.; Lubbers, L. J.; Hoorntje, Th.; Blom, N.A.; Van Langen, I.M.; Sreeram, N.; Wilde, A.A.M.

2002-01-01

We examined 29 pediatric patients with long-Qt-syndrome in three academic hospitals. The mean age was 10 years (3-17). Of these patients 22 used betablocker therapy, in three combined with pacemaker. Genotyping has been performed in 22 children. LQTSI (mutation in the KCNQ1 gene) was found in

Genetics Home Reference: Ohdo syndrome, Say-Barber-Biesecker-Young-Simpson variant

Science.gov (United States)

... SBBYS variant Ohdo syndrome, Say-Barber-Biesecker-Young-Simpson variant Printable PDF Open All Close All Enable ... collapse boxes. Description The Say-Barber-Biesecker-Young-Simpson (SBBYS) variant of Ohdo syndrome is a rare ...

Spectrum of pathogenic mutations and associated polymorphisms in a cohort of 44 unrelated patients with long QT syndrome.

Science.gov (United States)

Millat, G; Chevalier, P; Restier-Miron, L; Da Costa, A; Bouvagnet, P; Kugener, B; Fayol, L; Gonzàlez Armengod, C; Oddou, B; Chanavat, V; Froidefond, E; Perraudin, R; Rousson, R; Rodriguez-Lafrasse, C

2006-09-01

Long QT syndrome (LQTS) is a rare and clinically heterogeneous inherited disorder characterized by a long QT interval on the electrocardiogram, increased risk of syncope and sudden death caused by arrhythmias. This syndrome is mostly caused by mutations in genes encoding various cardiac ion channels. The clinical heterogeneity is usually attributed to variable penetrance. One of the reasons for this variability in expression could be the coexistence of common single nucleotide polymorphisms (SNPs) on LQTS-causing genes and/or unknown genes. Some synonymous and nonsynonymous exonic SNPs identified in LQTS-causing genes may have an effect on the cardiac repolarization process and modulate the clinical expression of a latent LQTS pathogenic mutation. We report the molecular pattern of 44 unrelated patients with LQTS using denaturing high-performance liquid chromatography analysis of the KCNQ1, KCNH2, SCN5A, KCNE1 and KCNE2 genes. Forty-five disease-causing mutations (including 24 novel ones) were identified in this cohort. Most of our patients (84%) showed complex molecular pattern with one mutation (and even two for four patients) associated with several SNPs located in several LQTS genes.

Qt for Symbian

CERN Document Server

Fitzek, Frank H P; Torp, Tony

2009-01-01

Qt for Symbian takes a unique look at this cutting-edge programming environment. Step-by-step it explains Qt in an easy to access fashion, using simple examples throughout. A bible for all beginners it covers topics such as: Installing the developer platform / SDK; Explaining the basic Qt environment; The extension of Qt for Symbian modules. o Communication. o Sensors. o Etc; Simple examples for Qt for Symbian. This Nokia-endorsed primer written by developers involved in the new release of Qt will ultimately save you costs, development resources, and will help you get to market faster!.

Reduced Penetrance and Variable Expression of SCN5A Mutations and the Importance of Co-inherited Genetic Variants: Case Report and Review of the Literature

Directory of Open Access Journals (Sweden)

T. Robyns, MD.

2014-05-01

Full Text Available Mutations in the SCN5A gene are responsible for multiple phenotypical presentations including Brugada syndrome, long QT syndrome, progressive familial heart block, sick sinus syndrome, dilated cardiomyopathy, lone atrial fibrillation and multiple overlap syndromes. These different phenotypic expressions of a mutation in a single gene can be explained by variable expression and reduced penetrance. One of the possible explanations of these phenomena is the co-inheritance of genetic variants. We describe a family where the individuals exhibit a compound heterozygosity in the SCN5A gene including a mutation (R1632H and a new variant (M858L. Individuals with both the mutation and new variant present with a more severe phenotype including spontaneous atrial tachyarrhythmia at young age. We give an overview of the different phenotypes of "SCN5A disease" and discuss the importance of co-inherited genetic variants in the expression of SCN5A disease.

Mutations in conserved amino acids in the KCNQ1 channel and risk of cardiac events in type-1 long-QT syndrome

DEFF Research Database (Denmark)

Jons, Christian; Moss, Arthur J; Lopes, Coeli M

2009-01-01

BACKGROUND: Type-1 long-QT syndrome (LQT1) is caused by mutations in the KCNQ1 gene. The purpose of this study was to investigate whether KCNQ1 mutations in highly conserved amino acid residues within the voltage-gated potassium channel family are associated with an increased risk of cardiac even...

QT-RR relationships and suitable QT correction formulas for halothane-anesthetized dogs.

Science.gov (United States)

Tabo, Mitsuyasu; Nakamura, Mikiko; Kimura, Kazuya; Ito, Shigeo

2006-10-01

Several QT correction (QTc) formulas have been used for assessing the QT liability of drugs. However, they are known to under- and over-correct the QT interval and tend to be specific to species and experimental conditions. The purpose of this study was to determine a suitable formula for halothane-anesthetized dogs highly sensitive to drug-induced QT interval prolongation. Twenty dogs were anesthetized with 1.5% halothane and the relationship between the QT and RR intervals were obtained by changing the heart rate under atrial pacing conditions. The QT interval was corrected for the RR interval by applying 4 published formulas (Bazett, Fridericia, Van de Water, and Matsunaga); Fridericia's formula (QTcF = QT/RR(0.33)) showed the least slope and lowest R(2) value for the linear regression of QTc intervals against RR intervals, indicating that it dissociated changes in heart rate most effectively. An optimized formula (QTcX = QT/RR(0.3879)) is defined by analysis of covariance and represents a correction algorithm superior to Fridericia's formula. For both Fridericia's and the optimized formula, QT-prolonging drugs (d,l-sotalol, astemizole) showed QTc interval prolongation. A non-QT-prolonging drug (d,l-propranolol) failed to prolong the QTc interval. In addition, drug-induced changes in QTcF and QTcX intervals were highly correlated with those of the QT interval paced at a cycle length of 500 msec. These findings suggest that Fridericia's and the optimized formula, although the optimized is a little bit better, are suitable for correcting the QT interval in halothane-anesthetized dogs and help to evaluate the potential QT prolongation of drugs with high accuracy.

Multifactorial QT Interval Prolongation and Takotsubo Cardiomyopathy

Directory of Open Access Journals (Sweden)

Michael Gysel

2014-01-01

Full Text Available A 71-year-old woman collapsed while working as a grocery store cashier. CPR was performed and an AED revealed torsades de pointes (TdP. She was subsequently defibrillated resulting in restoration of sinus rhythm with a QTc interval of 544 msec. Further evaluation revealed a diagnosis of Takotsubo Cardiomyopathy (TCM contributing to the development of a multifactorial acquired long QT syndrome (LQTS. The case highlights the role of TCM as a cause of LQTS in the setting of multiple risk factors including old age, female gender, hypokalemia, and treatment with QT prolonging medications. It also highlights the multifactorial nature of acquired LQTS and lends support to growing evidence of an association with TCM.

Programming with Qt

CERN Document Server

Dalheimer, Matthias Kalle

2002-01-01

The popular open source KDE desktop environment for Unix was built with Qt, a C++ class library for writing GUI applications that run on Unix, Linux, Windows 95/98, Windows 2000, and Windows NT platforms. Qt emulates the look and feel of Motif, but is much easier to use. Best of all, after you have written an application with Qt, all you have to do is recompile it to have a version that works on Windows. Qt also emulates the look and feel of Windows, so your users get native-looking interfaces. Platform independence is not the only benefit. Qt is flexible and highly optimized. You'll find th

Using the genome aggregation database, computational pathogenicity prediction tools, and patch clamp heterologous expression studies to demote previously published long QT syndrome type 1 mutations from pathogenic to benign.

Science.gov (United States)

Clemens, Daniel J; Lentino, Anne R; Kapplinger, Jamie D; Ye, Dan; Zhou, Wei; Tester, David J; Ackerman, Michael J

2018-04-01

Mutations in the KCNQ1-encoded Kv7.1 potassium channel cause long QT syndrome (LQTS) type 1 (LQT1). It has been suggested that ∼10%-20% of rare LQTS case-derived variants in the literature may have been published erroneously as LQT1-causative mutations and may be "false positives." The purpose of this study was to determine which previously published KCNQ1 case variants are likely false positives. A list of all published, case-derived KCNQ1 missense variants (MVs) was compiled. The occurrence of each MV within the Genome Aggregation Database (gnomAD) was assessed. Eight in silico tools were used to predict each variant's pathogenicity. Case-derived variants that were either (1) too frequently found in gnomAD or (2) absent in gnomAD but predicted to be pathogenic by ≤2 tools were considered potential false positives. Three of these variants were characterized functionally using whole-cell patch clamp technique. Overall, there were 244 KCNQ1 case-derived MVs. Of these, 29 (12%) were seen in ≥10 individuals in gnomAD and are demotable. However, 157 of 244 MVs (64%) were absent in gnomAD. Of these, 7 (4%) were predicted to be pathogenic by ≤2 tools, 3 of which we characterized functionally. There was no significant difference in current density between heterozygous KCNQ1-F127L, -P477L, or -L619M variant-containing channels compared to KCNQ1-WT. This study offers preliminary evidence for the demotion of 32 (13%) previously published LQT1 MVs. Of these, 29 were demoted because of their frequent sighting in gnomAD. Additionally, in silico analysis and in vitro functional studies have facilitated the demotion of 3 ultra-rare MVs (F127L, P477L, L619M). Copyright © 2017 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Calmodulin is essential for cardiac IKS channel gating and assembly: impaired function in long-QT mutations

DEFF Research Database (Denmark)

Shamgar, Liora; Ma, Lijuan; Schmitt, Nicole

2006-01-01

The slow IKS K+ channel plays a major role in repolarizing the cardiac action potential and consists of the assembly of KCNQ1 and KCNE1 subunits. Mutations in either KCNQ1 or KCNE1 genes produce the long-QT syndrome, a life-threatening ventricular arrhythmia. Here, we show that long-QT mutations ...

Application development with Qt creator

CERN Document Server

Rischpater, Ray

2014-01-01

This book is great for developers who are new to Qt and Qt Creator and who are interested in harnessing the power of Qt for cross-platform development. If you have basic experience programming in C++, you have what it takes to create engaging cross-platform applications using Qt and Qt Creator!

Application development with Qt creator

CERN Document Server

Rischpater, Ray

2013-01-01

Written in a concise and easy-to-follow approach, this book will guide you to develop your first application with Qt with illustrated examples and screenshots.If you are a developer who is new to Qt and Qt Creator and is interested in harnessing the power of Qt for cross-platform development, this book is great for you. If you have basic experience programming in C++, you have what it takes to create great cross-platform applications using Qt and Qt Creator!

Genetics Home Reference: Jervell and Lange-Nielsen syndrome

Science.gov (United States)

... Home Edition for Patients and Caregivers: Long QT Syndrome and Torsades de Pointes Ventricular Tachycardia Orphanet: Familial long QT syndrome Orphanet: Jervell and Lange-Nielsen syndrome Patient Support ...

Cardiovascular drugs inducing QT prolongation: facts and evidence.

Science.gov (United States)

Taira, Carlos A; Opezzo, Javier A W; Mayer, Marcos A; Höcht, Christian

2010-01-01

Acquired QT syndrome is mainly caused by the administration of drugs that prolong ventricular repolarization. On the other hand, the risk of drug-induced torsades de pointes is increased by numerous predisposing factors, such as genetic predisposition, female sex, hypokalemia and cardiac dysfunction. This adverse reaction is induced by different chemical compounds used for the treatment of a variety of pathologies, including arrhythmias. As it is known, antiarrhythmic agents and other cardiovascular drugs can prolong the QT interval, causing this adverse reaction. Of the 20 most commonly reported drugs, 10 were cardiovascular agents and these appeared in 348 of the reports (46%). Class Ia antiarrhythmic agents have frequently been linked to inducing arrhythmia, including torsades de pointes. Sotalol and amiodarone, class III antiarrhythmics, are known to prolong the QT interval by blocking I(Kr). Due to the severity of events caused by the therapeutic use of these drugs, in this work of revision the cardiovascular drugs that present this property and the factors and evidence will be mentioned.

Cross-platform software development with Qt

CERN Multimedia

CERN. Geneva

2018-01-01

Overview of the Qt framework, new features of Qt 5.10 and preview of the Qt roadmap Introduction of the Qt framework as well as the new features and improvements of Qt 5.10. Showcase the different Qt UI technologies such as Widgets and Qml, overview of the automation suite and preview of the new features to come in Qt Creator. Elaborating on the Qt 3D offering and preview of the Qt roadmap. Presenting use cases of Qt integration in the medical and automation sectors. About the speaker Ionut is a serial entrepreneur, now working as Qt Adviser for The Qt Company. He studied biomedical engineering in Montreal, Canada and worked for 4 years as a Senior Software Developer at a software company in the life science and medical imaging area. He founded two interactive media companies, one in Montreal, Canada and another one in Berlin, Germany. Ionut has also more than 10 years of experience in the digital signage industry. He has been working with the Qt framework since 2006 and is a huge fan of it.   &...

Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants.

Science.gov (United States)

Johnston, Jennifer J; van der Smagt, Jasper J; Rosenfeld, Jill A; Pagnamenta, Alistair T; Alswaid, Abdulrahman; Baker, Eva H; Blair, Edward; Borck, Guntram; Brinkmann, Julia; Craigen, William; Dung, Vu Chi; Emrick, Lisa; Everman, David B; van Gassen, Koen L; Gulsuner, Suleyman; Harr, Margaret H; Jain, Mahim; Kuechler, Alma; Leppig, Kathleen A; McDonald-McGinn, Donna M; Can, Ngoc Thi Bich; Peleg, Amir; Roeder, Elizabeth R; Rogers, R Curtis; Sagi-Dain, Lena; Sapp, Julie C; Schäffer, Alejandro A; Schanze, Denny; Stewart, Helen; Taylor, Jenny C; Verbeek, Nienke E; Walkiewicz, Magdalena A; Zackai, Elaine H; Zweier, Christiane; Zenker, Martin; Lee, Brendan; Biesecker, Leslie G

2018-02-22

PurposeTo characterize the molecular genetics of autosomal recessive Noonan syndrome.MethodsFamilies underwent phenotyping for features of Noonan syndrome in children and their parents. Two multiplex families underwent linkage analysis. Exome, genome, or multigene panel sequencing was used to identify variants. The molecular consequences of observed splice variants were evaluated by reverse-transcription polymerase chain reaction.ResultsTwelve families with a total of 23 affected children with features of Noonan syndrome were evaluated. The phenotypic range included mildly affected patients, but it was lethal in some, with cardiac disease and leukemia. All of the parents were unaffected. Linkage analysis using a recessive model supported a candidate region in chromosome 22q11, which includes LZTR1, previously shown to harbor mutations in patients with Noonan syndrome inherited in a dominant pattern. Sequencing analyses of 21 live-born patients and a stillbirth identified biallelic pathogenic variants in LZTR1, including putative loss-of-function, missense, and canonical and noncanonical splicing variants in the affected children, with heterozygous, clinically unaffected parents and heterozygous or normal genotypes in unaffected siblings.ConclusionThese clinical and genetic data confirm the existence of a form of Noonan syndrome that is inherited in an autosomal recessive pattern and identify biallelic mutations in LZTR1.Genet Med advance online publication, 22 February 2018; doi:10.1038/gim.2017.249.

Waardenburg syndrome with familial unilateral renal agenesis: a new syndrome variant?

Science.gov (United States)

Webb, Katie M; Smith, Alisha J; Dansby, Linda M; Diskin, Charles J

2015-06-01

A 64-year-old man with Waardenburg syndrome presented with anuria and was subsequently discovered by renal ultrasound to have unilateral renal agenesis. The patient is one of three generations with incidental finding of renal agenesis also marked by the presence of Waardenburg syndrome. To our knowledge, there has been no mention elsewhere in the scientific literature of a variant of Waardenburg syndrome with associated renal agenesis. © 2014 The Authors. Therapeutic Apheresis and Dialysis © 2014 International Society for Apheresis.

In silico investigation of the short QT syndrome, using human ventricle models incorporating electromechanical coupling

Directory of Open Access Journals (Sweden)

Ismail eAdeniran

2013-07-01

Full Text Available Introduction Genetic forms of the Short QT Syndrome (SQTS arise due to cardiac ion channel mutations leading to accelerated ventricular repolarisation, arrhythmias and sudden cardiac death. Results from experimental and simulation studies suggest that changes to refractoriness and tissue vulnerability produce a substrate favourable to re-entry. Potential electromechanical consequences of the SQTS are less well understood. The aim of this study was to utilize electromechanically coupled human ventricle models to explore electromechanical consequences of the SQTS. Methods and results: The Rice et al. mechanical model was coupled to the ten Tusscher et al. ventricular cell model. Previously validated K+ channel formulations for SQT variants 1 and 3 were incorporated. Functional effects of the SQTS mutations on transients, sarcomere length shortening and contractile force at the single cell level were evaluated with and without the consideration of stretch activated channel current (Isac. Without Isac, the SQTS mutations produced dramatic reductions in the amplitude of transients, sarcomere length shortening and contractile force. When Isac was incorporated, there was a considerable attenuation of the effects of SQTS-associated action potential shortening on Ca2+ transients, sarcomere shortening and contractile force. Single cell models were then incorporated into 3D human ventricular tissue models. The timing of maximum deformation was delayed in the SQTS setting compared to control. Conclusion: The incorporation of Isac appears to be an important consideration in modelling functional effects of SQT 1 and 3 mutations on cardiac electro-mechanical coupling. Whilst there is little evidence of profoundly impaired cardiac contractile function in SQTS patients, our 3D simulations correlate qualitatively with reported evidence for dissociation between ventricular repolarization and the end of mechanical systole.

Hyperglycemia and subsequent torsades de pointes with marked QT prolongation during refeeding.

Science.gov (United States)

Nakashima, Takashi; Kubota, Tomoki; Takasugi, Nobuhiro; Kitagawa, Yuichiro; Yoshida, Takahiro; Ushikoshi, Hiroaki; Kawasaki, Masanori; Nishigaki, Kazuhiko; Ogura, Shinji; Minatoguchi, Shinya

2017-01-01

A fatal cardiac complication can occasionally present in malnourished patients during refeeding; this is known as refeeding syndrome. However, to our knowledge, hyperglycemia preceding torsades de pointes with QT prolongation during refeeding has not been reported. In the present study, we present a case in which hyperglycemia preceded torsades de pointes with QT prolongation during refeeding. The aim of this study was to determine the possible mechanism underlying QT prolongation during refeeding and indicate how to prevent it. A 32-y-old severely malnourished woman (body mass index 14.57 kg/m 2 ) was admitted to the intensive care unit of our institution after resuscitation from cardiopulmonary arrest due to ventricular fibrillation. She was diagnosed with anorexia nervosa. Although no obvious electrolyte abnormalities were observed, her blood glucose level was 11 mg/dL. A 12-lead electrocardiogram at admission showed sinus rhythm with normal QT interval (QTc 0.448). Forty mL of 50% glucose (containing 20 g of glucose) was intravenously injected, followed by a drip infusion of glucose to maintain blood glucose level within normal range. After 9 h, the patient's blood glucose level increased to 569 mg/dL. However, after 38 h, an episode of marked QT prolongation (QTc 0.931) followed by torsades de pointes developed. Hyperglycemia during refeeding can present with QT prolongation; consequently, monitoring blood glucose levels may be useful in avoiding hyperglycemia, which can result in QT prolongation. Furthermore, additional monitoring of QT intervals using a 12-lead electrocardiogram should allow the early detection of QT prolongation when glucose solution is administered to a malnourished patient with (severe) hypoglycemia. Copyright © 2016 Elsevier Inc. All rights reserved.

The application of root mean square electrocardiography (RMS ECG) for the detection of acquired and congenital long QT syndrome.

Science.gov (United States)

Lux, Robert L; Sower, Christopher Todd; Allen, Nancy; Etheridge, Susan P; Tristani-Firouzi, Martin; Saarel, Elizabeth V

2014-01-01

Precise measurement of the QT interval is often hampered by difficulty determining the end of the low amplitude T wave. Root mean square electrocardiography (RMS ECG) provides a novel alternative measure of ventricular repolarization. Experimental data have shown that the interval between the RMS ECG QRS and T wave peaks (RTPK) closely reflects the mean ventricular action potential duration while the RMS T wave width (TW) tracks the dispersion of repolarization timing. Here, we tested the precision of RMS ECG to assess ventricular repolarization in humans in the setting of drug-induced and congenital Long QT Syndrome (LQTS). RMS ECG signals were derived from high-resolution 24 hour Holter monitor recordings from 68 subjects after receiving placebo and moxifloxacin and from standard 12 lead ECGs obtained in 97 subjects with LQTS and 97 age- and sex-matched controls. RTPK, QTRMS and RMS TW intervals were automatically measured using custom software and compared to traditional QT measures using lead II. All measures of repolarization were prolonged during moxifloxacin administration and in LQTS subjects, but the variance of RMS intervals was significantly smaller than traditional lead II measurements. TW was prolonged during moxifloxacin and in subjects with LQT-2, but not LQT-1 or LQT-3. These data validate the application of RMS ECG for the detection of drug-induced and congenital LQTS. RMS ECG measurements are more precise than the current standard of care lead II measurements.

Peeling skin syndrome associated with novel variant in FLG2 gene.

Science.gov (United States)

Alfares, Ahmed; Al-Khenaizan, Sultan; Al Mutairi, Fuad

2017-12-01

Peeling skin syndrome is a rare genodermatosis characterized by variably pruritic superficial generalized peeling of the skin with several genes involved until now little is known about the association between FLG2 and peeling skin syndrome. We describe multiple family members from a consanguineous Saudi family with peeling skin syndrome. Next Generation Sequencing identifies a cosegregating novel variant in FLG2 c.632C>G (p.Ser211*) as a likely etiology in this family. Here, we reported on the clinical manifestation of homozygous loss of function variant in FLG2 as a disease-causing gene for peeling skin syndrome and expand the dermatology findings. © 2017 Wiley Periodicals, Inc.

Variant of Rett syndrome and CDKL5 gene

DEFF Research Database (Denmark)

Pini, Giorgio; Bigoni, Stefania; Engerström, Ingegerd Witt

2012-01-01

UNLABELLED: Rett syndrome (RTT) is a severe neurodevelopmental disorder affecting almost exclusively females. The Hanefeld variant, or early-onset seizure variant, has been associated with mutations in CDKL5 gene. AIMS: In recent years more than 60 patients with mutations in the CDKL5 gene have...... been described in the literature, but the cardiorespiratory phenotype has not been reported. Our aim is to describe clinical and autonomic features of these girls. METHODS: 10 girls with CDKL5 mutations and a diagnosis of Hanefeld variant have been evaluated on axiological and clinical aspects. In all...

Combined gating and trafficking defect in Kv11.1 manifests as a malignant long QT syndrome phenotype in a large Danish p.F29L founder family

DEFF Research Database (Denmark)

Kanters, Jørgen K.; Skibsbye, Lasse; Hedley, Paula L.

2015-01-01

Background: Congenital long QT syndrome (LQTS) is a hereditary cardiac channelopathy characterized by delayedventricular repolarization, syncope, torsades de pointes and sudden cardiac death. Thirty-three members of fi ve apparently‘ unrelated ’Danish families carry the KCNH2:c.87C A; p.F29L...

Prolonged QT Syndrome and Seizure Secondary to Alkaline Earth Metal Deficiency: A Case Report

Directory of Open Access Journals (Sweden)

A. McKinney

2011-01-01

Full Text Available Introduction. Alkaline earth metal deficiency is recognized as a cause of both seizure and long QT syndrome. Their deficiency can have significant repercussions on the function of cells, tissues, and organs of the body. An understanding of the role of electrolytes allows an appreciation of the significance of depleted levels on cell function. Case Report. A 65-year-old lady was admitted with symptoms of chest discomfort, vomiting, increased stoma output, and dizziness. Two days following admission she suffered a tonic-clonic seizure. ECG review demonstrated a prolonged QTc interval, raising the possibility of an underlying Torsades de Pointes as the precipitant. This was attributed to electrolyte disturbance arising as a result of multiple aetiologies. Discussion. This paper highlights the multisystem effects of electrolyte disturbance, with emphasis upon its role in precipitating cardiac arrhythmia and neurological symptoms.

Evaluation of QT and P wave dispersion and mean platelet volume among inflammatory bowel disease patients.

Science.gov (United States)

Dogan, Yuksel; Soylu, Aliye; Eren, Gulay A; Poturoglu, Sule; Dolapcioglu, Can; Sonmez, Kenan; Duman, Habibe; Sevindir, Isa

2011-01-01

In inflammatory bowel disease (IBD) number of thromboembolic events are increased due to hypercoagulupathy and platelet activation. Increases in mean platelet volume (MPV) can lead to platelet activation, this leads to thromboembolic events and can cause acute coronary syndromes. In IBD patients, QT-dispersion and P-wave dispersion are predictors of ventricular arrhythmias and atrial fibrilation; MPV is accepted as a risk factor for acute coronary syndromes, we aimed at evaluating the correlations of these with the duration of disease, its localization and activity. The study group consisted of 69 IBD (Ulcerative colitis n: 54, Crohn's Disease n: 15) patients and the control group included 38 healthy individuals. Disease activity was evaluated both endoscopically and clinically. Patients with existing cardiac conditions, those using QT prolonging medications and having systemic diseases, anemia and electrolyte imbalances were excluded from the study. QT-dispersion, P-wave dispersion and MPV values of both groups were compared with disease activity, its localization, duration of disease and the antibiotics used. The P-wave dispersion values of the study group were significantly higher than those of the control group. Duration of the disease was not associated with QT-dispersion, and MPV levels. QT-dispersion, P-wave dispersion, MPV and platelet count levels were similar between the active and in mild ulcerative colitis patients. QT-dispersion levels were similar between IBD patients and the control group. No difference was observed between P-wave dispersion, QT-dispersion and MPV values; with regards to disease duration, disease activity, and localization in the study group (p>0.05). P-wave dispersion which is accepted as a risk factor for the development of atrial fibirilation was found to be high in our IBD patients. This demonstrates us that the risk of developing atrial fibrillation may be high in patients with IBD. No significant difference was found in the QT

Biophysical characterization of the short QT mutation hERG-N588K reveals a mixed gain-and loss-of-function

DEFF Research Database (Denmark)

Grunnet, M.; Diness, T.G.; Hansen, R.S.

2008-01-01

The short QT syndrome is a newly discovered pro-arrhythmic condition, which may cause ventricular fibrillation and sudden death. Short QT can originate from the apparent gain-of-function mutation N588K in the hERG potassium channel that conducts repolarising I(Kr) current. The present study...

Functional characterization of a novel hERG variant in a family with recurrent sudden infant death syndrome: Retracting a genetic diagnosis.

Science.gov (United States)

Sergeev, Valentine; Perry, Frances; Roston, Thomas M; Sanatani, Shubhayan; Tibbits, Glen F; Claydon, Thomas W

2018-03-01

Long QT syndrome (LQTS) is the most common cardiac ion channelopathy and has been found to be responsible for approximately 10% of sudden infant death syndrome (SIDS) cases. Despite increasing use of broad panels and now whole exome sequencing (WES) in the investigation of SIDS, the probability of identifying a pathogenic mutation in a SIDS victim is low. We report a family-based study who are afflicted by recurrent SIDS in which several members harbor a variant, p.Pro963Thr, in the C-terminal region of the human-ether-a-go-go (hERG) gene, published to be responsible for cases of LQTS type 2. Functional characterization was undertaken due to the variable phenotype in carriers, the discrepancy with published cases, and the importance of identifying a cause for recurrent deaths in a single family. Studies of the mutated ion channel in in vitro heterologous expression systems revealed that the mutation has no detectable impact on membrane surface expression, biophysical gating properties such as activation, deactivation and inactivation, or the amplitude of the protective current conducted by hERG channels during early repolarization. These observations suggest that the p.Pro963Thr mutation is not a monogenic disease-causing LQTS mutation despite evidence of co-segregation in two siblings affected by SIDS. Our findings demonstrate some of the potential pitfalls in post-mortem molecular testing and the importance of functional testing of gene variants in determining disease-causation, especially where the impacts of cascade screening can affect multiple generations. Copyright © 2017 Elsevier B.V. All rights reserved.

LATE POTENTIALS IN A BRADYCARDIA-DEPENDENT LONG QT-SYNDROME ASSOCIATED WITH SUDDEN-DEATH DURING SLEEP

NARCIS (Netherlands)

TOBE, TJM; DELANGEN, CDJ; BINKBOELKENS, MTE; MOOK, PH; VIERSMA, JW; LIE, KI; WESSELING, H

1992-01-01

The purpose of this study was to determine the incidence of late potentials and their relation to QT prolongation in a family with a high incidence of sudden death during sleep at a young age and bradycardia-dependent QT prolongation (n = 9) and to compare the findings with those in consanguineous

Exome analysis of a family with Wolff-Parkinson-White syndrome identifies a novel disease locus.

Science.gov (United States)

Bowles, Neil E; Jou, Chuanchau J; Arrington, Cammon B; Kennedy, Brett J; Earl, Aubree; Matsunami, Norisada; Meyers, Lindsay L; Etheridge, Susan P; Saarel, Elizabeth V; Bleyl, Steven B; Yost, H Joseph; Yandell, Mark; Leppert, Mark F; Tristani-Firouzi, Martin; Gruber, Peter J

2015-12-01

Wolff-Parkinson-White (WPW) syndrome is a common cause of supraventricular tachycardia that carries a risk of sudden cardiac death. To date, mutations in only one gene, PRKAG2, which encodes the 5'-AMP-activated protein kinase subunit γ-2, have been identified as causative for WPW. DNA samples from five members of a family with WPW were analyzed by exome sequencing. We applied recently designed prioritization strategies (VAAST/pedigree VAAST) coupled with an ontology-based algorithm (Phevor) that reduced the number of potentially damaging variants to 10: a variant in KCNE2 previously associated with Long QT syndrome was also identified. Of these 11 variants, only MYH6 p.E1885K segregated with the WPW phenotype in all affected individuals and was absent in 10 unaffected family members. This variant was predicted to be damaging by in silico methods and is not present in the 1,000 genome and NHLBI exome sequencing project databases. Screening of a replication cohort of 47 unrelated WPW patients did not identify other likely causative variants in PRKAG2 or MYH6. MYH6 variants have been identified in patients with atrial septal defects, cardiomyopathies, and sick sinus syndrome. Our data highlight the pleiotropic nature of phenotypes associated with defects in this gene. © 2015 Wiley Periodicals, Inc.

Exome Analysis of a Family with Wolff–Parkinson–White Syndrome Identifies a Novel Disease Locus

Science.gov (United States)

Bowles, Neil E.; Jou, Chuanchau J.; Arrington, Cammon B.; Kennedy, Brett J.; Earl, Aubree; Matsunami, Norisada; Meyers, Lindsay L.; Etheridge, Susan P.; Saarel, Elizabeth V.; Bleyl, Steven B.; Yost, H. Joseph; Yandell, Mark; Leppert, Mark F.; Tristani-Firouzi, Martin; Gruber, Peter J.

2016-01-01

Wolff–Parkinson–White (WPW) syndrome is a common cause of supraventricular tachycardia that carries a risk of sudden cardiac death. To date, mutations in only one gene, PRKAG2, which encodes the 5’ -AMP-activated protein kinase subunit γ-2, have been identified as causative for WPW. DNA samples from five members of a family with WPW were analyzed by exome sequencing. We applied recently designed prioritization strategies (VAAST/pedigree VAAST) coupled with an ontology-based algorithm (Phevor) that reduced the number of potentially damaging variants to 10: a variant in KCNE2 previously associated with Long QT syndrome was also identified. Of these 11 variants, only MYH6 p.E1885K segregated with the WPW phenotype in all affected individuals and was absent in 10 unaffected family members. This variant was predicted to be damaging by in silico methods and is not present in the 1,000 genome and NHLBI exome sequencing project databases. Screening of a replication cohort of 47 unrelated WPW patients did not identify other likely causative variants in PRKAG2 or MYH6. MYH6 variants have been identified in patients with atrial septal defects, cardiomyopathies, and sick sinus syndrome. Our data highlight the pleiotropic nature of phenotypes associated with defects in this gene. PMID:26284702

Epidemiology of symptomatic drug-induced long QT syndrome and Torsade de Pointes in Germany.

Science.gov (United States)

Sarganas, Giselle; Garbe, Edeltraut; Klimpel, Andreas; Hering, Rolf C; Bronder, Elisabeth; Haverkamp, Wilhelm

2014-01-01

Drug-induced long QT syndrome (diLQTS) leading to Torsade de Pointes (TdP) is a potentially lethal condition, which has led to several post-marketing drug withdrawals in the past decade. The true incidence of diLQTS/TdP is largely unknown. One explanation is under-reporting of this potentially life-threatening adverse event by physicians and other medical staff to pharmacovigilance agencies. To gain more insight into the incidence of diLQTS and TdP, the Berlin Pharmacovigilance Center (PVZ-FAKOS) has actively and prospectively identified patients who developed this particular type of drug-induced adverse event. Here, the basic characteristics of the affected patients are summarized and suspected drugs are discussed. Furthermore, an extrapolation of the Berlin incidence rates to the German Standard Population is presented. Using a Berlin-wide network of 51 collaborating hospitals (>180 clinical departments), adult patients presenting with long QT syndrome (LQTS/TdP) between 2008 and 2011 were identified by active surveillance of these hospitals. Drug exposures as well as other possible risk factors were obtained from the patient's files and in a face-to-face interview with the patient. One-hundred and seventy patients of possible LQTS/TdP were reported to the Pharmacovigilance Center of whom 58 cases were confirmed in a thorough validation process. The majority (66%) of these cases were female and 60% had developed LQTS/TdP in the outpatient setting. Thirty-five (60%) of 58 confirmed cases were assessed as drug-related based on a standardized causality assessment applying the criteria of the World Health Organization. Drugs assessed as related in more than two cases were metoclopramide, amiodarone, melperone, citalopram, and levomethadone. The age-standardized incidence of diLQTS/TdP in Berlin was estimated to be 2.5 per million per year for males and 4.0 per million per year for females. While European annual reporting rates based on spontaneous reports suggest an

Pathological assessment of mismatch repair gene variants in Lynch syndrome

DEFF Research Database (Denmark)

Rasmussen, Lene Juel; Heinen, Christopher D; Royer-Pokora, Brigitte

2012-01-01

Lynch syndrome (LS) is caused by germline mutations in DNA mismatch repair (MMR) genes and is the most prevalent hereditary colorectal cancer syndrome. A significant proportion of variants identified in MMR and other common cancer susceptibility genes are missense or noncoding changes whose...

Patients with Long QT Syndrome Due to Impaired hERG-encoded Kv11.1 Potassium Channel Have Exaggerated Endocrine Pancreatic and Incretin Function Associated with Reactive Hypoglycemia

DEFF Research Database (Denmark)

Hyltén-Cavallius, Louise; Iepsen, Eva W; Wewer Albrechtsen, Nicolai J

2017-01-01

Background -Loss-of-function mutations in hERG (encoding the Kv11.1 voltage-gated potassium channel) cause long QT syndrome (LQT2) due to prolonged cardiac repolarization. However, Kv11.1 is also present in pancreatic α and β cells and intestinal L and K cells, secreting glucagon, insulin, and th...

BAG3-related myopathy, polyneuropathy and cardiomyopathy with long QT syndrome.

Science.gov (United States)

Kostera-Pruszczyk, Anna; Suszek, Małgorzata; Płoski, Rafał; Franaszczyk, Maria; Potulska-Chromik, Anna; Pruszczyk, Piotr; Sadurska, Elżbieta; Karolczak, Justyna; Kamińska, Anna M; Rędowicz, Maria Jolanta

2015-12-01

BAG3 belongs to BAG family of molecular chaperone regulators interacting with HSP70 and anti-apoptotic protein Bcl-2. It is ubiquitously expressed with strong expression in skeletal and cardiac muscle, and is involved in a panoply of cellular processes. Mutations in BAG3 and aberrations in its expression cause fulminant myopathies, presenting with progressive limb and axial muscle weakness, and respiratory insufficiency and neuropathy. Herein, we report a sporadic case of a 15-years old girl with symptoms of myopathy, demyelinating polyneuropathy and asymptomatic long QT syndrome. Genetic testing demonstrated heterozygous mutation Pro209Leu (c.626C > T) in exon 3 of BAG3 gene causing severe myopathy and neuropathy, often associated with restrictive cardiomyopathy. We did not find a mutation in any known LQT syndrome genes. Analysis of muscle biopsy revealed profound disintegration of Z-discs with extensive accumulation of granular debris and large inclusions within fibers. We demonstrated profound alterations in BAG3 distribution as the protein localized to long filamentous structures present across the fibers that were positively stained not only for α-actinin but also for desmin and filamin indicating that those disintegrated Z-disc regions contained also other sarcomeric proteins. The mutation caused a decrease in the content of BAG3 and HSP70, and also of α-actinin desmin, filamin and fast myosin heavy chain, confirming its severe effect on the muscle fiber morphology and thus function. We provide further evidence that BAG3 is associated with Z-disc maintenance, and the Pro209Leu mutation may occur worldwide. We also provide a summary of cases associated with this mutation reported so far.

Circadian profile of QT interval and QT interval variability in 172 healthy volunteers

DEFF Research Database (Denmark)

Bonnemeier, Hendrik; Wiegand, Uwe K H; Braasch, Wiebke

2003-01-01

of sleep. QT and R-R intervals revealed a characteristic day-night-pattern. Diurnal profiles of QT interval variability exhibited a significant increase in the morning hours (6-9 AM; P ... lower at day- and nighttime. Aging was associated with an increase of QT interval mainly at daytime and a significant shift of the T wave apex towards the end of the T wave. The circadian profile of ventricular repolarization is strongly related to the mean R-R interval, however, there are significant...

Dynamic QT Interval Changes from Supine to Standing in Healthy Children.

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Dionne, Audrey; Fournier, Anne; Dahdah, Nagib; Abrams, Dominic; Khairy, Paul; Abadir, Sylvia

2018-01-01

QT-interval variations in response to exercise-induced increases in heart rate have been reported in children and adults in the diagnosis of long QT syndrome (LQTS). A quick standing challenge has been proposed as an alternative provocative test in adults, with no pediatric data yet available. A standing test was performed in 100 healthy children (mean age, 9.7 ± 3.1 years) after 10 minutes in a supine position with continuous electrocardiographic recording. QT intervals were measured at baseline, at maximal heart rate, at maximal QT, and at each minute of a 5-minute recovery while standing. Measurements were taken in leads II/V 5 and were corrected for heart rate (QTc). On standing, the heart rate increased by 29 ± 10 beats per minute (bpm). The QT interval was similar at baseline and on standing (394 ± 34 ms vs 394 ± 34 ms; P = 1.0). However, QTc increased from 426 ± 21 to 509 ± 41 ms (P < 0.001). The 95th percentile for QTc at baseline and maximal heart rate was 457 ms and 563 ms, respectively. At 1 minute of recovery, the QT interval was shorter (375 ± 31 ms) compared with baseline (394 ± 34 ms; P < 0.001) and standing (394 ± 34 ms; P < 0.001). QTc reached baseline values after 1 minute of recovery and remained stable thereafter (423 ± 23 ms at 1 minute; 426 ± 22 ms at 5 minutes; P = 1.0). This first characterization of QTc changes on standing in children shows substantial alterations, which are greater than those seen in adults. Two-thirds of the children would have been misclassified as having LQTS by adult criteria, indicating the need to create child-specific standards. Copyright © 2017 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

Variant of Coffin-Siris syndrome or previously undescribed syndrome?

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Braun-Quentin, C; Kapferer, L; Kotzot, D

1996-09-06

We describe a 23-year-old woman with growth and mental retardation, hypoplasia of the nails and distal phalanges, particularly of the fifth fingers and toes, hirsutism, and a "coarse" face with large mouth and large tongue, and bushy eyebrows. Follow-up from birth to adulthood showed that developmental delay and hypoplasia of nails and distal phalanges are permanent signs. Sparse scalp hair, hypotonia, and feeding difficulties were present in early infancy. Later, growth retardation, hirsutism, and a "coarse" face with midface hypoplasia, broad nose, and large mouth became more impressive. Differential diagnosis includes a number of conditions, particularly Coffin-Siris syndrome, which is the most likely but not completely convincing diagnosis. Therefore, this woman might represent a variant of Coffin-Siris syndrome or a new entity.

Quality of drug label information on QT interval prolongation

DEFF Research Database (Denmark)

Warnier, Miriam J; Holtkamp, Frank A; Rutten, Frans H

2014-01-01

BACKGROUND: Information regarding QT-prolongation in the drug label may vary between products. This could lead to suboptimal risk minimization strategies. OBJECTIVE: To systematically assess the variation in the extent and content of information on QT prolongation in the summary of product......-prolongation'/'QT-prolongation') and the advice on cautionary measures pertaining to QT-prolongation in the label were examined, as well as their association. RESULTS: Of the 175 screened products, 44 contained information on QT in the SPC ('no QT-prolongation': 23%, 'unclear drug-QT association': 43%, 'possibly QT-prolongation': 16%, 'QT......-prolongation': 18%). 62% contained advices to act with caution in patients with additional risk factors for QT-prolongation. Products that more likely to have QT-prolonging properties according to the SPC provided more information on QT-prolongation in the SPC ('no prolongation': 10% and for the category 'QT...

Qt 5 blueprints

CERN Document Server

Huang, Symeon

2015-01-01

If you are a programmer looking for a truly cross-platform GUI framework to help you save your time by side-stepping the incompatibility between different platforms and building applications using Qt 5 for multiple targets, then this book is most certainly intended for you. It is assumed that you have a basic programming experience of C++ and fundamental knowledge about Qt.

ANKRD11 variants cause variable clinical features associated with KBG syndrome and Coffin–Siris-like syndrome

Science.gov (United States)

Miyatake, Satoko; Okamoto, Nobuhiko; Stark, Zornitza; Nabetani, Makoto; Tsurusaki, Yoshinori; Nakashima, Mitsuko; Miyake, Noriko; Mizuguchi, Takeshi; Ohtake, Akira; Saitsu, Hirotomo; Matsumoto, Naomichi

2017-01-01

KBG syndrome (KBGS) is an autosomal dominant multiple congenital anomaly-intellectual disability syndrome, characterized by developmental delay with neurological involvements, macrodontia of the upper central incisors, characteristic facial dysmorphism and skeletal anomalies. Variants in ANKRD11 cause KBGS. We present five individuals from four families with ANKRD11 variants identified by whole-exome sequencing. Four of the five were clinically affected, and their diagnoses were varied. One was typical KBGS, two were Coffin–Siris syndrome-like (CSS), and one was intellectual disability with infantile spasms. One individual showed extremely mild phenotype. All individuals fulfilled the proposed diagnostic criteria for KBGS. Phenotypic features overlap between KBGS and CSS to some extent, and characteristic dental and fifth finger/toe findings can indicate differential diagnosis. These findings indicate that patients with ANKRD11 variants occupy a wide spectrum of intellectual disability, including clinically normal individuals. This is the first report highlighting the clinical overlap between KBGS and CSS and supporting the recently proposed clinical concept, in which transcriptional machineries are disrupted. PMID:28250421

ANKRD11 variants cause variable clinical features associated with KBG syndrome and Coffin-Siris-like syndrome.

Science.gov (United States)

Miyatake, Satoko; Okamoto, Nobuhiko; Stark, Zornitza; Nabetani, Makoto; Tsurusaki, Yoshinori; Nakashima, Mitsuko; Miyake, Noriko; Mizuguchi, Takeshi; Ohtake, Akira; Saitsu, Hirotomo; Matsumoto, Naomichi

2017-08-01

KBG syndrome (KBGS) is an autosomal dominant multiple congenital anomaly-intellectual disability syndrome, characterized by developmental delay with neurological involvements, macrodontia of the upper central incisors, characteristic facial dysmorphism and skeletal anomalies. Variants in ANKRD11 cause KBGS. We present five individuals from four families with ANKRD11 variants identified by whole-exome sequencing. Four of the five were clinically affected, and their diagnoses were varied. One was typical KBGS, two were Coffin-Siris syndrome-like (CSS), and one was intellectual disability with infantile spasms. One individual showed extremely mild phenotype. All individuals fulfilled the proposed diagnostic criteria for KBGS. Phenotypic features overlap between KBGS and CSS to some extent, and characteristic dental and fifth finger/toe findings can indicate differential diagnosis. These findings indicate that patients with ANKRD11 variants occupy a wide spectrum of intellectual disability, including clinically normal individuals. This is the first report highlighting the clinical overlap between KBGS and CSS and supporting the recently proposed clinical concept, in which transcriptional machineries are disrupted.

Safety information on QT-interval prolongation

DEFF Research Database (Denmark)

Warnier, Miriam J; Holtkamp, Frank A; Rutten, Frans H

2014-01-01

Prolongation of the QT interval can predispose to fatal ventricular arrhythmias. Differences in QT-labeling language can result in miscommunication and suboptimal risk mitigation. We systematically compared the phraseology used to communicate on QT-prolonging properties of 144 drugs newly approve...

Clinical diagnostic criteria for typical and atypical variants of Rett syndrome in children

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S. Ya. Volgina

2016-01-01

Full Text Available Rett Syndrome is one of the most socially significant neuropsychiatric hereditary diseases in children. This syndrome is mainly found in girls: its frequency is 1:10000–15000. Currently mutations in X-linked gene MESR2 considered as the main cause of the syndrome. Diagnosis of typical and atypical variants of the syndrome is based on the use of clinical criteria, determining gene mutations МЕСР2, CDKL5 and FOXG1. In 2010, the Expert Consortium for Rett syndrome have revised the existing diagnostic criteria for the syndrome and come to a new consensus. If there is a regression of mental development for the diagnosis of Rett syndrome exemplary embodiment only four basic criteria for the diagnosis of atypical variant — two of the four main criteria, and five of the eleven additional criteria. 

Generation of human induced pluripotent stem cell line from a patient with a long QT syndrome type 2

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Azra Fatima

2016-03-01

Full Text Available We report here the generation of human iPS cell line UKKi009-A from dermal fibroblasts of a patient carrying heterozygous mutation c.3035-3045delTCCCTCGATGC, p.Leu1012Pro (fs*55 in KCNH2 gene leading to long QT syndrome type 2 (LQT2. We used the Sleeping Beauty transposon-based plasmids expressing OSKM along with microRNAs 307/367 to reprogram the fibroblasts. The iPS cells possess pluripotent stem cell characteristics and differentiate to cell lineages of all three germ layers. This cell line can serve as a source for in vitro modeling of LQT2. This cell line is distributed by the European Collection of Authenticated Cell Cultures (ECACC.

The prevalence and significance of a short QT interval in 18,825 low-risk individuals including athletes.

Science.gov (United States)

Dhutia, Harshil; Malhotra, Aneil; Parpia, Sameer; Gabus, Vincent; Finocchiaro, Gherardo; Mellor, Greg; Merghani, Ahmed; Millar, Lynne; Narain, Rajay; Sheikh, Nabeel; Behr, Elijah R; Papadakis, Michael; Sharma, Sanjay

2016-01-01

The short QT syndrome is a cardiac channelopathy characterised by accelerated repolarisation which manifests as a short QT interval on the ECG. The definition of a short QT interval is debated, ranging from <390 to ≤320 ms, and its clinical significance in healthy young individuals is unknown. We assessed the prevalence and medium-term significance of an isolated short QT interval in a diverse young British population. Between 2005 and 2013, 18 825 apparently healthy people aged 14-35 years underwent cardiovascular evaluation with history, physical examination and ECG. QT intervals were measured by cardiologists using 4 recommended guidelines (Seattle 2013, Heart Rhythm Society 2013, European Society of Cardiology 2010 and American Heart Association 2009). The prevalence of a short QT interval was 0.1% (26 patients, ≤320 ms), 0.2% (44 patients, ≤330 ms), 7.9% (1478 patients, <380 ms), 15.8% (2973 patients, <390 ms). Male gender and Afro-Caribbean ethnicity had the strongest association with short QT intervals. Athletes had shorter QT intervals than non-athletes but athletic status did not predict short QT intervals. Individuals with short QT intervals ≤320 ms did not report syncope or a sinister family history, and during a follow-up period of 5.3±1.2 years, there were no deaths in this group. The prevalence of a short QT interval depends on the recommended cut-off value. Even at values ≤320 ms, there was an excellent medium-term prognosis among 14 people followed. We conclude that a definition of ≤320 ms is realistic to prevent overdiagnosis and excessive investigations. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Usher syndrome associated with a variant of Dandy-Walker malformation.

Science.gov (United States)

Simsek, Tulay; Ozdamar, Yasemin; Simsek, Enver; Men, Gamze

2010-05-21

Three cases of Usher syndrome associated with a variant of Dandy-Walker malformation in three siblings from consanguineous Turkish parents are described. The siblings had retinitis pigmentosa and hearing loss. Two of the siblings also had mental retardation, which is not a constant finding in Usher syndrome. Dandy-Walker malformation might have contributed to the mental retardation in two of these patients and might be a coincidental finding with Usher syndrome. Copyright 2010, SLACK Incorporated.

Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome.

Science.gov (United States)

Yamamoto, Guilherme Lopes; Aguena, Meire; Gos, Monika; Hung, Christina; Pilch, Jacek; Fahiminiya, Somayyeh; Abramowicz, Anna; Cristian, Ingrid; Buscarilli, Michelle; Naslavsky, Michel Satya; Malaquias, Alexsandra C; Zatz, Mayana; Bodamer, Olaf; Majewski, Jacek; Jorge, Alexander A L; Pereira, Alexandre C; Kim, Chong Ae; Passos-Bueno, Maria Rita; Bertola, Débora Romeo

2015-06-01

Noonan syndrome is an autosomal dominant, multisystemic disorder caused by dysregulation of the RAS/mitogen activated protein kinase (MAPK) pathway. Heterozygous, pathogenic variants in 11 known genes account for approximately 80% of cases. The identification of novel genes associated with Noonan syndrome has become increasingly challenging, since they might be responsible for very small fractions of the cases. A cohort of 50 Brazilian probands negative for pathogenic variants in the known genes associated with Noonan syndrome was tested through whole-exome sequencing along with the relatives in the familial cases. Families from the USA and Poland with mutations in the newly identified genes were included subsequently. We identified rare, segregating or de novo missense variants in SOS2 and LZTR1 in 4% and 8%, respectively, of the 50 Brazilian probands. SOS2 and LZTR1 variants were also found to segregate in one American and one Polish family. Notably, SOS2 variants were identified in patients with marked ectodermal involvement, similar to patients with SOS1 mutations. We identified two novel genes, SOS2 and LZTR1, associated with Noonan syndrome, thereby expanding the molecular spectrum of RASopathies. Mutations in these genes are responsible for approximately 3% of all patients with Noonan syndrome. While SOS2 is a natural candidate, because of its homology with SOS1, the functional role of LZTR1 in the RAS/MAPK pathway is not known, and it could not have been identified without the large pedigrees. Additional functional studies are needed to elucidate the role of LZTR1 in RAS/MAPK signalling and in the pathogenesis of Noonan syndrome. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Cardiovascular Effects of Energy Drinks in Familial Long QT Syndrome: A Randomized Cross-Over Study.

Science.gov (United States)

Gray, Belinda; Ingles, Jodie; Medi, Caroline; Driscoll, Timothy; Semsarian, Christopher

2017-03-15

Caffeinated energy drinks may trigger serious cardiac effects. The aim of this study was to determine the cardiovascular effects of caffeinated energy drink consumption in patients with familial long QT syndrome (LQTS). From 2014-2016, 24 LQTS patients aged 16-50 years were recruited to a randomized, double-blind, cross-over study of energy drink (ED) versus control (CD) with participants acting as their own controls (one week washout). The primary study outcome was an increase in corrected QT interval (QTc) by >20ms. Secondary outcomes were changes in systolic and diastolic blood pressure. In 24 patients with LQTS (no dropout), mean age was 29±9 years, 13/24 (54%) were female, and 8/24 (33%) were probands. Intention to treat analysis revealed no significant change in QTc with ED compared with CD (12±28ms vs 16±27ms, 3% vs 4%, p=0.71). The systolic and diastolic blood pressure significantly increased with ED compared to CD (peak change 7±16mmHg vs 1±16mmHg, 6% vs 0.8%, p=0.046 and 8±10 vs 2±9mmHg, 11% vs 3% p=0.01 respectively). These changes correlated with significant increases in serum caffeine (14.6±11.3 vs 0.5±0.1μmol/L, penergy drink consumption. Caffeinated energy drinks have significant haemodynamic effects in patients with LQTS, especifically an acute increase in blood pressure. Since dangerous QTc prolongation was seen in some LQTS patients, we recommend caution in young patients with LQTS consuming energy drinks. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Novel variant in the TP63 gene associated to ankyloblepharon-ectodermal dysplasia-cleft lip/palate (AEC) syndrome.

Science.gov (United States)

Gonzalez, Francisco; Loidi, Lourdes; Abalo-Lojo, Jose M

2017-01-01

Ankyloblepharon-ectodermal dysplasia-cleft lip/palate (AEC) syndrome is a disorder resulting from anomalous embryonic development of ectodermal tissues. There is evidence that AEC syndrome is caused by mutations in the TP63 gene, which encodes the p63 protein. This is an important regulatory protein involved in epidermal proliferation and differentiation. Genome sequencing was performed in DNA from peripheral blood leukocytes of a newborn with AEC syndrome and her parents. Variants were searched in all coding exons and intron-exon boundaries of the TP63 gene. A heterozygous missense variant (NM_003722.4:c.1063G>C (p.Asp355His) was found in the newborn patient. No variants were found in either of the parents. We identified a previously unreported variant in TP63 gene which seems to be involved in the somatic malformations found in the AEC syndrome. The absence of this variant in both parents suggests that the variant appeared de novo.

Long QT syndrome: an emerging role for inflammation and immunity

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Pietro Enea eLazzerini

2015-05-01

Full Text Available The Long QT Syndrome (LQTS, classified as congenital or acquired, is a multi-factorial disorder of myocardial repolarization predisposing to life-threatening ventricular arrhythmias, particularly torsades de pointes. In the latest years inflammation and immunity have been increasingly recognized as novel factors crucially involved in modulating ventricular repolarization. In the present paper we critically review the available information on this topic, also analyzing putative mechanisms and potential interplays with the other etiologic factors, either acquired and inherited.Accumulating data indicate inflammatory activation as a potential cause of acquired LQTS. The putative underlying mechanisms are complex but essentially cytokine-mediated, including both direct actions on cardiomyocyte ion channels expression and function, and indirect effects resulting from an increased central nervous system sympathetic drive on the heart. Autoimmunity represents another recently arising cause of acquired LQTS. Indeed, increasing evidence demonstrates that autoantibodies may affect myocardial electric properties by directly cross-reacting with the cardiomyocyte and interfering with specific ion currents as a result of molecular mimicry mechanisms. Intriguingly, recent data suggest that inflammation and immunity may be also involved in modulating the clinical expression of congenital forms of LQTS, possibly triggering or enhancing electrical instability in patients who already are genetically predisposed to arrhythmias. In this view, targeting immuno-inflammatory pathways may in the future represent an attractive therapeutic approach in a number of LQTS patients, thus opening new exciting avenues in antiarrhythmic therapy.

Lynch syndrome associated with two MLH1 promoter variants and allelic imbalance of MLH1 expression.

Science.gov (United States)

Hesson, Luke B; Packham, Deborah; Kwok, Chau-To; Nunez, Andrea C; Ng, Benedict; Schmidt, Christa; Fields, Michael; Wong, Jason W H; Sloane, Mathew A; Ward, Robyn L

2015-06-01

Lynch syndrome is a hereditary cancer syndrome caused by a constitutional mutation in one of the mismatch repair genes. The implementation of predictive testing and targeted preventative surveillance is hindered by the frequent finding of sequence variants of uncertain significance in these genes. We aimed to determine the pathogenicity of previously reported variants (c.-28A>G and c.-7C>T) within the MLH1 5'untranslated region (UTR) in two individuals from unrelated suspected Lynch syndrome families. We investigated whether these variants were associated with other pathogenic alterations using targeted high-throughput sequencing of the MLH1 locus. We also determined their relationship to gene expression and epigenetic alterations at the promoter. Sequencing revealed that the c.-28A>G and c.-7C>T variants were the only potentially pathogenic alterations within the MLH1 gene. In both individuals, the levels of transcription from the variant allele were reduced to 50% compared with the wild-type allele. Partial loss of expression occurred in the absence of constitutional epigenetic alterations within the MLH1 promoter. We propose that these variants may be pathogenic due to constitutional partial loss of MLH1 expression, and that this may be associated with intermediate penetrance of a Lynch syndrome phenotype. Our findings provide further evidence of the potential importance of noncoding variants in the MLH1 5'UTR in the pathogenesis of Lynch syndrome. © 2015 The Authors. **Human Mutation published by Wiley Periodicals, Inc.

A sibship with a mild variant of Zellweger syndrome

NARCIS (Netherlands)

Barth, P. G.; Schutgens, R. B.; Wanders, R. J.; Heymans, H. S.; Moser, A. E.; Moser, H. W.; Bleeker-Wagemakers, E. M.; Jansonius-Schultheiss, K.; Derix, M.; Nelck, G. F.

1987-01-01

A mild variant of Zellweger (cerebro-hepato-renal) syndrome was diagnosed in male and female siblings aged 7 and 2 years. They had mild facial dysmorphia, moderate psychomotor retardation, tapetoretinal degeneration, sensorineural deafness and hepatomegaly. Ultrastructural examination of a liver

The analysis of QT interval and repolarization morphology of the heart in chronic exposure to lead.

Science.gov (United States)

Kiełtucki, J; Dobrakowski, M; Pawlas, N; Średniawa, B; Boroń, M; Kasperczyk, S

2017-10-01

There are no common recommendations regarding electrocardiographic monitoring in occupationally exposed workers. Therefore, the present study was designed to investigate whether exposure to lead results in an increase of selected electrocardiography (ECG) pathologies, such as QT interval prolongation and repolarization disorders, in occupationally exposed workers. The study group included 180 workers occupationally exposed to lead compounds. The exposed group was divided according to the median of the mean blood lead level (PbB mean ) calculated based on a series of measurements performed during 5-year observation period (35 µg/dl) into two subgroups: low exposure (LE, PbB mean = 20.0-35.0 µg/dl) and high exposure (HE, PbB mean = 35.1-46.4 µg/dl). The control group consisted of 69 healthy workers without occupational exposure to lead. ECG evaluation included the analysis of heart rate (HR), QT interval and repolarization abnormalities. Mean QT interval was significantly greater in the exposed population than in the control group by 2%. In the HE group, mean QT interval was significantly greater than in the control group by 4% and significantly different from those noted in the LE group. Positive correlations between QT interval and lead exposure indices were also reported. Besides, there was a negative correlation between HR and blood lead level. Increased concentration of lead in the blood above 35 μg/dl is associated with the QT interval prolongation, which may trigger arrhythmias when combined with other abnormalities, such as long QT syndrome. Therefore, electrocardiographic evaluation should be a part of a routine monitoring of occupationally exposed populations.

Complex aberrant splicing in the induced pluripotent stem cell-derived cardiomyocytes from a patient with long-QT syndrome carrying KCNQ1-A344Aspl mutation.

Science.gov (United States)

Wuriyanghai, Yimin; Makiyama, Takeru; Sasaki, Kenichi; Kamakura, Tsukasa; Yamamoto, Yuta; Hayano, Mamoru; Harita, Takeshi; Nishiuchi, Suguru; Chen, Jiarong; Kohjitani, Hirohiko; Hirose, Sayako; Yokoi, Fumika; Gao, Jingshan; Chonabayashi, Kazuhisa; Watanabe, Ken; Ohno, Seiko; Yoshida, Yoshinori; Kimura, Takeshi; Horie, Minoru

2018-05-29

Long-QT syndrome type 1 (LQT1) is caused by mutations in KCNQ1, which encodes the α-subunit of the slow delayed rectifier potassium current (I Ks ) channel. We previously reported that a synonymous mutation, c.1032G>A, p.A344Aspl in KCNQ1 is most commonly identified in the genotyped LQT1 Japanese patients, and the aberrant splicing was analyzed in the lymphocytes isolated from patients' blood samples. However, the mechanisms underlying the observed processes in human cardiomyocytes remains unclear. To establish and analyze patient-specific human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) model carrying KCNQ1-A344Aspl. We generated hiPSCs from the peripheral blood mononuclear cells obtained from an LQT1 patient carrying KCNQ1-A344Aspl. Using the differentiated cardiomyocytes, we analyzed splicing variants and performed electrophysiological studies. We identified seven aberrant RNA variants in A344Aspl-hiPSC-CMs, more complex compared with those in the peripheral lymphocytes. Multi-electrode array analysis revealed that 1 μM isoproterenol significantly prolonged the duration of corrected field potential in A344Aspl-hiPSC-CMs, compared with that in the controls. Additionally, 100 nM E-4031, I Kr blocker, was shown to induce early afterdepolarization-like waveforms in A344Aspl-hiPSC-CMs. Action potential durations (APDs) did not significantly differ between the hiPSC-CM groups. After administrating 500 nM isoproterenol, APDs of A344Aspl-hiPSC-CMs were significantly longer than those of the controls. ML277 and phenylboronic acid, I Ks activators, ameliorated the APDs of hiPSC-CMs. We identified complex aberrant mRNA variants in the A344Aspl-hiPSC-CM model, and successfully recapitulated the clinical phenotypes of the patient with concealed LQT1. This model allows the investigation of the underlying mechanisms and development of novel therapies. Copyright © 2018. Published by Elsevier Inc.

Reconstruction of action potential of repolarization in patients with congenital long-QT syndrome

International Nuclear Information System (INIS)

Kandori, Akihiko; Shimizu, Wataru; Yokokawa, Miki; Kamakura, Shiro; Miyatake, Kunio; Murakami, Masahiro; Miyashita, Tsuyoshi; Ogata, Kuniomi; Tsukada, Keiji

2004-01-01

A method for reconstructing an action potential during the repolarization period was developed. This method uses a current distribution-plotted as a current-arrow map (CAM)-calculated using magnetocardiogram (MCG) signals. The current arrows are summarized during the QRS complex period and subtracted during the ST-T wave period in order to reconstruct the action-potential waveform. To ensure the similarity between a real action potential and the reconstructed action potential using CAM, a monophasic action potential (MAP) and an MCG of the same patient with type-I long-QT syndrome were measured. Although the MAP had one notch that was associated with early afterdepolarization (EAD), the reconstructed action potential had two large and small notches. The small notch timing agreed with the occurrence of the EAD in the MAP. On the other hand, the initiation time of an abnormal current distribution coincides with the appearance timing of the first large notch, and its end time coincides with that of the second small notch. These results suggest that a simple reconstruction method using a CAM based on MCG data can provide a similar action-potential waveform to a MAP waveform without having to introduce a catheter

A CACNA1C variant associated with reduced voltage-dependent inactivation, increased CaV1.2 channel window current, and arrhythmogenesis.

Directory of Open Access Journals (Sweden)

Jessica A Hennessey

Full Text Available Mutations in CACNA1C that increase current through the CaV1.2 L-type Ca2+ channel underlie rare forms of long QT syndrome (LQTS, and Timothy syndrome (TS. We identified a variant in CACNA1C in a male child of Filipino descent with arrhythmias and extracardiac features by candidate gene sequencing and performed functional expression studies to electrophysiologically characterize the effects of the variant on CaV1.2 channels. As a baby, the subject developed seizures and displayed developmental delays at 30 months of age. At age 5 years, he displayed a QTc of 520 ms and experienced recurrent VT. Physical exam at 17 years of age was notable for microcephaly, short stature, lower extremity weakness and atrophy with hyperreflexia, spastic diplegia, multiple dental caries and episodes of rhabdomyolysis. Candidate gene sequencing identified a G>C transversion at position 5731 of CACNA1C (rs374528680 predicting a glycine>arginine substitution at residue 1911 (p.G1911R of CaV1.2. The allele frequency of this variant is 0.01 in Malays, but absent in 984 Caucasian alleles and in the 1000 genomes project. In electrophysiological analyses, the variant decreased voltage-dependent inactivation, thus causing a gain of function of CaV1.2. We also observed a negative shift of V1/2 of activation and positive shift of V1/2 of channel inactivation, resulting in an increase of the window current. Together, these suggest a gain-of-function effect on CaV1.2 and suggest increased susceptibility for arrhythmias in certain clinical settings. The p.G1911R variant was also identified in a case of sudden unexplained infant death (SUID, for which an increasing number of clinical observations have demonstrated can be associated with arrhythmogenic mutations in cardiac ion channels. In summary, the combined effects of the CACNA1C variant to diminish voltage-dependent inactivation of CaV1.2 and increase window current expand our appreciation of mechanisms by which a gain of

Multiple cranial neuropathies without limb involvements: guillain-barre syndrome variant?

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Yu, Ju Young; Jung, Han Young; Kim, Chang Hwan; Kim, Hyo Sang; Kim, Myeong Ok

2013-10-01

Acute multiple cranial neuropathies are considered as variant of Guillain-Barre syndrome, which are immune-mediated diseases triggered by various cases. It is a rare disease which is related to infectious, inflammatory or systemic diseases. According to previous case reports, those affected can exhibit almost bilateral facial nerve palsy, then followed by bulbar dysfunctions (cranial nerves IX and X) accompanied by limb weakness and walking difficulties due to motor and/or sensory dysfunctions. Furthermore, reported cases of the acute multiple cranial neuropathies show electrophysiological abnormalities compatible with the typical Guillain-Barre syndromes (GBS). We recently experienced a patient with a benign infectious disease who subsequently developed symptoms of variant GBS. Here, we describe the case of a 48-year-old male patient who developed multiple symptoms of cranial neuropathy without limb weakness. His laboratory findings showed a positive result for anti-GQ1b IgG antibody. As compared with previously described variants of GBS, the patient exhibited widespread cranial neuropathy, which included neuropathies of cranial nerves III-XII, without limb involvement or ataxia.

Assessment of the predictive accuracy of five in silico prediction tools, alone or in combination, and two metaservers to classify long QT syndrome gene mutations.

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Leong, Ivone U S; Stuckey, Alexander; Lai, Daniel; Skinner, Jonathan R; Love, Donald R

2015-05-13

Long QT syndrome (LQTS) is an autosomal dominant condition predisposing to sudden death from malignant arrhythmia. Genetic testing identifies many missense single nucleotide variants of uncertain pathogenicity. Establishing genetic pathogenicity is an essential prerequisite to family cascade screening. Many laboratories use in silico prediction tools, either alone or in combination, or metaservers, in order to predict pathogenicity; however, their accuracy in the context of LQTS is unknown. We evaluated the accuracy of five in silico programs and two metaservers in the analysis of LQTS 1-3 gene variants. The in silico tools SIFT, PolyPhen-2, PROVEAN, SNPs&GO and SNAP, either alone or in all possible combinations, and the metaservers Meta-SNP and PredictSNP, were tested on 312 KCNQ1, KCNH2 and SCN5A gene variants that have previously been characterised by either in vitro or co-segregation studies as either "pathogenic" (283) or "benign" (29). The accuracy, sensitivity, specificity and Matthews Correlation Coefficient (MCC) were calculated to determine the best combination of in silico tools for each LQTS gene, and when all genes are combined. The best combination of in silico tools for KCNQ1 is PROVEAN, SNPs&GO and SIFT (accuracy 92.7%, sensitivity 93.1%, specificity 100% and MCC 0.70). The best combination of in silico tools for KCNH2 is SIFT and PROVEAN or PROVEAN, SNPs&GO and SIFT. Both combinations have the same scores for accuracy (91.1%), sensitivity (91.5%), specificity (87.5%) and MCC (0.62). In the case of SCN5A, SNAP and PROVEAN provided the best combination (accuracy 81.4%, sensitivity 86.9%, specificity 50.0%, and MCC 0.32). When all three LQT genes are combined, SIFT, PROVEAN and SNAP is the combination with the best performance (accuracy 82.7%, sensitivity 83.0%, specificity 80.0%, and MCC 0.44). Both metaservers performed better than the single in silico tools; however, they did not perform better than the best performing combination of in silico

Sex Hormones and the QT Interval: A Review

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Sedlak, Tara; Shufelt, Chrisandra; Iribarren, Carlos

2012-01-01

Abstract A prolonged QT interval is a marker for an increased risk of ventricular tachyarrhythmias. Both endogenous and exogenous sex hormones have been shown to affect the QT interval. Endogenous testosterone and progesterone shorten the action potential, and estrogen lengthens the QT interval. During a single menstrual cycle, progesterone levels, but not estrogen levels, have the dominant effect on ventricular repolarization in women. Studies of menopausal hormone therapy (MHT) in the form of estrogen-alone therapy (ET) and estrogen plus progesterone therapy (EPT) have suggested a counterbalancing effect of exogenous estrogen and progesterone on the QT. Specifically, ET lengthens the QT, whereas EPT has no effect. To date, there are no studies on oral contraception (OC) and the QT interval, and future research is needed. This review outlines the current literature on sex hormones and QT interval, including the endogenous effects of estrogen, progesterone, and testosterone and the exogenous effects of estrogen and progesterone therapy in the forms of MHT and hormone contraception. Further, we review the potential mechanisms and pathophysiology of sex hormones on the QT interval. PMID:22663191

Increased frequency of FBN1 truncating and splicing variants in Marfan syndrome patients with aortic events.

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Baudhuin, Linnea M; Kotzer, Katrina E; Lagerstedt, Susan A

2015-03-01

Marfan syndrome is a systemic disorder that typically involves FBN1 mutations and cardiovascular manifestations. We investigated FBN1 genotype-phenotype correlations with aortic events (aortic dissection and prophylactic aortic surgery) in patients with Marfan syndrome. Genotype and phenotype information from probands (n = 179) with an FBN1 pathogenic or likely pathogenic variant were assessed. A higher frequency of truncating or splicing FBN1 variants was observed in Ghent criteria-positive patients with an aortic event (n = 34) as compared with all other probands (n = 145) without a reported aortic event (79 vs. 39%; P Marfan syndrome patients with FBN1 truncating and splicing variants.Genet Med 17 3, 177-187.

Cost-effectiveness of genotyping in inherited arrhythmia syndromes: are we getting value for the money?

NARCIS (Netherlands)

Wilde, Arthur A. M.; Pinto, Yigal M.

2009-01-01

Over the last decade, the identification of the diverse genetic basis of most important inherited arrhythmia syndromes has remarkably changed our attitude toward these life-threatening diseases. Just over 10 years ago, long-QT syndrome (LQTS) was considered one disease entity, Brugada -QT syndrome

Variants in SLC18A3, vesicular acetylcholine transporter, cause congenital myasthenic syndrome

NARCIS (Netherlands)

O'Grady, Gina L.; Verschuuren, Corien; Yuen, Michaela; Webster, Richard; Menezes, Manoj; Fock, Johanna M.; Pride, Natalie; Best, Heather A.; Damm, Tatiana Benavides; Turner, Christian; Lek, Monkol; Engel, Andrew G.; North, Kathryn N.; Clarke, Nigel F.; MacArthur, Daniel G.; Kamsteeg, Erik-Jan; Cooper, Sandra T.

2016-01-01

Objective: To describe the clinical and genetic characteristics of presynaptic congenital myasthenic syndrome secondary to biallelic variants in SLC18A3. Methods: Individuals from 2 families were identified with biallelic variants in SLC18A3, the gene encoding the vesicular acetylcholine transporter

ACTG2 variants impair actin polymerization in sporadic Megacystis Microcolon Intestinal Hypoperistalsis Syndrome

NARCIS (Netherlands)

Halim, Danny; Hofstra, Robert M. W.; Signorile, Luca; Verdijk, Rob M.; van der Werf, Christine S.; Sribudiani, Yunia; Brouwer, Rutger W. W.; van IJcken, Wilfred F. J.; Dahl, Niklas; Verheij, Joke B. G. M.; Baumann, Clarisse; Kerner, John; van Bever, Yolande; Galjart, Niels; Wijnen, Rene M. H.; Tibboel, Dick; Burns, Alan J.; Muller, Franoise; Brooks, Alice S.; Alves, Maria M.

2016-01-01

Megacystis Microcolon Intestinal Hypoperistalsis Syndrome (MMIHS) is a rare congenital disorder, in which heterozygous missense variants in the Enteric Smooth Muscle actin gamma-2 (ACTG2) gene have been recently identified. To investigate the mechanism by which ACTG2 variants lead to MMIHS, we

An Integrative Data Science Pipeline to Identify Novel Drug Interactions that Prolong the QT Interval.

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Lorberbaum, Tal; Sampson, Kevin J; Woosley, Raymond L; Kass, Robert S; Tatonetti, Nicholas P

2016-05-01

Drug-induced prolongation of the QT interval on the electrocardiogram (long QT syndrome, LQTS) can lead to a potentially fatal ventricular arrhythmia known as torsades de pointes (TdP). Over 40 drugs with both cardiac and non-cardiac indications are associated with increased risk of TdP, but drug-drug interactions contributing to LQTS (QT-DDIs) remain poorly characterized. Traditional methods for mining observational healthcare data are poorly equipped to detect QT-DDI signals due to low reporting numbers and lack of direct evidence for LQTS. We hypothesized that LQTS could be identified latently using an adverse event (AE) fingerprint of more commonly reported AEs. We aimed to generate an integrated data science pipeline that addresses current limitations by identifying latent signals for QT-DDIs in the US FDA's Adverse Event Reporting System (FAERS) and retrospectively validating these predictions using electrocardiogram data in electronic health records (EHRs). We trained a model to identify an AE fingerprint for risk of TdP for single drugs and applied this model to drug pair data to predict novel DDIs. In the EHR at Columbia University Medical Center, we compared the QTc intervals of patients prescribed the flagged drug pairs with patients prescribed either drug individually. We created an AE fingerprint consisting of 13 latently detected side effects. This model significantly outperformed a direct evidence control model in the detection of established interactions (p = 1.62E-3) and significantly enriched for validated QT-DDIs in the EHR (p = 0.01). Of 889 pairs flagged in FAERS, eight novel QT-DDIs were significantly associated with prolonged QTc intervals in the EHR and were not due to co-prescribed medications. Latent signal detection in FAERS validated using the EHR presents an automated and data-driven approach for systematically identifying novel QT-DDIs. The high-confidence hypotheses flagged using this method warrant further investigation.

The prognostic value of the QT interval and QT interval dispersion in all-cause and cardiac mortality and morbidity in a population of Danish citizens.

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Elming, H; Holm, E; Jun, L; Torp-Pedersen, C; Køber, L; Kircshoff, M; Malik, M; Camm, J

1998-09-01

To evaluate the prognostic value of the QT interval and QT interval dispersion in total and in cardiovascular mortality, as well as in cardiac morbidity, in a general population. The QT interval was measured in all leads from a standard 12-lead ECG in a random sample of 1658 women and 1797 men aged 30-60 years. QT interval dispersion was calculated from the maximal difference between QT intervals in any two leads. All cause mortality over 13 years, and cardiovascular mortality as well as cardiac morbidity over 11 years, were the main outcome parameters. Subjects with a prolonged QT interval (430 ms or more) or prolonged QT interval dispersion (80 ms or more) were at higher risk of cardiovascular death and cardiac morbidity than subjects whose QT interval was less than 360 ms, or whose QT interval dispersion was less than 30 ms. Cardiovascular death relative risk ratios, adjusted for age, gender, myocardial infarct, angina pectoris, diabetes mellitus, arterial hypertension, smoking habits, serum cholesterol level, and heart rate were 2.9 for the QT interval (95% confidence interval 1.1-7.8) and 4.4 for QT interval dispersion (95% confidence interval 1.0-19-1). Fatal and non-fatal cardiac morbidity relative risk ratios were similar, at 2.7 (95% confidence interval 1.4-5.5) for the QT interval and 2.2 (95% confidence interval 1.1-4.0) for QT interval dispersion. Prolongation of the QT interval and QT interval dispersion independently affected the prognosis of cardiovascular mortality and cardiac fatal and non-fatal morbidity in a general population over 11 years.

Expression defect size among unclassified MLH1 variants determines pathogenicity in Lynch syndrome diagnosis

DEFF Research Database (Denmark)

Hinrichsen, Inga; Brieger, Angela; Trojan, Jörg

2013-01-01

Lynch syndrome is caused by a germline mutation in a mismatch repair gene, most commonly the MLH1 gene. However, one third of the identified alterations are missense variants with unclear clinical significance. The functionality of these variants can be tested in the laboratory, but the results...

QT Interval in Pregnant and Non-pregnant Women

Directory of Open Access Journals (Sweden)

Majid Zamani

2014-03-01

Full Text Available Introduction: Prolongation of QT interval might result in dangerous cardiac arrhythmias, including Torsades de Pointes (TdP, consequently leading to syncope or death. A limited number of studies carried out in this respect to date have shown that QT interval might increase during pregnancy. On the other hand, it has been shown that each pregnancy might result in an increase in the risk of cardiac accidents in patients with long QT interval. Therefore, the present study was undertaken to compare QT intervals in pregnant and non-pregnant women. Methods: Pregnant women group consisted of 40 women in the second and third trimesters of pregnancy and the non-pregnant control group consisted of healthy women 18-35 years of age. All the patients underwent standard 12-lead electrocardiogram (ECG. The QT interval was measured for each patient at lead II. The mean corrected QT interval (QTc and QT dispersions (QTd were compared between the two groups. Results: Mean heart rates in the pregnant and non-pregnant groups were 98.55±14.09 and 72.53±13.17 beats/minutes (P<0.001. QTd and QTc means were in the normal range in both groups; however, these variables were 49.50±12.80 and 43.03±18.47 milliseconds in the pregnant group and 39.5±9.59 and 40.38±17.20 milliseconds in the control group, respectively (P<0.001. Conclusion: The QT interval was longer in pregnant women compared to non-pregnant women; however, it was in the normal range in both groups. Therefore, it is important to monitor and manage risk factors involved in prolongation of QT interval and prevent concurrence of these factors with pregnancy.

QT dynamics during treatment with sertindole

DEFF Research Database (Denmark)

Nielsen, Jimmi; Wang, Fan; Graff, Claus

2015-01-01

be revealed by dynamic measures of the QT interval such as the ratio of QT variability to heart rate variability (variability ratio [VR]). The aim of this study was to investigate the effect of sertindole on QT dynamics. METHODS: QTc and the VR were assessed in an observational study using 24-hour Holter...... monitoring at baseline and after 3 weeks of treatment with sertindole 16 mg. The VR was calculated by dividing the standard deviation of QT intervals with the standard deviation of heart rates. Outcome measures were compared using paired t-test. RESULTS: A total of 18 patients participated in the study, two...... were excluded from further analysis due to low amplitude of the T-wave. When patients were shifted to sertindole, the VR increased from 0.192 (SD 0.045) to 0.223 (SD 0.061), p = 0.02. The QTcF interval increased from 388 (SD 16) to 403 ms (SD 14), p = 0.002. There was no difference in heart rate 78 bpm...

Arrhythmia phenotype in mouse models of human long QT.

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Salama, Guy; Baker, Linda; Wolk, Robert; Barhanin, Jacques; London, Barry

2009-03-01

Enhanced dispersion of repolarization (DR) was proposed as a unifying mechanism, central to arrhythmia genesis in the long QT (LQT) syndrome. In mammalian hearts, K(+) channels are heterogeneously expressed across the ventricles resulting in 'intrinsic' DR that may worsen in long QT. DR was shown to be central to the arrhythmia phenotype of transgenic mice with LQT caused by loss of function of the dominant mouse K(+) currents. Here, we investigated the arrhythmia phenotype of mice with targeted deletions of KCNE1 and KCNH2 genes which encode for minK/IsK and Merg1 (mouse homolog of human ERG) proteins resulting in loss of function of I(Ks) and I(Kr), respectively. Both currents are important human K(+) currents associated with LQT5 and LQT2. Loss of minK, a protein subunit that interacts with KvLQT1, results in a marked reduction of I(Ks) giving rise to the Jervell and Lange-Nielsen syndrome and the reduced KCNH2 gene reduces MERG and I(Kr). Hearts were perfused, stained with di-4-ANEPPS and optically mapped to compare action potential durations (APDs) and arrhythmia phenotype in homozygous minK (minK(-/-)) and heterozygous Merg1 (Merg(+/-)) deletions and littermate control mice. MinK(-/-) mice has similar APDs and no arrhythmias (n = 4). Merg(+/-) mice had prolonged APDs (from 20 +/- 6 to 32 +/- 9 ms at the base, p mice (60% vs. 10%). A comparison of mouse models of LQT based on K(+) channel mutations important to human and mouse repolarization emphasizes DR as a major determinant of arrhythmia vulnerability.

Ophthalmoplegic and lower cranial nerve variants merge into each other and into classical Guillain-Barre syndrome

NARCIS (Netherlands)

ter Bruggen, JP; van der Meche, FGA; de Jager, AEJ; Polman, CH

We delineated the place of cranial nerve variants within the concept of clinically defined Guillain-Barre syndrome (GBS), In the ophthalmoplegic variant (n = 7) the oculomotor nerves were early involved, In a lower cranial nerve variant (n = 9) the cranial nerves IX, X, and XI were early involved.

QT interval in healthy dogs: which method of correcting the QT interval in dogs is appropriate for use in small animal clinics?

Directory of Open Access Journals (Sweden)

Maira S. Oliveira

2014-05-01

Full Text Available The electrocardiography (ECG QT interval is influenced by fluctuations in heart rate (HR what may lead to misinterpretation of its length. Considering that alterations in QT interval length reflect abnormalities of the ventricular repolarisation which predispose to occurrence of arrhythmias, this variable must be properly evaluated. The aim of this work is to determine which method of correcting the QT interval is the most appropriate for dogs regarding different ranges of normal HR (different breeds. Healthy adult dogs (n=130; German Shepherd, Boxer, Pit Bull Terrier, and Poodle were submitted to ECG examination and QT intervals were determined in triplicates from the bipolar limb II lead and corrected for the effects of HR through the application of three published formulae involving quadratic, cubic or linear regression. The mean corrected QT values (QTc obtained using the diverse formulae were significantly different (ρ<0.05, while those derived according to the equation QTcV = QT + 0.087(1- RR were the most consistent (linear regression. QTcV values were strongly correlated (r=0.83 with the QT interval and showed a coefficient of variation of 8.37% and a 95% confidence interval of 0.22-0.23 s. Owing to its simplicity and reliability, the QTcV was considered the most appropriate to be used for the correction of QT interval in dogs.

Three novel GJB2 (connexin 26) variants associated with autosomal dominant syndromic and nonsyndromic hearing loss.

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DeMille, Desiree; Carlston, Colleen M; Tam, Oliver H; Palumbos, Janice C; Stalker, Heather J; Mao, Rong; Zori, Roberto T; Viskochil, David H; Park, Albert H; Carey, John C

2018-04-01

Connexin 26 (Cx26), encoded by the GJB2 gene, is a key protein involved in the formation of gap junctions in epithelial organs including the inner ear and palmoplantar epidermis. Pathogenic variants in GJB2 are responsible for approximately 50% of inherited sensorineural deafness. The majority of these variants are associated with autosomal recessive inheritance; however, rare reports of dominantly co-segregating variants have been published. Since we began offering GJB2 testing in 2003, only about 2% of detected GJB2 variants from our laboratory have been classified as dominant. Here we report three novel dominant GJB2 variants (p.Thr55Ala, p.Gln57_Pro58delinsHisSer, and p.Trp44Gly); two associated with syndromic sensorineural hearing loss and one with nonsyndromic hearing loss. In the kindred with the p.Thr55Ala variant, the proband and his father present with only leukonychia as a cutaneous finding of their syndromic hearing loss. This phenotype has been previously documented in conjunction with palmoplantar hyperkeratosis, but isolated leukonychia is a novel finding likely associated with the unique threonine to alanine change at codon 55 (other variants at this codon have been reported in cases of nonsyndromic hearing loss). This report contributes to the short list of GJB2 variants associated with autosomal dominant hearing loss, highlights the variability of skin and nail findings associated with such cases, and illustrates the occurrence of both syndromic and nonsyndromic presentations with changes in the same gene. © 2018 Wiley Periodicals, Inc.

Cross-Ethnic meta-Analysis of genetic variants for polycystic ovary syndrome

NARCIS (Netherlands)

Y.V. Louwers (Yvonne); L. Stolk (Lisette); A.G. Uitterlinden (André); J.S.E. Laven (Joop)

2013-01-01

textabstractContext: Genome-wide association studies (GWAS) have revealed new susceptibility loci for Chinese patients with polycystic ovary syndrome (PCOS). Because ethnic background adds to phenotypic diversities in PCOS, it seems plausible that genetic variants associated with PCOS act

The prognostic value of the QT interval and QT interval dispersion in all-cause and cardiac mortality and morbidity in a population of Danish citizens

DEFF Research Database (Denmark)

Elming, H; Holm, E; Jun, L

1998-01-01

with a prolonged QT interval (430 ms or more) or prolonged QT interval dispersion (80 ms or more) were at higher risk of cardiovascular death and cardiac morbidity than subjects whose QT interval was less than 360 ms, or whose QT interval dispersion was less than 30 ms. Cardiovascular death relative risk ratios...

QT measurement and heart rate correction during hypoglycemia

DEFF Research Database (Denmark)

Christensen, Toke Folke; Randløv, Jette; Christensen, Leif Engmann

2010-01-01

induced by intravenous injection of two insulin types in a cross-over design. QT measurements were done using the slope-intersect (SI) and manual annotation (MA) methods. Heart rate correction was done using Bazett's (QTcB) and Fridericia's (QTcF) formulas. Results. The SI method showed significant......Introduction. Several studies show that hypoglycemia causes QT interval prolongation. The aim of this study was to investigate the effect of QT measurement methodology, heart rate correction, and insulin types during hypoglycemia. Methods. Ten adult subjects with type 1 diabetes had hypoglycemia...... prolongation at hypoglycemia for QTcB (42(6) ms; P measuring the QT interval has...

Drug-induced Inhibition and Trafficking Disruption of ion Channels: Pathogenesis of QT Abnormalities and Drug-induced Fatal Arrhythmias

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Cubeddu, Luigi X.

2016-01-01

Risk of severe and fatal ventricular arrhythmias, presenting as Torsade de Pointes (TdP), is increased in congenital and acquired forms of long QT syndromes (LQTS). Drug-induced inhibition of K+ currents, IKs, IKr, IK1, and/or Ito, delay repolarization, prolong QT, and increase the risk of TdP. Drug-induced interference with IKr is the most common cause of acquired LQTS/TdP. Multiple drugs bind to KNCH2-hERG-K+ channels affecting IKr, including antiarrythmics, antibiotics, antivirals, azole-antifungals, antimalarials, anticancer, antiemetics, prokinetics, antipsychotics, and antidepressants. Azithromycin has been recently added to this list. In addition to direct channel inhibition, some drugs interfere with the traffic of channels from the endoplasmic reticulum to the cell membrane, decreasing mature channel membrane density; e.g., pentamidine, geldalamicin, arsenic trioxide, digoxin, and probucol. Other drugs, such as ketoconazole, fluoxetine, norfluoxetine, citalopram, escitalopram, donepezil, tamoxifen, endoxifen, atazanavir, and roxitromycin, induce both direct channel inhibition and impaired channel trafficking. Although many drugs prolong the QT interval, TdP is a rare event. The following conditions increase the risk of drug-induced TdP: a) Disease states/electrolyte levels (heart failure, structural cardiac disease, bradycardia, hypokalemia); b) Pharmacogenomic variables (presence of congenital LQTS, subclinical ion-channel mutations, history of or having a relative with history of drug-induced long QT/TdP); c) Pharmacodynamic and kinetic factors (high doses, women, elderly, metabolism inhibitors, combining two or more QT prolonging drugs, drugs that prolong the QT and increase QT dispersion, and drugs with multiple actions on ion channels). Because most of these conditions are preventable, careful evaluation of risk factors and increased knowledge of drug use associated with repolarization abnormalities are strongly recommended. PMID:26926294

Bullous Variant of Sweet’s Syndrome after Herpes Zoster Virus Infection

OpenAIRE

Yuichiro Endo; Miki Tanioka; Hideaki Tanizaki; Minako Mori; Hiroshi Kawabata; Yoshiki Miyachi

2011-01-01

Aim: Cutaneous manifestations of Sweet’s syndrome (SS) are typically painful plaque-forming erythematous papules, while bullae are quite uncommon. We present a case of bullous variant of SS in acute myeloid leukaemia. In this case, herpes infection of the left mandible had preceded the development of SS. Case Report: A 75-year-old male with myelodysplastic syndrome first presented with herpes zoster virus infection-like bullae and erosive plaques on the left side of the face and neck. Treatme...

The Germline MLH1 K618A Variant and Susceptibility to Lynch Syndrome-Associated Tumors

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Medeiros, Fabiola; Lindor, Noralane M.; Couch, Fergus J.; Highsmith, W. Edward

2013-01-01

Missense variants discovered during sequencing of cancer susceptibility genes can be problematic for clinical interpretation. MLH1 K618A, which results from a 2-bp alteration (AAG→GCG) leading to a substitution of lysine to alanine in codon 618, has variously been interpreted as a pathogenic mutation, a variant of unknown significance, and a benign polymorphism. We evaluated the role of MLH1 K618A in predisposition to cancer by genotyping 1512 control subjects to assess its frequency in the general population. We also reviewed the literature concerning MLH1 K618A in families with colorectal cancer. The measured allele frequency of the K618A variant was 0.40%, which is remarkably close to the 0.44% summarized from 2491 control subjects in the literature. K618A was over-represented in families with suspected Lynch syndrome. In 1366 families, the allele frequency was 0.88% (OR = 2.1, 95% CI = 1.3 to 3.5; P = 0.006). In studies of sporadic cancers of the type associated with Lynch syndrome, K618A was over-represented in 1742 cases (allele frequency of 0.83) (OR = 2.0, 95% CI = 1.2 to 3.2; P = 0.008). We conclude that MLH1 K618A is not a fully penetrant Lynch syndrome mutation, although it is not without effect, appearing to increase the risk of Lynch syndrome-associated tumors approximately twofold. Our systematic assessment approach may be useful for variants in other genes. PMID:22426235

Arima syndrome caused by CEP290 specific variant and accompanied with pathological cilium; clinical comparison with Joubert syndrome and its related diseases.

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Itoh, Masayuki; Ide, Shuhei; Iwasaki, Yuji; Saito, Takashi; Narita, Keishi; Dai, Hongmei; Yamakura, Shinji; Furue, Takeki; Kitayama, Hirotsugu; Maeda, Keiko; Takahashi, Eihiko; Matsui, Kiyoshi; Goto, Yu-Ichi; Takeda, Sen; Arima, Masataka

2018-04-01

Arima syndrome (AS) is a rare disease and its clinical features mimic those of Joubert syndrome or Joubert syndrome-related diseases (JSRD). Recently, we clarified the AS diagnostic criteria and its severe phenotype. However, genetic evidence of AS remains unknown. We explored causative genes of AS and compared the clinical and genetic features of AS with the other JSRD. We performed genetic analyses of 4 AS patients of 3 families with combination of whole-exome sequencing and Sanger sequencing. Furthermore, we studied cell biology with the cultured fibroblasts of 3 AS patients. All patients had a specific homozygous variant (c.6012-12T>A, p.Arg2004Serfs*7) or compound heterozygous variants (c.1711+1G>A; c.6012-12T>A, p.Gly570Aspfs*19;Arg2004Serfs*7) in centrosomal protein 290 kDa (CEP290) gene. These unique variants lead to abnormal splicing and premature termination. Morphological analysis of cultured fibroblasts from AS patients revealed a marked decrease of the CEP290-positive cell number with significantly longer cilium and naked and protruded ciliary axoneme without ciliary membrane into the cytoplasm. AS resulted in cilia dysfunction from centrosome disruption. The unique variant of CEP290 could be strongly linked to AS pathology. Here, we provided AS specific genetic evidence, which steers the structure and functions of centrosome that is responsible for normal ciliogenesis. This is the first report that has demonstrated the molecular basis of Arima syndrome. Copyright © 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Design Scheme of Remote Monitoring System Based on Qt

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Xu Dawei

2015-01-01

Full Text Available This paper introduces a design scheme of remote monitoring system based on Qt, the scheme of remote monitoring system based on S3C2410 and Qt, with the aid of cross platform development tools Qt and powerful ARM platform design and implementation. The development of remote video surveillance system based on embedded terminal has practical significance and value.

QT variability during initial exposure to sotalol

DEFF Research Database (Denmark)

Weeke, Peter; Delaney, Jessica; Mosley, Jonathan D

2013-01-01

A prolonged QT interval is associated with increased risk of Torsades de pointes (TdP) and may be fatal. We sought to investigate the extent to which clinical covariates affect the change in QT interval among 'real-world' patients treated with sotalol and followed in an electronic medical record...

The Static and Dynamic QT/RR Coupling and QT Parameters

Czech Academy of Sciences Publication Activity Database

Halámek, Josef; Jurák, Pavel; Villa, M.; Fráňa, P.; Novák, M.; Lipoldová, J.; Leinveber, P.; Vondra, Vlastimil; Somers, V. K.; Kára, T.

2008-01-01

Roč. 6, č. 1 (2008), s. 533 ISSN 1556-7451. [World Congress on Heart Disease /14./. 26.07.2008-29.07.2008, Toronto] Institutional research plan: CEZ:AV0Z20650511 Keywords : QT parameters Subject RIV: FA - Cardiovascular Disease s incl. Cardiotharic Surgery

Assessing QT interval prolongation and its associated risks with antipsychotics

DEFF Research Database (Denmark)

Nielsen, Jimmi; Graff, Claus; Kanters, Jørgen K.

2011-01-01

markers for TdP have been developed but none of them is clinically implemented yet and QT interval prolongation is still considered the most valid surrogate marker. Although automated QT interval determination may offer some assistance, QT interval determination is best performed by a cardiologist skilled...

Implantable cardioverter-defibrillator explantation for overdiagnosed or overtreated congenital long QT syndrome.

Science.gov (United States)

Gaba, Prakriti; Bos, J Martijn; Cannon, Bryan C; Cha, Yong-Mei; Friedman, Paul A; Asirvatham, Samuel J; Ackerman, Michael J

2016-04-01

Primary treatment of long QT syndrome (LQTS) currently consists of beta-blocker therapy, although an implantable cardioverter-defibrillator (ICD) is considered for high-risk patients. However, both overdiagnosis and overtreatment must be avoided because their sequelae can be significant. The purpose of this study was to evaluate the prevalence and details of ICD explants in a cohort of patients from a tertiary genetic heart rhythm clinic for a previously rendered diagnosis of LQTS. Overall, 1227 consecutive patients were included in the study. All patients had been referred to the Mayo Clinic for evaluation of possible LQTS and subsequently were either diagnosed with LQTS or dismissed as normal. Further stratification of patients was conducted to assess how many patients had an ICD and how many had a subsequent ICD explant. In total, 170 patients (14%) had an ICD, including 157 of 670 patients (23%) with confirmed LQTS and 13 of 557 patients (2%) who did not have LQTS. Among these, 12 of 1227 (1%) had the ICD removed: 7 of 157 LQTS patients (4.5%) compared to 5 of 14 non-LQTS patients (36%). Before explant, 5 of 12 patients (42%) experienced inappropriate shocks, ranging from 2 to as many as 54 shocks. In addition, 4 had a device-related infection, and 9 had device malfunction (including lead dysfunction or fracture). None of these patients had a breakthrough cardiac event since removal of their ICD during 5.5 ± 3.5 years of follow-up. Implications of overdiagnosis and overtreatment are profound because unnecessary ICD placement can be associated with infection, malfunction, inappropriate shocks, and subsequent anxiety. Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

[Association analysis of SNP-63 and indel-19 variant in the calpain-10 gene with polycystic ovary syndrome in women of reproductive age].

Science.gov (United States)

Flores-Martínez, Silvia Esperanza; Castro-Martínez, Anna Gabriela; López-Quintero, Andrés; García-Zapién, Alejandra Guadalupe; Torres-Rodríguez, Ruth Noemí; Sánchez-Corona, José

2015-01-01

Polycystic ovary syndrome is a complex and heterogeneous disease involving both reproductive and metabolic problems. It has been suggested a genetic predisposition in the etiology of this syndrome. The identification of calpain-10 gene (CAPN10) as the first candidate gene for type 2 diabetes mellitus, has focused the interest in investigating their possible relation with the polycystic ovary syndrome, because this syndrome is associated with hyperinsulinemia and insulin resistance, two metabolic abnormalities associated with type 2 diabetes mellitus. To investigate if there is association between the SNP-63 and the variant indel-19 of the CAPN10 gene and polycystic ovary syndrome in women of reproductive age. This study included 101 women (55 with polycystic ovary syndrome and 46 without polycystic ovary syndrome). The genetic variant indel-19 was identified by electrophoresis of the amplified fragments by PCR, and the SNP-63 by PCR-RFLP. The allele and genotype frequencies of the two variants do not differ significatly between women with polycystic ovary syndrome and control women group. The haplotype 21 (defined by the insertion allele of indel-19 variant and C allele of SNP-63) was found with higher frequency in both study groups, being more frequent in the polycystic ovary syndrome patients group, however, this difference was not statistically significant (p = 0.8353). The results suggest that SNP-63 and indel-19 variant of the CAPN10 gene do not represent a risk factor for polycystic ovary syndrome in our patients group. Copyright © 2015. Published by Masson Doyma México S.A.

A novel variant in the SLC12A1 gene in two families with antenatal Bartter syndrome.

Science.gov (United States)

Breinbjerg, Anders; Siggaard Rittig, Charlotte; Gregersen, Niels; Rittig, Søren; Hvarregaard Christensen, Jane

2017-01-01

Bartter syndrome is an autosomal-recessive inherited disease in which patients present with hypokalaemia and metabolic alkalosis. We present two apparently nonrelated cases with antenatal Bartter syndrome type I, due to a novel variant in the SLC12A1 gene encoding the bumetanide-sensitive sodium-(potassium)-chloride cotransporter 2 in the thick ascending limb of the loop of Henle. Blood samples were received from the two cases and 19 of their relatives, and deoxyribonucleic acid was extracted. The coding regions of the SLC12A1 gene were amplified using polymerase chain reaction, followed by bidirectional direct deoxyribonucleic acid sequencing. Each affected child in the two families was homozygous for a novel inherited variant in the SLC12A1gene, c.1614T>A. The variant predicts a change from a tyrosine codon to a stop codon (p.Tyr538Ter). The two cases presented antenatally and at six months of age, respectively. The two cases were homozygous for the same variant in the SLC12A1 gene, but presented clinically at different ages. This could eventually be explained by the presence of other gene variants or environmental factors modifying the phenotypes. The phenotypes of the patients were similar to other patients with antenatal Bartter syndrome. ©2016 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

Genetics Home Reference: Andersen-Tawil syndrome

Science.gov (United States)

... abnormal side-to-side curvature of the spine ( scoliosis ). The signs and symptoms of Andersen-Tawil syndrome ... Information from MedlinePlus (5 links) Diagnostic Tests Drug Therapy Genetic ... from the Nemours Foundation: Arrhythmias Merck Manual Consumer Version: Long QT Syndrome and Torsades de ...

Rare copy number variants identified in prune belly syndrome.

Science.gov (United States)

Boghossian, Nansi S; Sicko, Robert J; Giannakou, Andreas; Dimopoulos, Aggeliki; Caggana, Michele; Tsai, Michael Y; Yeung, Edwina H; Pankratz, Nathan; Cole, Benjamin R; Romitti, Paul A; Browne, Marilyn L; Fan, Ruzong; Liu, Aiyi; Kay, Denise M; Mills, James L

2018-03-01

Prune belly syndrome (PBS), also known as Eagle-Barrett syndrome, is a rare congenital disorder characterized by absence or hypoplasia of the abdominal wall musculature, urinary tract anomalies, and cryptorchidism in males. The etiology of PBS is largely unresolved, but genetic factors are implicated given its recurrence in families. We examined cases of PBS to identify novel pathogenic copy number variants (CNVs). A total of 34 cases (30 males and 4 females) with PBS identified from all live births in New York State (1998-2005) were genotyped using Illumina HumanOmni2.5 microarrays. CNVs were prioritized if they were absent from in-house controls, encompassed ≥10 consecutive probes, were ≥20 Kb in size, had ≤20% overlap with common variants in population reference controls, and had ≤20% overlap with any variant previously detected in other birth defect phenotypes screened in our laboratory. We identified 17 candidate autosomal CNVs; 10 cases each had one CNV and four cases each had two CNVs. The CNVs included a 158 Kb duplication at 4q22 that overlaps the BMPR1B gene; duplications of different sizes carried by two cases in the intron of STIM1 gene; a 67 Kb duplication 202 Kb downstream of the NOG gene, and a 1.34 Mb deletion including the MYOCD gene. The identified rare CNVs spanned genes involved in mesodermal, muscle, and urinary tract development and differentiation, which might help in elucidating the genetic contribution to PBS. We did not have parental DNA and cannot identify whether these CNVs were de novo or inherited. Further research on these CNVs, particularly BMP signaling is warranted to elucidate the pathogenesis of PBS. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Correlation of prolonged QT interval and severity of cirrhosis of liver

International Nuclear Information System (INIS)

Tarique, S.; Sarwar, S.

2011-01-01

To determine correlation between prolonged QT interval and severity of disease in patients of cirrhosis of liver. Study Design: Descriptive cross sectional study. Patients and Methods: One hundred and seventeen patients of cirrhosis were included. Baseline haematological and biochemical parameters were determined. Model for end stage liver disease (MELD) score was determined for all patients to document stage of liver disease. Corrected QT interval was determined from electrocardiography of each patient using QT cirrhosis formula. Correlation between QT interval and MELD score was determined using Pearson correlation and Receiver Operating Characteristic (ROC) curve. Results: One hundred and seventeen included patients had mean age of 53.58 (+- 12.11) while male to female ratio was 1.78/1 (75 / 42). Mean MELD score was 17.08 (+- 6.54) in study patients varying between 6 and 37 while mean corrected QT interval was 0.44 seconds (+- 0.06). Pearson correlation revealed no significant relation between severity of liver disease as determined with MELD score and prolonged QT interval (p value 0.18) Area under curve with ROC curve for correlation between prolonged QT interval and severity of liver disease was 0.42. Conclusion: Prolonged QT interval is not an indicator of severity of disease in cirrhosis of liver. (author)

Pharmacometabolomic approach to predict QT prolongation in guinea pigs.

Directory of Open Access Journals (Sweden)

Jeonghyeon Park

Full Text Available Drug-induced torsades de pointes (TdP, a life-threatening arrhythmia associated with prolongation of the QT interval, has been a significant reason for withdrawal of several medicines from the market. Prolongation of the QT interval is considered as the best biomarker for predicting the torsadogenic risk of a new chemical entity. Because of the difficulty assessing the risk for TdP during drug development, we evaluated the metabolic phenotype for predicting QT prolongation induced by sparfloxacin, and elucidated the metabolic pathway related to the QT prolongation. We performed electrocardiography analysis and liquid chromatography-mass spectroscopy-based metabolic profiling of plasma samples obtained from 15 guinea pigs after administration of sparfloxacin at doses of 33.3, 100, and 300 mg/kg. Principal component analysis and partial least squares modelling were conducted to select the metabolites that substantially contributed to the prediction of QT prolongation. QTc increased significantly with increasing dose (r = 0.93. From the PLS analysis, the key metabolites that showed the highest variable importance in the projection values (>1.5 were selected, identified, and used to determine the metabolic network. In particular, cytidine-5'-diphosphate (CDP, deoxycorticosterone, L-aspartic acid and stearic acid were found to be final metabolomic phenotypes for the prediction of QT prolongation. Metabolomic phenotypes for predicting drug-induced QT prolongation of sparfloxacin were developed and can be applied to cardiac toxicity screening of other drugs. In addition, this integrative pharmacometabolomic approach would serve as a good tool for predicting pharmacodynamic or toxicological effects caused by changes in dose.

Novel and rare functional genomic variants in multiple autoimmune syndrome and Sjögren's syndrome.

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Johar, Angad S; Mastronardi, Claudio; Rojas-Villarraga, Adriana; Patel, Hardip R; Chuah, Aaron; Peng, Kaiman; Higgins, Angela; Milburn, Peter; Palmer, Stephanie; Silva-Lara, Maria Fernanda; Velez, Jorge I; Andrews, Dan; Field, Matthew; Huttley, Gavin; Goodnow, Chris; Anaya, Juan-Manuel; Arcos-Burgos, Mauricio

2015-06-02

Multiple autoimmune syndrome (MAS), an extreme phenotype of autoimmune disorders, is a very well suited trait to tackle genomic variants of these conditions. Whole exome sequencing (WES) is a widely used strategy for detection of protein coding and splicing variants associated with inherited diseases. The DNA of eight patients affected by MAS [all of whom presenting with Sjögren's syndrome (SS)], four patients affected by SS alone and 38 unaffected individuals, were subject to WES. Filters to identify novel and rare functional (pathogenic-deleterious) homozygous and/or compound heterozygous variants in these patients and controls were applied. Bioinformatics tools such as the Human gene connectome as well as pathway and network analysis were applied to test overrepresentation of genes harbouring these variants in critical pathways and networks involved in autoimmunity. Eleven novel and rare functional variants were identified in cases but not in controls, harboured in: MACF1, KIAA0754, DUSP12, ICA1, CELA1, LRP1/STAT6, GRIN3B, ANKLE1, TMEM161A, and FKRP. These were subsequently subject to network analysis and their functional relatedness to genes already associated with autoimmunity was evaluated. Notably, the LRP1/STAT6 novel mutation was homozygous in one MAS affected patient and heterozygous in another. LRP1/STAT6 disclosed the strongest plausibility for autoimmunity. LRP1/STAT6 are involved in extracellular and intracellular anti-inflammatory pathways that play key roles in maintaining the homeostasis of the immune system. Further; networks, pathways, and interaction analyses showed that LRP1 is functionally related to the HLA-B and IL10 genes and it has a substantial impact within immunological pathways and/or reaction to bacterial and other foreign proteins (phagocytosis, regulation of phospholipase A2 activity, negative regulation of apoptosis and response to lipopolysaccharides). Further, ICA1 and STAT6 were also closely related to AIRE and IRF5, two very

High Prevalence of Long QT Syndrome Associated SCN5A Variants in Patients with Early-Onset Lone Atrial Fibrillation

DEFF Research Database (Denmark)

Olesen, Morten S; Yuan, Lei; Liang, Bo

2012-01-01

a mechanistic overlap between LQTS3 and early-onset lone AF. In 9 of 10 identified mutations and rare variants, we observed compromised biophysical properties affecting the transient peak current. CONCLUSIONS: In a cohort of patients with early-onset lone AF, we identified a high prevalence of SCN5A mutations...

New population-based exome data question the pathogenicity of some genetic variants previously associated with Marfan syndrome

DEFF Research Database (Denmark)

Yang, Ren-Qiang; Jabbari, Javad; Cheng, Xiao-Shu

2014-01-01

BACKGROUND: Marfan syndrome (MFS) is a rare autosomal dominantly inherited connective tissue disorder with an estimated prevalence of 1:5,000. More than 1000 variants have been previously reported to be associated with MFS. However, the disease-causing effect of these variants may be questionable...

A brainstem variant of reversible posterior leukoencephalopathy syndrome

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Kitaguchi, H.; Tomimoto, H.; Terada, K. [Kyoto University, Department of Neurology, Graduate School of Medicine, Sakyo-ku, Kyoto (Japan); Miki, Y.; Yamamoto, A. [Kyoto University, Department of Nuclear Medicine and Diagnostic Imaging, Graduate School of Medicine, Sakyo-ku, Kyoto (Japan); Satoi, H.; Kanda, M. [Ijinkai Takeda General Hospital, Department of Neurology, Fushimi-ku, Kyoto (Japan); Fukuyama, H. [Kyoto University, Human Brain Research Center, Graduate School of Medicine, Sakyo-ku, Kyoto (Japan)

2005-09-01

Reversible posterior leukoencephalopathy syndrome (RPLS) is caused by various heterogeneous factors, the commonest being hypertension, followed by nonhypertensive causes such as eclampsia, renal diseases and immunosuppressive therapy. Patients with RPLS exhibit bilateral white and gray matter abnormalities in the posterior aspects of the cerebral hemispheres. However, this syndrome may affect the brainstem predominantly, and these cases are designated as hypertensive brainstem encephalopathy. We present here two patients with reversible brainstem encephalopathy: one with hypertension and the other without hypertension. These patients presented with swelling and diffuse hyperintensities of the brainstem in fluid-attenuated inversion-recovery (FLAIR) and T2-weighted MRI, but with relatively mild clinical symptoms. They recovered without major neurological deficits, but had residual lacunar lesions in the pons. Reversible brainstem encephalopathy with characteristic MRI features was found in both hypertensive and nonhypertensive patients. These patients were diagnosed with a brainstem variant of RPLS, which is potentially fully reversible after an adequate treatment, and therefore should be carefully differentiated from other brainstem disease conditions. (orig.)

A brainstem variant of reversible posterior leukoencephalopathy syndrome

International Nuclear Information System (INIS)

Kitaguchi, H.; Tomimoto, H.; Terada, K.; Miki, Y.; Yamamoto, A.; Satoi, H.; Kanda, M.; Fukuyama, H.

2005-01-01

Reversible posterior leukoencephalopathy syndrome (RPLS) is caused by various heterogeneous factors, the commonest being hypertension, followed by nonhypertensive causes such as eclampsia, renal diseases and immunosuppressive therapy. Patients with RPLS exhibit bilateral white and gray matter abnormalities in the posterior aspects of the cerebral hemispheres. However, this syndrome may affect the brainstem predominantly, and these cases are designated as hypertensive brainstem encephalopathy. We present here two patients with reversible brainstem encephalopathy: one with hypertension and the other without hypertension. These patients presented with swelling and diffuse hyperintensities of the brainstem in fluid-attenuated inversion-recovery (FLAIR) and T2-weighted MRI, but with relatively mild clinical symptoms. They recovered without major neurological deficits, but had residual lacunar lesions in the pons. Reversible brainstem encephalopathy with characteristic MRI features was found in both hypertensive and nonhypertensive patients. These patients were diagnosed with a brainstem variant of RPLS, which is potentially fully reversible after an adequate treatment, and therefore should be carefully differentiated from other brainstem disease conditions. (orig.)

Sequence variants of the DFNB31 gene among Usher syndrome patients of diverse origin

Science.gov (United States)

Aller, Elena; Jaijo, Teresa; van Wijk, Erwin; Ebermann, Inga; Kersten, Ferry; García-García, Gema; Voesenek, Krysta; Aparisi, María José; Hoefsloot, Lies; Cremers, Cor; Díaz-Llopis, Manuel; Pennings, Ronald; Bolz, Hanno J.; Kremer, Hannie; Millán, José M.

2010-01-01

Purpose It has been demonstrated that mutations in deafness, autosomal recessive 31 (DFNB31), the gene encoding whirlin, is responsible for nonsyndromic hearing loss (NSHL; DFNB31) and Usher syndrome type II (USH2D). We screened DFNB31 in a large cohort of patients with different clinical subtypes of Usher syndrome (USH) to determine the prevalence of DFNB31 mutations among USH patients. Methods DFNB31 was screened in 149 USH2, 29 USH1, six atypical USH, and 11 unclassified USH patients from diverse ethnic backgrounds. Mutation detection was performed by direct sequencing of all coding exons. Results We identified 38 different variants among 195 patients. Most variants were clearly polymorphic, but at least two out of the 15 nonsynonymous variants (p.R350W and p.R882S) are predicted to impair whirlin structure and function, suggesting eventual pathogenicity. No putatively pathogenic mutation was found in the second allele of patients with these mutations. Conclusions DFNB31 is not a major cause of USH. PMID:20352026

Truncating variants in the majority of the cytoplasmic domain of PCDH15 are unlikely to cause Usher syndrome 1F.

Science.gov (United States)

Perreault-Micale, Cynthia; Frieden, Alexander; Kennedy, Caleb J; Neitzel, Dana; Sullivan, Jessica; Faulkner, Nicole; Hallam, Stephanie; Greger, Valerie

2014-11-01

Loss of function variants in the PCDH15 gene can cause Usher syndrome type 1F, an autosomal recessive disease associated with profound congenital hearing loss, vestibular dysfunction, and retinitis pigmentosa. The Ashkenazi Jewish population has an increased incidence of Usher syndrome type 1F (founder variant p.Arg245X accounts for 75% of alleles), yet the variant spectrum in a panethnic population remains undetermined. We sequenced the coding region and intron-exon borders of PCDH15 using next-generation DNA sequencing technology in approximately 14,000 patients from fertility clinics. More than 600 unique PCDH15 variants (single nucleotide changes and small indels) were identified, including previously described pathogenic variants p.Arg3X, p.Arg245X (five patients), p.Arg643X, p.Arg929X, and p.Arg1106X. Novel truncating variants were also found, including one in the N-terminal extracellular domain (p.Leu877X), but all other novel truncating variants clustered in the exon 33 encoded C-terminal cytoplasmic domain (52 patients, 14 variants). One variant was observed predominantly in African Americans (carrier frequency of 2.3%). The high incidence of truncating exon 33 variants indicates that they are unlikely to cause Usher syndrome type 1F even though many remove a large portion of the gene. They may be tolerated because PCDH15 has several alternate cytoplasmic domain exons and differentially spliced isoforms may function redundantly. Effects of some PCDH15 truncating variants were addressed by deep sequencing of a panethnic population. Copyright © 2014 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

Cryo-EM Structure of a KCNQ1/CaM Complex Reveals Insights into Congenital Long QT Syndrome.

Science.gov (United States)

Sun, Ji; MacKinnon, Roderick

2017-06-01

KCNQ1 is the pore-forming subunit of cardiac slow-delayed rectifier potassium (I Ks ) channels. Mutations in the kcnq1 gene are the leading cause of congenital long QT syndrome (LQTS). Here, we present the cryoelectron microscopy (cryo-EM) structure of a KCNQ1/calmodulin (CaM) complex. The conformation corresponds to an "uncoupled," PIP 2 -free state of KCNQ1, with activated voltage sensors and a closed pore. Unique structural features within the S4-S5 linker permit uncoupling of the voltage sensor from the pore in the absence of PIP 2 . CaM contacts the KCNQ1 voltage sensor through a specific interface involving a residue on CaM that is mutated in a form of inherited LQTS. Using an electrophysiological assay, we find that this mutation on CaM shifts the KCNQ1 voltage-activation curve. This study describes one physiological form of KCNQ1, depolarized voltage sensors with a closed pore in the absence of PIP 2 , and reveals a regulatory interaction between CaM and KCNQ1 that may explain CaM-mediated LQTS. Copyright © 2017 Elsevier Inc. All rights reserved.

High incidence of recurrent copy number variants in patients with isolated and syndromic Müllerian aplasia.

Science.gov (United States)

Nik-Zainal, Serena; Strick, Reiner; Storer, Mekayla; Huang, Ni; Rad, Roland; Willatt, Lionel; Fitzgerald, Tomas; Martin, Vicki; Sandford, Richard; Carter, Nigel P; Janecke, Andreas R; Renner, Stefan P; Oppelt, Patricia G; Oppelt, Peter; Schulze, Christine; Brucker, Sara; Hurles, Matthew; Beckmann, Matthias W; Strissel, Pamela L; Shaw-Smith, Charles

2011-03-01

Congenital malformations involving the Müllerian ducts are observed in around 5% of infertile women. Complete aplasia of the uterus, cervix, and upper vagina, also termed Müllerian aplasia or Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome, occurs with an incidence of around 1 in 4500 female births, and occurs in both isolated and syndromic forms. Previous reports have suggested that a proportion of cases, especially syndromic cases, are caused by variation in copy number at different genomic loci. In order to obtain an overview of the contribution of copy number variation to both isolated and syndromic forms of Müllerian aplasia, copy number assays were performed in a series of 63 cases, of which 25 were syndromic and 38 isolated. A high incidence (9/63, 14%) of recurrent copy number variants in this cohort is reported here. These comprised four cases of microdeletion at 16p11.2, an autism susceptibility locus not previously associated with Müllerian aplasia, four cases of microdeletion at 17q12, and one case of a distal 22q11.2 microdeletion. Microdeletions at 16p11.2 and 17q12 were found in 4/38 (10.5%) cases with isolated Müllerian aplasia, and at 16p11.2, 17q12 and 22q11.2 (distal) in 5/25 cases (20%) with syndromic Müllerian aplasia. The finding of microdeletion at 16p11.2 in 2/38 (5%) of isolated and 2/25 (8%) of syndromic cases suggests a significant contribution of this copy number variant alone to the pathogenesis of Müllerian aplasia. Overall, the high incidence of recurrent copy number variants in all forms of Müllerian aplasia has implications for the understanding of the aetiopathogenesis of the condition, and for genetic counselling in families affected by it.

Imaging findings in the rare catastrophic variant of the primary antiphospholipid syndrome

Energy Technology Data Exchange (ETDEWEB)

Thuerl, Christina; Altehoefer, Carsten; Laubenberger, Joerg [Freiburg Univ. (Germany). Abt. Radiologie; Spyridonidis, Alexandros [Freiburg Univ. (DE). Abt. Innere Medizin 1 (Haematologie und Onkologie)

2002-03-01

We report imaging findings in a case of the rare catastrophic variant of antiphospholipid syndrome (CAPS) characterized by widespread microvascular occlusions, which may lead to multiple organ failure. We present a case of a 66-year-old woman with bone marrow necrosis, acute acalculous cholecystitis (AAC), focal liver necrosis, subtle patchy splenic infarctions, and bilateral adrenal infarction. The demonstration of multiple microvascular organ involvement (three or more) is crucial for the diagnosis of the catastrophic variant of APS. This can be performed radiologically intra-vitam. Imaging can even reveal subclinical microinfarctions, which are often only diagnosed at autopsy. (orig.)

Imaging findings in the rare catastrophic variant of the primary antiphospholipid syndrome

International Nuclear Information System (INIS)

Thuerl, Christina; Altehoefer, Carsten; Laubenberger, Joerg

2002-01-01

We report imaging findings in a case of the rare catastrophic variant of antiphospholipid syndrome (CAPS) characterized by widespread microvascular occlusions, which may lead to multiple organ failure. We present a case of a 66-year-old woman with bone marrow necrosis, acute acalculous cholecystitis (AAC), focal liver necrosis, subtle patchy splenic infarctions, and bilateral adrenal infarction. The demonstration of multiple microvascular organ involvement (three or more) is crucial for the diagnosis of the catastrophic variant of APS. This can be performed radiologically intra-vitam. Imaging can even reveal subclinical microinfarctions, which are often only diagnosed at autopsy. (orig.)

Relationship Between Two Common Lipoprotein Lipase Variants and the Metabolic Syndrome and Its Individual Components

DEFF Research Database (Denmark)

Vishram, Julie K. K.; Hansen, Tine W; Torp-Pedersen, Christian

2016-01-01

BACKGROUND: Common lipoprotein lipase (LPL) variants are important determinants of triglycerides (TG) and high-density lipoprotein (HDL) cholesterol (C) concentrations. High TG/low HDL-C tend to cluster with hypertension, glucose intolerance, and abdominal obesity and comprise the metabolic...... syndrome (MetS). The role of LPL variants as a cause of MetS is unclear. This study investigated the relationship between two common LPL variants and the presence of MetS and its individual components. METHODS: Cross-sectional study, including 2348 Danish women (50.7%) and men, age 41-72 years, without...

The effect of esmolol on corrected-QT interval, corrected-QT interval dispersion changes seen during anesthesia induction in hypertensive patients taking an angiotensin-converting enzyme inhibitor

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Zahit Çeker

2015-02-01

Full Text Available BACKGROUND AND OBJECTIVES: The importance of minimizing the exaggerated sympatho-adrenergic responses and QT interval and QT interval dispersion changes that may develop due to laryngoscopy and tracheal intubation during anesthesia induction in the hypertensive patients is clear. Esmolol decreases the hemodynamic response to laryngoscopy and intubation. However, the effect of esmolol in decreasing the prolonged QT interval and QT interval dispersion as induced by laryngoscopy and intubation is controversial. We investigated the effect of esmolol on the hemodynamic, and corrected-QT interval and corrected-QT interval dispersion changes seen during anesthesia induction in hypertensive patients using angiotensin converting enzyme inhibitors. METHODS: 60 ASA I-II patients, with essential hypertension using angiotensin converting enzyme inhibitors were included in the study. The esmolol group received esmolol at a bolus dose of 500 mcg/kg followed by a 100 mcg/kg/min infusion which continued until the 4th min after intubation. The control group received 0.9% saline similar to the esmolol group. The mean blood pressure, heart rate values and the electrocardiogram records were obtained as baseline values before the anesthesia, 5 min after esmolol and saline administration, 3 min after the induction and 30 s, 2 min and 4 min after intubation. RESULTS: The corrected-QT interval was shorter in the esmolol group (p = 0.012, the corrected-QT interval dispersion interval was longer in the control group (p = 0.034 and the mean heart rate was higher in the control group (p = 0.022 30 s after intubation. The risk of arrhythmia frequency was higher in the control group in the 4-min period following intubation (p = 0.038. CONCLUSION: Endotracheal intubation was found to prolong corrected-QT interval and corrected-QT interval dispersion, and increase the heart rate during anesthesia induction with propofol in hypertensive patients using angiotensin converting

Диспластические синдромы и фенотипы в оценке изменений интервала QT при малых аномалиях сердца

Directory of Open Access Journals (Sweden)

А. В. Ягода

2011-01-01

Full Text Available To assess relation of dysplastic syndromes and phenotypes to pathological QT interval in patients with minor cardiac anomalies, 128 patients aged 18–35 years were examined. A statistically significant increase in the prevalence of QT interval disorder was found. Pathological QT interval without clinical features was observed more frequently. Correlations were revealed between the QT interval disorder and myxomatous mitral valve prolapse, phenotype similar to Marfan syndrome, and benign joints hypermobility.

Psychotropic Pharmacotherapy Associated With QT Prolongation Among Veterans With Posttraumatic Stress Disorder.

Science.gov (United States)

Stock, Eileen M; Zeber, John E; McNeal, Catherine J; Banchs, Javier E; Copeland, Laurel A

2018-04-01

In 2012, the Food and Drug Administration issued Drug Safety Communications on several drugs associated with QT prolongation and fatal ventricular arrhythmias. Among these was citalopram, a selective serotonin reuptake inhibitor (SSRI) approved for depression and commonly used for posttraumatic stress disorder (PTSD). Evaluation of the risk for QT prolongation among other psychotropic drugs for individuals with PTSD remains limited. Explore psychotropic drugs associated with QT prolongation among veterans with PTSD. Patients in the Veterans Health Administration in 2006-2009 with PTSD and QT prolongation (176 cases) were matched 1:4 on age, gender, visit date and setting, and physical comorbidity. Classification trees assessed QT prolongation risk among prescribed medications (n=880). Receipt of any drug with known risk of QT prolongation varied by group (23% QT cases vs 15% control, prisks included ziprasidone (3% vs 1%, p=0.02) and buspirone (6% vs 2%, p=0.01). Increased risk was not observed for the SSRIs, citalopram and fluoxetine. Classification trees found that sotalol and amitriptyline carried greater risk among cardiac patients and methadone, especially if prescribed with quetiapine, among noncardiac patients. Per adjusted survival model, patients with QT prolongation were at increased risk for death (hazard ratio=1.60; 95% CI=1.04-2.44). Decision models are particularly advantageous when exploring nonlinear relationships or nonadditive interactions. These findings may potentially affect clinical decision-making concerning treatment for PTSD. For patients at higher risk of QT prolongation, antidepressants other than amitriptyline should be considered. Medications for comorbid conditions should also be closely monitored for heightened QT prolongation risk.

Multiple Cranial Neuropathies Without Limb Involvements: Guillain-Barre Syndrome Variant?

OpenAIRE

Yu, Ju Young; Jung, Han Young; Kim, Chang Hwan; Kim, Hyo Sang; Kim, Myeong Ok

2013-01-01

Acute multiple cranial neuropathies are considered as variant of Guillain-Barre syndrome, which are immune-mediated diseases triggered by various cases. It is a rare disease which is related to infectious, inflammatory or systemic diseases. According to previous case reports, those affected can exhibit almost bilateral facial nerve palsy, then followed by bulbar dysfunctions (cranial nerves IX and X) accompanied by limb weakness and walking difficulties due to motor and/or sensory dysfunction...

Boosted protease inhibitors and the electrocardiographic measures of QT and PR durations

DEFF Research Database (Denmark)

Soliman, Elsayed Z; Lundgren, Jens D; Roediger, Mollie P

2011-01-01

There are contradictory reports regarding the effects of protease inhibitors on the ECG measures of QT and PR interval durations. The effect of interrupting use of protease inhibitors on QT and PR progression is also unknown.......There are contradictory reports regarding the effects of protease inhibitors on the ECG measures of QT and PR interval durations. The effect of interrupting use of protease inhibitors on QT and PR progression is also unknown....

Molecular Background of Colorectal Tumors From Patients with Lynch Syndrome Associated With Germline Variants in PMS2.

Science.gov (United States)

Ten Broeke, S W; van Bavel, T C; Jansen, A M L; Gómez-García, E; Hes, F J; van Hest, L P; Letteboer, T G W; Olderode-Berends, M J W; Ruano, D; Spruijt, L; Suerink, M; Tops, C M; van Eijk, R; Morreau, H; van Wezel, T; Nielsen, M

2018-05-11

Germline variants in the mismatch repair genes MLH1, MSH2 (EPCAM), MSH6, or PMS2 cause Lynch syndrome. Patients with these variants have an increased risk of developing colorectal cancers (CRCs) that differ from sporadic CRCs in genetic and histologic features. It has been a challenge to study CRCs associated with PMS2 variants (PMS2-associated CRCs) because these develop less frequently and in patients of older ages than colorectal tumors with variants in the other mismatch repair genes. We analyzed 20 CRCs associated with germline variants in PMS2, 22 sporadic CRCs, 18 CRCs with germline variants in MSH2, and 24 CRCs from patients with germline variants in MLH1. Tumor tissue blocks were collected from Dutch pathology departments in 2017. After extraction of tumor DNA, we used a platform designed to detect approximately 3000 somatic hotspot variants in 55 genes (including KRAS, APC, CTNNB1, and TP53). Somatic variant frequencies were compared using the Fisher's exact test. None of the PMS2-associated CRCs contained any somatic variants in the catenin beta 1 gene (CTNNB1), which encodes β-catenin, whereas 14/24 MLH1-associated CRCs (58%) contained variants in CTNNB1. Half of PMS2-associated CRCs contained KRAS variants, but only 20% of these were in hotspots that encoded G12D or G13D. These hotspot variants occurred more frequently in CRCs associated with variants in MLH1 (37.5%, P=.44) and MSH2 (and 71.4%, P=.035) than with variants in PMS2. In a genetic analysis of 84 colorectal tumors, we found tumors from patients with PMS2-associated Lynch syndrome to be distinct from colorectal tumors associated with defects in other mismatch repair genes. This might account for differences in development and less frequent occurrence. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

Gene variants of unknown clinical significance in Lynch syndrome. An introduction for clinicians

NARCIS (Netherlands)

Sijmons, Rolf H.; Greenblatt, Marc S.; Genuardi, Maurizio

Clinicians referring patients for genetic testing for Lynch syndrome will sooner or later receive results for DNA Mismatch Repair (MMR) genes reporting DNA changes that are unclear from a clinical point of view. These changes are referred to as variants of unknown, or unclear, clinical significance

Pharmacological activation of Kv11.1 in transgenic long QT-1 rabbits

DEFF Research Database (Denmark)

Bentzen, Bo Hjorth; Bahrke, Sophia; Wu, Kezhong

2011-01-01

Transgenic rabbits expressing pore mutants of K(V)7.1 display a long QT syndrome 1 (LQT1) phenotype. Recently, NS1643 has been described to increase I(Kr).We hypothesized that NS1643 would shorten the action potential duration (APD(90)) in LQT1 rabbits. Transgenic LQT1 rabbits were compared...... with littermate control (LMC) rabbits. In vivo electrocardiogram studies in sedated animals were performed at baseline and during 45 minutes of intravenous infusion of NS1643 or vehicle in a crossover design. Ex vivo monophasic action potentials were recorded from Langendorff-perfused hearts at baseline...

[The effect of esmolol on corrected-QT interval, corrected-QT interval dispersion changes seen during anesthesia induction in hypertensive patients taking an angiotensin-converting enzyme inhibitor].

Science.gov (United States)

Ceker, Zahit; Takmaz, Suna Akın; Baltaci, Bülent; Başar, Hülya

2015-01-01

The importance of minimizing the exaggerated sympatho-adrenergic responses and QT interval and QT interval dispersion changes that may develop due to laryngoscopy and tracheal intubation during anesthesia induction in the hypertensive patients is clear. Esmolol decreases the hemodynamic response to laryngoscopy and intubation. However, the effect of esmolol in decreasing the prolonged QT interval and QT interval dispersion as induced by laryngoscopy and intubation is controversial. We investigated the effect of esmolol on the hemodynamic, and corrected-QT interval and corrected-QT interval dispersion changes seen during anesthesia induction in hypertensive patients using angiotensin converting enzyme inhibitors. 60 ASA I-II patients, with essential hypertension using angiotensin converting enzyme inhibitors were included in the study. The esmolol group received esmolol at a bolus dose of 500mcg/kg followed by a 100mcg/kg/min infusion which continued until the 4th min after intubation. The control group received 0.9% saline similar to the esmolol group. The mean blood pressure, heart rate values and the electrocardiogram records were obtained as baseline values before the anesthesia, 5min after esmolol and saline administration, 3min after the induction and 30s, 2min and 4min after intubation. The corrected-QT interval was shorter in the esmolol group (p=0.012), the corrected-QT interval dispersion interval was longer in the control group (p=0.034) and the mean heart rate was higher in the control group (p=0.022) 30s after intubation. The risk of arrhythmia frequency was higher in the control group in the 4-min period following intubation (p=0.038). Endotracheal intubation was found to prolong corrected-QT interval and corrected-QT interval dispersion, and increase the heart rate during anesthesia induction with propofol in hypertensive patients using angiotensin converting enzyme inhibitors. These effects were prevented with esmolol (500mcg/kg bolus, followed by

Mixed Bartter-Gitelman syndrome: an inbred family with a heterogeneous phenotype expression of a novel variant in the CLCNKB gene.

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Al-Shibli, Amar; Yusuf, Madinah; Abounajab, Issam; Willems, Patrick J

2014-01-01

Patients with renal diseases associated with salt-losing tubulopathies categorized as Gitelman and classic form of Bartter syndrome have undergone genetic screening for possible mutation capture in two different genes: SLC12A3 and CLCNKB. Clinical symptoms of these two diseases may overlap. Bartter syndrome and Gitelman syndrome are autosomal recessive salt-losing tubulopathies with hypokalemia, metabolic alkalosis, hyperreninemia, hyperplasia of the juxtaglomerular apparatus, hyperaldosteronism, and, in some patients, hypomagnesemia. Here we describe four patients from an inbred family with a novel missense variant in the CLCNKB gene. All of patients are asymptomatic; yet they have the typical metabolic abnormality of salt losing tubulopathies. One of those patients had hypomagnesaemia while others not. Clinical and laboratory data of all patients was described. All 4 patients have a homozygous c.490G > T missense variant in exon 5 of the CLCNKB gene. This variant alters a glycine into a cysteine on amino acid position 164 of the resulting protein (p.Gly164Cys). The c.490G > T variant is a novel variant not previously described in other patients nor controls. Polyphen analysis predicts the variation to be possibly damaging. Analysis of SLC12A3 was normal. Here in we are describing a novel homozygous c.490G > T missense variation was identified in exon 5 of the CLCNKB gene was identified in an Emirati patients with a mild manifestation of Bartter - Gitelman syndrome.

High prevalence of genetic variants previously associated with Brugada syndrome in new exome data

DEFF Research Database (Denmark)

Risgaard, B; Jabbari, R; Refsgaard, L

2013-01-01

More than 300 variants in 12 genes have been associated with Brugada syndrome (BrS) which has a prevalence ranging between 1:2000 and 1:100,000. Until recently, there has been little knowledge regarding the distribution of genetic variations in the general population. This problem was partly solved......, when exome data from the NHLI GO Exome Sequencing Project (ESP) was published. In this study, we aimed to report the prevalence of previously BrS-associated variants in the ESP population. We performed a search in ESP for variants previously associated with BrS. In addition, four variants in ESP were...... to a surprisingly high genotype prevalence of 1:23 (274:6258). Genotyping the four common ESP-derived variants CACNA2D1 S709N, SCN5A F2004L, CACNB2 S143F, and CACNB2 T450I in the Danish controls, we found a genotype prevalence comparable with that found in ESP. We suggest that exome data are used in research...

Co-Prescription of QT-Interval Prolonging Drugs: An Analysis in a Large Cohort of Geriatric Patients.

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Simone Schächtele

Full Text Available Drug-induced QT-interval prolongation is associated with occurrence of potentially fatal Torsades de Pointes arrhythmias (TdP. So far, data regarding the overall burden of QT-interval prolonging drugs (QT-drugs in geriatric patients are limited.This study was performed to assess the individual burden of QT-interval prolonging drugs (QT-drugs in geriatric polymedicated patients and to identify the most frequent and risky combinations of QT-drugs.In the discharge medication of geriatric patients between July 2009 and June 2013 from the Geriatrics in Bavaria-Database (GiB-DAT (co-prescriptions of QT-drugs were investigated. QT-drugs were classified according to a publicly available reference site (CredibleMeds® as ALL-QT-drugs (associated with any QT-risk or High-risk-QT-drugs (corresponding to QT-drugs with known risk of Torsades de Pointes according to CredibleMeds® and in addition as SmPC-high-risk-QT-drugs (according to the German prescribing information (SmPC contraindicated co-prescription with other QT-drugs.Of a cohort of 130,434 geriatric patients (mean age 81 years, 67% women, prescribed a median of 8 drugs, 76,594 patients (58.7% received at least one ALL-QT-drug. Co-prescriptions of two or more ALL-QT-drugs were observed in 28,768 (22.1% patients. Particularly risky co-prescriptions of High-risk-QT-drugs or SmPC-high-risk-QT-drugs with at least on further QT-drug occurred in 55.9% (N = 12,633 and 54.2% (N = 12,429 of these patients, respectively. Consideration of SmPCs (SmPC-high-risk-QT-drugs allowed the identification of an additional 15% (N = 3,999 patients taking a risky combination that was not covered by the commonly used CredibleMeds® classification. Only 20 drug-drug combinations accounted for more than 90% of these potentially most dangerous co-prescriptions.In a geriatric study population co-prescriptions of two and more QT-drugs were common. A considerable proportion of QT-drugs with higher risk only could be detected by

A Rare Form of Guillan Barre Syndrome: A Child Diagnosed with Anti-GD1a and Anti-GD1b Positive Pharyngeal-Cervical-Brachial Variant

OpenAIRE

Uysalol, Metin; Tatlı, Burak; Uzel, Nedret; Çıtak, Agop; Aygün, Erhan; Kayaoğlu, Semra

2013-01-01

Background: Pharyngeal-cervical-brachial (PCB) variant is a rare form of Guillan-Barre Syndrome (GBS). Antibodies against other membrane proteins like GM1b and GD1a have been found only in a small number of patients with Guillan Barre syndrome variant. Case Report: Here, we report a 5.5 year-old boy diagnosed early with positive GD1a and GD1b gangliosides of Guillan-Barre syndrome pharyngeal cervical-Brachial variant, who improved and recovered fully in a short period. This is in co...

A Rare Form of Guillan Barre Syndrome: A Child Diagnosed with Anti-GD1a and Anti-GD1b Positive Pharyngeal-Cervical-Brachial Variant

OpenAIRE

Uysalol, Metin; Tatlı, Burak; Uzel, Nedret; Çıtak, Agop; Aygün, Erhan; Kayaoğlu, Semra

2014-01-01

Background: Pharyngeal-cervical-brachial (PCB) variant is a rare form of Guillan-Barre Syndrome (GBS). Antibodies against other membrane proteins like GM1b and GD1a have been found only in a small number of patients with Guillan Barre syndrome variant. Case Report: Here, we report a 5.5 year-old boy diagnosed early with positive GD1a and GD1b gangliosides of Guillan-Barre syndrome pharyngeal cervical-Brachial variant, who improved and recovered fully in a short period. This is in cont...

An Overlapping Case of Miller Fisher Syndrome, Bickerstaff’s Encephalitis, and the ASMAN Variant of Guillain-Barre Syndrome

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E. J. Pegg

2016-01-01

Full Text Available A 56-year-old man presented with a 3-day history of progressive tingling of the hands, unsteadiness, and diplopia. He was initially diagnosed clinically with Miller Fisher Syndrome (MFS but later developed limb weakness consistent with Guillain-Barre Syndrome (GBS and subsequently reduced consciousness consistent with Bickerstaff’s brainstem encephalitis (BBE. Neurophysiology revealed an axonal motor and sensory neuropathy, in keeping with the Acute Motor and Sensory Axonal Neuropathy (AMSAN variant of GBS. We believe that our patient had an MFS-AMSAN-BBE overlap syndrome. This is supported by his glycolipid antibody profile with high titres of anti-GQ1b IgG antibody and anti-GD1a IgG antibody. Anti-GQ1b antibodies are frequently found in both MFS and BBE and the anti-GD1a antibody is associated with axonal forms of GBS. Overlapping cases of MFS and BBE are well described, and because the same antibody is often found in both conditions, it is thought that they share a common autoimmune mechanism. BBE has also been previously reported in association with GBS lending support that it also lies on the same spectrum. This overlapping case of ASMAN variant of GBS, MFS, and BBE provides further support that these conditions are part of the same spectrum.

Germline MLH1, MSH2 and MSH6 variants in Brazilian patients with colorectal cancer and clinical features suggestive of Lynch Syndrome.

Science.gov (United States)

Schneider, Nayê Balzan; Pastor, Tatiane; Paula, André Escremim de; Achatz, Maria Isabel; Santos, Ândrea Ribeiro Dos; Vianna, Fernanda Sales Luiz; Rosset, Clévia; Pinheiro, Manuela; Ashton-Prolla, Patricia; Moreira, Miguel Ângelo Martins; Palmero, Edenir Inêz

2018-05-01

Lynch syndrome (LS) is the most common hereditary colorectal cancer syndrome, caused by germline mutations in one of the major genes involved in mismatch repair (MMR): MLH1, MSH2, MSH6 and more rarely, PMS2. Recently, germline deletions in EPCAM have been also associated to the syndrome. Most of the pathogenic MMR mutations found in LS families occur in MLH1 or MSH2. Gene variants include missense, nonsense, frameshift mutations, large genomic rearrangements and splice-site variants and most of the studies reporting the molecular characterization of LS families have been conducted outside South America. In this study, we analyzed 60 unrelated probands diagnosed with colorectal cancer and LS criteria. Testing for germline mutations and/or rearrangements in the most commonly affected MMR genes (MLH1, MSH2, EPCAM and MSH6) was done by Sanger sequencing and MLPA. Pathogenic or likely pathogenic variants were identified in MLH1 or MSH2 in 21 probands (35.0%). Of these, approximately one-third were gene rearrangements. In addition, nine variants of uncertain significance (VUS) were identified in 10 (16.6%) of the sixty probands analyzed. Other four novel variants were identified, only in MLH1. Our results suggest that MSH6 pathogenic variants are not common among Brazilian LS probands diagnosed with CRC and that MMR gene rearrangements account for a significant proportion of the germline variants in this population underscoring the need to include rearrangement analysis in the molecular testing of Brazilian individuals with suspected Lynch syndrome. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

The human Nav1.5 F1486 deletion associated with long QT syndrome leads to impaired sodium channel inactivation and reduced lidocaine sensitivity

Science.gov (United States)

Song, Weihua; Xiao, Yucheng; Chen, Hanying; Ashpole, Nicole M; Piekarz, Andrew D; Ma, Peilin; Hudmon, Andy; Cummins, Theodore R; Shou, Weinian

2012-01-01

The deletion of phenylalanine 1486 (F1486del) in the human cardiac voltage-gated sodium channel (hNav1.5) is associated with fatal long QT (LQT) syndrome. In this study we determined how F1486del impairs the functional properties of hNav1.5 and alters action potential firing in heterologous expression systems (human embryonic kidney (HEK) 293 cells) and their native cardiomyocyte background. Cells expressing hNav1.5-F1486del exhibited a loss-of-function alteration, reflected by an 80% reduction of peak current density, and several gain-of-function alterations, including reduced channel inactivation, enlarged window current, substantial augmentation of persistent late sodium current and an increase in ramp current. We also observed substantial action potential duration (APD) prolongation and prominent early afterdepolarizations (EADs) in neonatal cardiomyocytes expressing the F1486del channels, as well as in computer simulations of myocyte activity. In addition, lidocaine sensitivity was dramatically reduced, which probably contributed to the poor therapeutic outcome observed in the patient carrying the hNav1.5-F1486del mutation. Therefore, despite the significant reduction in peak current density, the F1486del mutation also leads to substantial gain-of-function alterations that are sufficient to cause APD prolongation and EADs, the predominant characteristic of LQTs. These data demonstrate that hNav1.5 mutations can have complex functional consequences and highlight the importance of identifying the specific molecular defect when evaluating potential treatments for individuals with prolonged QT intervals. PMID:22826127

Long QT 1 mutation KCNQ1A344V increases local anesthetic sensitivity of the slowly activating delayed rectifier potassium current

DEFF Research Database (Denmark)

Siebrands, Cornelia C; Binder, Stephan; Eckhoff, Ulrike

2006-01-01

BACKGROUND: Anesthesia in patients with long QT syndrome (LQTS) is a matter of concern. Congenital LQTS is most frequently caused by mutations in KCNQ1 (Kv7.1), whereas drug-induced LQTS is a consequence of HERG (human ether-a-go-go-related gene) channel inhibition. The aim of this study was to i...

Mixed models for data from thorough QT studies: part 2. One-step assessment of conditional QT prolongation.

Science.gov (United States)

Schall, Robert

2011-01-01

We investigate mixed analysis of covariance models for the 'one-step' assessment of conditional QT prolongation. Initially, we consider three different covariance structures for the data, where between-treatment covariance of repeated measures is modelled respectively through random effects, random coefficients, and through a combination of random effects and random coefficients. In all three of those models, an unstructured covariance pattern is used to model within-treatment covariance. In a fourth model, proposed earlier in the literature, between-treatment covariance is modelled through random coefficients but the residuals are assumed to be independent identically distributed (i.i.d.). Finally, we consider a mixed model with saturated covariance structure. We investigate the precision and robustness of those models by fitting them to a large group of real data sets from thorough QT studies. Our findings suggest: (i) Point estimates of treatment contrasts from all five models are similar. (ii) The random coefficients model with i.i.d. residuals is not robust; the model potentially leads to both under- and overestimation of standard errors of treatment contrasts and therefore cannot be recommended for the analysis of conditional QT prolongation. (iii) The combined random effects/random coefficients model does not always converge; in the cases where it converges, its precision is generally inferior to the other models considered. (iv) Both the random effects and the random coefficients model are robust. (v) The random effects, the random coefficients, and the saturated model have similar precision and all three models are suitable for the one-step assessment of conditional QT prolongation. Copyright © 2010 John Wiley & Sons, Ltd.

Malan syndrome: Sotos-like overgrowth with de novo NFIX sequence variants and deletions in six new patients and a review of the literature.

Science.gov (United States)

Klaassens, Merel; Morrogh, Deborah; Rosser, Elisabeth M; Jaffer, Fatima; Vreeburg, Maaike; Bok, Levinus A; Segboer, Tim; van Belzen, Martine; Quinlivan, Ros M; Kumar, Ajith; Hurst, Jane A; Scott, Richard H

2015-05-01

De novo monoallelic variants in NFIX cause two distinct syndromes. Whole gene deletions, nonsense variants and missense variants affecting the DNA-binding domain have been seen in association with a Sotos-like phenotype that we propose is referred to as Malan syndrome. Frameshift and splice-site variants thought to avoid nonsense-mediated RNA decay have been seen in Marshall-Smith syndrome. We report six additional patients with Malan syndrome and de novo NFIX deletions or sequence variants and review the 20 patients now reported. The phenotype is characterised by moderate postnatal overgrowth and macrocephaly. Median height and head circumference in childhood are 2.0 and 2.3 standard deviations (SD) above the mean, respectively. There is overlap of the facial phenotype with NSD1-positive Sotos syndrome in some cases including a prominent forehead, high anterior hairline, downslanting palpebral fissures and prominent chin. Neonatal feeding difficulties and/or hypotonia have been reported in 30% of patients. Developmental delay/learning disability have been reported in all cases and are typically moderate. Ocular phenotypes are common, including strabismus (65%), nystagmus (25% ) and optic disc pallor/hypoplasia (25%). Other recurrent features include pectus excavatum (40%) and scoliosis (25%). Eight reported patients have a deletion also encompassing CACNA1A, haploinsufficiency of which causes episodic ataxia type 2 or familial hemiplegic migraine. One previous case had episodic ataxia and one case we report has had cyclical vomiting responsive to pizotifen. In individuals with this contiguous gene deletion syndrome, awareness of possible later neurological manifestations is important, although their penetrance is not yet clear.

Cardiac channelopathies and sudden infant death syndrome

DEFF Research Database (Denmark)

Tfelt-Hansen, Jacob; Winkel, Bo Gregers; Grunnet, Morten

2011-01-01

Sudden infant death syndrome (SIDS) is always a devastating and unexpected occurrence. SIDS is the leading cause of death in the first 6 months after birth in the industrialized world. Since the discovery in 1998 of long QT syndrome as an underlying substrate for SIDS, around 10-20% of SIDS cases...

Effect of intravenous ondansetron on QT interval prolongation in patients with cardiovascular disease and additional risk factors for torsades: a prospective, observational study

Directory of Open Access Journals (Sweden)

Hafermann MJ

2011-10-01

Full Text Available Matthew J Hafermann1, Rocsanna Namdar2, Gretchen E Seibold2,3, Robert Lee Page 2nd2,31University of Washington Medical Center, Department of Pharmacy, Seattle, WA; 2University of Colorado Anschutz Medical Campus, School of Pharmacy, Aurora, CO; 3University of Colorado Hospital, Department of Pharmacy, Aurora, CO USABackground: The 5-hydroxytryptamine type 3 antagonists, or setrons (eg, ondansetron, are commonly used for nausea and vomiting in the hospital setting. In 2001, droperidol was given a black box warning because it was found to prolong the QT interval and induce arrhythmias. The setrons share with droperidol the same potential proarrhythmic mechanisms, but limited data exist concerning their effects on the QT interval in individuals at high risk for torsades de pointes.Methods: Forty hospitalized patients admitted for heart failure or acute coronary syndromes with one or more risk factors for torsades de pointes and an order for intravenous ondansetron 4 mg were enrolled in this prospective, observational study. The QT interval corrected for heart rate (QTc was obtained via a 12-lead electrocardiogram on admission and again 120 minutes after the first dose of ondansetron in order to determine the mean change in QTc following ondansetron exposure.Results: The mean time interval between obtaining the baseline electrocardiogram and the second electrocardiogram following ondansetron administration was 3.5 ± 2.14 hours. In the total population, the QTc interval was prolonged by 19.3 ± 18 msec (P < 0.0001 120 minutes after ondansetron administration. For patients with an acute coronary syndrome and those with heart failure, QTc was prolonged by 18.3 ± 20 msec (P < 0.0001 and 20.6 ± 20 msec (P < 0.0012, respectively. Following ondansetron exposure, 31% and 46% in the heart failure and acute coronary syndromes groups, respectively, met gender-related thresholds for a prolonged QTc.Conclusion: Our study found QTc prolongation due to

Characterization of a rare variant (c.2635-2A>G) of the MSH2 gene in a family with Lynch syndrome.

Science.gov (United States)

Cariola, Filomena; Disciglio, Vittoria; Valentini, Anna M; Lotesoriere, Claudio; Fasano, Candida; Forte, Giovanna; Russo, Luciana; Di Carlo, Antonio; Guglielmi, Floranna; Manghisi, Andrea; Lolli, Ivan; Caruso, Maria L; Simone, Cristiano

2018-04-01

Lynch syndrome is caused by germline mutations in one of the mismatch repair genes ( MLH1, MSH2, MSH6, and PMS2) or in the EPCAM gene. Lynch syndrome is defined on the basis of clinical, pathological, and genetic findings. Accordingly, the identification of predisposing genes allows for accurate risk assessment and tailored screening protocols. Here, we report a family case with three family members manifesting the Lynch syndrome phenotype, all of which harbor the rare variant c.2635-2A>G affecting the splice site consensus sequence of intron 15 of the MSH2 gene. This mutation was previously described only in one family with Lynch syndrome, in which mismatch repair protein expression in tumor tissues was not assessed. In this study, we report for the first time the molecular characterization of the MSH2 c.2635-2A>G variant through in silico prediction analysis, microsatellite instability, and mismatch repair protein expression experiments on tumor tissues of Lynch syndrome patients. The potential effect of the splice site variant was revealed by three splicing prediction bioinformatics tools, which suggested the generation of a new cryptic splicing site. The potential pathogenic role of this variant was also revealed by the presence of microsatellite instability and the absence of MSH2/MSH6 heterodimer protein expression in the tumor cells of cancer tissues of the affected family members. We provide compelling evidence in favor of the pathogenic role of the MSH2 variant c.2635-2A>G, which could induce an alteration of the canonical splice site and consequently an aberrant form of the protein product (MSH2).

Jervell and Lange-Nielson Syndrome masquerading as intractable epilepsy

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Jagdish P Goyal

2012-01-01

Full Text Available The long QT syndrome (LQTS is a cause of syncope and sudden death. Jervell and Lange-Nielson syndrome (JLNS is an uncommon form of LQTS, having autosomal recessive transmission, and is associated with congenital deafness. We report a case of JLNS in a child who presented to us with refractory epilepsy. The cardiac cause of seizures was suspected as the child was hypotensive and pulseless during the episode of seizures. The child was diagnosed as JLNS based on Schwartz diagnostic criteria for LQTS and congenital sensorineural deafness. The child responded well to β-blocker therapy. Antiepileptic drugs were stopped. The screening of family members with ECG revealed a QT interval more than required for diagnosis of LQTS but they were asymptomatic. All asymptomatic family members were also put on metoprolol. All of them showed great improvement with the reduction of the QT interval on ECG. The patient was doing well on immediate follow-up.

Genetic variants in the cell cycle control pathways contribute to early onset colorectal cancer in Lynch syndrome.

Science.gov (United States)

Chen, Jinyun; Etzel, Carol J; Amos, Christopher I; Zhang, Qing; Viscofsky, Nancy; Lindor, Noralane M; Lynch, Patrick M; Frazier, Marsha L

2009-11-01

Lynch syndrome is an autosomal dominant syndrome of familial malignancies resulting from germ line mutations in DNA mismatch repair (MMR) genes. Our goal was to take a pathway-based approach to investigate the influence of polymorphisms in cell cycle-related genes on age of onset for Lynch syndrome using a tree model. We evaluated polymorphisms in a panel of cell cycle-related genes (AURKA, CDKN2A, TP53, E2F2, CCND1, TP73, MDM2, IGF1, and CDKN2B) in 220 MMR gene mutation carriers from 129 families. We applied a novel statistical approach, tree modeling (Classification and Regression Tree), to the analysis of data on patients with Lynch syndrome to identify individuals with a higher probability of developing colorectal cancer at an early age and explore the gene-gene interactions between polymorphisms in cell cycle genes. We found that the subgroup with CDKN2A C580T wild-type genotype, IGF1 CA-repeats >or=19, E2F2 variant genotype, AURKA wild-type genotype, and CCND1 variant genotype had the youngest age of onset, with a 45-year median onset age, while the subgroup with CDKN2A C580T wild-type genotype, IGF1 CA-repeats >or=19, E2F2 wild-type genotype, and AURKA variant genotype had the latest median age of onset, which was 70 years. Furthermore, we found evidence of a possible gene-gene interaction between E2F2 and AURKA genes related to CRC age of onset. Polymorphisms in these cell cycle-related genes work together to modify the age at the onset of CRC in patients with Lynch syndrome. These studies provide an important part of the foundation for development of a model for stratifying age of onset risk among those with Lynch syndrome.

Evaluation of Tp-Te Interval and Tp-Te/QT Ratio in Patients with Coronary Slow Flow Tp-Te/QT Ratio and Coronary Slow Flow.

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Tenekecioglu, Erhan; Karaagac, Kemal; Yontar, Osman Can; Agca, Fahriye Vatansever; Ozluk, Ozlem Arican; Tutuncu, Ahmet; Arslan, Burhan; Yilmaz, Mustafa

2015-06-01

Coronary slow flow (CSF) phenomenon is described by angiographically normal coronary arteries with delayed opacification of the distal vasculature. Several studies have suggested that the interval from the peak to the end of the electrocardiographic T wave (Tp-Te) may correspond to the transmural dispersion of the repolarization and that increased Tp-Te interval and Tp-Te/QT ratio are associated with malignant ventricular arrhythmias. The aim of this study was to evaluate the ventricular repolarization by using Tp-Te interval and Tp-Te/QT ratio in patients with CSF. This study included 50 CSF patients (40 male, mean age 48.6±12.5 years) and 40 control individuals (23 male, mean age 47.8±12.5 years). Tp-Te interval and Tp-Te/QT ratio were measured from the 12-lead electrocardiogram. These parameters were compared in groups. Baseline characteristics of the study groups were comparable. In electrocardiographic parameters analysis, QT and corrected QT were similar in CSF patients compared to the controls (357±35.2 vs 362±38.0 milliseconds and 419±25.8 vs 430±44.2 milliseconds, all p value >0.05). Tp-Te interval, Tp-Te/QT and Tp-Te/QTc ratio were significantly higher in CSF patients (85±13.7 vs 74±9.9 milliseconds and 0.24±0.03 vs 0.20±0.02 and 0.20±0.03 vs 0.17±0.02 all p value ratio are prolonged in patients with CSF.

Translating QT interval prolongation from conscious dogs to humans.

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Dubois, Vincent F S; Smania, Giovanni; Yu, Huixin; Graf, Ramona; Chain, Anne S Y; Danhof, Meindert; Della Pasqua, Oscar

2017-02-01

In spite of screening procedures in early drug development, uncertainty remains about the propensity of new chemical entities (NCEs) to prolong the QT/QTc interval. The evaluation of proarrhythmic activity using a comprehensive in vitro proarrhythmia assay does not fully account for pharmacokinetic-pharmacodynamic (PKPD) differences in vivo. In the present study, we evaluated the correlation between drug-specific parameters describing QT interval prolongation in dogs and in humans. Using estimates of the drug-specific parameter, data on the slopes of the PKPD relationships of nine compounds with varying QT-prolonging effects (cisapride, sotalol, moxifloxacin, carabersat, GSK945237, SB237376 and GSK618334, and two anonymized NCEs) were analysed. Mean slope estimates varied between -0.98 ms μM -1 and 6.1 ms μM -1 in dogs and -10 ms μM -1 and 90 ms μM -1 in humans, indicating a wide range of effects on the QT interval. Linear regression techniques were then applied to characterize the correlation between the parameter estimates across species. For compounds without a mixed ion channel block, a correlation was observed between the drug-specific parameter in dogs and humans (y = -1.709 + 11.6x; R 2  = 0.989). These results show that per unit concentration, the drug effect on the QT interval in humans is 11.6-fold larger than in dogs. Together with information about the expected therapeutic exposure, the evidence of a correlation between the compound-specific parameter in dogs and in humans represents an opportunity for translating preclinical safety data before progression into the clinic. Whereas further investigation is required to establish the generalizability of our findings, this approach can be used with clinical trial simulations to predict the probability of QT prolongation in humans. © 2016 The British Pharmacological Society.

Food and Insulin Effect on QT/QTC Interval of ECG

Science.gov (United States)

2014-08-19

Effects of Different Meals on the QT/QTc Interval; Insulin and Oral Hypoglycemic [Antidiabetic] Drugs Causing Adverse Effects in Therapeutic Use; C-Peptide Effects on the QT/QTc Interval; Moxifloxacin ECG Profile in Fed and Fasted State; Japanese vs. Caucasian TQT Comparison

Qt-sovelluksen kehittäminen Symbian-alustalle

OpenAIRE

Väyrynen, Jani

2012-01-01

Työn tavoitteena on kehittää toimiva Qt-sovellus Symbian-alustalle, joka toimii valvontakamerana. Työssä käsitellään Symbian-kehitysalustaa, sekä tutustutaan Qt-ohjelmointiin Symbian-alustalle. Tässä työssä kehitetään QVideoVahti -sovellusta, jonka tarkoituksena on tehdä älypuhelimesta langaton ”valvontakamera”. Sovelluksen päätoimintana on lähettää älypuhelimen tallentamia kuvia FTP-palvelimelle verkkoyhteyttä käyttäen. Sovelluksen muita toimintoja ovat muun muassa liikkeentunnistus, j...

Solving the TTC 2013 Flowgraphs Case with FunnyQT

Directory of Open Access Journals (Sweden)

Tassilo Horn

2013-11-01

Full Text Available FunnyQT is a model querying and model transformation library for the functional Lisp-dialect Clojure providing a rich and efficient querying and transformation API. This paper describes the FunnyQT solution to the TTC 2013 Flowgraphs Transformation Case. It solves all four tasks, and it has won the best efficiency award for this case.

Novel PIGT Variant in Two Brothers: Expansion of the Multiple Congenital Anomalies-Hypotonia Seizures Syndrome 3 Phenotype

OpenAIRE

Skauli, Nadia; Wallace, Sean; Chiang, Samuel C. C.; Bar?y, Tuva; Holmgren, Asbj?rn; Stray-Pedersen, Asbj?rg; Bryceson, Yenan T.; Str?mme, Petter; Frengen, Eirik; Misceo, Doriana

2016-01-01

Biallelic PIGT variants were previously reported in seven patients from three families with Multiple Congenital Anomalies-Hypotonia Seizures Syndrome 3 (MCAHS3), characterized by epileptic encephalopathy, hypotonia, global developmental delay/intellectual disability, cerebral and cerebellar atrophy, craniofacial dysmorphisms, and skeletal, ophthalmological, cardiac, and genitourinary abnormalities. We report a novel homozygous PIGT missense variant c.1079G>T (p.Gly360Val) in two brothers w...

Dispersion of repolarization and refractoriness are determinants of arrhythmia phenotype in transgenic mice with long QT.

Science.gov (United States)

London, Barry; Baker, Linda C; Petkova-Kirova, Polina; Nerbonne, Jeanne M; Choi, Bum-Rak; Salama, Guy

2007-01-01

Enhanced dispersion of repolarization (DR) and refractoriness may be a unifying mechanism central to arrhythmia genesis in the long QT (LQT) syndrome. The role of DR in promoting arrhythmias was investigated in several strains of molecularly engineered mice: (a) Kv4.2 dominant negative transgenic (Kv4.2DN) that lacks the fast component of the transient outward current, I(to,f), have action potential (AP) and QT prolongation, but no spontaneous arrhythmias, (b) Kv1.4 targeted mice (Kv1.4-/-) that lack the slow component of I(to) (I(to,s)), have no QT prolongation and no spontaneous arrhythmias, and (c) double transgenic (Kv4.2DN x Kv1.4-/-) mice that lack both I(to,f) and I(to,s), have AP and QT prolongation, and spontaneous ventricular tachyarrhythmias. Hearts were perfused, stained with di-4-ANEPPS and optically mapped. Activation patterns and conduction velocities were similar between the strains but AP duration at 75% recovery (APD75) was longer in Kv4.2DN (28.0 +/- 2.5 ms, P mice than controls (20.3 +/- 1.0 ms, n = 5). Dispersion of refractoriness between apex and base was markedly reduced in Kv4.2DN (0.3 +/- 0.5 ms, n = 6, P mice compared with controls (10 +/- 2 ms, n = 5). A premature pulse elicited ventricular tachycardia (VT) in Kv1.4-/- (n = 4/5) and Kv4.2DN x Kv1.4-/- hearts (n = 5/5) but not Kv4.2DN hearts (n = 0/6). Voltage-clamp recordings showed that I(to,f) was 30% greater in myocytes from the apex than base which may account for the absence of DR in Kv4.2DN mice. Thus, dispersion of repolarization (DR) appears to be an important determinant of arrhythmia vulnerability.

A model of cardiac ryanodine receptor gating predicts experimental Ca2+-dynamics and Ca2+-triggered arrhythmia in the long QT syndrome

Science.gov (United States)

Wilson, Dan; Ermentrout, Bard; Němec, Jan; Salama, Guy

2017-09-01

Abnormal Ca2+ handling is well-established as the trigger of cardiac arrhythmia in catecholaminergic polymorphic ventricular tachycardia and digoxin toxicity, but its role remains controversial in Torsade de Pointes (TdP), the arrhythmia associated with the long QT syndrome (LQTS). Recent experimental results show that early afterdepolarizations (EADs) that initiate TdP are caused by spontaneous (non-voltage-triggered) Ca2+ release from Ca2+-overloaded sarcoplasmic reticulum (SR) rather than the activation of the L-type Ca2+-channel window current. In bradycardia and long QT type 2 (LQT2), a second, non-voltage triggered cytosolic Ca2+ elevation increases gradually in amplitude, occurs before overt voltage instability, and then precedes the rise of EADs. Here, we used a modified Shannon-Puglisi-Bers model of rabbit ventricular myocytes to reproduce experimental Ca2+ dynamics in bradycardia and LQT2. Abnormal systolic Ca2+-oscillations and EADs caused by SR Ca2+-release are reproduced in a modified 0-dimensional model, where 3 gates in series control the ryanodine receptor (RyR2) conductance. Two gates control RyR2 activation and inactivation and sense cytosolic Ca2+ while a third gate senses luminal junctional SR Ca2+. The model predicts EADs in bradycardia and low extracellular [K+] and cessation of SR Ca2+-release terminate salvos of EADs. Ca2+-waves, systolic cell-synchronous Ca2+-release, and multifocal diastolic Ca2+ release seen in subcellular Ca2+-mapping experiments are observed in the 2-dimensional version of the model. These results support the role of SR Ca2+-overload, abnormal SR Ca2+-release, and the subsequent activation of the electrogenic Na+/Ca2+-exchanger as the mechanism of TdP. The model offers new insights into the genesis of cardiac arrhythmia and new therapeutic strategies.

A rare variant in MYH6 is associated with high risk of sick sinus syndrome

DEFF Research Database (Denmark)

Holm, Hilma; Gudbjartsson, Daniel F; Sulem, Patrick

2011-01-01

Through complementary application of SNP genotyping, whole-genome sequencing and imputation in 38,384 Icelanders, we have discovered a previously unidentified sick sinus syndrome susceptibility gene, MYH6, encoding the alpha heavy chain subunit of cardiac myosin. A missense variant in this gene, ...

Long QT Syndrome–Associated Mutations in Intrauterine Fetal Death

Science.gov (United States)

Crotti, Lia; Tester, David J.; White, Wendy M.; Bartos, Daniel C.; Insolia, Roberto; Besana, Alessandra; Kunic, Jennifer D.; Will, Melissa L.; Velasco, Ellyn J.; Bair, Jennifer J.; Ghidoni, Alice; Cetin, Irene; Van Dyke, Daniel L.; Wick, Myra J.; Brost, Brian; Delisle, Brian P.; Facchinetti, Fabio; George, Alfred L.; Schwartz, Peter J.; Ackerman, Michael J.

2013-01-01

Importance Intrauterine fetal death or stillbirth occurs in approximately 1 out of every 160 pregnancies and accounts for 50% of all perinatal deaths. Postmortem evaluation fails to elucidate an underlying cause in many cases. Long QT syndrome (LQTS) may contribute to this problem. Objective To determine the spectrum and prevalence of mutations in the 3 most common LQTS susceptible genes (KCNQ1, KCNH2, and SCN5A) for a cohort of unexplained cases. Design, Setting, and Patients In this case series, retrospective postmortem genetic testing was conducted on a convenience sample of 91 unexplained intrauterine fetal deaths (mean [SD] estimated gestational age at fetal death, 26.3 [8.7] weeks) that were collected from 2006-2012 by the Mayo Clinic, Rochester, Minnesota, or the Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. More than 1300 ostensibly healthy individuals served as controls. In addition, publicly available exome databases were assessed for the general population frequency of identified genetic variants. Main Outcomes and Measures Comprehensive mutational analyses of KCNQ1 (KV7.1, LQTS type 1), KCNH2 (HERG/KV11.1, LQTS type 2), and SCN5A (NaV1.5, LQTS type 3) were performed using denaturing high-performance liquid chromatography and direct DNA sequencing on genomic DNA extracted from decedent tissue. Functional analyses of novel mutations were performed using heterologous expression and patch-clamp recording. Results The 3 putative LQTS susceptibility missense mutations (KCNQ1, p.A283T; KCNQ1, p.R397W; and KCNH2[1b], p.R25W), with a heterozygous frequency of less than 0.05% in more than 10000 publicly available exomes and absent in more than 1000 ethnically similar control patients, were discovered in 3 intrauterine fetal deaths (3.3% [95% CI, 0.68%-9.3%]). Both KV7.1-A283T (16-week male) and KV7.1-R397W (16-week female) mutations were associated with marked KV7.1 loss-of-function consistent with in utero LQTS type 1, whereas the HERG1b-R25W mutation

Influence of gender and types of sports training on QT variables in young elite athletes.

Science.gov (United States)

Omiya, Kazuto; Sekizuka, Hiromitsu; Kida, Keisuke; Suzuki, Kengo; Akashi, Yoshihiro J; Ohba, Haruo; Musha, Haruki

2014-01-01

Influence of gender and sports training on QT variables such as QT interval and dispersion (QT dispersion: QTD) in young elite athletes were evaluated. Subjects included 104 male and 97 female Japanese elite athletes (mean age 21.6 years). Sports included basketball, fencing, gymnastics, judo, swimming, tennis, track and field and volleyball. Age-matched healthy non-athletes (32 men and 20 women) were enrolled as controls. QT measurements were manually obtained from a 12-lead resting electrocardiogram and QTD was calculated as the difference between the longest and shortest QT intervals. A corrected QT interval (QTc) was obtained using Bazett's formula. Subjects were divided into two groups; an endurance training group and a static training group on the basis of their training types. Maximum and minimum QTc were significantly longer in female athletes than in male athletes (max: 414.2 vs. 404.5 ms, min: 375.1 vs. 359.2 ms, pgender and different characteristics of sports training may affect QT variables even in young elite athletes. Vigorous static exercise training may independently prolong QT variables.

A novel homozygous variant in the SMOC1 gene underlying Waardenburg anophthalmia syndrome.

Science.gov (United States)

Ullah, Asmat; Umair, Muhammad; Ahmad, Farooq; Muhammad, Dost; Basit, Sulman; Ahmad, Wasim

2017-01-01

Waardenburg anophthalmia syndrome (WAS), also known as ophthalmo-acromelic syndrome or anophthalmia-syndactyly, is a rare congenital disorder that segregates in an autosomal recessive pattern. Clinical features of the syndrome include malformation of the eyes and the skeleton. Mostly, WAS is caused by mutations in the SMOC-1 gene. The present report describes a large consanguineous family of Pakistani origin segregating Waardenburg anophthalmia syndrome in an autosomal recessive pattern. Genotyping followed by Sanger sequencing was performed to search for a candidate gene. SNP genotyping using AffymetrixGeneChip Human Mapping 250K Nsp array established a single homozygous region among affected members on chromosome 14q23.1-q24.3 harboring the SMOC1 gene. Sequencing of the gene revealed a novel homozygous missense mutation (c.812G>A; p.Cys271Tyr) in the family. This is the first report of Waardenburg anophthalmia syndrome caused by a SMOC1 variant in a Pakistani population. The mutation identified in the present investigation extends the body of evidence implicating the gene SMOC-1 in causing WAS.

High-risk Long QT Syndrome Mutations in the Kv7.1 (KCNQ1) Pore Disrupt the Molecular Basis for Rapid K+ Permeation

Science.gov (United States)

Burgess, Don E.; Bartos, Daniel C.; Reloj, Allison R.; Campbell, Kenneth S.; Johnson, Jonathan N.; Tester, David J.; Ackerman, Michael J.; Fressart, Véronique; Denjoy, Isabelle; Guicheney, Pascale; Moss, Arthur J.; Ohno, Seiko; Horie, Minoru; Delisle, Brian P.

2012-01-01

Type 1 long QT syndrome (LQT1) syndrome is caused by loss-of-function mutations in the KCNQ1, which encodes the K+ channel (Kv7.1) that underlies the slowly activating delayed rectifier K+ current in the heart. Intragenic risk stratification suggests LQT1 mutations that disrupt conserved amino acid residues in the pore are an independent risk factor for LQT1-related cardiac events. The purpose of this study is to determine possible molecular mechanisms that underlie the loss-of-function for these high-risk mutations. Extensive genotype-phenotype analyses of LQT1 patients showed that T322M-, T322A-, or G325R-Kv7.1 confer a high risk for LQT1-related cardiac events. Heterologous expression of these mutations with KCNE1 revealed they generated non-functional channels and caused dominant negative suppression of WT-Kv7.1 current. Molecular dynamic simulations (MDS) of analogous mutations in KcsA (T85M-, T85A-, and G88R-KcsA) demonstrated that they disrupted the symmetrical distribution of the carbonyl oxygen atoms in the selectivity filter, which upset the balance between the strong attractive and K+-K+ repulsive forces required for rapid K+ permeation. We conclude high-risk LQT1 mutations in the pore likely disrupt the architectural and physical properties of the K+ channel selectivity filter. PMID:23092362

A Case of QT Prolongation Associated with Panhypopituitarism

Directory of Open Access Journals (Sweden)

Dilek Arpaci

2013-01-01

Full Text Available We describe a 37-year-old patient with panhypopituitarism who experienced symptoms and signs of hormonal insufficiency and QT prolongation on electrocardiogram without electrolyte disturbances. After hormonal (steroidal and thyroid replacement therapy electrocardiographic findings were normalized. Hormonal disorders should be considered as a cause of long QT intervals which may lead to torsade de pointes, even if plasma electrolyte levels are normal, because life-threatening arrhythmia is treatable by supplementation of the hormone that is lacking.

The importance of the family history in caring for families with long QT syndrome and dilated cardiomyopathy.

Science.gov (United States)

Ruiter, Jolien S; Berkenbosch-Nieuwhof, Karin; van den Berg, Maarten P; van Dijk, Rene; Middel, Berrie; van Tintelen, J Peter

2010-03-01

In potentially inherited cardiac diseases, the family history is of great importance. We looked at the way cardiologists take a family history in patients with idiopathic dilated cardiomyopathy (DCM) or long QT syndrome (LQTS) and whether this led to screening of relatives or other follow-up. We performed retrospective cross-sectional analyses of adult index patients with DCM or LQTS in a general hospital (GH) or a University Medical Center (UMC). We identified 82 index patients with DCM (34 GH; 48 UMC) and 20 with LQTS (all UMC) between 1996 and 2005. Mean follow-up was 58 months. A family history was recorded in 90% of both LQTS and DCM patients most of the cases restricted to first-degree family members. The genetic aspects, counseling and screening of family members was discussed significantly more often with LQTS than DCM patients (all P family members, DNA analysis and referral) was performed significantly more often in LQTS than DCM patients. Cardiologists in the UMC referred DCM index patients for genetic counseling more often than those in the GH (25% vs. 6%; P familial. Since early recognition and treatment may reduce morbidity and mortality we recommend cardiologists take a more thorough family history and always consider referring to a clinical genetics department in such index patients. (c) 2010 Wiley-Liss, Inc.

Qt based control system software for Low Energy Accelerator Facility

International Nuclear Information System (INIS)

Basu, A.; Singh, S.; Nagraju, S.B.V.; Gupta, S.; Singh, P.

2012-01-01

Qt based control system software for Low Energy Accelerating Facility (LEAF) is operational at Bhabha Atomic Research Centre (BARC), Trombay, Mumbai. LEAF is a 50 keV negative ion electrostatic accelerator based on SNICS ion source. Control system uses Nokia Trolltech's QT 4.x API for control system software. Ni 6008 USB based multifunction cards has been used for control and read back field equipments such as power supplies, pumps, valves etc. Control system architecture is designed to be client server. Qt is chosen for its excellent GUI capability and platform independent nature. Control system follows client server architecture. The paper will describe the control system. (author)

Increased Short-Term Beat-To-Beat Variability of QT Interval in Patients with Acromegaly

Science.gov (United States)

Orosz, Andrea; Csajbók, Éva; Czékus, Csilla; Gavallér, Henriette; Magony, Sándor; Valkusz, Zsuzsanna; Várkonyi, Tamás T.; Nemes, Attila; Baczkó, István; Forster, Tamás; Wittmann, Tibor; Papp, Julius Gy.; Varró, András; Lengyel, Csaba

2015-01-01

Cardiovascular diseases, including ventricular arrhythmias are responsible for increased mortality in patients with acromegaly. Acromegaly may cause repolarization abnormalities such as QT prolongation and impairment of repolarization reserve enhancing liability to arrhythmia. The aim of this study was to determine the short-term beat-to-beat QT variability in patients with acromegaly. Thirty acromegalic patients (23 women and 7 men, mean age±SD: 55.7±10.4 years) were compared with age- and sex-matched volunteers (mean age 51.3±7.6 years). Cardiac repolarization parameters including frequency corrected QT interval, PQ and QRS intervals, duration of terminal part of T waves (Tpeak-Tend) and short-term variability of QT interval were evaluated. All acromegalic patients and controls underwent transthoracic echocardiographic examination. Autonomic function was assessed by means of five standard cardiovascular reflex tests. Comparison of the two groups revealed no significant differences in the conventional ECG parameters of repolarization (QT: 401.1±30.6 ms vs 389.3±16.5 ms, corrected QT interval: 430.1±18.6 ms vs 425.6±17.3 ms, QT dispersion: 38.2±13.2 ms vs 36.6±10.2 ms; acromegaly vs control, respectively). However, short-term beat-to-beat QT variability was significantly increased in acromegalic patients (4.23±1.03 ms vs 3.02±0.80, Pacromegaly in spite of unchanged conventional parameters of ventricular repolarization. This enhanced temporal QT variability may be an early indicator of increased liability to arrhythmia. PMID:25915951

Short limbed dwarfism, genital hypoplasia, sparse hair, and vertebral anomalies: a variant of Ellis-van Creveld syndrome?

OpenAIRE

Fryns, J P; Moerman, P

1993-01-01

A male newborn with acromesomelic short limbed dwarfism, genital hypoplasia, and vertebral anomalies is reported. As the child had an important number of clinical and radiological symptoms seen in patients with Ellis-van Creveld syndrome, we raise the question of whether he may represent a variant example of this syndrome despite the absence of cardinal symptoms such as postaxial polydactyly and ectodermal changes (nail hypoplasia).

A Large Candidate Gene Survey Identifies the KCNE1 D85N Polymorphism as a Possible Modulator of Drug-Induced Torsades de Pointes

NARCIS (Netherlands)

Kaeaeb, Stefan; Crawford, Dana C.; Sinner, Moritz F.; Behr, Elijah R.; Kannankeril, Prince J.; Wilde, Arthur A. M.; Bezzina, Connie R.; Schulze-Bahr, Eric; Guicheney, Pascale; Bishopric, Nanette H.; Myerburg, Robert J.; Schott, Jean-Jacques; Pfeufer, Arne; Beckmann, Britt-Maria; Martens, Eimo; Zhang, Taifang; Stallmeyer, Birgit; Zumhagen, Sven; Denjoy, Isabelle; Bardai, Abdennasser; Van Gelder, Isabelle C.; Jamshidi, Yalda; Dalageorgou, Chrysoula; Marshall, Vanessa; Jeffery, Steve; Shakir, Saad; Camm, A. John; Steinbeck, Gerhard; Perz, Siegfried; Lichtner, Peter; Meitinger, Thomas; Peters, Annette; Wichmann, H. -Erich; Ingram, Christiana; Bradford, Yuki; Carter, Shannon; Norris, Kris; Ritchie, Marylyn D.; George, Alfred L.; Roden, Dan M.

Background-Drug-induced long-QT syndrome (diLQTS) is an adverse drug effect that has an important impact on drug use, development, and regulation. We tested the hypothesis that common variants in key genes controlling cardiac electric properties modify the risk of diLQTS. Methods and Results-In a

A Large Candidate Gene Survey Identifies the KCNE1 D85N Polymorphism as a Possible Modulator of Drug-Induced Torsades de Pointes

NARCIS (Netherlands)

Kääb, Stefan; Crawford, Dana C.; Sinner, Moritz F.; Behr, Elijah R.; Kannankeril, Prince J.; Wilde, Arthur A. M.; Bezzina, Connie R.; Schulze-Bahr, Eric; Guicheney, Pascale; Bishopric, Nanette H.; Myerburg, Robert J.; Schott, Jean-Jacques; Pfeufer, Arne; Beckmann, Britt-Maria; Martens, Eimo; Zhang, Taifang; Stallmeyer, Birgit; Zumhagen, Sven; Denjoy, Isabelle; Bardai, Abdennasser; van Gelder, Isabelle C.; Jamshidi, Yalda; Dalageorgou, Chrysoula; Marshall, Vanessa; Jeffery, Steve; Shakir, Saad; Camm, A. John; Steinbeck, Gerhard; Perz, Siegfried; Lichtner, Peter; Meitinger, Thomas; Peters, Annette; Wichmann, H.-Erich; Ingram, Christiana; Bradford, Yuki; Carter, Shannon; Norris, Kris; Ritchie, Marylyn D.; George, Alfred L.; Roden, Dan M.

2012-01-01

Background-Drug-induced long-QT syndrome (diLQTS) is an adverse drug effect that has an important impact on drug use, development, and regulation. We tested the hypothesis that common variants in key genes controlling cardiac electric properties modify the risk of diLQTS. Methods and Results-In a

Unintended consequences of reducing QT-alert overload in a computerized physician order entry system

NARCIS (Netherlands)

I.H. van der Sijs (Heleen); R. Kowlesar (Ravi); J.E.C.M. Aarts (Jos); M. Berg (Marc); A.G. Vulto (Arnold); T. van Gelder (Teun)

2009-01-01

textabstractPurpose: After complaints of too many low-specificity drug-drug interaction (DDI) alerts on QT prolongation, the rules for QT alerting in the Dutch national drug database were restricted in 2007 to obviously QT-prolonging drugs. The aim of this virtual study was to investigate whether

Collaborative development of the EPICS Qt framework Phase I Final Report

Energy Technology Data Exchange (ETDEWEB)

Mayssat, Robert E. [Lyncean Technologies, Inc., Palo Alto, CA (United States)

2015-01-15

At Lyncean, a private company spun-off from technology developed at the SLAC National Lab, we have been using EPICS for over a decade. EPICS is ubiquitous on our flagship product – the Compact Light Source. EPICS is not only used to control our laser and accelerator systems, but also to control our x-ray beamlines. The goal of this SBIR is for Lyncean Technologies to spearhead a worldwide collaborative effort for the development of control system tools for EPICS using the Qt framework, a C++-based coding environment that could serve as a competitive alternative to the Java-based Control System Studio (CSS). This grant's Phase I, not unlike a feasibility study, is designed for planning and scoping the preparatory work needed for Phase II or other funding opportunities. The three main objectives of this Phase I are (1) to become better acquainted with the existing EPICS Qt software and Qt framework in order to evaluate the best options for ongoing development, (2) to demonstrate that our engineers can lead the EPICS community and jump-start the Qt collaboration, and (3) to identify a scope for our future work with solicited feedback from the EPICS community. This Phase I report includes key technical findings. It clarifies the differences between the two apparently-competing EPICS Qt implementations, caQtDM and the QE Framework; it explains how to create python-bindings, and compares Qt graphical libraries. But this report is also a personal story that narrates the birth of a collaboration. Starting a collaboration is not the work of a single individual, but the work of many. Therefore this report is also an attempt to publicly give credit to many who supported the effort. The main take-away from this grant is the successful birth of an EPICS Qt collaboration, seeded with existing software from the PSI and the Australian Synchrotron. But a lot more needs to be done for the collaboration founders' vision to be realized, and for the collaboration to reach

Short limbed dwarfism, genital hypoplasia, sparse hair, and vertebral anomalies: a variant of Ellis-van Creveld syndrome?

Science.gov (United States)

Fryns, J P; Moerman, P

1993-01-01

A male newborn with acromesomelic short limbed dwarfism, genital hypoplasia, and vertebral anomalies is reported. As the child had an important number of clinical and radiological symptoms seen in patients with Ellis-van Creveld syndrome, we raise the question of whether he may represent a variant example of this syndrome despite the absence of cardinal symptoms such as postaxial polydactyly and ectodermal changes (nail hypoplasia). Images PMID:8487282

Safety information on QT-interval prolongation : comparison of European Union and United States drug labeling

NARCIS (Netherlands)

Warnier, Miriam J.; Holtkamp, Frank A.; Rutten, Frans H.; Hoes, Arno W.; de Boer, Anthonius; Mol, Peter G M; De Bruin, Marie L.

Prolongation of the QT interval can predispose to fatal ventricular arrhythmias. Differences in QT-labeling language can result in miscommunication and suboptimal risk mitigation. We systematically compared the phraseology used to communicate on QT-prolonging properties of 144 drugs newly approved

Safety information on QT-interval prolongation : Comparison of European Union and United States drug labeling

NARCIS (Netherlands)

Warnier, Miriam J.; Holtkamp, Frank A.; Rutten, Frans H.; Hoes, Arno W.; de Boer, Anthonius; Mol, Peter G. M.; De Bruin, Marie L.

Prolongation of the QT interval can predispose to fatal ventricular arrhythmias. Differences in QT-labeling language can result in miscommunication and suboptimal risk mitigation. We systematically compared the phraseology used to communicate on QT-prolonging properties of 144 drugs newly approved

Intragenic FMR1 disease-causing variants: a significant mutational mechanism leading to Fragile-X syndrome

Science.gov (United States)

Quartier, Angélique; Poquet, Hélène; Gilbert-Dussardier, Brigitte; Rossi, Massimiliano; Casteleyn, Anne-Sophie; Portes, Vincent des; Feger, Claire; Nourisson, Elsa; Kuentz, Paul; Redin, Claire; Thevenon, Julien; Mosca-Boidron, Anne-Laure; Callier, Patrick; Muller, Jean; Lesca, Gaetan; Huet, Frédéric; Geoffroy, Véronique; El Chehadeh, Salima; Jung, Matthieu; Trojak, Benoit; Le Gras, Stéphanie; Lehalle, Daphné; Jost, Bernard; Maury, Stéphanie; Masurel, Alice; Edery, Patrick; Thauvin-Robinet, Christel; Gérard, Bénédicte; Mandel, Jean-Louis; Faivre, Laurence; Piton, Amélie

2017-01-01

Fragile-X syndrome (FXS) is a frequent genetic form of intellectual disability (ID). The main recurrent mutagenic mechanism causing FXS is the expansion of a CGG repeat sequence in the 5′-UTR of the FMR1 gene, therefore, routinely tested in ID patients. We report here three FMR1 intragenic pathogenic variants not affecting this sequence, identified using high-throughput sequencing (HTS): a previously reported hemizygous deletion encompassing the last exon of FMR1, too small to be detected by array-CGH and inducing decreased expression of a truncated form of FMRP protein, in three brothers with ID (family 1) and two splice variants in boys with sporadic ID: a de novo variant c.990+1G>A (family 2) and a maternally inherited c.420-8A>G variant (family 3). After clinical reevaluation, the five patients presented features consistent with FXS (mean Hagerman's scores=15). We conducted a systematic review of all rare non-synonymous variants previously reported in FMR1 in ID patients and showed that six of them are convincing pathogenic variants. This study suggests that intragenic FMR1 variants, although much less frequent than CGG expansions, are a significant mutational mechanism leading to FXS and demonstrates the interest of HTS approaches to detect them in ID patients with a negative standard work-up. PMID:28176767

Germline variants in Hamartomatous Polyposis Syndrome-associated genes from patients with one or few hamartomatous polyps

DEFF Research Database (Denmark)

Jelsig, Anne Marie; Brusgaard, Klaus; Hansen, Tine Plato

2016-01-01

OBJECTIVE: A subgroup of patients with hamartomatous polyps in the GI tract has a hereditary Hamartomatous Polyposis Syndrome with an increased risk of cancer. The distinction between patients with one or few polyps and patients with a syndrome can be difficult. A pathogenic germline mutation can...... significance of genetic variants can be difficult to interpret. A family history of polyps, cancer, or extraintestinal findings or a minimum of 3-5 polyps seems to be relevant information to include before genetic testing....

A putative Lynch syndrome family carrying MSH2 and MSH6 variants of uncertain significance-functional analysis reveals the pathogenic one

DEFF Research Database (Denmark)

Kantelinen, Jukka; Hansen, Thomas V O; Kansikas, Minttu

2011-01-01

Inherited pathogenic mutations in the mismatch repair (MMR) genes, MSH2, MLH1, MSH6, and PMS2 predispose to Lynch syndrome (LS). However, the finding of a variant or variants of uncertain significance (VUS) in affected family members complicates the risk assessment. Here, we describe a putative LS...

Relation between the behaviors of P-wave and QT dispersions in elderly patients with heart failure

Directory of Open Access Journals (Sweden)

Szlejf Cláudia

2002-01-01

Full Text Available OBJECTIVE: To assess the relation between P-wave and QT dispersions in elderly patients with heart failure. METHODS: Forty-seven elderly patients (75.6±6 years with stable heart failure in NYHA functional classes II or III and with ejection fractions of 37±6% underwent body surface mapping to analyze P-wave and QT dispersions. The degree of correlation between P-wave and QT dispersions was assessed, and P-wave dispersion values in patients with QT dispersion greater than and smaller than 100 ms were compared. RESULTS: The mean values of P-wave and QT dispersions were 54±14 ms and 68±27 ms, respectively. The correlation between the 2 variables was R=0.41 (p=0.04. In patients with QT dispersion values > 100 ms, P-wave dispersion was significantly greater than in those with QT dispersion values < 100 ms (58±16 vs 53±12 ms, p=0.04 . CONCLUSION: Our results suggest that, in elderly patients with heart failure, a correlation between the values of P-wave and QT dispersions exists. These findings may have etiopathogenic, pathophysiologic, prognostic, and therapeutic implications, which should be investigated in other studies.

PENGARUH MODEL PEMBELAJARAN QUANTUM TEACHING BERBANTUAN MODUL QT-BILINGUAL TERHADAP HASIL BELAJAR SISWA

Directory of Open Access Journals (Sweden)

Husna Amalana

2015-11-01

Full Text Available Quantum teaching learning model supported by QT(Quantum Teaching-bilingual module emphasize optimization all multiple intelligences and learning style of students in learning activities with TANDUR frame. This research aimed to find out the effect of quantum teaching learning model supported by QT-bilingual module to the achievement of X grade students of SMA in Kedungwuni, how much the effect magnitude, and how student response. This research uses true experimental design with X.1 and X.8 classes as reasearch samples which determined by cluster random sampling technique. Data were collected through documentation, test, observation and questionnaire method. The results of hypothesis test analysis showed correlation and determination coefficient are 0.54 and 29.16%. The results of questionnaire stated that the students’ response is very good to quantum teaching learning model assisted by QT-bilingual module. Based on the analysis, it can be concluded that quantum teaching learning model assisted by QT-bilingual module effects on student learning outcomes by achieving the medium level of effect with contribution is 29.16%. Students’ response is very good actually to quantum teaching learning model supported by QT-bilingual module.Keywords: Quantum Teaching, QT-Bilingual Module 

Circadian rhythm in QT interval is preserved in mice deficient of potassium channel interacting protein 2.

Science.gov (United States)

Gottlieb, Lisa A; Lubberding, Anniek; Larsen, Anders Peter; Thomsen, Morten B

2017-01-01

Potassium Channel Interacting Protein 2 (KChIP2) is suggested to be responsible for the circadian rhythm in repolarization duration, ventricular arrhythmias, and sudden cardiac death. We investigated the hypothesis that there is no circadian rhythm in QT interval in the absence of KChIP2. Implanted telemetric devices recorded electrocardiogram continuously for 5 days in conscious wild-type mice (WT, n = 9) and KChIP2 -/- mice (n = 9) in light:dark periods and in complete darkness. QT intervals were determined from all RR intervals and corrected for heart rate (QT 100 = QT/(RR/100) 1/2 ). Moreover, QT intervals were determined from complexes within the RR range of mean-RR ± 1% in the individual mouse (QT mean-RR ). We find that RR intervals are 125 ± 5 ms in WT and 123 ± 4 ms in KChIP2 -/- (p = 0.81), and QT intervals are 52 ± 1 and 52 ± 1 ms, respectively(p = 0.89). No ventricular arrhythmias or sudden cardiac deaths were observed. We find similar diurnal (light:dark) and circadian (darkness) rhythms of RR intervals in WT and KChIP2 -/- mice. Circadian rhythms in QT 100 intervals are present in both groups, but at physiological small amplitudes: 1.6 ± 0.2 and 1.0 ± 0.3 ms in WT and KChIP2 -/- , respectively (p = 0.15). A diurnal rhythm in QT 100 intervals was only found in WT mice. QT mean-RR intervals display clear diurnal and circadian rhythms in both WT and KChIP2 -/- . The amplitude of the circadian rhythm in QT mean-RR is 4.0 ± 0.3 and 3.1 ± 0.5 ms in WT and KChIP2 -/- , respectively (p = 0.16). In conclusion, KChIP2 expression does not appear to underlie the circadian rhythm in repolarization duration.

Dispersion durations of P-wave and QT interval in children treated with a ketogenic diet.

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Doksöz, Önder; Güzel, Orkide; Yılmaz, Ünsal; Işgüder, Rana; Çeleğen, Kübra; Meşe, Timur

2014-04-01

Limited data are available on the effects of a ketogenic diet on dispersion duration of P-wave and QT-interval measures in children. We searched for the changes in these measures with serial electrocardiograms in patients treated with a ketogenic diet. Twenty-five drug-resistant patients with epilepsy treated with a ketogenic diet were enrolled in this study. Electrocardiography was performed in all patients before the beginning and at the sixth month after implementation of the ketogenic diet. Heart rate, maximum and minimum P-wave duration, P-wave dispersion, and maximum and minimum corrected QT interval and QT dispersion were manually measured from the 12-lead surface electrocardiogram. Minimum and maximum corrected QT and QT dispersion measurements showed nonsignificant increase at month 6 compared with baseline values. Other previously mentioned electrocardiogram parameters also showed no significant changes. A ketogenic diet of 6 months' duration has no significant effect on electrocardiogram parameters in children. Further studies with larger samples and longer duration of follow-up are needed to clarify the effects of ketogenic diet on P-wave dispersion and corrected QT and QT dispersion. Copyright © 2014 Elsevier Inc. All rights reserved.

Cardiovascular safety of tyrosine kinase inhibitors: Putting their “QT-phobia” in perspective

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Rashmi Shah

2016-10-01

Full Text Available Many potentially valuable drugs, including protein kinase inhibitors (PKI, risk being dropped from further development, without exploration of their clinical benefits, if early studies show these drugs to inhibit hERG channel and therefore, to have a potential for prolonging ventricular repolarisation (QT interval. This QT-phobia results from a perceived possibility of the clinical risks of QT-related ventricular proarrhythmia, further aggravated by uncertainties surrounding the regulatory evaluation of the risk and either approvability or restrictive labelling of the drug concerned. In reality, QT interval prolongation per se is only an imperfect surrogate of the proarrhythmia risk which is much smaller than perceived and compared to their other cardiovascular and non-cardiovascular risks. PKI-induced clinical hepatotoxicity, also evaluated on the basis of surrogate markers (serum transaminases and bilirubin is another risk that far exceeds any risk arising from PKI-induced QT interval prolongation. This review of the currently approved 28 PKIs places the QT-phobia surrounding the development of PKIs in its perspective by juxta-positioning their potential to induce ventricular dysfunction, arterial thrombotic events and hepatotoxicity. Available evidence suggests that hERG channel may prove to be a valuable therapeutic target in oncology. Therefore, the development, approval and labelling of such vital oncology drugs requires careful assessment of their benefits and their risk/benefit generally, without being overtly consumed by their potential QT-liability, in terms of their more direct consequences on clinically relevant endpoints of morbidity, mortality and quality of life.

Evidence for classification of c.1852_1853AA>GC in MLH1 as a neutral variant for Lynch syndrome

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Llor Xavier

2011-01-01

Full Text Available Abstract Background Lynch syndrome (LS is an autosomal dominant inherited cancer syndrome characterized by early onset cancers of the colorectum, endometrium and other tumours. A significant proportion of DNA variants in LS patients are unclassified. Reports on the pathogenicity of the c.1852_1853AA>GC (p.Lys618Ala variant of the MLH1 gene are conflicting. In this study, we provide new evidence indicating that this variant has no significant implications for LS. Methods The following approach was used to assess the clinical significance of the p.Lys618Ala variant: frequency in a control population, case-control comparison, co-occurrence of the p.Lys618Ala variant with a pathogenic mutation, co-segregation with the disease and microsatellite instability in tumours from carriers of the variant. We genotyped p.Lys618Ala in 1034 individuals (373 sporadic colorectal cancer [CRC] patients, 250 index subjects from families suspected of having LS [revised Bethesda guidelines] and 411 controls. Three well-characterized LS families that fulfilled the Amsterdam II Criteria and consisted of members with the p.Lys618Ala variant were included to assess co-occurrence and co-segregation. A subset of colorectal tumour DNA samples from 17 patients carrying the p.Lys618Ala variant was screened for microsatellite instability using five mononucleotide markers. Results Twenty-seven individuals were heterozygous for the p.Lys618Ala variant; nine had sporadic CRC (2.41%, seven were suspected of having hereditary CRC (2.8% and 11 were controls (2.68%. There were no significant associations in the case-control and case-case studies. The p.Lys618Ala variant was co-existent with pathogenic mutations in two unrelated LS families. In one family, the allele distribution of the pathogenic and unclassified variant was in trans, in the other family the pathogenic variant was detected in the MSH6 gene and only the deleterious variant co-segregated with the disease in both

Polycystic ovary syndrome is not associated with genetic variants that mark risk of type 2 diabetes.

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Saxena, R; Welt, C K

2013-06-01

Polycystic ovary syndrome (PCOS) is a disorder of irregular menses, hyperandrogenism and/or polycystic ovary morphology. A large proportion of women with PCOS also exhibit insulin resistance, β-cell dysfunction, impaired glucose tolerance and/or type 2 diabetes (T2D). We therefore hypothesized that genetic variants that predispose to risk of T2D also result in risk of PCOS. Variants robustly associated with T2D in candidate gene or genome-wide association studies (GWAS; n = 56 SNPs from 33 loci) were genotyped in women of European ancestry with PCOS (n = 525) and controls (n = 472), aged 18-45 years. Metabolic, reproductive and anthropomorphic data were examined as a function of the T2D variants. All genetic association analyses were adjusted for age, BMI and ancestry and were reported after correction for multiple testing. There was a nominal association between variants in KCNJ11 and risk of PCOS. However, a risk score of 33 independent T2D-associated variants from GWAS was not significantly associated with PCOS. T2D variants were associated with PCOS phenotype parameters including those in THADA and WFS1 with testosterone levels, ENPP/PC1 with triglyceride levels, FTO with glucose levels and KCNJ11 with FSH levels. Diabetes risk variants are not important risk variants for PCOS.

Ehlers-Danlos Syndrome Caused by Biallelic TNXB Variants in Patients with Congenital Adrenal Hyperplasia.

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Chen, Wuyan; Perritt, Ashley F; Morissette, Rachel; Dreiling, Jennifer L; Bohn, Markus-Frederik; Mallappa, Ashwini; Xu, Zhi; Quezado, Martha; Merke, Deborah P

2016-09-01

Some variants that cause autosomal-recessive congenital adrenal hyperplasia (CAH) also cause hypermobility type Ehlers-Danlos syndrome (EDS) due to the monoallelic presence of a chimera disrupting two flanking genes: CYP21A2, encoding 21-hydroxylase, necessary for cortisol and aldosterone biosynthesis, and TNXB, encoding tenascin-X, an extracellular matrix protein. Two types of CAH tenascin-X (CAH-X) chimeras have been described with a total deletion of CYP21A2 and characteristic TNXB variants. CAH-X CH-1 has a TNXB exon 35 120-bp deletion resulting in haploinsufficiency, and CAH-X CH-2 has a TNXB exon 40 c.12174C>G (p.Cys4058Trp) variant resulting in a dominant-negative effect. We present here three patients with biallelic CAH-X and identify a novel dominant-negative chimera termed CAH-X CH-3. Compared with monoallelic CAH-X, biallelic CAH-X results in a more severe phenotype with skin features characteristic of classical EDS. We present evidence for disrupted tenascin-X function and computational data linking the type of TNXB variant to disease severity. © 2016 WILEY PERIODICALS, INC.

Suspected Lynch syndrome associated MSH6 variants: A functional assay to determine their pathogenicity.

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Hellen Houlleberghs

2017-05-01

Full Text Available Lynch syndrome (LS is a hereditary cancer predisposition caused by inactivating mutations in DNA mismatch repair (MMR genes. Mutations in the MSH6 DNA MMR gene account for approximately 18% of LS cases. Many LS-associated sequence variants are nonsense and frameshift mutations that clearly abrogate MMR activity. However, missense mutations whose functional implications are unclear are also frequently seen in suspected-LS patients. To conclusively diagnose LS and enroll patients in appropriate surveillance programs to reduce morbidity as well as mortality, the functional consequences of these variants of uncertain clinical significance (VUS must be defined. We present an oligonucleotide-directed mutagenesis screen for the identification of pathogenic MSH6 VUS. In the screen, the MSH6 variant of interest is introduced into mouse embryonic stem cells by site-directed mutagenesis. Subsequent selection for MMR-deficient cells using the DNA damaging agent 6-thioguanine (6TG allows the identification of MMR abrogating VUS because solely MMR-deficient cells survive 6TG exposure. We demonstrate the efficacy of the genetic screen, investigate the phenotype of 26 MSH6 VUS and compare our screening results to clinical data from suspected-LS patients carrying these variant alleles.

Genetic screens to identify pathogenic gene variants in the common cancer predisposition Lynch syndrome

DEFF Research Database (Denmark)

Drost, Mark; Lützen, Anne; van Hees, Sandrine

2013-01-01

In many individuals suspected of the common cancer predisposition Lynch syndrome, variants of unclear significance (VUS), rather than an obviously pathogenic mutations, are identified in one of the DNA mismatch repair (MMR) genes. The uncertainty of whether such VUS inactivate MMR, and therefore...... function. When a residue identified as mutated in an individual suspected of Lynch syndrome is listed as critical in such a reverse diagnosis catalog, there is a high probability that the corresponding human VUS is pathogenic. To investigate the applicability of this approach, we have generated....... Nearly half of these critical residues match with VUS previously identified in individuals suspected of Lynch syndrome. This aids in the assignment of pathogenicity to these human VUS and validates the approach described here as a diagnostic tool. In a wider perspective, this work provides a model...

Numerous Brugada syndrome-associated genetic variants have no effect on J-point elevation, syncope susceptibility, malignant cardiac arrhythmia, and all-cause mortality

DEFF Research Database (Denmark)

Ghouse, Jonas; Have, Christian T; Skov, Morten W

2017-01-01

PURPOSE: We investigated whether Brugada syndrome (BrS)-associated variants identified in the general population have an effect on J-point elevation as well as whether carriers of BrS variants were more prone to experience syncope and malignant ventricular arrhythmia and had increased mortality c...

Evaluation of Electrocardiographic T-Peak to T-End Interval in Patients with Cardiac Syndrome X

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Ozgur Kaplan

2016-04-01

Full Text Available Aim: The relationship between metabolic syndrome X (MSX and atrial arrhythmia such as atrial fibrillation (AF has been shown in previous studies. The aim of this study was to evaluate ventricular repolarization by using Tp-e interval and Tp-e/QT ratio in patients with cardiac syndrome X (CSX.Material and Method: A total of 65 consecutive subjects were included in the present study. Diagnostic coronary angiography was performed on patients who had a positive stress test and suspected myocardial scintigraphy or coronary artery disease (CAD. 35 patients who were diagnosed as having CSX (Group I and 30 patients with normal coronary angiograms (Group II were included in this study. QT parameters, Tp-e intervals, and Tp-e/QT ratio were measured from the 12-lead electrocardiogram. Results: The Tp-e interval (83.4 ± 6 vs. 75 ± 5, p

Genome wide analysis of drug-induced torsades de pointes: lack of common variants with large effect sizes.

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Elijah R Behr

Full Text Available Marked prolongation of the QT interval on the electrocardiogram associated with the polymorphic ventricular tachycardia Torsades de Pointes is a serious adverse event during treatment with antiarrhythmic drugs and other culprit medications, and is a common cause for drug relabeling and withdrawal. Although clinical risk factors have been identified, the syndrome remains unpredictable in an individual patient. Here we used genome-wide association analysis to search for common predisposing genetic variants. Cases of drug-induced Torsades de Pointes (diTdP, treatment tolerant controls, and general population controls were ascertained across multiple sites using common definitions, and genotyped on the Illumina 610k or 1M-Duo BeadChips. Principal Components Analysis was used to select 216 Northwestern European diTdP cases and 771 ancestry-matched controls, including treatment-tolerant and general population subjects. With these sample sizes, there is 80% power to detect a variant at genome-wide significance with minor allele frequency of 10% and conferring an odds ratio of ≥2.7. Tests of association were carried out for each single nucleotide polymorphism (SNP by logistic regression adjusting for gender and population structure. No SNP reached genome wide-significance; the variant with the lowest P value was rs2276314, a non-synonymous coding variant in C18orf21 (p  =  3×10(-7, odds ratio = 2, 95% confidence intervals: 1.5-2.6. The haplotype formed by rs2276314 and a second SNP, rs767531, was significantly more frequent in controls than cases (p  =  3×10(-9. Expanding the number of controls and a gene-based analysis did not yield significant associations. This study argues that common genomic variants do not contribute importantly to risk for drug-induced Torsades de Pointes across multiple drugs.

A novel classification system to predict the pathogenic effects of CHD7 missense variants in CHARGE syndrome

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Bergman, Jorieke E H; Janssen, Nicole; van der Sloot, Almer M

2012-01-01

CHARGE syndrome is characterized by the variable occurrence of multisensory impairment, congenital anomalies, and developmental delay, and is caused by heterozygous mutations in the CHD7 gene. Correct interpretation of CHD7 variants is essential for genetic counseling. This is particularly diffic...

A novel homozygous missense variant in NECTIN4 (PVRL4) causing ectodermal dysplasia cutaneous syndactyly syndrome.

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Ahmad, Farooq; Nasir, Abdul; Thiele, Holger; Umair, Muhammad; Borck, Guntram; Ahmad, Wasim

2018-02-12

Ectodermal dysplasia syndactyly syndrome 1 (EDSS1) is a rare form of ectodermal dysplasia including anomalies of hair, nails, and teeth along with bilateral cutaneous syndactyly of hands and feet. In the present report, we performed a clinical and genetic characterization of a consanguineous Pakistani family with four individuals affected by EDSS1. We performed exome sequencing using DNA of one affected individual. Exome data analysis identified a novel homozygous missense variant (c.242T>C; p.(Leu81Pro)) in NECTIN4 (PVRL4). Sanger sequencing validated this variant and confirmed its cosegregation with the disease phenotype in the family members. Thus, our report adds a novel variant to the NECTIN4 mutation spectrum and contributes to the NECTIN4-related clinical characterization. © 2018 John Wiley & Sons Ltd/University College London.

Dynamic Properties of QT Intervals

Czech Academy of Sciences Publication Activity Database

Halámek, Josef; Jurák, Pavel; Vondra, Vlastimil; Lipoldová, J.; Leinveber, Pavel; Plachý, M.; Fráňa, P.; Kára, T.

2009-01-01

Roč. 36, - (2009), s. 517-520 ISSN 0276-6574 R&D Projects: GA ČR GA102/08/1129; GA MŠk ME09050 Institutional research plan: CEZ:AV0Z20650511 Keywords : QT Intervals * arrhythmia diagnosis Subject RIV: JA - Electronics ; Optoelectronics, Electrical Engineering http://cinc.mit.edu/archives/2009/pdf/0517.pdf

UMD-USHbases: a comprehensive set of databases to record and analyse pathogenic mutations and unclassified variants in seven Usher syndrome causing genes.

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Baux, David; Faugère, Valérie; Larrieu, Lise; Le Guédard-Méreuze, Sandie; Hamroun, Dalil; Béroud, Christophe; Malcolm, Sue; Claustres, Mireille; Roux, Anne-Françoise

2008-08-01

Using the Universal Mutation Database (UMD) software, we have constructed "UMD-USHbases", a set of relational databases of nucleotide variations for seven genes involved in Usher syndrome (MYO7A, CDH23, PCDH15, USH1C, USH1G, USH3A and USH2A). Mutations in the Usher syndrome type I causing genes are also recorded in non-syndromic hearing loss cases and mutations in USH2A in non-syndromic retinitis pigmentosa. Usher syndrome provides a particular challenge for molecular diagnostics because of the clinical and molecular heterogeneity. As many mutations are missense changes, and all the genes also contain apparently non-pathogenic polymorphisms, well-curated databases are crucial for accurate interpretation of pathogenicity. Tools are provided to assess the pathogenicity of mutations, including conservation of amino acids and analysis of splice-sites. Reference amino acid alignments are provided. Apparently non-pathogenic variants in patients with Usher syndrome, at both the nucleotide and amino acid level, are included. The UMD-USHbases currently contain more than 2,830 entries including disease causing mutations, unclassified variants or non-pathogenic polymorphisms identified in over 938 patients. In addition to data collected from 89 publications, 15 novel mutations identified in our laboratory are recorded in MYO7A (6), CDH23 (8), or PCDH15 (1) genes. Information is given on the relative involvement of the seven genes, the number and distribution of variants in each gene. UMD-USHbases give access to a software package that provides specific routines and optimized multicriteria research and sorting tools. These databases should assist clinicians and geneticists seeking information about mutations responsible for Usher syndrome.

Readthrough of long-QT syndrome type 1 nonsense mutations rescues function but alters the biophysical properties of the channel.

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Harmer, Stephen C; Mohal, Jagdeep S; Kemp, Duncan; Tinker, Andrew

2012-05-01

The nonsense mutations R518X-KCNQ1 and Q530X-KCNQ1 cause LQT1 (long-QT syndrome type 1) and result in a complete loss of I(Ks) channel function. In the present study we attempted to rescue the function of these mutants, in HEK (human embryonic kidney)-293 cells, by promoting readthrough of their PTCs (premature termination codons) using the pharmacological agents G-418, gentamicin and PTC124. Gentamicin and G-418 acted to promote full-length channel protein expression from R518X at 100 μM and from Q530X at 1 mM. In contrast, PTC124 did not, at any dose tested, induce readthrough of either mutant. G-418 (1 mM) treatment also acted to significantly (Pbiophysical properties of the currents produced from R518X, while similar, were not identical with wild-type as the voltage-dependence of activation was significantly (P<0.05) shifted by +25 mV. Overall, these findings indicate that although functional rescue of LQT1 nonsense mutations is possible, it is dependent on the degree of readthrough achieved and the effect on channel function of the amino acid substituted for the PTC. Such considerations will determine the success of future therapies.

Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features

DEFF Research Database (Denmark)

Santiago-Sim, Teresa; Burrage, Lindsay C; Ebstein, Frédéric

2017-01-01

regulators of the ubiquitin system. OTUD6B encodes a member of the ovarian tumor domain (OTU)-containing subfamily of deubiquitinating enzymes. Herein, we report biallelic pathogenic variants in OTUD6B in 12 individuals from 6 independent families with an intellectual disability syndrome associated...

Angiokeratoma circumscriptum naeviforme with soft tissue hypertrophy and deep venous malformation: A variant of Klippel-Trenaunay syndrome?

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Vaishali Wankhade

2014-01-01

Full Text Available Klippel-Trenaunay syndrome (KTS is a cutaneous capillary malformation on a limb in association with soft tissue swelling with or without bony hypertrophy and atypical varicosity. The capillary malformation associated with KTS is port wine stain. Angiokeratoma circumscriptum naeviforme (ACN is a congenital variant of angiokeratoma commonly present on the lower limb as a hyperkeratotic plaque. ACN is rarely associated with KTS. We report a case of ACN with soft tissue hypertrophy and deep venous malformation (possibly a variant of Klippel-Trenaunay in a 4-year-old male child.

Qt based GUI system for EPICS control systems

International Nuclear Information System (INIS)

Rhyder, A.; Fernandes, R.N.; Starritt, A.

2012-01-01

The Qt-based GUI system developed at the Australian Synchrotron for use on EPICS control systems has recently been enhanced to including support for imaging, plotting, user login, logging and configuration recipes. Plans are also being made to broaden its appeal within the wider EPICS community by expanding the range of development options and adding support for EPICS V4. Current features include graphical and non-graphical application development as well as simple 'code-free' GUI design. Additional features will allow developers to let the GUI system handle its own data using Qt-based EPICS-aware classes or, as an alternative, use other control systems data such as PSI's CAFE. (author)

Prolonged Tp-e Interval in Down Syndrome Patients with Congenitally Normal Hearts.

Science.gov (United States)

Kucuk, Mehmet; Karadeniz, Cem; Ozdemir, Rahmi; Meşe, Timur

2018-03-25

Heterogeneity of ventricular repolarization has been assessed by using the QT dispersion in Down syndrome (DS) patients with congenitally normal hearts. However, novel repolarization indexes, the Tp-e interval and Tp-e/QT ratio, have not previously been evaluated in these patients. The aim of this study was to evaluate the Tp-e interval and Tp-e/QT ratio in DS patients without congenital heart defects. Twelve-lead surface electrocardiograms of 160 DS patients and 110 age- and sex-matched healthy controls were used to evaluate and compare the Tp-e interval, Tp-e dispersion, and Tp-e/QT ratio. Heart rate, Tp-e interval, Tp-e dispersion, Tp-e/QT and Tp-e/QTc ratios were significantly higher in DS group than in the controls. Myocardial repolarization indexes in DS patients with congenitally normal hearts were found to be prolonged compared to those in normal controls. Further evaluation is warranted to reveal a relationship between prolonged repolarization indexes and arrhythmic events in these patients. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

A Challenging Form of Non-autoimmune Insulin-Dependent Diabetes in a Wolfram Syndrome Patient with a Novel Sequence Variant.

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Paris, Liliana P; Usui, Yoshihiko; Serino, Josefina; Sá, Joaquim; Friedlander, Martin

2015-06-01

Wolfram syndrome type 1 is a rare, autosomal recessive, neurodegenerative disorder that is diagnosed when insulin-dependent diabetes of non-auto-immune origin and optic atrophy are concomitantly present. Wolfram syndrome is also designated by DIDMOAD that stands for its most frequent manifestations: diabetes insipidus, diabetes mellitus, optic atrophy and deafness. With disease progression, patients also commonly develop severe neurological and genito-urinary tract abnormalities. When compared to the general type 1 diabetic population, patients with Wolfram Syndrome have been reported to have a form of diabetes that is more easily controlled and with less microvascular complications, such as diabetic retinopathy. We report a case of Wolfram syndrome in a 16-year-old male patient who presented with progressive optic atrophy and severe diabetes with very challenging glycemic control despite intensive therapy since diagnosis at the age of 6. Despite inadequate metabolic control he did not develop any diabetic microvascular complications during the 10-year follow-up period. To further investigate potential causes for this metabolic idiosyncrasy, we performed genetic analyses that revealed a novel combination of homozygous sequence variants that are likely the cause of the syndrome in this family. The identified genotype included a novel sequence variant in the Wolfram syndrome type 1 gene along with a previously described one, which had initially been associated with isolated low frequency sensorineural hearing loss (LFSNHL). Interestingly, our patient did not show any abnormal findings with audiometry testing.

A Challenging Form of Non-autoimmune Insulin-Dependent Diabetes in a Wolfram Syndrome Patient with a Novel Sequence Variant

Science.gov (United States)

Paris, Liliana P; Usui, Yoshihiko; Serino, Josefina; Sá, Joaquim; Friedlander, Martin

2015-01-01

Wolfram syndrome type 1 is a rare, autosomal recessive, neurodegenerative disorder that is diagnosed when insulin-dependent diabetes of non-auto-immune origin and optic atrophy are concomitantly present. Wolfram syndrome is also designated by DIDMOAD that stands for its most frequent manifestations: diabetes insipidus, diabetes mellitus, optic atrophy and deafness. With disease progression, patients also commonly develop severe neurological and genito-urinary tract abnormalities. When compared to the general type 1 diabetic population, patients with Wolfram Syndrome have been reported to have a form of diabetes that is more easily controlled and with less microvascular complications, such as diabetic retinopathy. We report a case of Wolfram syndrome in a 16-year-old male patient who presented with progressive optic atrophy and severe diabetes with very challenging glycemic control despite intensive therapy since diagnosis at the age of 6. Despite inadequate metabolic control he did not develop any diabetic microvascular complications during the 10-year follow-up period. To further investigate potential causes for this metabolic idiosyncrasy, we performed genetic analyses that revealed a novel combination of homozygous sequence variants that are likely the cause of the syndrome in this family. The identified genotype included a novel sequence variant in the Wolfram syndrome type 1 gene along with a previously described one, which had initially been associated with isolated low frequency sensorineural hearing loss (LFSNHL). Interestingly, our patient did not show any abnormal findings with audiometry testing. PMID:26819810

In Vitro and In Silico Risk Assessment in Acquired Long QT Syndrome: The Devil Is in the Details.

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Lee, William; Windley, Monique J; Vandenberg, Jamie I; Hill, Adam P

2017-01-01

Acquired long QT syndrome, mostly as a result of drug block of the Kv11. 1 potassium channel in the heart, is characterized by delayed cardiac myocyte repolarization, prolongation of the T interval on the ECG, syncope and sudden cardiac death due to the polymorphic ventricular arrhythmia Torsade de Pointes (TdP). In recent years, efforts are underway through the Comprehensive in vitro proarrhythmic assay (CiPA) initiative, to develop better tests for this drug induced arrhythmia based in part on in silico simulations of pharmacological disruption of repolarization. However, drug binding to Kv11.1 is more complex than a simple binary molecular reaction, meaning simple steady state measures of potency are poor surrogates for risk. As a result, there is a plethora of mechanistic detail describing the drug/Kv11.1 interaction-such as drug binding kinetics, state preference, temperature dependence and trapping-that needs to be considered when developing in silico models for risk prediction. In addition to this, other factors, such as multichannel pharmacological profile and the nature of the ventricular cell models used in simulations also need to be considered in the search for the optimum in silico approach. Here we consider how much of mechanistic detail needs to be included for in silico models to accurately predict risk and further, how much of this detail can be retrieved from protocols that are practical to implement in high throughout screens as part of next generation of preclinical in silico drug screening approaches?

QTc interval length and QT dispersion as predictors of mortality in patients with non-insulin-dependent diabetes

DEFF Research Database (Denmark)

Christensen, P K; Gall, M A; Major-Pedersen, A

2000-01-01

Patients with non-insulin-dependent diabetes (NIDDM) are at independent risk of cardiovascular death. The reason is only partially understood. The aim of our study was therefore to evaluate the impact of corrected QT interval length (QTc) and QT dispersion (QT-disp) on mortality in a cohort of 32....... Our study showed a high prevalence of QTc and QT-disp abnormalities and indicated that QTc-max but not QT-disp is an independent predictor of all cause and cardiovascular mortality in NIDDM patients.......-seven percent of the patients with PQTc died compared with 17% with normal QTc interval (pcause mortality; QTc-max (p....01), retinopathy (pcreatinine (p

Germ-line variants identified by next generation sequencing in a panel of estrogen and cancer associated genes correlate with poor clinical outcome in Lynch syndrome patients.

Science.gov (United States)

Jóri, Balazs; Kamps, Rick; Xanthoulea, Sofia; Delvoux, Bert; Blok, Marinus J; Van de Vijver, Koen K; de Koning, Bart; Oei, Felicia Trups; Tops, Carli M; Speel, Ernst Jm; Kruitwagen, Roy F; Gomez-Garcia, Encarna B; Romano, Andrea

2015-12-01

The risk to develop colorectal and endometrial cancers among subjects testing positive for a pathogenic Lynch syndrome mutation varies, making the risk prediction difficult. Genetic risk modifiers alter the risk conferred by inherited Lynch syndrome mutations, and their identification can improve genetic counseling. We aimed at identifying rare genetic modifiers of the risk of Lynch syndrome endometrial cancer. A family based approach was used to assess the presence of genetic risk modifiers among 35 Lynch syndrome mutation carriers having either a poor clinical phenotype (early age of endometrial cancer diagnosis or multiple cancers) or a neutral clinical phenotype. Putative genetic risk modifiers were identified by Next Generation Sequencing among a panel of 154 genes involved in endometrial physiology and carcinogenesis. A simple pipeline, based on an allele frequency lower than 0.001 and on predicted non-conservative amino-acid substitutions returned 54 variants that were considered putative risk modifiers. The presence of two or more risk modifying variants in women carrying a pathogenic Lynch syndrome mutation was associated with a poor clinical phenotype. A gene-panel is proposed that comprehends genes that can carry variants with putative modifying effects on the risk of Lynch syndrome endometrial cancer. Validation in further studies is warranted before considering the possible use of this tool in genetic counseling.

Expanding the cardiac spectrum of Noonan syndrome with RIT1 variant: Left main coronary artery atresia causing sudden death.

Science.gov (United States)

Ramond, Francis; Duband, Sébastien; Croisille, Pierre; Cavé, Hélène; Teyssier, Georges; Adouard, Véronique; Touraine, Renaud

2017-06-01

Noonan syndrome is a well-known genetic condition associating congenital heart defects, short stature, and distinctive facial features. Pulmonary valve stenosis and hypertrophic cardiomyopathy are the most frequent cardiac abnormalities, the latter being associated with a higher mortality. Here we report for the first time, a case of congenital left main coronary artery atresia in a Noonan syndrome associated with RIT1 variant, leading to unrescued sudden death. This case-report supports the already-suspected severity of the RIT1-related Noonan syndrome compared to average Noonan syndrome, and should encourage clinicians to be very cautious with these patients. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

MYO7A and USH2A gene sequence variants in Italian patients with Usher syndrome.

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Sodi, Andrea; Mariottini, Alessandro; Passerini, Ilaria; Murro, Vittoria; Tachyla, Iryna; Bianchi, Benedetta; Menchini, Ugo; Torricelli, Francesca

2014-01-01

To analyze the spectrum of sequence variants in the MYO7A and USH2A genes in a group of Italian patients affected by Usher syndrome (USH). Thirty-six Italian patients with a diagnosis of USH were recruited. They received a standard ophthalmologic examination, visual field testing, optical coherence tomography (OCT) scan, and electrophysiological tests. Fluorescein angiography and fundus autofluorescence imaging were performed in selected cases. All the patients underwent an audiologic examination for the 0.25-8,000 Hz frequencies. Vestibular function was evaluated with specific tests. DNA samples were analyzed for sequence variants of the MYO7A gene (for USH1) and the USH2A gene (for USH2) with direct sequencing techniques. A few patients were analyzed for both genes. In the MYO7A gene, ten missense variants were found; three patients were compound heterozygous, and two were homozygous. Thirty-four USH2A gene variants were detected, including eight missense variants, nine nonsense variants, six splicing variants, and 11 duplications/deletions; 19 patients were compound heterozygous, and three were homozygous. Four MYO7A and 17 USH2A variants have already been described in the literature. Among the novel mutations there are four USH2A large deletions, detected with multiplex ligation dependent probe amplification (MLPA) technology. Two potentially pathogenic variants were found in 27 patients (75%). Affected patients showed variable clinical pictures without a clear genotype-phenotype correlation. Ten variants in the MYO7A gene and 34 variants in the USH2A gene were detected in Italian patients with USH at a high detection rate. A selective analysis of these genes may be valuable for molecular analysis, combining diagnostic efficiency with little time wastage and less resource consumption.

QT/RR Coupling and Gender Differences

Czech Academy of Sciences Publication Activity Database

Halámek, Josef; Jurák, Pavel; Lipoldová, J.; Leinveber, Pavel

2010-01-01

Roč. 37, - (2010), s. 365-368 ISSN 0276-6574 R&D Projects: GA ČR GA102/08/1129 Institutional research plan: CEZ:AV0Z20650511 Keywords : THEW * QT/RR model * EXPDC Subject RIV: JA - Electronics ; Optoelectronics, Electrical Engineering http://cinc.mit.edu/archives/2010/pdf/0365.pdf

Effects of Single Dose Energy Drink on QT and P-Wave Dispersion

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Huseyin Arinc

2013-12-01

Full Text Available INTRODUCTION: Aim of this study is to evaluate the cardiac electrophysiological effects of energy drink (Red Bull on QT and P duration and dispersion on surface electrocardiogram. METHODS: Twenty healthy volunteers older than 17 years of age were included the study. Subjects with a cardiac rhythm except sinus rhythm, history of atrial or ventricular arrhythmia, family history of premature sudden cardiac death, palpitations, T-wave abnormalities, QTc interval greater than 440 milliseconds, or those P-waves and QT intervals unavailable in at least eight ECG leads were excluded. Subjects having insomnia, lactose intolerance, caffeine allergy, recurrent headaches, depression, any psychiatric condition, and history of alcohol or drug abuse, pregnant or lactating women were also excluded from participation. 12 lead ECG was obtained before and after consumption of 250 cc enegry drink. QT and P-wave dispersion was calculated. RESULTS: No significant difference have occurred in heart rate (79 ± 14 vs.81 ±13, p=0.68, systolic pressure (114 ± 14 vs.118 ± 16,p=0.38, diastolic blood pressure (74 ± 12 vs.76 ± 14, p=0.64, QT dispersion (58 ± 12 vs. 57 ± 22, p= 0.785 and P-wave dispersion (37 ± 7 vs. 36 ± 13, p= 0.755 between before and 2 hours after consumption of energy drink. DISCUSSION AND CONCLUSION: Consumption of single dose energy drink doesn't affect QT dispersion and P-wave dispersion, heart rate and blood pressure in healthy adults.

Functional characterization of MLH1 missense variants identified in Lynch Syndrome patients

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Andersen, Sofie Dabros; Liberti, Sascha Emilie; Lützen, Anne

2012-01-01

Germline mutations in the human DNA mismatch repair (MMR) genes MSH2 and MLH1 are associated with the inherited cancer disorder Lynch Syndrome (LS), also known as Hereditary Nonpolyposis Colorectal Cancer or HNPCC. A proportion of MSH2 and MLH1 mutations found in suspected LS patients give rise...... localization and protein-protein interaction with the dimer partner PMS2 and the MMR-associated exonuclease 1. We show that a significant proportion of examined variant proteins have functional defects in either subcellular localization or protein-protein interactions, which is suspected to lead to the cancer...

Variant Carvajal syndrome with additional dental anomalies.

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Barber, Sophy; Day, Peter; Judge, Mary; Toole, Edell O'; Fayle, Stephen

2012-09-01

This paper aims to review the case of a girl who presented with a number of dental anomalies, in addition to unusual skin, nail and hair conditions. Tragically an undiagnosed cardiomyopathy caused unexpected sudden death. The case is discussed with reference to a number of dermatological and oral conditions which were considered as possible diagnoses. AW had been under long term dental care for prepubertal periodontitis, premature root resorption of primary teeth, soft tissue and dental anomalies, and angular cheilitis. Separately she had also been seen by several dermatologists with respect to palmar plantar keratosis, striae keratoderma, wiry hair and abnormal finger nails. Tragically the patient suffered a sudden unexpected death and the subsequent post mortem identified an undiagnosed dilated cardiomyopathy. The most likely diagnosis is that this case is a variant of Carvajal Syndrome with additional dental anomalies. To date we have been unable to identify mutations in the desoplakin gene. We aim to emphasise the importance of recognising these dental and dermatological signs when they present together as a potential risk factor for cardiac abnormalities. © 2012 The Authors. International Journal of Paediatric Dentistry © 2012 BSPD, IAPD and Blackwell Publishing Ltd.

Screening for single nucleotide variants, small indels and exon deletions with a next-generation sequencing based gene panel approach for Usher syndrome.

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Krawitz, Peter M; Schiska, Daniela; Krüger, Ulrike; Appelt, Sandra; Heinrich, Verena; Parkhomchuk, Dmitri; Timmermann, Bernd; Millan, Jose M; Robinson, Peter N; Mundlos, Stefan; Hecht, Jochen; Gross, Manfred

2014-09-01

Usher syndrome is an autosomal recessive disorder characterized both by deafness and blindness. For the three clinical subtypes of Usher syndrome causal mutations in altogether 12 genes and a modifier gene have been identified. Due to the genetic heterogeneity of Usher syndrome, the molecular analysis is predestined for a comprehensive and parallelized analysis of all known genes by next-generation sequencing (NGS) approaches. We describe here the targeted enrichment and deep sequencing for exons of Usher genes and compare the costs and workload of this approach compared to Sanger sequencing. We also present a bioinformatics analysis pipeline that allows us to detect single-nucleotide variants, short insertions and deletions, as well as copy number variations of one or more exons on the same sequence data. Additionally, we present a flexible in silico gene panel for the analysis of sequence variants, in which newly identified genes can easily be included. We applied this approach to a cohort of 44 Usher patients and detected biallelic pathogenic mutations in 35 individuals and monoallelic mutations in eight individuals of our cohort. Thirty-nine of the sequence variants, including two heterozygous deletions comprising several exons of USH2A, have not been reported so far. Our NGS-based approach allowed us to assess single-nucleotide variants, small indels, and whole exon deletions in a single test. The described diagnostic approach is fast and cost-effective with a high molecular diagnostic yield.

QT interval prolongation related to psychoactive drug treatment: a comparison of monotherapy versus polytherapy

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Piccinelli Marco

2005-01-01

Full Text Available Abstract Background Several antipsychotic agents are known to prolong the QT interval in a dose dependent manner. Corrected QT interval (QTc exceeding a threshold value of 450 ms may be associated with an increased risk of life threatening arrhythmias. Antipsychotic agents are often given in combination with other psychotropic drugs, such as antidepressants, that may also contribute to QT prolongation. This observational study compares the effects observed on QT interval between antipsychotic monotherapy and psychoactive polytherapy, which included an additional antidepressant or lithium treatment. Method We examined two groups of hospitalized women with Schizophrenia, Bipolar Disorder and Schizoaffective Disorder in a naturalistic setting. Group 1 was composed of nineteen hospitalized women treated with antipsychotic monotherapy (either haloperidol, olanzapine, risperidone or clozapine and Group 2 was composed of nineteen hospitalized women treated with an antipsychotic (either haloperidol, olanzapine, risperidone or quetiapine with an additional antidepressant (citalopram, escitalopram, sertraline, paroxetine, fluvoxamine, mirtazapine, venlafaxine or clomipramine or lithium. An Electrocardiogram (ECG was carried out before the beginning of the treatment for both groups and at a second time after four days of therapy at full dosage, when blood was also drawn for determination of serum levels of the antipsychotic. Statistical analysis included repeated measures ANOVA, Fisher Exact Test and Indipendent T Test. Results Mean QTc intervals significantly increased in Group 2 (24 ± 21 ms however this was not the case in Group 1 (-1 ± 30 ms (Repeated measures ANOVA p Conclusions No significant prolongation of the QT interval was found following monotherapy with an antipsychotic agent, while combination of these drugs with antidepressants caused a significant QT prolongation. Careful monitoring of the QT interval is suggested in patients taking a

Development of in vitro and in vivo functional assays to enable diagnosis of Variants of Uncertain Significance in the common cancer predisposition Lynch syndrome

NARCIS (Netherlands)

Drost, Mark

2014-01-01

Lynch syndrome (LS) is caused by germline mutations in DNA mismatch repair (MMR) genes and is the most prevalent hereditary colorectal cancer syndrome. A significant proportion of variants identified in MMR and other common cancer susceptibility genes are missense or noncoding changes whose

Short QT interval is unreliable marker of anabolic androgenic steroid abuse in competitive athletes

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Đorđević Vitomir

2012-01-01

Full Text Available Introduction. Previous animal and human studies provided the evidence that testosterone may affect ventricular repolarization by shortening of the QT interval. Synthetic derivatives of testosterone, modified to enhance its anabolic properties, are occasionally abused by some competitive athletes. Objective. We assessed whether the QT interval duration could discriminate androgenic anabolic steroids (AAS-using strength athletes (SA from drug-free endurance athletes (EA, by comparing 25 formulas for QT interval correction. Methods. We recruited 22 elite male athletes involved in long-term strength or endurance training and 20 sedentary controls. All elite

Cardiac Channelopathies and Sudden Death: Recent Clinical and Genetic Advances.

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Fernández-Falgueras, Anna; Sarquella-Brugada, Georgia; Brugada, Josep; Brugada, Ramon; Campuzano, Oscar

2017-01-29

Sudden cardiac death poses a unique challenge to clinicians because it may be the only symptom of an inherited heart condition. Indeed, inherited heart diseases can cause sudden cardiac death in older and younger individuals. Two groups of familial diseases are responsible for sudden cardiac death: cardiomyopathies (mainly hypertrophic cardiomyopathy, dilated cardiomyopathy, and arrhythmogenic cardiomyopathy) and channelopathies (mainly long QT syndrome, Brugada syndrome, short QT syndrome, and catecholaminergic polymorphic ventricular tachycardia). This review focuses on cardiac channelopathies, which are characterized by lethal arrhythmias in the structurally normal heart, incomplete penetrance, and variable expressivity. Arrhythmias in these diseases result from pathogenic variants in genes encoding cardiac ion channels or associated proteins. Due to a lack of gross structural changes in the heart, channelopathies are often considered as potential causes of death in otherwise unexplained forensic autopsies. The asymptomatic nature of channelopathies is cause for concern in family members who may be carrying genetic risk factors, making the identification of these genetic factors of significant clinical importance.

QT Interval Prolongation as a Biomarker for Torsades de Pointes and Sudden Death in Drug Development

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Gregory D. Sides

2002-01-01

Full Text Available Prolongation of the QT interval on the surface 12-lead electrocardiogram is widely accepted as a biomarker for the potential of a drug to produce torsades de pointes and/or sudden death. Detection of drug-induced prolongation of the QT interval in animals and man is frequently confounded by extrinsic and intrinsic factors that limit the ability to detect a true drug effect. In particular drugs that increase heart rate show an apparent increase in QT interval that confounds assessment of a true drug effect on cardiac ventricular repolarization. The basis for the use of the QT interval as a biomarker will be examined.

Acute effects of smoking on QT dispersion in healthy males

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Mohammad Ali Akbarzadeh

2014-03-01

Full Text Available 800x600 BACKGROUND: Cigarette smoking increases the risk of ventricular fibrillation and sudden cardiac death (SCD. QT dispersion (QTD is an important predictor of cardiac arrhythmia. The aim of this study was to assess the acute effect of smoking a single standard cigarette containing 1.7 mg nicotine on QT interval and QTD in healthy smokers and nonsmokers. METHODS: The study sample population consisted of 40 healthy male hospital staff, including 20 smokers and 20 nonsmokers. They were asked to refrain from smoking at least 6 h before attending the study. A 12-lead surface electrocardiogram (ECG, recorded at paper speed of 50 mm/s, was obtained from all participants before and 10 min after smoking of a single complete cigarette. QT interval, corrected QT interval, QTD, and corrected QT dispersion (QTcD were measured before and after smoking. RESULTS: Smokers and nonsmokers did not have any significant differences in heart rate (HR (before smoking = 67.35 ± 5.14 vs. 67.70 ± 5.07, after smoking = 76.70 ± 6.50 vs. 76.85 ± 6.50, respectively, QTD (before smoking = 37.75 ± 7.16 vs. 39.15 ± 6.55, after smoking = 44.75 ± 11.97 vs. 45.50 ± 9.58, respectively, and QTcD (before smoking = 39.85 ± 7.40 vs. 41.55 ± 6.57, after smoking = 50.70 ± 14.31 vs. 51.50 ± 11.71, respectively. However, after smoking a single cigarette, HR, mean QTD, and QTcD significantly increased (all had P value <0.001 in comparison to the measures before smoking. CONCLUSION: Smoking of a single complete cigarette in both smokers and nonsmokers results in significant QTD increase, which can cause arrhythmia and SCD.   Keywords: Cardiac, Death, Electrocardiography, Smoking, Sudden  Normal 0 false false false EN-US X-NONE FA MicrosoftInternetExplorer4

In Vitro and In Silico Risk Assessment in Acquired Long QT Syndrome: The Devil Is in the Details

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William Lee

2017-11-01

Full Text Available Acquired long QT syndrome, mostly as a result of drug block of the Kv11. 1 potassium channel in the heart, is characterized by delayed cardiac myocyte repolarization, prolongation of the T interval on the ECG, syncope and sudden cardiac death due to the polymorphic ventricular arrhythmia Torsade de Pointes (TdP. In recent years, efforts are underway through the Comprehensive in vitro proarrhythmic assay (CiPA initiative, to develop better tests for this drug induced arrhythmia based in part on in silico simulations of pharmacological disruption of repolarization. However, drug binding to Kv11.1 is more complex than a simple binary molecular reaction, meaning simple steady state measures of potency are poor surrogates for risk. As a result, there is a plethora of mechanistic detail describing the drug/Kv11.1 interaction—such as drug binding kinetics, state preference, temperature dependence and trapping—that needs to be considered when developing in silico models for risk prediction. In addition to this, other factors, such as multichannel pharmacological profile and the nature of the ventricular cell models used in simulations also need to be considered in the search for the optimum in silico approach. Here we consider how much of mechanistic detail needs to be included for in silico models to accurately predict risk and further, how much of this detail can be retrieved from protocols that are practical to implement in high throughout screens as part of next generation of preclinical in silico drug screening approaches?

Variant of Rett syndrome and CDKL5 gene: clinical and autonomic description of 10 cases.

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Pini, Giorgio; Bigoni, Stefania; Engerström, Ingegerd Witt; Calabrese, Olga; Felloni, Beatrice; Scusa, Maria Flora; Di Marco, Pietro; Borelli, Paolo; Bonuccelli, Ubaldo; Julu, Peter O O; Nielsen, Jytte Bieber; Morin, Bodil; Hansen, Stig; Gobbi, Giuseppe; Visconti, Paola; Pintaudi, Maria; Edvige, Veneselli; Romanelli, Anna; Bianchi, Fabrizio; Casarano, Manuela; Battini, Roberta; Cioni, Giovanni; Ariani, Francesca; Renieri, Alessandra; Benincasa, Alberto; Delamont, Robert S; Zappella, Michele

2012-02-01

Rett syndrome (RTT) is a severe neurodevelopmental disorder affecting almost exclusively females. The Hanefeld variant, or early-onset seizure variant, has been associated with mutations in CDKL5 gene. In recent years more than 60 patients with mutations in the CDKL5 gene have been described in the literature, but the cardiorespiratory phenotype has not been reported. Our aim is to describe clinical and autonomic features of these girls. 10 girls with CDKL5 mutations and a diagnosis of Hanefeld variant have been evaluated on axiological and clinical aspects. In all subjects an evaluation of the autonomic system was performed using the Neuroscope. Common features were gaze avoidance, repetitive head movements and hand stereotypies. The autonomic evaluation disclosed eight cases with the Forceful breather cardiorespiratory phenotype and two cases with the Apneustic breather phenotype. The clinical picture remains within the RTT spectrum but some symptoms are more pronounced in addition to the very early onset of seizures. The cardiorespiratory phenotype was dominated by Forceful breathers, while Feeble breathers were not found, differently from the general Rett population, suggesting a specific behavioral and cardiorespiratory phenotype of the RTT the Hanefeld variant. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Syndromic intellectual disability: a new phenotype caused by an aromatic amino acid decarboxylase gene (DDC) variant.

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Graziano, Claudio; Wischmeijer, Anita; Pippucci, Tommaso; Fusco, Carlo; Diquigiovanni, Chiara; Nõukas, Margit; Sauk, Martin; Kurg, Ants; Rivieri, Francesca; Blau, Nenad; Hoffmann, Georg F; Chaubey, Alka; Schwartz, Charles E; Romeo, Giovanni; Bonora, Elena; Garavelli, Livia; Seri, Marco

2015-04-01

The causative variant in a consanguineous family in which the three patients (two siblings and a cousin) presented with intellectual disability, Marfanoid habitus, craniofacial dysmorphisms, chronic diarrhea and progressive kyphoscoliosis, has been identified through whole exome sequencing (WES) analysis. WES study identified a homozygous DDC variant in the patients, c.1123C>T, resulting in p.Arg375Cys missense substitution. Mutations in DDC cause a recessive metabolic disorder (aromatic amino acid decarboxylase, AADC, deficiency, OMIM #608643) characterized by hypotonia, oculogyric crises, excessive sweating, temperature instability, dystonia, severe neurologic dysfunction in infancy, and specific abnormalities of neurotransmitters and their metabolites in the cerebrospinal fluid (CSF). In our family, analysis of neurotransmitters and their metabolites in patient's CSF shows a pattern compatible with AADC deficiency, although the clinical signs are different from the classic form. Our work expands the phenotypic spectrum associated with DDC variants, which therefore can cause an additional novel syndrome without typical movement abnormalities. Copyright © 2015 Elsevier B.V. All rights reserved.

Mitigating prolonged QT interval in cancer nanodrug development for accelerated clinical translation.

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Ranjan, Amalendu P; Mukerjee, Anindita; Helson, Lawrence; Vishwanatha, Jamboor K

2013-12-14

Cardiac toxicity is the foremost reason for drug discontinuation from development to clinical evaluation and post market surveillance [Fung 35:293-317, 2001; Piccini 158:317-326 2009]. The Food and Drug Administration (FDA) has rejected many potential pharmaceutical agents due to QT prolongation effects. Since drug development and FDA approval takes an enormous amount of time, money and effort with high failure rates, there is an increased focus on rescuing drugs that cause QT prolongation. If these otherwise safe and potent drugs were formulated in a unique way so as to mitigate the QT prolongation associated with them, these potent drugs may get FDA approval for clinical use. Rescuing these compounds not only benefit the patients who need them but also require much less time and money thus leading to faster clinical translation. In this study, we chose curcumin as our drug of choice since it has been shown to posses anti-tumor properties against various cancers with limited toxicity. The major limitations with this pharmacologically active drug are (a) its ability to prolong QT by inhibiting the hERG channel and (b) its low bioavailability. In our previous studies, we found that lipids have protective actions against hERG channel inhibition and therefore QT prolongation. Results of the manual patch clamp assay of HEK 293 cells clearly illustrated that our hybrid nanocurcumin formulation prevented the curcumin induced inhibition of hERG K+ channel at concentrations higher than the therapeutic concentrations of curcumin. Comparing the percent inhibition, the hybrid nanocurcumin limited inhibition to 24.8% at a high curcumin equivalent concentration of 18 μM. Liposomal curcumin could only decrease this inhibition upto 30% only at lower curcumin concentration of 6 μM but not at 18 μM concentration. Here we show a curcumin encapsulated lipopolymeric hybrid nanoparticle formulation which could protect against QT prolongation and also render increased

Onset of decreased heart work is correlated with increased heart rate and shortened QT interval in high-carbohydrate fed overweight rats.

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Durak, Aysegul; Olgar, Yusuf; Tuncay, Erkan; Karaomerlioglu, Irem; Kayki Mutlu, Gizem; Arioglu Inan, Ebru; Altan, Vecdi Melih; Turan, Belma

2017-11-01

Mechanical activity of the heart is adversely affected in metabolic syndrome (MetS) characterized by increased body mass and marked insulin resistance. Herein, we examined the effects of high carbohydrate intake on cardiac function abnormalities by evaluating in situ heart work, heart rate, and electrocardiograms (ECGs) in rats. MetS was induced in male Wistar rats by adding 32% sucrose to drinking water for 22-24 weeks and was confirmed by insulin resistance, increased body weight, increased blood glucose and serum insulin, and increased systolic and diastolic blood pressures in addition to significant loss of left ventricular integrity and increased connective tissue around myofibrils. Analysis of in situ ECG recordings showed a markedly shortened QT interval and decreased QRS amplitude with increased heart rate. We also observed increased oxidative stress and decreased antioxidant defense characterized by decreases in serum total thiol level and attenuated paraoxonase and arylesterase activities. Our data indicate that increased heart rate and a shortened QT interval concomitant with higher left ventricular developed pressure in response to β-adrenoreceptor stimulation as a result of less cyclic AMP release could be regarded as a natural compensation mechanism in overweight rats with MetS. In addition to the persistent insulin resistance and obesity associated with MetS, one should consider the decreased heart work, increased heart rate, and shortened QT interval associated with high carbohydrate intake, which may have more deleterious effects on the mammalian heart.

Conventional QT Variability Measurement vs. Template Matching Techniques: Comparison of Performance Using Simulated and Real ECG

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Baumert, Mathias; Starc, Vito; Porta, Alberto

2012-01-01

Increased beat-to-beat variability in the QT interval (QTV) of ECG has been associated with increased risk for sudden cardiac death, but its measurement is technically challenging and currently not standardized. The aim of this study was to investigate the performance of commonly used beat-to-beat QT interval measurement algorithms. Three different methods (conventional, template stretching and template time shifting) were subjected to simulated data featuring typical ECG recording issues (broadband noise, baseline wander, amplitude modulation) and real short-term ECG of patients before and after infusion of sotalol, a QT interval prolonging drug. Among the three algorithms, the conventional algorithm was most susceptible to noise whereas the template time shifting algorithm showed superior overall performance on simulated and real ECG. None of the algorithms was able to detect increased beat-to-beat QT interval variability after sotalol infusion despite marked prolongation of the average QT interval. The QTV estimates of all three algorithms were inversely correlated with the amplitude of the T wave. In conclusion, template matching algorithms, in particular the time shifting algorithm, are recommended for beat-to-beat variability measurement of QT interval in body surface ECG. Recording noise, T wave amplitude and the beat-rejection strategy are important factors of QTV measurement and require further investigation. PMID:22860030

Conventional QT variability measurement vs. template matching techniques: comparison of performance using simulated and real ECG.

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Mathias Baumert

Full Text Available Increased beat-to-beat variability in the QT interval (QTV of ECG has been associated with increased risk for sudden cardiac death, but its measurement is technically challenging and currently not standardized. The aim of this study was to investigate the performance of commonly used beat-to-beat QT interval measurement algorithms. Three different methods (conventional, template stretching and template time shifting were subjected to simulated data featuring typical ECG recording issues (broadband noise, baseline wander, amplitude modulation and real short-term ECG of patients before and after infusion of sotalol, a QT interval prolonging drug. Among the three algorithms, the conventional algorithm was most susceptible to noise whereas the template time shifting algorithm showed superior overall performance on simulated and real ECG. None of the algorithms was able to detect increased beat-to-beat QT interval variability after sotalol infusion despite marked prolongation of the average QT interval. The QTV estimates of all three algorithms were inversely correlated with the amplitude of the T wave. In conclusion, template matching algorithms, in particular the time shifting algorithm, are recommended for beat-to-beat variability measurement of QT interval in body surface ECG. Recording noise, T wave amplitude and the beat-rejection strategy are important factors of QTV measurement and require further investigation.

Rare Copy Number Variants in a Population Based Investigation of Hypoplastic Right Heart Syndrome

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Dimopoulos, Aggeliki; Sicko, Robert J.; Kay, Denise M.; Rigler, Shannon L.; Druschel, Charlotte M.; Caggana, Michele; Browne, Marilyn L.; Fan, Ruzong; Romitti, Paul A.; Brody, Lawrence C.; Mills, James L.

2016-01-01

Background Hypoplastic right heart syndrome (HRHS) is a rare congenital defect characterized by underdevelopment of the right heart structures commonly accompanied by an atrial septal defect. Familial HRHS reports suggest genetic factor involvement. We examined the role of copy number variants (CNVs) in HRHS. Methods We genotyped 32 HRHS cases identified from all New York State live births (1998–2005) using Illumina HumanOmni2.5 microarrays. CNVs were called with PennCNV and prioritized if they were ≥20Kb, contained ≥10 SNPs and had minimal overlap with CNVs from in-house controls, the Database of Genomic Variants, HapMap3 and CHOP database. Results We identified 28 CNVs in 17 cases; several encompassed genes important for right heart development. One case had a 2p16–2p23 duplication spanning LBH, a limb and heart development transcription factor. Lbh mis-expression results in right ventricular hypoplasia and pulmonary valve defects. This duplication also encompassed SOS1, a factor associated with pulmonary valve stenosis in Noonan syndrome. Sos1−/− mice display thin and poorly trabeculated ventricles. In another case, we identified a 1.5Mb deletion associated with Williams Beuren syndrome, a disorder that includes valvular malformations. A third case had a 24Kb deletion upstream of the TGFβ ligand ITGB8. Embryos genetically null for Itgb8, and its intracellular interactant Band 4.1B, display lethal cardiac phenotypes. Conclusions To our knowledge, this is the first study of CNVs in HRHS. We identified several rare CNVs that overlap genes related to right ventricular wall and valve development, suggesting that genetics plays a role in HRHS and providing clues for further investigation. PMID:28009100

Leigh-Like Syndrome Due to Homoplasmic m.8993T>G Variant with Hypocitrullinemia and Unusual Biochemical Features Suggestive of Multiple Carboxylase Deficiency (MCD).

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Balasubramaniam, Shanti; Lewis, B; Mock, D M; Said, H M; Tarailo-Graovac, M; Mattman, A; van Karnebeek, C D; Thorburn, D R; Rodenburg, R J; Christodoulou, J

2017-01-01

Leigh syndrome (LS), or subacute necrotizing encephalomyelopathy, is a genetically heterogeneous, relentlessly progressive, devastating neurodegenerative disorder that usually presents in infancy or early childhood. A diagnosis of Leigh-like syndrome may be considered in individuals who do not fulfil the stringent diagnostic criteria but have features resembling Leigh syndrome.We describe a unique presentation of Leigh-like syndrome in a 3-year-old boy with elevated 3-hydroxyisovalerylcarnitine (C5-OH) on newborn screening (NBS). Subsequent persistent plasma elevations of C5-OH and propionylcarnitine (C3) as well as fluctuating urinary markers were suggestive of multiple carboxylase deficiency (MCD). Normal enzymology and mutational analysis of genes encoding holocarboxylase synthetase (HLCS) and biotinidase (BTD) excluded MCD. Biotin uptake studies were normal excluding biotin transporter deficiency. His clinical features at 13 months of age comprised psychomotor delay, central hypotonia, myopathy, failure to thrive, hypocitrullinemia, recurrent episodes of decompensation with metabolic keto-lactic acidosis and an episode of hyperammonemia. Biotin treatment from 13 months of age was associated with increased patient activity, alertness, and attainment of new developmental milestones, despite lack of biochemical improvements. Whole exome sequencing (WES) analysis failed to identify any other variants which could likely contribute to the observed phenotype, apart from the homoplasmic (100%) m.8993T>G variant initially detected by mitochondrial DNA (mtDNA) sequencing.Hypocitrullinemia has been reported in patients with the m.8993T>G variant and other mitochondrial disorders. However, persistent plasma elevations of C3 and C5-OH have previously only been reported in one other patient with this homoplasmic mutation. We suggest considering the m.8993T>G variant early in the diagnostic evaluation of MCD-like biochemical disturbances, particularly when associated with

MSX ₁ gene variant and non-syndromic clefting: association or rejection?

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Reddy, Naveen Admala; Gopinath, Adusumilli; Reddy, Jayaprakash Thirumala; Devanna, Raghu; Saravanan, Pichai; Rohra, Mayur G

2014-01-01

Non-syndromic cleft lip/palate (NSCL/P) is a congenital anomaly with significant medical, psychological and social ramifications. There is sufficient evidence to hypothesize that locus for this condition can be identified by candidate genes. The aim of this study is to amplify the chosen region (799 G >T) of MSX 1 gene, investigate the degree of association and perform a mutation research from Raichur cleft lip and palate patient sample. Case history and clinical examination of the patient were recorded to rule. Written consent was obtained from patients and controls for in vivo study. STUDY WAS DESIGNED IN FOUR STEPS AS FOLLOWS: a. Collection of a blood sample; b. Genomic deoxyribonucleic acid (DNA) extraction; c. Polymerase chain reaction (PCR); d. Restriction fragment length polymorphism (RFLP). Blood samples were collected from 50 subjects having NSCL/P and 50 controls. Genomic DNA was extracted, PCR and RFLP was performed for digestion products that were evaluated. Chi-square test with P value at 95% confidence intervals. The results showed a positive correlation between MSX 1 799 G >T gene variant and NSCL/P patients in Raichur patients. From a genetically diverse etiology MSX 1 799 G >T gene variant may be a good screening marker for NSCL/P in Raichur patients.

Association Between ACE Gene Polymorphism and QT Dispersion in Patients with Acute Myocardial Infarction.

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Karahan, Zulkuf; Ugurlu, Murat; Ucaman, Berzal; Veysel Ulug, Ali; Kaya, Ilyas; Cevik, Kemal; Sahin Adiyaman, Mehmet; Oztürk, Onder; Iyem, Hikmet; Ozdemir, Ferit

2016-01-01

Angiotensin converting enzyme (ACE) gene polymorphism is associated with high renin-angiotensin system causing myocardial fibrosis and ventricular repolarization abnormality. Based on these findings, this study was designed to determine the association between ACE gene insertion/deletion (I/D) polymorphism and QT dispersion after acute myocardial infarction (MI). The study included 108 patients with acute MI. Blood samples were obtained from all the patients for genomic DNA analysis. ECGs were recorded at baseline and at the end of a 6-month follow up. The OT dispersion was manually calculated. The mean age of the patients was 57.5 ±9.9 years (ranging from 36 to 70). The patients with DD genotype showed longer QT dispersion than patients with II or DI genotype at the baseline, while at the end of the six-month follow up the patients with DI genotype showed longer QT dispersion than patients with DD or II genotypes. However, the magnitude of the QT dispersion prolongation was higher in patients carrying the ACE D allele than patients who were not carrying it, at baseline and at the end of six-month follow up (52.5 ±2.6 msn vs. 47.5±2.1 msn at baseline, 57±3.2 msn vs. 53±2.6 msn in months, P: 0.428 and P: 0.613, respectively). Carriers of the D allele of ACE gene I/D polymorphism may be associated with QT dispersion prolongation in patients with MI.An interaction of QT dispersion and ACE gene polymorphism may be associated with an elevation of serum type I-C terminal pro-collagen concentration, possibly leading to myocardial fibrosis, and increased action potential duration.

Cardiac conductive disturbance in patients with polycystic ovary syndrome.

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Huang, Jen-Hung; Tsai, Jen-Chen; Hsu, Ming-I; Chen, Yi-Jen

2010-12-01

Polycystic ovary syndrome (PCOS) is the most common endocrine abnormality of reproductive-aged women and increases the risk of cardiovascular disease. However, the effects of PCOS on electrocardiograms (ECGs) are not fully elucidated. The aim of this study was to evaluate the characteristics of ECGs in patients with PCOS. This study included 24 patients with PCOS and 12 patients without PCOS. The heart rate, PR interval, QRS duration, Sokolow-Lyon voltage (SV1 + RV5/6), Cornell voltage (RaVL + SV3), QT interval and QTc interval were measured in 12-lead ECGs. The QRS duration was wider in patients with PCOS than those without PCOS (91 ± 8 vs. 81 ± 10 ms, p heart rate, PR interval, Sokolow-Lyon voltage, product of the QRS duration times Cornell voltage combination, QT interval, QTc interval, QT dispersion and QTc dispersion were similar between the two groups. PCOS is associated with a widening QRS duration, which may contribute to its increased cardiovascular risks.

Novel PIGT Variant in Two Brothers: Expansion of the Multiple Congenital Anomalies-Hypotonia Seizures Syndrome 3 Phenotype

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Nadia Skauli

2016-11-01

Full Text Available Biallelic PIGT variants were previously reported in seven patients from three families with Multiple Congenital Anomalies-Hypotonia Seizures Syndrome 3 (MCAHS3, characterized by epileptic encephalopathy, hypotonia, global developmental delay/intellectual disability, cerebral and cerebellar atrophy, craniofacial dysmorphisms, and skeletal, ophthalmological, cardiac, and genitourinary abnormalities. We report a novel homozygous PIGT missense variant c.1079G>T (p.Gly360Val in two brothers with several of the typical features of MCAHS3, but in addition, pyramidal tract neurological signs. Notably, they are the first patients with MCAHS3 without skeletal, cardiac, or genitourinary anomalies. PIGT encodes a crucial subunit of the glycosylphosphatidylinositol (GPI transamidase complex, which catalyzes the attachment of proteins to GPI-anchors, attaching the proteins to the cell membrane. In vitro studies in cells from the two brothers showed reduced levels of GPI-anchors and GPI-anchored proteins on the cell surface, supporting the pathogenicity of the novel PIGT variant.

Strategies to reduce the risk of drug-induced QT interval prolongation: a pharmaceutical company perspective.

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Pollard, C E; Valentin, J-P; Hammond, T G

2008-08-01

Drug-induced prolongation of the QT interval is having a significant impact on the ability of the pharmaceutical industry to develop new drugs. The development implications for a compound causing a significant effect in the 'Thorough QT/QTc Study' -- as defined in the clinical regulatory guidance (ICH E14) -- are substantial. In view of this, and the fact that QT interval prolongation is linked to direct inhibition of the hERG channel, in the early stages of drug discovery the focus is on testing for and screening out hERG activity. This has led to understanding of how to produce low potency hERG blockers whilst retaining desirable properties. Despite this, a number of factors mean that when an integrated risk assessment is generated towards the end of the discovery phase (by conducting at least an in vivo QT assessment) a QT interval prolongation risk is still often apparent; inhibition of hERG channel trafficking and partitioning into cardiac tissue are just two confounding factors. However, emerging information suggests that hERG safety margins have high predictive value and that when hERG and in vivo non-clinical data are combined, their predictive value to man, whilst not perfect, is >80%. Although understanding the anomalies is important and is being addressed, of greater importance is developing a better understanding of TdP, with the aim of being able to predict TdP rather than using an imperfect surrogate marker (QT interval prolongation). Without an understanding of how to predict TdP risk, high-benefit drugs for serious indications may never be marketed.

UrQt: an efficient software for the Unsupervised Quality trimming of NGS data.

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Modolo, Laurent; Lerat, Emmanuelle

2015-04-29

Quality control is a necessary step of any Next Generation Sequencing analysis. Although customary, this step still requires manual interventions to empirically choose tuning parameters according to various quality statistics. Moreover, current quality control procedures that provide a "good quality" data set, are not optimal and discard many informative nucleotides. To address these drawbacks, we present a new quality control method, implemented in UrQt software, for Unsupervised Quality trimming of Next Generation Sequencing reads. Our trimming procedure relies on a well-defined probabilistic framework to detect the best segmentation between two segments of unreliable nucleotides, framing a segment of informative nucleotides. Our software only requires one user-friendly parameter to define the minimal quality threshold (phred score) to consider a nucleotide to be informative, which is independent of both the experiment and the quality of the data. This procedure is implemented in C++ in an efficient and parallelized software with a low memory footprint. We tested the performances of UrQt compared to the best-known trimming programs, on seven RNA and DNA sequencing experiments and demonstrated its optimality in the resulting tradeoff between the number of trimmed nucleotides and the quality objective. By finding the best segmentation to delimit a segment of good quality nucleotides, UrQt greatly increases the number of reads and of nucleotides that can be retained for a given quality objective. UrQt source files, binary executables for different operating systems and documentation are freely available (under the GPLv3) at the following address: https://lbbe.univ-lyon1.fr/-UrQt-.html .

Pharmacokinetics and effect on the corrected QT interval of single-dose escitalopram in healthy elderly compared with younger adults.

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Chung, Hyewon; Kim, Anhye; Lim, Kyoung Soo; Park, Sang-In; Yu, Kyung-Sang; Yoon, Seo Hyun; Cho, Joo-Youn; Chung, Jae-Yong

2017-01-01

Escitalopram is the (S)-enantiomer of citalopram that has a potential QT prolonging effect. In this study, 12 healthy elderly individuals received a single oral dose of escitalopram (20 mg), and their pharmacokinetics and QT effect data were compared with data from 33 younger adults obtained in a previous study. Serial blood samples for pharmacokinetic analysis were collected and ECG was performed up to 48 h postdose. The elderly and younger adults showed similar pharmacokinetic profiles. The geometric mean ratios (90% confidence interval) of the elderly compared with the younger adults were 1.02 (0.89-1.17) and 1.01 (0.86-1.17) for the maximum plasma concentration and area under the concentration-time curve, respectively. The mean baseline-adjusted QT (dQT) time profiles were similar and the mean values of maximum dQT were not significantly different between the elderly and the younger adults. The linear mixed-effect model indicated a weak but positive relationship between the escitalopram concentration and dQT, with an estimated coefficient of concentration of 0.43-0.54. In conclusion, the pharmacokinetics and QT effect of a single dose of escitalopram observed in the elderly without comorbidities and younger adults were generally similar.

Coffee, alcohol, smoking, physical activity and QT interval duration: results from the Third National Health and Nutrition Examination Survey.

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Yiyi Zhang

2011-02-01

Full Text Available Abnormalities in the electrocardiographic QT interval duration have been associated with an increased risk of ventricular arrhythmias and sudden cardiac death. However, there is substantial uncertainty about the effect of modifiable factors such as coffee intake, cigarette smoking, alcohol consumption, and physical activity on QT interval duration.We studied 7795 men and women from the Third National Health and Nutrition Survey (NHANES III, 1988-1994. Baseline QT interval was measured from the standard 12-lead electrocardiogram. Coffee and tea intake, alcohol consumption, leisure-time physical activities over the past month, and lifetime smoking habits were determined using validated questionnaires during the home interview.In the fully adjusted model, the average differences in QT interval comparing participants drinking ≥6 cups/day to those who did not drink any were -1.2 ms (95% CI -4.4 to 2.0 for coffee, and -2.0 ms (-11.2 to 7.3 for tea, respectively. The average differences in QT interval duration comparing current to never smokers was 1.2 ms (-0.6 to 2.9 while the average difference in QT interval duration comparing participants drinking ≥7 drinks/week to non-drinkers was 1.8 ms (-0.5 to 4.0. The age, race/ethnicity, and RR-interval adjusted differences in average QT interval duration comparing men with binge drinking episodes to non-drinkers or drinkers without binge drinking were 2.8 ms (0.4 to 5.3 and 4.0 ms (1.6 to 6.4, respectively. The corresponding differences in women were 1.1 (-2.9 to 5.2 and 1.7 ms (-2.3 to 5.7. Finally, the average differences in QT interval comparing the highest vs. the lowest categories of total physical activity was -0.8 ms (-3.0 to 1.4.Binge drinking was associated with longer QT interval in men but not in women. QT interval duration was not associated with other modifiable factors including coffee and tea intake, smoking, and physical activity.

Coffee, alcohol, smoking, physical activity and QT interval duration: results from the Third National Health and Nutrition Examination Survey.

Science.gov (United States)

Zhang, Yiyi; Post, Wendy S; Dalal, Darshan; Blasco-Colmenares, Elena; Tomaselli, Gordon F; Guallar, Eliseo

2011-02-28

Abnormalities in the electrocardiographic QT interval duration have been associated with an increased risk of ventricular arrhythmias and sudden cardiac death. However, there is substantial uncertainty about the effect of modifiable factors such as coffee intake, cigarette smoking, alcohol consumption, and physical activity on QT interval duration. We studied 7795 men and women from the Third National Health and Nutrition Survey (NHANES III, 1988-1994). Baseline QT interval was measured from the standard 12-lead electrocardiogram. Coffee and tea intake, alcohol consumption, leisure-time physical activities over the past month, and lifetime smoking habits were determined using validated questionnaires during the home interview. In the fully adjusted model, the average differences in QT interval comparing participants drinking ≥6 cups/day to those who did not drink any were -1.2 ms (95% CI -4.4 to 2.0) for coffee, and -2.0 ms (-11.2 to 7.3) for tea, respectively. The average differences in QT interval duration comparing current to never smokers was 1.2 ms (-0.6 to 2.9) while the average difference in QT interval duration comparing participants drinking ≥7 drinks/week to non-drinkers was 1.8 ms (-0.5 to 4.0). The age, race/ethnicity, and RR-interval adjusted differences in average QT interval duration comparing men with binge drinking episodes to non-drinkers or drinkers without binge drinking were 2.8 ms (0.4 to 5.3) and 4.0 ms (1.6 to 6.4), respectively. The corresponding differences in women were 1.1 (-2.9 to 5.2) and 1.7 ms (-2.3 to 5.7). Finally, the average differences in QT interval comparing the highest vs. the lowest categories of total physical activity was -0.8 ms (-3.0 to 1.4). Binge drinking was associated with longer QT interval in men but not in women. QT interval duration was not associated with other modifiable factors including coffee and tea intake, smoking, and physical activity.

Do the exome: A case of Williams-Beuren syndrome with severe epilepsy due to a truncating de novo variant in GABRA1.

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Popp, Bernt; Trollmann, Regina; Büttner, Christian; Caliebe, Almuth; Thiel, Christian T; Hüffmeier, Ulrike; Reis, André; Zweier, Christiane

2016-10-01

Williams-Beuren syndrome (WBS) is a relatively common, clinically recognizable microdeletion syndrome. In most cases the typical heterozygous deletion of 1.5 Mb on chromosome 7q11.23 spanning about 26 genes can be identified. Also some larger or smaller atypical deletions have been reported and associated with additional or atypical phenotypic aspects. We report on an individual with typical WBS due to the common deletion and with refractory infantile spasms. Using trio-exome sequencing, we identified a de novo truncating variant c.1200del, p (Lys401Serfs*25) in GABRA1 as the likely cause of the early onset epilepsy. This unique case not only allows to further define the phenotypic spectrum of infantile epileptic encephalopathy associated with rare de novo GABRA1 variants but exemplifies the need for a sensitive review of unclear associations in clinically defined syndromes and for extended diagnostic work-up in individuals with unusual presentations of a genetically confirmed diagnosis. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci

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Aung, Tin; Ozaki, Mineo; Lee, Mei Chin

2017-01-01

Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A, have previously been associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS c...

The Half RR Rule: A Poor Rule of Thumb and Not a Risk Assessment Tool for QT Interval Prolongation.

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Berling, Ingrid; Isbister, Geoffrey K

2015-10-01

Measuring the QT interval on an electrocardiogram (ECG) is integral to risk assessment of Torsade de Pointes (TdP). This study aimed to investigate the accuracy of the 1/2 RR rule as a risk assessment tool for drug-induced TdP, comparing it to the QT nomogram, Bazett's corrected QT (QTcB), and Fridericia's corrected QT (QTcF). The authors calculated sensitivity and specificity of the 1/2 RR rule using a published data set of 129 cases of drug-induced TdP and 316 controls (noncardiotoxic overdoses), compared to the QT nomogram, QTcB > 500 msec and QTcF > 500 msec. To further determine the value of the 1/2 RR rule, its observed positive, and negative agreement were calculated when compared to the QT nomogram for determining an abnormal QT in eight samples of different drugs in overdose. The sensitivity and specificity of the 1/2 RR rule were 88% (95% confidence interval [CI] = 80% to 93%) and 53% (95% CI = 47% to 58%), respectively, compared to the QT nomogram (sensitivity = 97%, 95% CI = 92% to 99%; specificity = 99%, 95% CI = 97% to 100%). It was also less sensitive than QTcB > 500 msec and had a lower specificity than QTcB > 500 msec and QTcF > 500 msec. In drug overdose patients, the 1/2 RR rule had poor observed agreement averaging 41%, which was mainly due to poor positive agreement, except for amisulpride where there was good agreement. The 1/2 RR rule was not as sensitive as the QT nomogram or QTcB > 500 msec for drug-induced TdP. It had poor positive agreement in almost all overdose patients, resulting in over half of patients receiving unnecessary cardiac monitoring and repeat ECGs. © 2015 by the Society for Academic Emergency Medicine.

Medicamentos que podem induzir prolongamento do intervalo QT utilizados por idosos em domicílio

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Josiane Macêdo Martins

2015-10-01

Full Text Available O intervalo QT (iQT, parâmetro eletrocardiográfico, é um biomarcador não invasivo da repolarização ventricular. O aumento do iQT é uma alteração que pode ser de considerável importância clínica, pois predispõe a torsade de pointes e morte cardíaca súbita. O objetivo do presente trabalho é identificar os medicamentos utilizados em domicílio por idosos, que podem induzir o prolongamento do iQT. Trata-se de um estudo quantitativo descritivo exploratório e retrospectivo, realizado em um hospital público de ensino. Foram incluídos 190 idosos com informação sobre uso domiciliar de medicamentos registrada em prontuário. A mediana da idade foi de 69,5 anos, sendo 99 (52,1% mulheres. O número de medicamentos utilizados por paciente em domicílio apresentou mediana de 4,0. Foram identificados 159 fármacos, sendo que 23 (14,5% apresentavam capacidade de induzir prolongamento do iQT. Entre os idosos, 39 (20,5% usavam estes fármacos, sendo os mais prevalentes a amiodarona, amitriptilina, nortriptilina, citalopram e fluoxetina. A hipertensão arterial foi o fator de risco mais frequente dentre aqueles que predispõem a prolongamento do iQT. As utilizações de medicamentos que induzem prolongamento do iQT e a presença de fatores de risco predisponentes mostram que os idosos estão expostos ao risco de desenvolvimento de torsade de pointes. A identificação dos fármacos que induzem prolongamento do iQT, das interações medicamentosas e das condições clínicas que predispõem a esse prolongamento são importantes para garantia da segurança da farmacoterapia de idosos e para evitar eventos adversos graves.Palavras-chave: Prolongamento do intervalo QT. Medicamentos. Idosos. Torsades de pointes. ABSTRACT The QT interval (QTi, an electrocardiographic parameter, is a noninvasive biomarker of ventricular repolarization. Increased QTi is a change that may have clinical importance because predisposes to torsade de pointes and sudden

High-risk long QT syndrome mutations in the Kv7.1 (KCNQ1) pore disrupt the molecular basis for rapid K(+) permeation.

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Burgess, Don E; Bartos, Daniel C; Reloj, Allison R; Campbell, Kenneth S; Johnson, Jonathan N; Tester, David J; Ackerman, Michael J; Fressart, Véronique; Denjoy, Isabelle; Guicheney, Pascale; Moss, Arthur J; Ohno, Seiko; Horie, Minoru; Delisle, Brian P

2012-11-13

Type 1 long QT syndrome (LQT1) is caused by loss-of-function mutations in the KCNQ1 gene, which encodes the K(+) channel (Kv7.1) that underlies the slowly activating delayed rectifier K(+) current in the heart. Intragenic risk stratification suggests LQT1 mutations that disrupt conserved amino acid residues in the pore are an independent risk factor for LQT1-related cardiac events. The purpose of this study is to determine possible molecular mechanisms that underlie the loss of function for these high-risk mutations. Extensive genotype-phenotype analyses of LQT1 patients showed that T322M-, T322A-, or G325R-Kv7.1 confers a high risk for LQT1-related cardiac events. Heterologous expression of these mutations with KCNE1 revealed they generated nonfunctional channels and caused dominant negative suppression of WT-Kv7.1 current. Molecular dynamics simulations of analogous mutations in KcsA (T85M-, T85A-, and G88R-KcsA) demonstrated that they disrupted the symmetrical distribution of the carbonyl oxygen atoms in the selectivity filter, which upset the balance between the strong attractive and K(+)-K(+) repulsive forces required for rapid K(+) permeation. We conclude high-risk LQT1 mutations in the pore likely disrupt the architectural and physical properties of the K(+) channel selectivity filter.

Evaluation of Tp-E Interval and Tp-E/QT Ratio in Patients with Aortic Stenosis.

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Yayla, Çağrı; Bilgin, Murat; Akboğa, Mehmet Kadri; Gayretli Yayla, Kadriye; Canpolat, Uğur; Dinç Asarcikli, Lale; Doğan, Mehmet; Turak, Osman; Çay, Serkan; Özeke, Özcan; Akyel, Ahmet; Yeter, Ekrem; Aydoğdu, Sinan

2016-05-01

The risk of syncope and sudden cardiac death due to ventricular arrhythmias increased in patients with aortic stenosis (AS). Recently, it was shown that Tp-e interval, Tp-e/QT, and Tp-e/QTc ratio can be novel indicators for prediction of ventricular arrhythmias and mortality. We aimed to investigate the association between AS and ventricular repolarization using Tp-e interval and Tp-e/QT ratio. Totally, 105 patients with AS and 60 control subjects were enrolled to this study. The severity of AS was defined by transthoracic echocardiographic examination. Tp-e interval, Tp-e/QT, and Tp-e/QTc ratios were measured from the 12-lead electrocardiogram. Tp-e interval, Tp-e/QT, and Tp-e/QTc ratios were significantly increased in parallel to the severity of AS (P ratio had significant positive correlation with mean aortic gradient (r = 0.192, P = 0.049). In multivariate logistic regression analysis, Tp-e/QTc ratio and left ventricular mass were found to be independent predictors of severe AS (P = 0.03 and P = 0.04, respectively). Our study showed that Tp-e interval, Tp-e/QT, and Tp-e/QTc ratios were increased in patients with severe AS. Tp-e/QTc ratio and left ventricular mass were found as independent predictors of severe AS. © 2015 Wiley Periodicals, Inc.

Impacto do uso de psicotrópicos na dispersão do intervalo QT em pacientes adultos

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Bruno de Queiroz Claudio

2014-06-01

Full Text Available Fundamento: A dispersão do intervalo QT induzida por fármacos tem sido associada a arritmias ventriculares potencialmente fatais. Pouco se conhece sobre o uso de psicotrópicos, isolados ou em combinação com outros fármacos, na dispersão do QT. Objetivo: Avaliar o impacto do uso psicotrópicos na dispersão do intervalo QT em pacientes adultos. Métodos: Estudo de coorte observacional, envolvendo 161 pacientes hospitalizados em um departamento de emergência de hospital terciário, estratificados em usuários e não usuários de psicotrópicos. Dados demográficos, clínicos, laboratoriais e de fármacos em uso foram coletados à admissão, bem como o eletrocardiograma de 12 derivações, com a mensuração do intervalo e da dispersão do QT. Resultados: A dispersão do intervalo QT foi significativamente maior no grupo de usuário de psicotrópicos comparado ao grupo não usuário (69,25 ± 25,5 ms vs. 57,08 ± 23,4 ms; p = 0,002. O intervalo QT corrigido pela fórmula de Bazzett também se mostrou maior no grupo de usuário de psicotrópicos, com significância estatística (439,79 ± 31,14 ms vs. 427,71 ± 28,42 ms; p = 0,011. A análise por regressão linear mostrou associação positiva entre o número absoluto de psicotrópicos utilizados e a dispersão do intervalo QT, com r = 0,341 e p < 0,001. Conclusão: Na população amostral estudada, o uso de psicotrópicos se mostrou associado ao aumento da dispersão do intervalo QT, e esse incremento se acentuou em função do maior número de psicotrópicos utilizados.

The Tatton-Brown-Rahman Syndrome: A clinical study of 55 individuals with de novo constitutive DNMT3A variants [version 1; referees: 2 approved

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Katrina Tatton-Brown

2018-04-01

Full Text Available Tatton-Brown-Rahman syndrome (TBRS; OMIM 615879, also known as the DNMT3A-overgrowth syndrome, is an overgrowth intellectual disability syndrome first described in 2014 with a report of 13 individuals with constitutive heterozygous DNMT3A variants. Here we have undertaken a detailed clinical study of 55 individuals with de novo DNMT3A variants, including the 13 previously reported individuals. An intellectual disability and overgrowth were reported in >80% of individuals with TBRS and were designated major clinical associations. Additional frequent clinical associations (reported in 20-80% individuals included an evolving facial appearance with low-set, heavy, horizontal eyebrows and prominent upper central incisors; joint hypermobility (74%; obesity (weight ³2SD, 67%; hypotonia (54%; behavioural/psychiatric issues (most frequently autistic spectrum disorder, 51%; kyphoscoliosis (33% and afebrile seizures (22%. One individual was diagnosed with acute myeloid leukaemia in teenage years. Based upon the results from this study, we present our current management for individuals with TBRS

Identifying drug-induced repolarization abnormalities from distinct ECG patterns in congenital long QT syndrome: a study of sotalol effects on T-wave morphology

DEFF Research Database (Denmark)

Graff, Claus; Andersen, Mads P; Xue, Joel Q

2009-01-01

BACKGROUND: The electrocardiographic QT interval is used to identify drugs with potential harmful effects on cardiac repolarization in drug trials, but the variability of the measurement can mask drug-induced ECG changes. The use of complementary electrocardiographic indices of abnormal repolariz......BACKGROUND: The electrocardiographic QT interval is used to identify drugs with potential harmful effects on cardiac repolarization in drug trials, but the variability of the measurement can mask drug-induced ECG changes. The use of complementary electrocardiographic indices of abnormal...... are typical ECG patterns in LQT2. Blinded to labels, the new morphology measures were tested in a third group of 39 healthy subjects receiving sotalol. Over 3 days the sotalol group received 0, 160 and 320 mg doses, respectively, and a 12-lead Holter ECG was recorded for 22.5 hours each day. Drug...... with QTcF, p ECG patterns in LQT2 carriers effectively quantified repolarization changes induced by sotalol. Further studies are needed to validate whether this measure has...

Differences in the electrocardiographic QT interval of various breeds of athletic horses during rest and exercise

DEFF Research Database (Denmark)

Pedersen, Philip Juul; Karlsson, Madeleine; Madsen, Mette Flethøj

2016-01-01

is influenced to some extent by heart rate, age, body weight (BW), sex, autonomic tone, and environment. In horses, there is substantial inter-breed variation in size and training, and the aims of this study were therefore to determine the best model describing the QT to RR relationship in breeds of various...... athletic horses and to test for differences in the QT interval. ANIMALS: Ten Icelandic horses, 10 Arabian horses, 10 Thoroughbreds, 10 Standardbreds, six Coldblood trotters, 10 Warmbloods (dressage) and 10 Warmbloods (show jumping). All horses were geldings. METHODS: QT intervals were measured from resting...

Changes in heart rate variability and QT variability during the first trimester of pregnancy.

Science.gov (United States)

Carpenter, R E; D'Silva, L A; Emery, S J; Uzun, O; Rassi, D; Lewis, M J

2015-03-01

The risk of new-onset arrhythmia during pregnancy is high, presumably relating to changes in both haemodynamic and cardiac autonomic function. The ability to non-invasively assess an individual's risk of developing arrhythmia during pregnancy would therefore be clinically significant. We aimed to quantify electrocardiographic temporal characteristics during the first trimester of pregnancy and to compare these with non-pregnant controls. Ninety-nine pregnant women and sixty-three non-pregnant women underwent non-invasive cardiovascular and haemodynamic assessment during a protocol consisting of various physiological states (postural manoeurvres, light exercise and metronomic breathing). Variables measured included stroke volume, cardiac output, heart rate, heart rate variability, QT and QT variability and QTVI (a measure of the variability of QT relative to that of RR). Heart rate (p pregnancy only during the supine position (p pregnancy in all physiological states (p pregnancy in all states (p pregnancy is associated with substantial changes in heart rate variability, reflecting a reduction in parasympathetic tone and an increase in sympathetic activity. QTVI shifted to a less favourable value, reflecting a greater than normal amount of QT variability. QTVI appears to be a useful method for quantifying changes in QT variability relative to RR (or heart rate) variability, being sensitive not only to physiological state but also to gestational age. We support the use of non-invasive markers of cardiac electrical variability to evaluate the risk of arrhythmic events in pregnancy, and we recommend the use of multiple physiological states during the assessment protocol.

Evaluation of Presumably Disease Causing SCN1A Variants in a Cohort of Common Epilepsy Syndromes.

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Lal, Dennis; Reinthaler, Eva M; Dejanovic, Borislav; May, Patrick; Thiele, Holger; Lehesjoki, Anna-Elina; Schwarz, Günter; Riesch, Erik; Ikram, M Arfan; van Duijn, Cornelia M; Uitterlinden, Andre G; Hofman, Albert; Steinböck, Hannelore; Gruber-Sedlmayr, Ursula; Neophytou, Birgit; Zara, Federico; Hahn, Andreas; Gormley, Padhraig; Becker, Felicitas; Weber, Yvonne G; Cilio, Maria Roberta; Kunz, Wolfram S; Krause, Roland; Zimprich, Fritz; Lemke, Johannes R; Nürnberg, Peter; Sander, Thomas; Lerche, Holger; Neubauer, Bernd A

2016-01-01

The SCN1A gene, coding for the voltage-gated Na+ channel alpha subunit NaV1.1, is the clinically most relevant epilepsy gene. With the advent of high-throughput next-generation sequencing, clinical laboratories are generating an ever-increasing catalogue of SCN1A variants. Variants are more likely to be classified as pathogenic if they have already been identified previously in a patient with epilepsy. Here, we critically re-evaluate the pathogenicity of this class of variants in a cohort of patients with common epilepsy syndromes and subsequently ask whether a significant fraction of benign variants have been misclassified as pathogenic. We screened a discovery cohort of 448 patients with a broad range of common genetic epilepsies and 734 controls for previously reported SCN1A mutations that were assumed to be disease causing. We re-evaluated the evidence for pathogenicity of the identified variants using in silico predictions, segregation, original reports, available functional data and assessment of allele frequencies in healthy individuals as well as in a follow up cohort of 777 patients. We identified 8 known missense mutations, previously reported as pathogenic, in a total of 17 unrelated epilepsy patients (17/448; 3.80%). Our re-evaluation indicates that 7 out of these 8 variants (p.R27T; p.R28C; p.R542Q; p.R604H; p.T1250M; p.E1308D; p.R1928G; NP_001159435.1) are not pathogenic. Only the p.T1174S mutation may be considered as a genetic risk factor for epilepsy of small effect size based on the enrichment in patients (P = 6.60 x 10-4; OR = 0.32, fishers exact test), previous functional studies but incomplete penetrance. Thus, incorporation of previous studies in genetic counseling of SCN1A sequencing results is challenging and may produce incorrect conclusions.

Angiokeratoma circumscriptum naeviforme with soft tissue hypertrophy and deep venous malformation: A variant of Klippel-Trenaunay syndrome?

OpenAIRE

Wankhade, Vaishali; Singh, Rajesh; Sadhwani, Venus; Kodate, Purnima; Disawal, Amit

2014-01-01

Klippel-Trenaunay syndrome (KTS) is a cutaneous capillary malformation on a limb in association with soft tissue swelling with or without bony hypertrophy and atypical varicosity. The capillary malformation associated with KTS is port wine stain. Angiokeratoma circumscriptum naeviforme (ACN) is a congenital variant of angiokeratoma commonly present on the lower limb as a hyperkeratotic plaque. ACN is rarely associated with KTS. We report a case of ACN with soft tissue hypertrophy and deep ven...

Variants in DENND1A are associated with polycystic ovary syndrome in women of European ancestry.

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Welt, Corrine K; Styrkarsdottir, Unnur; Ehrmann, David A; Thorleifsson, Gudmar; Arason, Gudmundur; Gudmundsson, Jens A; Ober, Carole; Rosenfield, Robert L; Saxena, Richa; Thorsteinsdottir, Unnur; Crowley, William F; Stefansson, Kari

2012-07-01

A genome-wide association study has identified three loci (five independent signals) that confer risk for polycystic ovary syndrome (PCOS) in Han Chinese women. Replication is necessary to determine whether the same variants confer risk for PCOS in women of European ancestry. The objective of the study was to test whether these PCOS risk variants in Han Chinese women confer risk for PCOS in women of European ancestry. This was a case-control study. The study was conducted at deCODE Genetics in Iceland and two academic medical centers in the United States. Cases were 376 Icelandic women and 565 and 203 women from Boston, MA, and Chicago, IL, respectively, all diagnosed with PCOS by the National Institutes of Health criteria. Controls were 16,947, 483, and 189 women not known to have PCOS from Iceland, Boston, and Chicago, respectively. There were no interventions. Main outcomes were allele frequencies for seven variants in PCOS cases and controls. Two strongly correlated Han Chinese PCOS risk variants on chromosome 9q33.3, rs10986105[C], and rs10818854[A], were replicated in samples of European ancestry with odds ratio of 1.68 (P = 0.00033) and odds ratio of 1.53 (P = 0.0019), respectively. Other risk variants at 2p16.3 (rs13405728), 2p21 (rs12468394, rs12478601, and rs13429458), and 9q33.3 (rs2479106), or variants correlated with them, did not associate with PCOS. The same allele of rs10986105 that increased the risk of PCOS also increased the risk of hyperandrogenism in women without PCOS from Iceland and demonstrated a stronger risk for PCOS defined by the National Institutes of Health criteria than the Rotterdam criteria. We replicated one of the five Chinese PCOS association signals, represented by rs10986105 and rs10818854 on 9q33, in individuals of European ancestry. Examination of the subjects meeting at least one of the Rotterdam criteria for PCOS suggests that the variant may be involved in the hyperandrogenism and possibly the irregular menses of PCOS.

Computational Cardiac Modeling Reveals Mechanisms of Ventricular Arrhythmogenesis in Long QT Syndrome Type 8: CACNA1C R858H Mutation Linked to Ventricular Fibrillation

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Jieyun Bai

2017-10-01

Full Text Available Functional analysis of the L-type calcium channel has shown that the CACNA1C R858H mutation associated with severe QT interval prolongation may lead to ventricular fibrillation (VF. This study investigated multiple potential mechanisms by which the CACNA1C R858H mutation facilitates and perpetuates VF. The Ten Tusscher-Panfilov (TP06 human ventricular cell models incorporating the experimental data on the kinetic properties of L-type calcium channels were integrated into one-dimensional (1D fiber, 2D sheet, and 3D ventricular models to investigate the pro-arrhythmic effects of CACNA1C mutations by quantifying changes in intracellular calcium handling, action potential profiles, action potential duration restitution (APDR curves, dispersion of repolarization (DOR, QT interval and spiral wave dynamics. R858H “mutant” L-type calcium current (ICaL augmented sarcoplasmic reticulum calcium content, leading to the development of afterdepolarizations at the single cell level and focal activities at the tissue level. It also produced inhomogeneous APD prolongation, causing QT prolongation and repolarization dispersion amplification, rendering R858H “mutant” tissue more vulnerable to the induction of reentry compared with other conditions. In conclusion, altered ICaL due to the CACNA1C R858H mutation increases arrhythmia risk due to afterdepolarizations and increased tissue vulnerability to unidirectional conduction block. However, the observed reentry is not due to afterdepolarizations (not present in our model, but rather to a novel blocking mechanism.

Prognostic Significance Of QT Interval Prolongation In Adult ...

African Journals Online (AJOL)

Prognostic survival studies for heart-rate corrected QT interval in patients with chronic heart failure are few; although these patients are known to have a high risk of sudden cardiac death. This study was aimed at determining the mortality risk associated with prolonged QTc in Nigerians with heart failure. Ninety-six ...

RELATIONSHIP OF SLEEP DURATION AND QT INTERVAL IN OBESE AND NON-OBESE MEDICAL STUDENTS

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Hariprasad

2016-02-01

Full Text Available BACKGROUND Sleep deprivation has become a major concern in the modern era. It is found to have an inverse relation with obesity increasing cardiovascular diseases. This study was done to correlate effects of sleep deprivation & obesity with QT interval. OBJECTIVES 1. To assess sleep deprivation in medical students. 2. To measure QT interval and QTc in obese and normal weight medical students. 3. To correlate these QT interval and QTc values with sleep deprivation and obesity. METHODOLOGY In this cross sectional study by simple random sampling 30 obese and 30 normal weight individuals were selected based on Quetelet Index. They were further sub- grouped into Group A with 2-4 hrs., Group B with 4-6 hrs. and Group C with 6-8 hrs. of sleep duration, respectively. Electrocardiography was recorded and QT & QTc was measured. The mean and standard deviations were calculated and by 2 tailed t-test for equality of means, significance was established. RESULTS The QT interval measured in Group A has a mean 363±25.1 in normal weight whereas 374±31.6 in obese which is increased. In all groups QTc interval was within normal limits though more in obese individuals. But in group A obese 431±31.6 which shows borderline QTc prolongation (≥430-451ms in men. Thus severe sleep deprivation contributes to obesity and prolongs QTc interval to pathologically. CONCLUSIONS Our study concludes that sleep deprivation has significant correlation with QTc interval. Mild to moderate sleep deprivation affects obese more than normal weight & Severe sleep deprivation with obesity may lead to borderline QTc prolongation.

Oxaliplatin-induced acquired long QT syndrome with torsades de pointes and myocardial injury in a patient with dilated cardiomyopathy and rectal cancer

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Rei-Yeuh Chang

2013-08-01

Full Text Available A 67-year-old woman presented with a history of dilated cardiomyopathy with congestive heart failure since 2003, who subsequently developed lower rectal cancer (adenocarcinoma with liver, bone, and lymph node metastasis. Abdominoperineal resection and hepatectomy were performed. The patient received two rounds of intravenous chemotherapy, including 12 and six courses of FOLFOX4 (5-fluorouracil, leucovorin, and oxaliplatin; 85 mg/m2 per cycle. She underwent a third round of intravenous FOLFOX4 because of tumor progression. During the 21st course of FOLFOX4 regimen, the patient developed ST segment depression in lead II and prolongation of QT interval with polymorphic ventricular tachycardia, torsades de pointes right after the start of oxaliplatin infusion. Immediate defibrillation and cardiopulmonary resuscitation were administered, and the patient regained spontaneous circulation and consciousness. Twelve-lead electrocardiogram showed ST segment elevation in III, aVF, and ST segment depression in V4–6 after resuscitation. To our knowledge, prolongation of QT interval with torsades de pointes and coronary spasm with myocardial injury that were stabilized in one patient following oxaliplatin infusion has not been reported. We present a patient with these rare complications.

PK/PD Modelling of the QT Interval: a Step Towards Defining the Translational Relationship Between In Vitro, Awake Beagle Dogs, and Humans.

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Marostica, Eleonora; Van Ammel, Karel; Teisman, Ard; Gallacher, David; Van Bocxlaer, Jan; De Ridder, Filip; Boussery, Koen; Vermeulen, An

2016-07-01

Inhibiting the human ether-a-go-go-related gene (hERG)-encoded potassium ion channel is positively correlated with QT-interval prolongation in vivo, which is considered a risk factor for the occurrence of Torsades de Pointes (TdP). A pharmacokinetic/pharmacodynamic model was developed for four compounds that reached the clinic, to relate drug-induced QT-interval change in awake dogs and humans and to derive a translational scaling factor a 1. Overall, dogs were more sensitive than humans to QT-interval change, an a 1 of 1.5 was found, and a 10% current inhibition in vitro produced a higher percent QT-interval change in dogs as compared to humans. The QT-interval changes in dogs were predictive for humans. In vitro and in vivo information could reliably describe the effects in humans. Robust translational knowledge is likely to reduce the need for expensive thorough QT studies; therefore, expanding this work to more compounds is recommended.

The effect of thrombolytic therapy on QT dispersion in acute ...

African Journals Online (AJOL)

2013-07-02

Jul 2, 2013 ... intraventricular conduction defect or atrial fibrillation were excluded from the study. .... detection and their benign characteristics. In some series including .... Glancy JM, Garratt CJ, Woods KL, de Bono DP. QT dispersion and ...

Refinement and fracture mechanisms of as-cast QT700-6 alloy by alloying method

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Min-qiang Gao

2017-01-01

Full Text Available The as-cast QT700-6 alloy was synthesized with addition of a certain amount of copper, nickel, niobium and stannum elements by alloying method in a medium frequency induction furnace, aiming at improving its strength and toughness. Microstructures of the as-cast QT700-6 alloy were observed using a scanning-electron microscope (SEM and the mechanical properties were investigated using a universal tensile test machine. Results indicate that the ratio of pearlite/ferrite is about 9:1 and the graphite size is less than 40 μm in diameter in the as-cast QT700-6 alloy. The predominant refinement mechanism is attributed to the formation of niobium carbides, which increases the heterogeneous nucleus and hinders the growth of graphite. Meanwhile, niobium carbides also exist around the grain boundaries, which improve the strength of the ductile iron. The tensile strength and elongation of the as-cast QT700-6 alloy reach over 700 MPa and 6%, respectively, when the addition amount of niobium is 0.8%. The addition of copper and nickel elements contributed to the decrease of eutectoid transformation temperature, resulting in the decrease of pearlite lamellar spacing (about 248 nm, which is also beneficial to enhancing the tensile strength. The main fracture mechanism is cleavage fracture with the appearance of a small amount of dimples.

Genotype–phenotype correlations in individuals with pathogenic RERE variants

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Jordan, Valerie K.; Fregeau, Brieana; Ge, Xiaoyan; Giordano, Jessica; Wapner, Ronald J.; Balci, Tugce B.; Carter, Melissa T.; Bernat, John A.; Moccia, Amanda N.; Srivastava, Anshika; Martin, Donna M.; Bielas, Stephanie L.; Pappas, John; Svoboda, Melissa D.; Rio, Marlène; Boddaert, Nathalie; Cantagrel, Vincent; Lewis, Andrea M.; Scaglia, Fernando; Kohler, Jennefer N.; Bernstein, Jonathan A.; Dries, Annika M.; Rosenfeld, Jill A.; DeFilippo, Colette; Thorson, Willa; Yang, Yaping; Sherr, Elliott H.; Bi, Weimin; Scott, Daryl A.

2018-01-01

Heterozygous variants in the arginine-glutamic acid dipeptide repeats gene (RERE) have been shown to cause neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH). Here, we report nine individuals with NEDBEH who carry partial deletions or deleterious sequence variants in RERE. These variants were found to be de novo in all cases in which parental samples were available. An analysis of data from individuals with NEDBEH suggests that point mutations affecting the Atrophin-1 domain of RERE are associated with an increased risk of structural eye defects, congenital heart defects, renal anomalies, and sensorineural hearing loss when compared with loss-of-function variants that are likely to lead to haploinsufficiency. A high percentage of RERE pathogenic variants affect a histidine-rich region in the Atrophin-1 domain. We have also identified a recurrent two-amino-acid duplication in this region that is associated with the development of a CHARGE syndrome-like phenotype. We conclude that mutations affecting RERE result in a spectrum of clinical phenotypes. Genotype–phenotype correlations exist and can be used to guide medical decision making. Consideration should also be given to screening for RERE variants in individuals who fulfill diagnostic criteria for CHARGE syndrome but do not carry pathogenic variants in CHD7. PMID:29330883

AB093. Report of a SMARCA4 variant identified in a patient with Coffin-Siris syndrome

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Loke, Mun Fai; Jamuar, Saumya Shekhar; Lim, Eileen Chew Ping; Tan, Ene Choo

2017-01-01

Background Coffin-Siris syndrome (CSS, OMIM 614609) is a rare condition that affects multiple body systems. Hallmarks of this condition include developmental disability, abnormalities of the fifth fingers or toes, and characteristic facial features. Here, the case of a 4-year-old Chinese boy with lateral flaring and thick eyebrows, long eyelashes, coarse facies, left single palmar crease, absent of both fifth toenails, posterior cleft palate, umbilical hernia and congenital nystagmus is presented. The boy also has bilateral developmental dysplasia of the hip, which has not been reported in CSS. Methods Genomic DNA was extracted from peripheral blood samples collected from the patient and parents. Targeted next generation sequencing of the patient sample was performed on the Illumina MiSeq system using the TruSight One panel that covers >4,800 clinically relevant genes. Alignment and variant calling was carried out using the on-instrument MiSeq Reporter software, and the VCF file generated was annotated and filtered using WANNOVAR. The presence of the variant and the de novo status was confirmed by Sanger sequencing of patient and parental samples. Results A heterozygous c.3127C>T variant was detected in exon 23 of the SMARCA4 gene in the patient. It was not present in his parents. The de novo variant is predicted to cause a p. (Arg1043Trp) missense substitution of a highly conserved amino acid in the SNF2-related domain of the SMARCA4 protein, and can be classified as likely pathogenic for CSS based on the ACMG/AMP 2015 guidelines. This variant is not in the Exome Sequencing Project, 1000 Genomes Project and Exome Aggregation Consortium databases, although it has been reported previously in a patient with CSS. Conclusions The SMARCA4 gene encodes the ATP-hydroxylase containing subunits of the BAF complex and variants are expected to influence the ATP-hydrolase activity and affect downstream processes such as DNA packaging and gene expression.

Evaluation of Presumably Disease Causing SCN1A Variants in a Cohort of Common Epilepsy Syndromes.

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Dennis Lal

Full Text Available The SCN1A gene, coding for the voltage-gated Na+ channel alpha subunit NaV1.1, is the clinically most relevant epilepsy gene. With the advent of high-throughput next-generation sequencing, clinical laboratories are generating an ever-increasing catalogue of SCN1A variants. Variants are more likely to be classified as pathogenic if they have already been identified previously in a patient with epilepsy. Here, we critically re-evaluate the pathogenicity of this class of variants in a cohort of patients with common epilepsy syndromes and subsequently ask whether a significant fraction of benign variants have been misclassified as pathogenic.We screened a discovery cohort of 448 patients with a broad range of common genetic epilepsies and 734 controls for previously reported SCN1A mutations that were assumed to be disease causing. We re-evaluated the evidence for pathogenicity of the identified variants using in silico predictions, segregation, original reports, available functional data and assessment of allele frequencies in healthy individuals as well as in a follow up cohort of 777 patients.We identified 8 known missense mutations, previously reported as pathogenic, in a total of 17 unrelated epilepsy patients (17/448; 3.80%. Our re-evaluation indicates that 7 out of these 8 variants (p.R27T; p.R28C; p.R542Q; p.R604H; p.T1250M; p.E1308D; p.R1928G; NP_001159435.1 are not pathogenic. Only the p.T1174S mutation may be considered as a genetic risk factor for epilepsy of small effect size based on the enrichment in patients (P = 6.60 x 10-4; OR = 0.32, fishers exact test, previous functional studies but incomplete penetrance. Thus, incorporation of previous studies in genetic counseling of SCN1A sequencing results is challenging and may produce incorrect conclusions.

Evaluation of Tp-e interval and Tp-e/QT ratio in patients with ankylosing spondylitis.

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Acar, Gurkan; Yorgun, Hikmet; Inci, Mehmet Fatih; Akkoyun, Murat; Bakan, Betul; Nacar, Alper Bugra; Dirnak, Imran; Cetin, Gozde Yildirim; Bozoglan, Orhan

2014-03-01

Ankylosing spondylitis (AS) is a chronic multi-systemic inflammatory rheumatic disorder. Several studies have suggested that the interval from the peak to the end of the electrocardiographic T wave (Tp-e) may correspond to the transmural dispersion of repolarization and that increased Tp-e interval and Tp-e/QT ratio are associated with malignant ventricular arrhythmias. The aim of this study was to evaluate ventricular repolarization by using Tp-e interval and Tp-e/QT ratio in patients with AS, and to assess the relation with inflammation. Sixty-two patients with AS and 50 controls were included. Tp-e interval and Tp-e/QT ratio were measured from a 12-lead electrocardiogram, and the Tp-e interval corrected for heart rate. The plasma level of high sensitive C-reactive protein (hsCRP) was measured. These parameters were compared between groups. In electrocardiographic parameters analysis, QT dispersion (QTd) and corrected QTd were significantly increased in AS patients compared to the controls (31.7 ± 9.6 vs 28.2 ± 7.4 and 35.8 ± 11.5 vs 30.6 ± 7.9 ms, P = 0.03 and P = 0.007, respectively). cTp-e interval and Tp-e/QT ratio were also significantly higher in AS patients (92.1 ± 10.2 vs 75.8 ± 8.4 and 0.22 ± 0.02 vs 0.19 ± 0.02 ms, all P values ratio were significantly correlated with hsCRP (r = 0.63, P ratio were increased in AS patients. These electrocardiographic ventricular repolarization indexes were significantly correlated with the plasma level of hsCRP.

QT interval prolongation in users of selective serotonin reuptake inhibitors in an elderly surgical population

DEFF Research Database (Denmark)

van Haelst, Ingrid M M; van Klei, Wilton A; Doodeman, Hieronymus J

2014-01-01

OBJECTIVE: To investigate the association between the use of a selective serotonin reuptake inhibitor (SSRI) and the occurrence of QT interval prolongation in an elderly surgical population. METHOD: A cross-sectional study was conducted among patients (> 60 years) scheduled for outpatient...... preanesthesia evaluation in the period 2007 until 2012. The index group included elderly users of an SSRI. The reference group of nonusers of antidepressants was matched to the index group on sex and year of scheduled surgery (ratio, 1:1). The primary outcome was the occurrence of QT interval prolongation shown...... on electrocardiogram. The QT interval was corrected for heart rate (QTc interval). The secondary outcome was the duration of the QTc interval. The outcomes were adjusted for confounding by using regression techniques. RESULTS: The index and reference groups included 397 users of an SSRI and 397 nonusers, respectively...

Co-occurring Down syndrome and SUCLA2-related mitochondrial depletion syndrome.

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Couser, Natario L; Marchuk, Daniel S; Smith, Laurie D; Arreola, Alexandra; Kaiser-Rogers, Kathleen A; Muenzer, Joseph; Pandya, Arti; Gucsavas-Calikoglu, Muge; Powell, Cynthia M

2017-10-01

Mitochondrial DNA depletion syndrome 5 (MIM 612073) is a rare autosomal recessive disorder caused by homozygous or compound heterozygous pathogenic variants in the beta subunit of the succinate-CoA ligase gene located within the 13q14 band. We describe two siblings of Hispanic descent with SUCLA2-related mitochondrial depletion syndrome (encephalomyopathic form with methylmalonic aciduria); the older sibling is additionally affected with trisomy 21. SUCLA2 sequencing identified homozygous p.Arg284Cys pathogenic variants in both patients. This mutation has previously been identified in four individuals of Italian and Caucasian descent. The older sibling with concomitant disease has a more severe phenotype than what is typically described in patients with either SUCLA2-related mitochondrial depletion syndrome or Down syndrome alone. The younger sibling, who has a normal female chromosome complement, is significantly less affected compared to her brother. While the clinical and molecular findings have been reported in about 50 patients affected with a deficiency of succinate-CoA ligase caused by pathogenic variants in SUCLA2, this report describes the first known individual affected with both a mitochondrial depletion syndrome and trisomy 21. © 2017 Wiley Periodicals, Inc.

Are quantitative trait-dependent sampling designs cost-effective for analysis of rare and common variants?

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Yilmaz, Yildiz E; Bull, Shelley B

2011-11-29

Use of trait-dependent sampling designs in whole-genome association studies of sequence data can reduce total sequencing costs with modest losses of statistical efficiency. In a quantitative trait (QT) analysis of data from the Genetic Analysis Workshop 17 mini-exome for unrelated individuals in the Asian subpopulation, we investigate alternative designs that sequence only 50% of the entire cohort. In addition to a simple random sampling design, we consider extreme-phenotype designs that are of increasing interest in genetic association analysis of QTs, especially in studies concerned with the detection of rare genetic variants. We also evaluate a novel sampling design in which all individuals have a nonzero probability of being selected into the sample but in which individuals with extreme phenotypes have a proportionately larger probability. We take differential sampling of individuals with informative trait values into account by inverse probability weighting using standard survey methods which thus generalizes to the source population. In replicate 1 data, we applied the designs in association analysis of Q1 with both rare and common variants in the FLT1 gene, based on knowledge of the generating model. Using all 200 replicate data sets, we similarly analyzed Q1 and Q4 (which is known to be free of association with FLT1) to evaluate relative efficiency, type I error, and power. Simulation study results suggest that the QT-dependent selection designs generally yield greater than 50% relative efficiency compared to using the entire cohort, implying cost-effectiveness of 50% sample selection and worthwhile reduction of sequencing costs.

Genomic DNA Methylation Signatures Enable Concurrent Diagnosis and Clinical Genetic Variant Classification in Neurodevelopmental Syndromes.

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Aref-Eshghi, Erfan; Rodenhiser, David I; Schenkel, Laila C; Lin, Hanxin; Skinner, Cindy; Ainsworth, Peter; Paré, Guillaume; Hood, Rebecca L; Bulman, Dennis E; Kernohan, Kristin D; Boycott, Kym M; Campeau, Philippe M; Schwartz, Charles; Sadikovic, Bekim

2018-01-04

Pediatric developmental syndromes present with systemic, complex, and often overlapping clinical features that are not infrequently a consequence of Mendelian inheritance of mutations in genes involved in DNA methylation, establishment of histone modifications, and chromatin remodeling (the "epigenetic machinery"). The mechanistic cross-talk between histone modification and DNA methylation suggests that these syndromes might be expected to display specific DNA methylation signatures that are a reflection of those primary errors associated with chromatin dysregulation. Given the interrelated functions of these chromatin regulatory proteins, we sought to identify DNA methylation epi-signatures that could provide syndrome-specific biomarkers to complement standard clinical diagnostics. In the present study, we examined peripheral blood samples from a large cohort of individuals encompassing 14 Mendelian disorders displaying mutations in the genes encoding proteins of the epigenetic machinery. We demonstrated that specific but partially overlapping DNA methylation signatures are associated with many of these conditions. The degree of overlap among these epi-signatures is minimal, further suggesting that, consistent with the initial event, the downstream changes are unique to every syndrome. In addition, by combining these epi-signatures, we have demonstrated that a machine learning tool can be built to concurrently screen for multiple syndromes with high sensitivity and specificity, and we highlight the utility of this tool in solving ambiguous case subjects presenting with variants of unknown significance, along with its ability to generate accurate predictions for subjects presenting with the overlapping clinical and molecular features associated with the disruption of the epigenetic machinery. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Frequency of a FAS ligand gene variant associated with inherited feline autoimmune lymphoproliferative syndrome in British shorthair cats in New Zealand.

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Aberdein, D; Munday, J S; Dittmer, K E; Heathcott, R W; Lyons, L A

2017-11-01

AIMS To determine the frequency of the FAS-ligand gene (FASLG) variant associated with feline autoimmune lymphoproliferative syndrome (FALPS) and the proportion of carriers of the variant in three British shorthair (BSH) breeding catteries in New Zealand. METHODS Buccal swabs were collected from all cats in two BSH breeding catteries from the South Island and one from the North Island of New Zealand. DNA was extracted and was tested for the presence of the FASLG variant using PCR. Cats with the FASLG variant were identified and the frequency of the FASLG variant allele calculated. Pedigree analysis was performed and inbreeding coefficients were calculated for cats with the FASLG variant. RESULTS Of 32 BSH cats successfully tested for the presence of the FASLG variant, one kitten (3%) was homozygous (FALPS-affected), and seven (22%) cats were heterozygous (carriers) for the FASLG variant allele, and 24 (75%) cats were homozygous for the wild type allele. The overall frequency of the FASLG variant allele in these 32 cats was 0.14. Cats carrying the FASLG variant were from all three breeding catteries sampled, including two catteries that had not previously reported cases of FALPS. Pedigree analysis revealed common ancestry of FALPS-affected and carrier cats within six generations, as well as frequent inbreeding, with inbreeding coefficients >0.12 for five cats with the FASLG variant. CONCLUSIONS AND CLINICAL RELEVANCE There was a high frequency of the FASLG variant allele (0.14) in this small sample of BSH cats, with 22% of healthy cats identified as carriers of the FASLG variant. For an inherited disease, lethal at a young age, in a small population in which inbreeding is common, these results are significant. To prevent future cases of disease and stop further spread of the FASLG variant allele within the BSH population in New Zealand, it is recommended that all BSH and BSH-cross cats be tested for the presence of the FASLG variant before mating. Cats identified as

Ibrutinib does not prolong the corrected QT interval in healthy subjects: results from a thorough QT study.

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de Jong, Jan; Hellemans, Peter; Jiao, James Juhui; Huang, Yuhan; Mesens, Sofie; Sukbuntherng, Juthamas; Ouellet, Daniele

2017-12-01

Ibrutinib is an orally administered, irreversible Bruton's tyrosine kinase inhibitor for treatment of B-cell malignancy. This study evaluated the effects of single-dose ibrutinib at therapeutic and supratherapeutic exposures on cardiac repolarization in healthy subjects. Part 1 used an open-label, two-period sequential design to assess the safety and pharmacokinetics of single doses of ibrutinib 840 and 1680 mg in eight subjects. Part 2 was a randomized, placebo- and positive (moxifloxacin)-controlled, double-blind, single dose, four-way cross-over study to assess the effect of ibrutinib (840 and 1680 mg) on QT/QTc interval. 64 healthy subjects were planned to be enrolled. Baseline-adjusted QT (QTc) intervals for ibrutinib and moxifloxacin (assay sensitivity) were compared to placebo using linear mixed-effect model. A concentration-QTc analysis was also conducted. No clinically relevant safety observations were noted in Part 1. During Part 2, one subject experienced Grade 4 ALT/AST elevations with ibrutinib 1680 mg, leading to study termination and limiting the enrollment to 20 subjects. Ibrutinib demonstrated dose-dependent increases in exposure. The upper bounds of the 90% CIs for the mean difference in change from baseline in QTc between ibrutinib and placebo were Ibrutinib caused a concentration-dependent mild shortening of QTc and mild PR prolongation, but these effects were not considered clinically meaningful. Therapeutic and supratherapeutic concentrations of ibrutinib do not prolong the QTc interval. CLINICALTRIALS.GOV: NCT02271438.

Impaired Interoceptive Accuracy in Semantic Variant Primary Progressive Aphasia

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Charles R. Marshall

2017-11-01

Full Text Available BackgroundInteroception (the perception of internal bodily sensations is strongly linked to emotional experience and sensitivity to the emotions of others in healthy subjects. Interoceptive impairment may contribute to the profound socioemotional symptoms that characterize frontotemporal dementia (FTD syndromes, but remains poorly defined.MethodsPatients representing all major FTD syndromes and healthy age-matched controls performed a heartbeat counting task as a measure of interoceptive accuracy. In addition, patients had volumetric MRI for voxel-based morphometric analysis, and their caregivers completed a questionnaire assessing patients’ daily-life sensitivity to the emotions of others.ResultsInteroceptive accuracy was impaired in patients with semantic variant primary progressive aphasia relative to healthy age-matched individuals, but not in behavioral variant frontotemporal dementia and nonfluent variant primary progressive aphasia. Impaired interoceptive accuracy correlated with reduced daily-life emotional sensitivity across the patient cohort, and with atrophy of right insula, cingulate, and amygdala on voxel-based morphometry in the impaired semantic variant group, delineating a network previously shown to support interoceptive processing in the healthy brain.ConclusionInteroception is a promising novel paradigm for defining mechanisms of reduced emotional reactivity, empathy, and self-awareness in neurodegenerative syndromes and may yield objective measures for these complex symptoms.

MSX1 gene variant - its presence in tooth absence - a case control genetic study.

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Reddy, Naveen Admala; Adusumilli, Gopinath; Devanna, Raghu; Pichai, Saravanan; Rohra, Mayur Gobindram; Arjunan, Sharmila

2013-10-01

Non Syndromic tooth agenesis is a congenital anomaly with significant medical, psychological and social ramifications. There is sufficient evidence to hypothesize that locus for this condition can be identified by candidate genes. The aim of this study was to test whether MSX1 671 T>C gene variant was involved in etiology of Non Syndromic tooth agenesis in Raichur Patients. Blood samples were collected with informed consent from 50 subjects having Non Syndromic tooth agenesis and 50 controls. Genomic DNA was extracted from the blood samples, Polymerase Chain Reaction was performed (PCR) and Restriction Fragment Length Polymorphism (RFLP) was performed for digestion products that were evaluated. The RESULTS showed positive correlation between MSX1671 T>C gene variant and Non Syndromic tooth agenesis in Raichur Patients. MSX1 671 T>C gene variant may be a good screening marker for Non Syndromic tooth agenesis in Raichur Patients . How to cite this article:Reddy NA, Adusumilli G, Devanna R, Pichai S, Rohra MG, Arjunan S. Msx1 Gene Variant - Its Presence in Tooth Absence - A Case Control Genetic Study. J Int Oral Health 2013; 5(5):20-6.

Availability of human induced pluripotent stem cell-derived cardiomyocytes in assessment of drug potential for QT prolongation

International Nuclear Information System (INIS)

Nozaki, Yumiko; Honda, Yayoi; Tsujimoto, Shinji; Watanabe, Hitoshi; Kunimatsu, Takeshi; Funabashi, Hitoshi

2014-01-01

Field potential duration (FPD) in human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs), which can express QT interval in an electrocardiogram, is reported to be a useful tool to predict K + channel and Ca 2+ channel blocker effects on QT interval. However, there is no report showing that this technique can be used to predict multichannel blocker potential for QT prolongation. The aim of this study is to show that FPD from MEA (Multielectrode array) of hiPS-CMs can detect QT prolongation induced by multichannel blockers. hiPS-CMs were seeded onto MEA and FPD was measured for 2 min every 10 min for 30 min after drug exposure for the vehicle and each drug concentration. I Kr and I Ks blockers concentration-dependently prolonged corrected FPD (FPDc), whereas Ca 2+ channel blockers concentration-dependently shortened FPDc. Also, the multichannel blockers Amiodarone, Paroxetine, Terfenadine and Citalopram prolonged FPDc in a concentration dependent manner. Finally, the I Kr blockers, Terfenadine and Citalopram, which are reported to cause Torsade de Pointes (TdP) in clinical practice, produced early afterdepolarization (EAD). hiPS-CMs using MEA system and FPDc can predict the effects of drug candidates on QT interval. This study also shows that this assay can help detect EAD for drugs with TdP potential. - Highlights: • We focused on hiPS-CMs to replace in vitro assays in preclinical screening studies. • hiPS-CMs FPD is useful as an indicator to predict drug potential for QT prolongation. • MEA assay can help detect EAD for drugs with TdP potentials. • MEA assay in hiPS-CMs is useful for accurately predicting drug TdP risk in humans

Availability of human induced pluripotent stem cell-derived cardiomyocytes in assessment of drug potential for QT prolongation

Energy Technology Data Exchange (ETDEWEB)

Nozaki, Yumiko, E-mail: yumiko-nozaki@ds-pharma.co.jp [Preclinical Research Laboratories, Dainippon Sumitomo Pharma. Co., Ltd., Suita, Osaka 564-0053 (Japan); Honda, Yayoi, E-mail: yayoi-honda@ds-pharma.co.jp [Preclinical Research Laboratories, Dainippon Sumitomo Pharma. Co., Ltd., Suita, Osaka 564-0053 (Japan); Tsujimoto, Shinji, E-mail: shinji-tsujimoto@ds-pharma.co.jp [Regenerative and Cellular Medicine Office, Dainippon Sumitomo Pharma. Co., Ltd., Chuo-ku, Tokyo 104-0031 (Japan); Watanabe, Hitoshi, E-mail: hitoshi-1-watanabe@ds-pharma.co.jp [Preclinical Research Laboratories, Dainippon Sumitomo Pharma. Co., Ltd., Suita, Osaka 564-0053 (Japan); Kunimatsu, Takeshi, E-mail: takeshi-kunimatsu@ds-pharma.co.jp [Preclinical Research Laboratories, Dainippon Sumitomo Pharma. Co., Ltd., Suita, Osaka 564-0053 (Japan); Funabashi, Hitoshi, E-mail: hitoshi-funabashi@ds-pharma.co.jp [Preclinical Research Laboratories, Dainippon Sumitomo Pharma. Co., Ltd., Suita, Osaka 564-0053 (Japan)

2014-07-01

Field potential duration (FPD) in human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs), which can express QT interval in an electrocardiogram, is reported to be a useful tool to predict K{sup +} channel and Ca{sup 2+} channel blocker effects on QT interval. However, there is no report showing that this technique can be used to predict multichannel blocker potential for QT prolongation. The aim of this study is to show that FPD from MEA (Multielectrode array) of hiPS-CMs can detect QT prolongation induced by multichannel blockers. hiPS-CMs were seeded onto MEA and FPD was measured for 2 min every 10 min for 30 min after drug exposure for the vehicle and each drug concentration. I{sub Kr} and I{sub Ks} blockers concentration-dependently prolonged corrected FPD (FPDc), whereas Ca{sup 2+} channel blockers concentration-dependently shortened FPDc. Also, the multichannel blockers Amiodarone, Paroxetine, Terfenadine and Citalopram prolonged FPDc in a concentration dependent manner. Finally, the I{sub Kr} blockers, Terfenadine and Citalopram, which are reported to cause Torsade de Pointes (TdP) in clinical practice, produced early afterdepolarization (EAD). hiPS-CMs using MEA system and FPDc can predict the effects of drug candidates on QT interval. This study also shows that this assay can help detect EAD for drugs with TdP potential. - Highlights: • We focused on hiPS-CMs to replace in vitro assays in preclinical screening studies. • hiPS-CMs FPD is useful as an indicator to predict drug potential for QT prolongation. • MEA assay can help detect EAD for drugs with TdP potentials. • MEA assay in hiPS-CMs is useful for accurately predicting drug TdP risk in humans.

Semantic prioritization of novel causative genomic variants

KAUST Repository

Boudellioua, Imene

2017-04-17

Discriminating the causative disease variant(s) for individuals with inherited or de novo mutations presents one of the main challenges faced by the clinical genetics community today. Computational approaches for variant prioritization include machine learning methods utilizing a large number of features, including molecular information, interaction networks, or phenotypes. Here, we demonstrate the PhenomeNET Variant Predictor (PVP) system that exploits semantic technologies and automated reasoning over genotype-phenotype relations to filter and prioritize variants in whole exome and whole genome sequencing datasets. We demonstrate the performance of PVP in identifying causative variants on a large number of synthetic whole exome and whole genome sequences, covering a wide range of diseases and syndromes. In a retrospective study, we further illustrate the application of PVP for the interpretation of whole exome sequencing data in patients suffering from congenital hypothyroidism. We find that PVP accurately identifies causative variants in whole exome and whole genome sequencing datasets and provides a powerful resource for the discovery of causal variants.

Semantic prioritization of novel causative genomic variants

KAUST Repository

Boudellioua, Imene; Mohamad Razali, Rozaimi; Kulmanov, Maxat; Hashish, Yasmeen; Bajic, Vladimir B.; Goncalves-Serra, Eva; Schoenmakers, Nadia; Gkoutos, Georgios V.; Schofield, Paul N.; Hoehndorf, Robert

2017-01-01

Discriminating the causative disease variant(s) for individuals with inherited or de novo mutations presents one of the main challenges faced by the clinical genetics community today. Computational approaches for variant prioritization include machine learning methods utilizing a large number of features, including molecular information, interaction networks, or phenotypes. Here, we demonstrate the PhenomeNET Variant Predictor (PVP) system that exploits semantic technologies and automated reasoning over genotype-phenotype relations to filter and prioritize variants in whole exome and whole genome sequencing datasets. We demonstrate the performance of PVP in identifying causative variants on a large number of synthetic whole exome and whole genome sequences, covering a wide range of diseases and syndromes. In a retrospective study, we further illustrate the application of PVP for the interpretation of whole exome sequencing data in patients suffering from congenital hypothyroidism. We find that PVP accurately identifies causative variants in whole exome and whole genome sequencing datasets and provides a powerful resource for the discovery of causal variants.

[Specificities of the logopenic variant of primary progressive aphasia].

Science.gov (United States)

Magnin, E; Teichmann, M; Martinaud, O; Moreaud, O; Ryff, I; Belliard, S; Pariente, J; Moulin, T; Vandel, P; Démonet, J-F

2015-01-01

The logopenic variant of primary progressive aphasia is a syndrome with neuropsychological and linguistic specificities, including phonological loop impairment for which diagnosis is currently mainly based on the exclusion of the two other variants, semantic and nonfluent/agrammatic primary progressive aphasia. The syndrome may be underdiagnosed due (1) to mild language difficulties during the early stages of the disease or (2) to being mistaken for mild cognitive impairment or Alzheimer's disease when the evaluation of episodic memory is based on verbal material and (3) finally, it is not uncommon that the disorders are attributed to psychiatric co-morbidities such as, for example, anxiety. Moreover, compared to other variants of primary progressive aphasia, brain abnormalities are different. The left temporoparietal junction is initially affected. Neuropathology and biomarkers (cerebrospinal fluid, molecular amyloid nuclear imaging) frequently reveal Alzheimer's disease. Consequently this variant of primary progressive aphasia does not fall under the traditional concept of frontotemporal lobar degeneration. These distinctive features highlight the utility of correct diagnosis, classification, and use of biomarkers to show the neuropathological processes underlying logopenic primary progressive aphasia. The logopenic variant of primary progressive aphasia is a specific form of Alzheimer's disease frequently presenting a rapid decline; specific linguistic therapies are needed. Further investigation of this syndrome is needed to refine screening, improve diagnostic criteria and better understand the epidemiology and the biological mechanisms involved. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Development of a genotyping microarray for Usher syndrome.

Science.gov (United States)

Cremers, Frans P M; Kimberling, William J; Külm, Maigi; de Brouwer, Arjan P; van Wijk, Erwin; te Brinke, Heleen; Cremers, Cor W R J; Hoefsloot, Lies H; Banfi, Sandro; Simonelli, Francesca; Fleischhauer, Johannes C; Berger, Wolfgang; Kelley, Phil M; Haralambous, Elene; Bitner-Glindzicz, Maria; Webster, Andrew R; Saihan, Zubin; De Baere, Elfride; Leroy, Bart P; Silvestri, Giuliana; McKay, Gareth J; Koenekoop, Robert K; Millan, Jose M; Rosenberg, Thomas; Joensuu, Tarja; Sankila, Eeva-Marja; Weil, Dominique; Weston, Mike D; Wissinger, Bernd; Kremer, Hannie

2007-02-01

Usher syndrome, a combination of retinitis pigmentosa (RP) and sensorineural hearing loss with or without vestibular dysfunction, displays a high degree of clinical and genetic heterogeneity. Three clinical subtypes can be distinguished, based on the age of onset and severity of the hearing impairment, and the presence or absence of vestibular abnormalities. Thus far, eight genes have been implicated in the syndrome, together comprising 347 protein-coding exons. To improve DNA diagnostics for patients with Usher syndrome, we developed a genotyping microarray based on the arrayed primer extension (APEX) method. Allele-specific oligonucleotides corresponding to all 298 Usher syndrome-associated sequence variants known to date, 76 of which are novel, were arrayed. Approximately half of these variants were validated using original patient DNAs, which yielded an accuracy of >98%. The efficiency of the Usher genotyping microarray was tested using DNAs from 370 unrelated European and American patients with Usher syndrome. Sequence variants were identified in 64/140 (46%) patients with Usher syndrome type I, 45/189 (24%) patients with Usher syndrome type II, 6/21 (29%) patients with Usher syndrome type III and 6/20 (30%) patients with atypical Usher syndrome. The chip also identified two novel sequence variants, c.400C>T (p.R134X) in PCDH15 and c.1606T>C (p.C536S) in USH2A. The Usher genotyping microarray is a versatile and affordable screening tool for Usher syndrome. Its efficiency will improve with the addition of novel sequence variants with minimal extra costs, making it a very useful first-pass screening tool.

Infantile variant of Bartter syndrome and sensorineural deafness: A new autosomal recessive disorder

Energy Technology Data Exchange (ETDEWEB)

Landau, D.; Shalev, H.; Carmi, Rivka; Ohaly, M. [Univ. of the Negev, Ashkelon (Israel)

1995-12-04

The infantile variant of Bartter syndrome (IBS) is usually associated with maternal polyhydramnios, premature birth, postnatal polyuria and hypokalemic hypochloremic metabolic alkalosis and a typical appearance. IBS is thought to be an autosomal recessive trait. Several congenital tubular defects are associated with sensorineural deafness (SND). However, an association between the IBS and SND has not been reported so far. Here we describe 5 children of an extended consanguineous Bedouin family with IBS and SND. In 3 of the cases, the typical electrolyte imbalance and facial appearance were detected neonatally. SND was detected as early as age 1 month, suggesting either coincidental homozygotization of 2 recessive genes or a pleiotropic effect of one autosomal recessive gene. This association suggests that evaluation of SND is warranted in every case of IBS. 35 refs., 2 figs., 2 tabs.

Acadian variant of Fanconi syndrome is caused by mitochondrial respiratory chain complex I deficiency due to a non-coding mutation in complex I assembly factor NDUFAF6

Czech Academy of Sciences Publication Activity Database

Hartmannová, H.; Piherová, L.; Tauchmannová, Kateřina; Kidd, K.; Acott, P. D.; Crocker, J. F. S.; Oussedik, Y.; Mallet, M.; Hodaňová, K.; Stránecký, V.; Přistoupilová, A.; Barešová, V.; Jedličková, I.; Živná, M.; Sovová, J.; Hůlková, H.; Robins, V.; Vrbacký, Marek; Pecina, Petr; Kaplanová, Vilma; Houštěk, Josef; Mráček, Tomáš; Thibeault, Y.; Bleyer, A. J.; Kmoch, S.

2016-01-01

Roč. 25, č. 18 (2016), s. 4062-4079 ISSN 0964-6906 R&D Projects: GA ČR(CZ) GB14-36804G; GA MŠk(CZ) LL1204 Institutional support: RVO:67985823 Keywords : Acadian variant of Fanconi syndrome * mitochondrial complex I deficiency * NDUFAF6 * C8ORF38 * non-coding mutation * alternative splicing variant * protein isoforms Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.340, year: 2016

Menopause, hormone replacement and RR and QT modulation during sleep

Czech Academy of Sciences Publication Activity Database

Lanfranchi, P. A.; Gosselin, N.; Kára, T.; Jurák, Pavel; Somers, V. K.; Denesle, R.; Petit, D.; Carrier, J.; Nadeau, R.; Montplaisir, J.

2005-01-01

Roč. 6, č. 6 (2005), s. 561-566 ISSN 1389-9457 R&D Projects: GA ČR(CZ) GA102/05/0402 Keywords : Sleep * Menopause * RR interval * QT interval * Gender * Hormones Subject RIV: FS - Medical Facilities ; Equipment Impact factor: 2.711, year: 2005

Toward Personalized Medicine: Using Cardiomyocytes Differentiated From Urine-Derived Pluripotent Stem Cells to Recapitulate Electrophysiological Characteristics of Type 2 Long QT Syndrome.

Science.gov (United States)

Jouni, Mariam; Si-Tayeb, Karim; Es-Salah-Lamoureux, Zeineb; Latypova, Xenia; Champon, Benoite; Caillaud, Amandine; Rungoat, Anais; Charpentier, Flavien; Loussouarn, Gildas; Baró, Isabelle; Zibara, Kazem; Lemarchand, Patricia; Gaborit, Nathalie

2015-09-01

Human genetically inherited cardiac diseases have been studied mainly in heterologous systems or animal models, independent of patients' genetic backgrounds. Because sources of human cardiomyocytes (CMs) are extremely limited, the use of urine samples to generate induced pluripotent stem cell-derived CMs would be a noninvasive method to identify cardiac dysfunctions that lead to pathologies within patients' specific genetic backgrounds. The objective was to validate the use of CMs differentiated from urine-derived human induced pluripotent stem (UhiPS) cells as a new cellular model for studying patients' specific arrhythmia mechanisms. Cells obtained from urine samples of a patient with long QT syndrome who harbored the HERG A561P gene mutation and his asymptomatic noncarrier mother were reprogrammed using the episomal-based method. UhiPS cells were then differentiated into CMs using the matrix sandwich method.UhiPS-CMs showed proper expression of atrial and ventricular myofilament proteins and ion channels. They were electrically functional, with nodal-, atrial- and ventricular-like action potentials recorded using high-throughput optical and patch-clamp techniques. Comparison of HERG expression from the patient's UhiPS-CMs to the mother's UhiPS-CMs showed that the mutation led to a trafficking defect that resulted in reduced delayed rectifier K(+) current (IKr). This phenotype gave rise to action potential prolongation and arrhythmias. UhiPS cells from patients carrying ion channel mutations can be used as novel tools to differentiate functional CMs that recapitulate cardiac arrhythmia phenotypes. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Recapitulation of Clinical Individual Susceptibility to Drug-Induced QT Prolongation in Healthy Subjects Using iPSC-Derived Cardiomyocytes

Directory of Open Access Journals (Sweden)

Tadahiro Shinozawa

2017-02-01

Full Text Available To predict drug-induced serious adverse events (SAE in clinical trials, a model using a panel of cells derived from human induced pluripotent stem cells (hiPSCs of individuals with different susceptibilities could facilitate major advancements in translational research in terms of safety and pharmaco-economics. However, it is unclear whether hiPSC-derived cells can recapitulate interindividual differences in drug-induced SAE susceptibility in populations not having genetic disorders such as healthy subjects. Here, we evaluated individual differences in SAE susceptibility based on an in vitro model using hiPSC-derived cardiomyocytes (hiPSC-CMs as a pilot study. hiPSCs were generated from blood samples of ten healthy volunteers with different susceptibilities to moxifloxacin (Mox-induced QT prolongation. Different Mox-induced field potential duration (FPD prolongation values were observed in the hiPSC-CMs from each individual. Interestingly, the QT interval was significantly positively correlated with FPD at clinically relevant concentrations (r > 0.66 in multiple analyses including concentration-QT analysis. Genomic analysis showed no interindividual significant differences in known target-binding sites for Mox and other drugs such as the hERG channel subunit, and baseline QT ranges were normal. The results suggest that hiPSC-CMs from healthy subjects recapitulate susceptibility to Mox-induced QT prolongation and provide proof of concept for in vitro preclinical trials.

An NMR investigation of the structure, function and role of the hERG channel selectivity filter in the long QT syndrome.

Science.gov (United States)

Gravel, Andrée E; Arnold, Alexandre A; Dufourc, Erick J; Marcotte, Isabelle

2013-06-01

The human ether-a-go-go-related gene (hERG) voltage-gated K(+) channels are located in heart cell membranes and hold a unique selectivity filter (SF) amino acid sequence (SVGFG) as compared to other K(+) channels (TVGYG). The hERG provokes the acquired long QT syndrome (ALQTS) when blocked, as a side effect of drugs, leading to arrhythmia or heart failure. Its pore domain - including the SF - is believed to be a cardiotoxic drug target. In this study combining solution and solid-state NMR experiments we examine the structure and function of hERG's L(622)-K(638) segment which comprises the SF, as well as its role in the ALQTS using reported active drugs. We first show that the SF segment is unstructured in solution with and without K(+) ions in its surroundings, consistent with the expected flexibility required for the change between the different channel conductive states predicted by computational studies. We also show that the SF segment has the potential to perturb the membrane, but that the presence of K(+) ions cancels this interaction. The SF moiety appears to be a possible target for promethazine in the ALQTS mechanism, but not as much for bepridil, cetirizine, diphenhydramine and fluvoxamine. The membrane affinity of the SF is also affected by the presence of drugs which also perturb model DMPC-based membranes. These results thus suggest that the membrane could play a role in the ALQTS by promoting the access to transmembrane or intracellular targets on the hERG channel, or perturbing the lipid-protein synergy. Copyright © 2013 Elsevier B.V. All rights reserved.

Functional Analyses of a Novel Splice Variant in the CHD7 Gene, Found by Next Generation Sequencing, Confirm Its Pathogenicity in a Spanish Patient and Diagnose Him with CHARGE Syndrome

Directory of Open Access Journals (Sweden)

Olatz Villate

2018-01-01

Full Text Available Mutations in CHD7 have been shown to be a major cause of CHARGE syndrome, which presents many symptoms and features common to other syndromes making its diagnosis difficult. Next generation sequencing (NGS of a panel of intellectual disability related genes was performed in an adult patient without molecular diagnosis. A splice donor variant in CHD7 (c.5665 + 1G > T was identified. To study its potential pathogenicity, exons and flanking intronic sequences were amplified from patient DNA and cloned into the pSAD® splicing vector. HeLa cells were transfected with this construct and a wild-type minigene and functional analysis were performed. The construct with the c.5665 + 1G > T variant produced an aberrant transcript with an insert of 63 nucleotides of intron 28 creating a premature termination codon (TAG 25 nucleotides downstream. This would lead to the insertion of 8 new amino acids and therefore a truncated 1896 amino acid protein. As a result of this, the patient was diagnosed with CHARGE syndrome. Functional analyses underline their usefulness for studying the pathogenicity of variants found by NGS and therefore its application to accurately diagnose patients.

Functional Analyses of a Novel Splice Variant in the CHD7 Gene, Found by Next Generation Sequencing, Confirm Its Pathogenicity in a Spanish Patient and Diagnose Him with CHARGE Syndrome.

Science.gov (United States)

Villate, Olatz; Ibarluzea, Nekane; Fraile-Bethencourt, Eugenia; Valenzuela, Alberto; Velasco, Eladio A; Grozeva, Detelina; Raymond, F L; Botella, María P; Tejada, María-Isabel

2018-01-01

Mutations in CHD7 have been shown to be a major cause of CHARGE syndrome, which presents many symptoms and features common to other syndromes making its diagnosis difficult. Next generation sequencing (NGS) of a panel of intellectual disability related genes was performed in an adult patient without molecular diagnosis. A splice donor variant in CHD7 (c.5665 + 1G > T) was identified. To study its potential pathogenicity, exons and flanking intronic sequences were amplified from patient DNA and cloned into the pSAD ® splicing vector. HeLa cells were transfected with this construct and a wild-type minigene and functional analysis were performed. The construct with the c.5665 + 1G > T variant produced an aberrant transcript with an insert of 63 nucleotides of intron 28 creating a premature termination codon (TAG) 25 nucleotides downstream. This would lead to the insertion of 8 new amino acids and therefore a truncated 1896 amino acid protein. As a result of this, the patient was diagnosed with CHARGE syndrome. Functional analyses underline their usefulness for studying the pathogenicity of variants found by NGS and therefore its application to accurately diagnose patients.

A putative Lynch syndrome family carrying MSH2 and MSH6 variants of uncertain significance-functional analysis reveals the pathogenic one

DEFF Research Database (Denmark)

Kantelinen, Jukka; Hansen, Thomas V O; Kansikas, Minttu

2011-01-01

Inherited pathogenic mutations in the mismatch repair (MMR) genes, MSH2, MLH1, MSH6, and PMS2 predispose to Lynch syndrome (LS). However, the finding of a variant or variants of uncertain significance (VUS) in affected family members complicates the risk assessment. Here, we describe a putative LS...... and the tumor pathological data suggested that the missense variation in MSH2, the more common susceptibility gene in LS, would be the predisposing alteration. However, MSH2 VUS was surprisingly found to be MMR proficient in an in vitro MMR assay and a tolerant alteration in silico. By supplying evidence...... identified VUS before predictive gene testing and genetic counseling are offered to a family....

Functional analysis in mouse embryonic stem cells reveals wild-type activity for three MSH6 variants found in suspected Lynch syndrome patients.

Directory of Open Access Journals (Sweden)

Eva A L Wielders

Full Text Available Lynch syndrome confers an increased risk to various types of cancer, in particular early onset colorectal and endometrial cancer. Mutations in mismatch repair (MMR genes underlie Lynch syndrome, with the majority of mutations found in MLH1 and MSH2. Mutations in MSH6 have also been found but these do not always cause a clear cancer predisposition phenotype and MSH6-defective tumors often do not show the standard characteristics of MMR deficiency, such as microsatellite instability. In particular, the consequences of MSH6 missense mutations are challenging to predict, which further complicates genetic counseling. We have previously developed a method for functional characterization of MSH2 missense mutations of unknown significance. This method is based on endogenous gene modification in mouse embryonic stem cells using oligonucleotide-directed gene targeting, followed by a series of functional assays addressing the MMR functions. Here we have adapted this method for the characterization of MSH6 missense mutations. We recreated three MSH6 variants found in suspected Lynch syndrome families, MSH6-P1087R, MSH6-R1095H and MSH6-L1354Q, and found all three to behave like wild type MSH6. Thus, despite suspicion for pathogenicity from clinical observations, our approach indicates these variants are not disease causing. This has important implications for counseling of mutation carriers.

QT Prolongation Complicated with Torsades de Pointes in Prosthetic Mitral Valve Endocarditis: A Case Report

Directory of Open Access Journals (Sweden)

A. Tounsi

2012-01-01

Full Text Available We present the case of a 49-year-old male patient with prosthetic mitral valve endocarditis associated with QT prolongation and torsades de pointes. He was asymptomatic until the end of January 2012, when he was admitted to our hospital emergency unit because of syncope, fever, and suspicion of endocarditis. Cardiologic evaluation was requested and the transthoracic (TTE and transesophageal (TEE echocardiograms revealed vegetations on the prosthetic mitral valve. All cultures were positive for methicillin-sensitive Staphylococcus aureus. The corrected QT (QTc interval was markedly prolonged upon admission (QTc 540 ms. He experienced torsades de pointes (TdP several times and he was recovered after bystander cardiopulmonary resuscitation. The clinical course and the long QTc interval with deep inverted T wave were completely normalized 4 weeks after. He continued on triple antibiotic therapy for 45 days with a good revolution. The clinical features and the possible mechanisms of QT prolongation (inflammation, infection of this patient are discussed.

Circadian variation in QT dispersion determined from a 12-lead Holter recording

DEFF Research Database (Denmark)

Hansen, Stig; Rasmussen, Verner; Larsen, Klaus

2007-01-01

Background: QT dispersion is considered to reflect inhomogeneity of myocardial repolarization. Method: The circadian variation of QT interval dispersion was examined in 95 healthy subjects using 24-hour Holter monitoring. Three different methods of lead selection were applied: all 12 leads (QTdisp...... circadian variation using mean values of QTdisp 12, QTdisp 6, or QTdisp 2 obtained every hour, every 2, or every 4 hours, except in QTdisp 6, which demonstrated a significant circadian variation (P ... a significant circadian variation in QTdisp 12 and QTdisp 6 (P circadian variation was seen in QTdisp 2. A subdivision into 10-year age groups revealed that subjects at age >50 years had a significant circadian variation in QTdisp 12 and QTdisp 6, but not in QTdisp 2. Only in males...

Atrioventricular junction (AVJ) motion tracking: a software tool with ITK/VTK/Qt.

Science.gov (United States)

Pengdong Xiao; Shuang Leng; Xiaodan Zhao; Hua Zou; Ru San Tan; Wong, Philip; Liang Zhong

2016-08-01

The quantitative measurement of the Atrioventricular Junction (AVJ) motion is an important index for ventricular functions of one cardiac cycle including systole and diastole. In this paper, a software tool that can conduct AVJ motion tracking from cardiovascular magnetic resonance (CMR) images is presented by using Insight Segmentation and Registration Toolkit (ITK), The Visualization Toolkit (VTK) and Qt. The software tool is written in C++ by using Visual Studio Community 2013 integrated development environment (IDE) containing both an editor and a Microsoft complier. The software package has been successfully implemented. From the software engineering practice, it is concluded that ITK, VTK, and Qt are very handy software systems to implement automatic image analysis functions for CMR images such as quantitative measure of motion by visual tracking.

Heart rate variability and QT dispersion study in brain death patients and comatose patients with normal brainstem function

International Nuclear Information System (INIS)

Vakilian, A.R.; Iranmanesh, F.; Nadimi, A.E.; Kahnali, J.A.

2011-01-01

To compare heart rate variability (HRV) and QT dispersion in comatose patients with normal brainstem function and with brain death. Fourteen brain death patients with clinical signs of imminent brain death and 15 comatose patients were examined by neurologist in intensive care unit. HRV, RR interval and QT dispersion on ECG were assessed for 24 hours in both groups. Independent t-test and chi-square test were used for statistical analysis to determine significance which was set at p < 0.05. According to Holter findings, mean of standard deviation of RR-interval in the comatose and brain death groups was 48.33 and 35 respectively (p = 0.045). Mean of covariance coefficient of RR-interval was 0.065 in the comatose group and 0.043 in the brain deaths (p = 0.006). QT dispersion was not significant difference in two groups. HRV and RR-interval analysis appeared as an early finding for the diagnosis of brainstem death in comparison to comatose patients with normal brainstem function. QT dispersion had not significant in this regard. (author)

Bartter syndrome presenting as poor weight gain and abdominal mass in an infant.

Science.gov (United States)

Heffernan, Annie; Steffensen, Thora S; Gilbert-Barness, Enid; Perlman, Sharon

2008-01-01

Bartter syndrome, a group of disorders that encompasses multiple genetic defects with similar clinical presentation, has been divided into six different genotypes, according to different genetic defects, and into three main clinical variants (or phenotypes). Classic laboratory findings in all variants include hypochloremia, hypokalemia, and metabolic alkalosis with excessive excretion of chloride and potassium. Classic Bartter syndrome, neonatal Bartter syndrome, and Gitelman syndrome are the three main clinical variants. Classic Bartter syndrome and neonatal Bartter syndrome have defects in genes that affect transport channels in the ascending loop of Henle, where as in Gitleman syndrome the defect occurs in the transport channels of the distal convoluted tubule. Classic Bartter syndrome and neonatal Bartter syndrome have similar presenting symptoms, potential outcomes, and treatment, but different ages at presentation. Gitelman syndrome, a more benign condition than the other clinical variants, has the classic hallmark finding of hypomagnesemia and low to normal excretion of calcium. This differentiates it from the classic and neonatal variants of the disease. With early diagnosis and proper treatment, Bartter syndrome has a good prognosis. But failure to identify it can lead to tubulointerstitial nephritis and renal failure. We present a case of a 6-month-old boy with Bartter syndrome who presented with poor weight gain and an abdominal mass.

An automated microfluidic DNA microarray platform for genetic variant detection in inherited arrhythmic diseases.

Science.gov (United States)

Huang, Shu-Hong; Chang, Yu-Shin; Juang, Jyh-Ming Jimmy; Chang, Kai-Wei; Tsai, Mong-Hsun; Lu, Tzu-Pin; Lai, Liang-Chuan; Chuang, Eric Y; Huang, Nien-Tsu

2018-03-12

In this study, we developed an automated microfluidic DNA microarray (AMDM) platform for point mutation detection of genetic variants in inherited arrhythmic diseases. The platform allows for automated and programmable reagent sequencing under precise conditions of hybridization flow and temperature control. It is composed of a commercial microfluidic control system, a microfluidic microarray device, and a temperature control unit. The automated and rapid hybridization process can be performed in the AMDM platform using Cy3 labeled oligonucleotide exons of SCN5A genetic DNA, which produces proteins associated with sodium channels abundant in the heart (cardiac) muscle cells. We then introduce a graphene oxide (GO)-assisted DNA microarray hybridization protocol to enable point mutation detection. In this protocol, a GO solution is added after the staining step to quench dyes bound to single-stranded DNA or non-perfectly matched DNA, which can improve point mutation specificity. As proof-of-concept we extracted the wild-type and mutant of exon 12 and exon 17 of SCN5A genetic DNA from patients with long QT syndrome or Brugada syndrome by touchdown PCR and performed a successful point mutation discrimination in the AMDM platform. Overall, the AMDM platform can greatly reduce laborious and time-consuming hybridization steps and prevent potential contamination. Furthermore, by introducing the reciprocating flow into the microchannel during the hybridization process, the total assay time can be reduced to 3 hours, which is 6 times faster than the conventional DNA microarray. Given the automatic assay operation, shorter assay time, and high point mutation discrimination, we believe that the AMDM platform has potential for low-cost, rapid and sensitive genetic testing in a simple and user-friendly manner, which may benefit gene screening in medical practice.

Development of a genotyping microarray for Usher syndrome

Science.gov (United States)

Cremers, Frans P M; Kimberling, William J; Külm, Maigi; de Brouwer, Arjan P; van Wijk, Erwin; te Brinke, Heleen; Cremers, Cor W R J; Hoefsloot, Lies H; Banfi, Sandro; Simonelli, Francesca; Fleischhauer, Johannes C; Berger, Wolfgang; Kelley, Phil M; Haralambous, Elene; Bitner‐Glindzicz, Maria; Webster, Andrew R; Saihan, Zubin; De Baere, Elfride; Leroy, Bart P; Silvestri, Giuliana; McKay, Gareth J; Koenekoop, Robert K; Millan, Jose M; Rosenberg, Thomas; Joensuu, Tarja; Sankila, Eeva‐Marja; Weil, Dominique; Weston, Mike D; Wissinger, Bernd; Kremer, Hannie

2007-01-01

Background Usher syndrome, a combination of retinitis pigmentosa (RP) and sensorineural hearing loss with or without vestibular dysfunction, displays a high degree of clinical and genetic heterogeneity. Three clinical subtypes can be distinguished, based on the age of onset and severity of the hearing impairment, and the presence or absence of vestibular abnormalities. Thus far, eight genes have been implicated in the syndrome, together comprising 347 protein‐coding exons. Methods: To improve DNA diagnostics for patients with Usher syndrome, we developed a genotyping microarray based on the arrayed primer extension (APEX) method. Allele‐specific oligonucleotides corresponding to all 298 Usher syndrome‐associated sequence variants known to date, 76 of which are novel, were arrayed. Results Approximately half of these variants were validated using original patient DNAs, which yielded an accuracy of >98%. The efficiency of the Usher genotyping microarray was tested using DNAs from 370 unrelated European and American patients with Usher syndrome. Sequence variants were identified in 64/140 (46%) patients with Usher syndrome type I, 45/189 (24%) patients with Usher syndrome type II, 6/21 (29%) patients with Usher syndrome type III and 6/20 (30%) patients with atypical Usher syndrome. The chip also identified two novel sequence variants, c.400C>T (p.R134X) in PCDH15 and c.1606T>C (p.C536S) in USH2A. Conclusion The Usher genotyping microarray is a versatile and affordable screening tool for Usher syndrome. Its efficiency will improve with the addition of novel sequence variants with minimal extra costs, making it a very useful first‐pass screening tool. PMID:16963483

[Chronic Koro-like Syndrome (KLS) in recurrent depressive disorder as a variant of Cotard's delusion in an italian male patient. A case report and historical review].

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Bandinelli, Pier Luca; Trevisi, Manuela; Kotzalidis, Giorgio Demetrio; Manfredi, Giovanni; Rapinesi, Chiara; Ducci, Giuseppe

2011-01-01

Cotard’s syndrome is a delusional syndrome, first described in the 1880ies by Cotard, characterized by a nihilistic delusions about the self and/or the world. In same other cases there is an intense nihilistic belief that the patient’s entire body or parts of it are disintegrated or dead. The syndrome is often associated with severe depression, but are also described neurological cases. Koro was described a little later from Asia and consisted in the belief that one’s own genitalia are shrinking or disappearing and death will ensue thereafter, but there are many cultural variants and the syndrome may present in an incomplete form. We report on a KLS sharing more features with annihilation delusions, such as Cotard’s syndrome. In KLS, the délire de négation may be limited to localized systems or organs. We believe that some complete and incomplete forms of Koro, when embedded in a depressive core, may represent a variant of Cotard’s delusion. In fact, our patient did not reach a complete denial of his entire body, but rather focused on sexual identity. We analysed the psychosexual issues of our case according to Kretschmer’s 1918 view of a “bipolar setting” between sthenic and asthenic characters of a patient suffering from sensitive delusions of (self-) reference. This view may allow us to relate the personological character to the genetic comprehensibility of the delusion.

Evaluation of Tp-e interval and Tp-e/QT ratio in patients with non-dipper hypertension.

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Demir, Mehmet; Uyan, Umut

2014-01-01

Non-dipper hypertension is associated with increased cardiovascular morbidity and mortality. Several studies have suggested that the interval from the peak to the end of the electrocardiographic T wave (Tp-e) may correspond to the transmural dispersion of repolarization and that increased Tp-e interval and Tp-e/QT ratio are associated with malignant ventricular arrhythmias. The aim of this study was to evaluate ventricular repolarization by using Tp-e interval and Tp-e/QT ratio in patients with non-dipper hypertension. This study included 80 hypertensive patients. Hypertensive patients were divided into two groups: 50 dipper patients (29 male, mean age 51.5 ± 8 years) and 30 non-dipper patients (17 male, mean age 50.6 ± 5.4 years). Tp-e interval and Tp-e/QT ratio were measured from the 12-lead electrocardiogram. These parameters were compared between groups. No statistically significant difference was found between two groups in terms of basic characteristics. In electrocardiographic parameters analysis, QT dispersion (QTd) and corrected QTd were significantly increased in non-dipper patients compared to the dippers (39.4 ± 11.5 versus 27.3 ± 7.5 ms and 37.5 ± 9.5 versus 29.2 ± 6.5 ms, p = 0.001 and p = 0.01, respectively). Tp-e interval and Tp-e/QT ratio were also significantly higher in non-dipper patients (97.5 ± 11.2 versus 84.2 ± 8.3 ms and 0.23 ± 0.02 versus 0.17 ± 0.02, all p value ratio are prolonged in patients with non-dipper hypertension.

Splicing analysis for exonic and intronic mismatch repair gene variants associated with Lynch syndrome confirms high concordance between minigene assays and patient RNA analyses

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van der Klift, Heleen M; Jansen, Anne M L; van der Steenstraten, Niki; Bik, Elsa C; Tops, Carli M J; Devilee, Peter; Wijnen, Juul T

2015-01-01

A subset of DNA variants causes genetic disease through aberrant splicing. Experimental splicing assays, either RT-PCR analyses of patient RNA or functional splicing reporter minigene assays, are required to evaluate the molecular nature of the splice defect. Here, we present minigene assays performed for 17 variants in the consensus splice site regions, 14 exonic variants outside these regions, and two deep intronic variants, all in the DNA mismatch-repair (MMR) genes MLH1, MSH2, MSH6, and PMS2, associated with Lynch syndrome. We also included two deep intronic variants in APC and PKD2. For one variant (MLH1 c.122A>G), our minigene assay and patient RNA analysis could not confirm the previously reported aberrant splicing. The aim of our study was to further investigate the concordance between minigene splicing assays and patient RNA analyses. For 30 variants results from patient RNA analyses were available, either performed by our laboratory or presented in literature. Some variants were deliberately included in this study because they resulted in multiple aberrant transcripts in patient RNA analysis, or caused a splice effect other than the prevalent exon skip. While both methods were completely concordant in the assessment of splice effects, four variants exhibited major differences in aberrant splice patterns. Based on the present and earlier studies, together showing an almost 100% concordance of minigene assays with patient RNA analyses, we discuss the weight given to minigene splicing assays in the current criteria proposed by InSiGHT for clinical classification of MMR variants. PMID:26247049

Serotonin-related FEV gene variant in the sudden infant death syndrome is a common polymorphism in the African-American population.

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Broadbelt, Kevin G; Barger, Melissa A; Paterson, David S; Holm, Ingrid A; Haas, Elisabeth A; Krous, Henry F; Kinney, Hannah C; Markianos, Kyriacos; Beggs, Alan H

2009-12-01

An important subset of the sudden infant death syndrome (SIDS) is associated with multiple serotonergic (5-HT) abnormalities in regions of the medulla oblongata. The mouse ortholog of the fifth Ewing variant gene (FEV) is critical for 5-HT neuronal development. A putatively rare intronic variant [IVS2-191_190insA, here referred to as c.128-(191_192)dupA] has been reported as a SIDS-associated mutation in an African-American population. We tested this association in an independent dataset: 137 autopsied cases (78 SIDS, 59 controls) and an additional 296 control DNA samples from Coriell Cell Repositories. In addition to the c.128-(191_192)dupA variant, we observed an associated single-base deletion [c.128-(301-306)delG] in a subset of the samples. Neither of the two FEV variants showed significant association with SIDS in either the African-American subgroup or the overall cohort. Although we found a significant association of c.128-(191_192)dupA with SIDS when San Diego Hispanic SIDS cases were compared with San Diego Hispanic controls plus Mexican controls (p = 0.04), this became nonsignificant after multiple testing correction. Among Coriell controls, 33 of 99 (33%) African-American and 0 of 197 (0%) of the remaining controls carry the polymorphism (c.128-(191_192)dupA). The polymorphism seems to be a common, likely nonpathogenic, variant in the African-American population.

A homozygous founder missense variant in arylsulfatase G abolishes its enzymatic activity causing atypical Usher syndrome in humans.

Science.gov (United States)

Khateb, Samer; Kowalewski, Björn; Bedoni, Nicola; Damme, Markus; Pollack, Netta; Saada, Ann; Obolensky, Alexey; Ben-Yosef, Tamar; Gross, Menachem; Dierks, Thomas; Banin, Eyal; Rivolta, Carlo; Sharon, Dror

2018-01-04

PurposeWe aimed to identify the cause of disease in patients suffering from a distinctive, atypical form of Usher syndrome.MethodsWhole-exome and genome sequencing were performed in five patients from three families of Yemenite Jewish origin, suffering from distinctive retinal degeneration phenotype and sensorineural hearing loss. Functional analysis of the wild-type and mutant proteins was performed in human fibrosarcoma cells.ResultsWe identified a homozygous founder missense variant, c.133G>T (p.D45Y) in arylsulfatase G (ARSG). All patients shared a distinctive retinal phenotype with ring-shaped atrophy along the arcades engirdling the fovea, resulting in ring scotoma. In addition, patients developed moderate to severe sensorineural hearing loss. Both vision and hearing loss appeared around the age of 40 years. The identified variant affected a fully conserved amino acid that is part of the catalytic site of the enzyme. Functional analysis of the wild-type and mutant proteins showed no basal activity of p.D45Y.ConclusionHomozygosity for ARSG-p.D45Y in humans leads to protein dysfunction, causing an atypical combination of late-onset Usher syndrome. Although there is no evidence for generalized clinical manifestations of lysosomal storage diseases in this set of patients, we cannot rule out the possibility that mild and late-onset symptoms may appear.GENETICS in MEDICINE advance online publication, 4 January 2018; doi:10.1038/gim.2017.227.

Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci.

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Aung, Tin; Ozaki, Mineo; Lee, Mei Chin; Schlötzer-Schrehardt, Ursula; Thorleifsson, Gudmar; Mizoguchi, Takanori; Igo, Robert P; Haripriya, Aravind; Williams, Susan E; Astakhov, Yury S; Orr, Andrew C; Burdon, Kathryn P; Nakano, Satoko; Mori, Kazuhiko; Abu-Amero, Khaled; Hauser, Michael; Li, Zheng; Prakadeeswari, Gopalakrishnan; Bailey, Jessica N Cooke; Cherecheanu, Alina Popa; Kang, Jae H; Nelson, Sarah; Hayashi, Ken; Manabe, Shin-Ichi; Kazama, Shigeyasu; Zarnowski, Tomasz; Inoue, Kenji; Irkec, Murat; Coca-Prados, Miguel; Sugiyama, Kazuhisa; Järvelä, Irma; Schlottmann, Patricio; Lerner, S Fabian; Lamari, Hasnaa; Nilgün, Yildirim; Bikbov, Mukharram; Park, Ki Ho; Cha, Soon Cheol; Yamashiro, Kenji; Zenteno, Juan C; Jonas, Jost B; Kumar, Rajesh S; Perera, Shamira A; Chan, Anita S Y; Kobakhidze, Nino; George, Ronnie; Vijaya, Lingam; Do, Tan; Edward, Deepak P; de Juan Marcos, Lourdes; Pakravan, Mohammad; Moghimi, Sasan; Ideta, Ryuichi; Bach-Holm, Daniella; Kappelgaard, Per; Wirostko, Barbara; Thomas, Samuel; Gaston, Daniel; Bedard, Karen; Greer, Wenda L; Yang, Zhenglin; Chen, Xueyi; Huang, Lulin; Sang, Jinghong; Jia, Hongyan; Jia, Liyun; Qiao, Chunyan; Zhang, Hui; Liu, Xuyang; Zhao, Bowen; Wang, Ya-Xing; Xu, Liang; Leruez, Stéphanie; Reynier, Pascal; Chichua, George; Tabagari, Sergo; Uebe, Steffen; Zenkel, Matthias; Berner, Daniel; Mossböck, Georg; Weisschuh, Nicole; Hoja, Ursula; Welge-Luessen, Ulrich-Christoph; Mardin, Christian; Founti, Panayiota; Chatzikyriakidou, Anthi; Pappas, Theofanis; Anastasopoulos, Eleftherios; Lambropoulos, Alexandros; Ghosh, Arkasubhra; Shetty, Rohit; Porporato, Natalia; Saravanan, Vijayan; Venkatesh, Rengaraj; Shivkumar, Chandrashekaran; Kalpana, Narendran; Sarangapani, Sripriya; Kanavi, Mozhgan R; Beni, Afsaneh Naderi; Yazdani, Shahin; Lashay, Alireza; Naderifar, Homa; Khatibi, Nassim; Fea, Antonio; Lavia, Carlo; Dallorto, Laura; Rolle, Teresa; Frezzotti, Paolo; Paoli, Daniela; Salvi, Erika; Manunta, Paolo; Mori, Yosai; Miyata, Kazunori; Higashide, Tomomi; Chihara, Etsuo; Ishiko, Satoshi; Yoshida, Akitoshi; Yanagi, Masahide; Kiuchi, Yoshiaki; Ohashi, Tsutomu; Sakurai, Toshiya; Sugimoto, Takako; Chuman, Hideki; Aihara, Makoto; Inatani, Masaru; Miyake, Masahiro; Gotoh, Norimoto; Matsuda, Fumihiko; Yoshimura, Nagahisa; Ikeda, Yoko; Ueno, Morio; Sotozono, Chie; Jeoung, Jin Wook; Sagong, Min; Park, Kyu Hyung; Ahn, Jeeyun; Cruz-Aguilar, Marisa; Ezzouhairi, Sidi M; Rafei, Abderrahman; Chong, Yaan Fun; Ng, Xiao Yu; Goh, Shuang Ru; Chen, Yueming; Yong, Victor H K; Khan, Muhammad Imran; Olawoye, Olusola O; Ashaye, Adeyinka O; Ugbede, Idakwo; Onakoya, Adeola; Kizor-Akaraiwe, Nkiru; Teekhasaenee, Chaiwat; Suwan, Yanin; Supakontanasan, Wasu; Okeke, Suhanya; Uche, Nkechi J; Asimadu, Ifeoma; Ayub, Humaira; Akhtar, Farah; Kosior-Jarecka, Ewa; Lukasik, Urszula; Lischinsky, Ignacio; Castro, Vania; Grossmann, Rodolfo Perez; Sunaric Megevand, Gordana; Roy, Sylvain; Dervan, Edward; Silke, Eoin; Rao, Aparna; Sahay, Priti; Fornero, Pablo; Cuello, Osvaldo; Sivori, Delia; Zompa, Tamara; Mills, Richard A; Souzeau, Emmanuelle; Mitchell, Paul; Wang, Jie Jin; Hewitt, Alex W; Coote, Michael; Crowston, Jonathan G; Astakhov, Sergei Y; Akopov, Eugeny L; Emelyanov, Anton; Vysochinskaya, Vera; Kazakbaeva, Gyulli; Fayzrakhmanov, Rinat; Al-Obeidan, Saleh A; Owaidhah, Ohoud; Aljasim, Leyla Ali; Chowbay, Balram; Foo, Jia Nee; Soh, Raphael Q; Sim, Kar Seng; Xie, Zhicheng; Cheong, Augustine W O; Mok, Shi Qi; Soo, Hui Meng; Chen, Xiao Yin; Peh, Su Qin; Heng, Khai Koon; Husain, Rahat; Ho, Su-Ling; Hillmer, Axel M; Cheng, Ching-Yu; Escudero-Domínguez, Francisco A; González-Sarmiento, Rogelio; Martinon-Torres, Frederico; Salas, Antonio; Pathanapitoon, Kessara; Hansapinyo, Linda; Wanichwecharugruang, Boonsong; Kitnarong, Naris; Sakuntabhai, Anavaj; Nguyn, Hip X; Nguyn, Giang T T; Nguyn, Trình V; Zenz, Werner; Binder, Alexander; Klobassa, Daniela S; Hibberd, Martin L; Davila, Sonia; Herms, Stefan; Nöthen, Markus M; Moebus, Susanne; Rautenbach, Robyn M; Ziskind, Ari; Carmichael, Trevor R; Ramsay, Michele; Álvarez, Lydia; García, Montserrat; González-Iglesias, Héctor; Rodríguez-Calvo, Pedro P; Fernández-Vega Cueto, Luis; Oguz, Çilingir; Tamcelik, Nevbahar; Atalay, Eray; Batu, Bilge; Aktas, Dilek; Kasım, Burcu; Wilson, M Roy; Coleman, Anne L; Liu, Yutao; Challa, Pratap; Herndon, Leon; Kuchtey, Rachel W; Kuchtey, John; Curtin, Karen; Chaya, Craig J; Crandall, Alan; Zangwill, Linda M; Wong, Tien Yin; Nakano, Masakazu; Kinoshita, Shigeru; den Hollander, Anneke I; Vesti, Eija; Fingert, John H; Lee, Richard K; Sit, Arthur J; Shingleton, Bradford J; Wang, Ningli; Cusi, Daniele; Qamar, Raheel; Kraft, Peter; Pericak-Vance, Margaret A; Raychaudhuri, Soumya; Heegaard, Steffen; Kivelä, Tero; Reis, André; Kruse, Friedrich E; Weinreb, Robert N; Pasquale, Louis R; Haines, Jonathan L; Thorsteinsdottir, Unnur; Jonasson, Fridbert; Allingham, R Rand; Milea, Dan; Ritch, Robert; Kubota, Toshiaki; Tashiro, Kei; Vithana, Eranga N; Micheal, Shazia; Topouzis, Fotis; Craig, Jamie E; Dubina, Michael; Sundaresan, Periasamy; Stefansson, Kari; Wiggs, Janey L; Pasutto, Francesca; Khor, Chiea Chuen

2017-07-01

Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A, have previously been associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results across populations, and to identify new variants associated with XFS. We identified a rare protective allele at LOXL1 (p.Phe407, odds ratio (OR) = 25, P = 2.9 × 10 -14 ) through deep resequencing of XFS cases and controls from nine countries. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 × 10 -8 ). We identified association signals at 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

Mutation in LEMD3 (Man1 Associated with Osteopoikilosis and Late-Onset Generalized Morphea: A New Buschke-Ollendorf Syndrome Variant

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Benjamin Korman

2016-01-01

Full Text Available Introduction. Buschke-Ollendorf syndrome (BOS is an uncommon syndrome characterized by osteopoikilosis and other bone abnormalities, accompanied by skin lesions, most frequently connective tissue nevi. BOS is caused by mutations in the LEMD3 gene, which encodes the inner nuclear membrane protein Man1. We describe a unique case of osteopoikilosis associated with late-onset localized scleroderma and familial LEMD3 mutations. Case Report. A 72-year-old woman presented with adult-onset diffuse morphea and bullous skin lesions. Evaluation revealed multiple hyperostotic lesions (osteopoikilosis suggestive of BOS. DNA sequencing identified a previously undescribed nonsense mutation (Trp621X in the LEMD3 gene encoding Man1. Two additional family members were found to have osteopoikilosis and carry the same LEMD3 mutation. Conclusions and Relevance. We report a unique familial LEMD3 mutation in an individual with osteopoikilosis and late-onset morphea. We propose that this constellation represents a novel syndromic variant of BOS.

A New Observation of an Atypical and Severe Variant of the Guillain-Barre Syndrome in a Child

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Manel, Véronique; Ville, Dorothée; Javouhey, Etienne; Bordet, Fabienne

2015-01-01

Guillain-Barré syndrome is a rare acute polyradiculoneuropathy. Several variants and unusual presentations have been described, particularly in pediatrics. In most cases, making an early diagnosis is challenging due to the treatments that consist in the rapid administration of intravenous immunoglobulin or plasma exchange. The authors present the case of a 7-year-old boy with an atypical and severe axonal Guillain-Barré syndrome, associated with Mycoplasma pneumonia. When he was admitted, febrile respiratory failure was the main focus, and then he presented signs of acute polyneuropathy with cranial nerve palsy and brief hyperreflexia. Mechanical ventilation was required for 48 days as well as 2 cycles of intravenous immunoglobulin. The authors describe all the medical challenges that the authors encountered. This case highlights the fact that respiratory distress can be the main clinical symptom in children. This delays the establishment of a correct diagnosis, even more so when neurological manifestations are abundant and unusual. PMID:28503595

Prediction of Thorough QT study results using action potential simulations based on ion channel screens.

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Mirams, Gary R; Davies, Mark R; Brough, Stephen J; Bridgland-Taylor, Matthew H; Cui, Yi; Gavaghan, David J; Abi-Gerges, Najah

2014-01-01

Detection of drug-induced pro-arrhythmic risk is a primary concern for pharmaceutical companies and regulators. Increased risk is linked to prolongation of the QT interval on the body surface ECG. Recent studies have shown that multiple ion channel interactions can be required to predict changes in ventricular repolarisation and therefore QT intervals. In this study we attempt to predict the result of the human clinical Thorough QT (TQT) study, using multiple ion channel screening which is available early in drug development. Ion current reduction was measured, in the presence of marketed drugs which have had a TQT study, for channels encoded by hERG, CaV1.2, NaV1.5, KCNQ1/MinK, and Kv4.3/KChIP2.2. The screen was performed on two platforms - IonWorks Quattro (all 5 channels, 34 compounds), and IonWorks Barracuda (hERG & CaV1.2, 26 compounds). Concentration-effect curves were fitted to the resulting data, and used to calculate a percentage reduction in each current at a given concentration. Action potential simulations were then performed using the ten Tusscher and Panfilov (2006), Grandi et al. (2010) and O'Hara et al. (2011) human ventricular action potential models, pacing at 1Hz and running to steady state, for a range of concentrations. We compared simulated action potential duration predictions with the QT prolongation observed in the TQT studies. At the estimated concentrations, simulations tended to underestimate any observed QT prolongation. When considering a wider range of concentrations, and conventional patch clamp rather than screening data for hERG, prolongation of ≥5ms was predicted with up to 79% sensitivity and 100% specificity. This study provides a proof-of-principle for the prediction of human TQT study results using data available early in drug development. We highlight a number of areas that need refinement to improve the method's predictive power, but the results suggest that such approaches will provide a useful tool in cardiac safety

Personality factors and profiles in variants of irritable bowel syndrome

Institute of Scientific and Technical Information of China (English)

无

2007-01-01

AIM: To study the association between irritable bowel syndrome (IBS) variants (constipation, diarrhea, or both)and personality traits in non-psychiatric patients.METHODS: IBS was diagnosed using the Rome Ⅱ diagnostic criteria after exclusion of organic bowel pathology. The entry of each patient was confirmed following a psychiatric interview. Personality traits and the score of each factor were evaluated using the NEO Five Factor Inventory.RESULTS: One hundred and fifty patients were studied.The mean age (±SD) was 33.4 (±11.0) year (62% female). Subjects scored higher in neuroticism (26.25±7.80 vs 22.92±9.54, P ＜ 0.0005), openness (26.25±5.22 vs 27.94±4.87, P ＜ 0.0005) and conscientiousness (32.90 ±7.80 vs 31.62±5.64, P ＜ 0.01) compared to our general population derived from universities of Iran. Our studied population consisted of 71 patients with Diarrhea dominant-IBS, 33 with Constipation dominant-IBS and 46 with Altering type-IBS. Scores of conscientiousness and neuroticism were significantly higher in C-IBS compared to D-IBS and A-IBS (35.79±5.65 vs 31.95±6.80,P = 0.035 and 31.97±9.87, P = 0.043, respectively).Conscientiousness was the highest dimension of personality in each of the variants. Patients with C-IBS had almost similar personality profiles, composed of higher scores for neuroticism and conscientiousness, with low levels of agreeableness, openness and extraversion that were close to those of the general population.CONCLUSION: Differences were observed between IBS patients and the general population, as well as between IBS subtypes, in terms of personality factors.Patients with constipation-predominant IBS showed similar personality profiles. Patients with each subtype of IBS may benefit from psychological interventions, which can be focused considering the characteristics of each subtype.

Prolonged Tp-e Interval, Tp-e/QT Ratio and Tp-e/QTc Ratio in Patients with Type 2 Diabetes Mellitus

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Alptug Tokatli

2016-03-01

Full Text Available BackgroundType 2 diabetes mellitus (T2DM is associated with increased risk of malignant ventricular arrhythmias. Cardiac electrical inhomogeneity may be the leading cause of the increased arrhythmic risk in patients with T2DM. The peak and the end of the T wave (Tp-e interval and associated Tp-e/QT ratio are promising measures of ventricular repolarization indicating transmural dispersion of repolarization. The aim of this study was to assess ventricular repolarization in patients with T2DM by using Tp-e interval, Tp-e/QT ratio and Tp-e/corrected QT interval (QTc ratio.MethodsForty-three patients with T2DM and 43 healthy control subjects, matched by gender and age, were studied. All participants underwent electrocardiography (ECG recording. PR, RR and QT intervals represents the ECG intervals. These are not abbreviations. In all literature these ECG intervals are written like in this text. Tp-e intervals were measured from 12-lead ECG. Rate QTc was calculated by using the Bazett's formula. Tp-e/QT ratio and Tp-e/QTc ratio were also calculated.ResultsMean Tp-e interval was significantly prolonged in patients with T2DM compared to controls (79.4±10.3, 66.4±8.1 ms, respectively; P<0.001. We also found significantly higher values of Tp-e/QT ratio and Tp-e/QTc ratio in patients with diabetes than controls (0.21±0.03, 0.17±0.02 and 0.19±0.02, 0.16±0.02, respectively; P<0.001. There was no difference in terms of the other ECG parameters between the groups.ConclusionTp-e interval, Tp-e/QT ratio and Tp-e/QTc ratio were prolonged in patients with T2DM. We concluded that T2DM leads to augmentation of transmural dispersion of repolarization suggesting increased risk for ventricular arrhythmogenesis.

Entropy Analysis of RR and QT Interval Variability during Orthostatic and Mental Stress in Healthy Subjects

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Mathias Baumert

2014-12-01

Full Text Available Autonomic activity affects beat-to-beat variability of heart rate and QT interval. The aim of this study was to explore whether entropy measures are suitable to detect changes in neural outflow to the heart elicited by two different stress paradigms. We recorded short-term ECG in 11 normal subjects during an experimental protocol that involved head-up tilt and mental arithmetic stress and computed sample entropy, cross-sample entropy and causal interactions based on conditional entropy from RR and QT interval time series. Head-up tilt resulted in a significant reduction in sample entropy of RR intervals and cross-sample entropy, while mental arithmetic stress resulted in a significant reduction in coupling directed from RR to QT. In conclusion, measures of entropy are suitable to detect changes in neural outflow to the heart and decoupling of repolarisation variability from heart rate variability elicited by orthostatic or mental arithmetic stress.

Refining the role of PMS2 in Lynch syndrome: germline mutational analysis improved by comprehensive assessment of variants.

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Borràs, Ester; Pineda, Marta; Cadiñanos, Juan; Del Valle, Jesús; Brieger, Angela; Hinrichsen, Inga; Cabanillas, Ruben; Navarro, Matilde; Brunet, Joan; Sanjuan, Xavier; Musulen, Eva; van der Klift, Helen; Lázaro, Conxi; Plotz, Guido; Blanco, Ignacio; Capellá, Gabriel

2013-08-01

The majority of mismatch repair (MMR) gene mutations causing Lynch syndrome (LS) occur either in MLH1 or MSH2. However, the relative contribution of PMS2 is less well defined. The aim of this study was to evaluate the role of PMS2 in LS by assessing the pathogenicity of variants of unknown significance (VUS) detected in the mutational analysis of PMS2 in a series of Spanish patients. From a cohort of 202 LS suspected patients, 13 patients showing loss of PMS2 expression in tumours were screened for germline mutations in PMS2, using a long range PCR based strategy and multiplex ligation dependent probe amplification (MLPA). Pathogenicity assessment of PMS2 VUS was performed evaluating clinicopathological data, frequency in control population and in silico and in vitro analyses at the RNA and protein level. Overall 25 different PMS2 DNA variants were detected. Fourteen were classified as polymorphisms. Nine variants were classified as pathogenic: seven alterations based on their molecular nature and two after demonstrating a functional defect (c.538-3C>G affected mRNA processing and c.137G>T impaired MMR activity). The c.1569C>G variant was classified as likely neutral while the c.384G>A remained as a VUS. We have also shown that the polymorphic variant c.59G>A is MMR proficient. Pathogenic PMS2 mutations were detected in 69% of patients harbouring LS associated tumours with loss of PMS2 expression. In all, PMS2 mutations account for 6% of the LS cases identified. The comprehensive functional analysis shown here has been useful in the classification of PMS2 VUS and contributes to refining the role of PMS2 in LS.

Monogenic diabetes syndromes

DEFF Research Database (Denmark)

Astuti, Dewi; Sabir, Ataf; Fulton, Piers

2017-01-01

(n = 268), and SLC19A2 (n = 48) for Wolfram type 1, Wolfram type 2, Alström, and Thiamine-responsive megaloblastic anemia syndromes, respectively; and included 23 previously unpublished novel germline variants in WFS1 and 17 variants in ALMS1. We then investigated genotype-phenotype relations...

Two deletion variants of Middle East respiratory syndrome coronavirus found in a patient with characteristic symptoms.

Science.gov (United States)

Xie, Qian; Cao, Yujuan; Su, Juan; Wu, Jie; Wu, Xianbo; Wan, Chengsong; He, Mingliang; Ke, Changwen; Zhang, Bao; Zhao, Wei

2017-08-01

Significant sequence variation of Middle East respiratory syndrome coronavirus (MERS CoV) has never been detected since it was first reported in 2012. A MERS patient came from Korea to China in late May 2015. The patient was 44 years old and had symptoms including high fever, dry cough with a little phlegm, and shortness of breath, which are roughly consistent with those associated with MERS, and had had close contact with individuals with confirmed cases of MERS.After one month of therapy with antiviral, anti-infection, and immune-enhancing agents, the patient recovered in the hospital and was discharged. A nasopharyngeal swab sample was collected for direct sequencing, which revealed two deletion variants of MERS CoV. Deletions of 414 and 419 nt occurred between ORF5 and the E protein, resulting in a partial protein fusion or truncation of ORF5 and the E protein. Functional analysis by bioinformatics and comparison to previous studies implied that the two variants might be defective in their ability to package MERS CoV. However, the mechanism of how these deletions occurred and what effects they have need to be further investigated.

Elevation of QT dispersion after obesity drug sibutramine.

Science.gov (United States)

Yalcin, Ahmet A; Yavuz, Bunyamin; Ertugrul, Derun T; Algul, Beyza; Yilmaz, Hamiyet; Deveci, Onur S; Kucukazman, Metin; Ata, Naim; Demirel, Gokhan; Dal, Kursat; Tutal, Emre

2010-11-01

QT dispersion (QTd) is an arrhythmia parameter that can be used to assess homogeneity of cardiac repolarization. An antiobesity drug sibutramine is linked with several cardiovascular adverse events, including arrhythmias. Previous studies showed that sibutramine may prolong the QT interval and may be associated with cardiac arrest. The aim of this study was to evaluate the effect of sibutramine on QTd. The study group consisted of 65 consecutive patients with obesity. All patients were to receive 15 mg of sibutramine once a day in addition to standard care for lifestyle change. Twelve-lead ECG was performed before the onset of the medication and after 16 weeks of treatment. QTd was calculated. Three individuals were withdrawn from the study because of the adverse effects of sibutramine. Sixty-two patients with obesity were recruited into the study. All patients were women (62, 100%). Body weight (106.3 ± 15.0 kg vs. 101.6 ± 16.9 kg, P sibutramine treatment. The increase in QTd was not correlated with the decrease in body weight. There was no correlation between QTd and any conditions such as diabetes or hypertension. This study has shown an elevation in QTd, which may lead to cardiac arrhythmias, after sibutramine treatment. Molecular mechanisms may play role in increasing QTd. Further randomized studies are needed to clarify cardiac adverse events of the sibutramine.

Klüver-Bucy syndrome associated with a recessive variant in HGSNAT in two siblings with Mucopolysaccharidosis type IIIC (Sanfilippo C).

Science.gov (United States)

Hu, Hao; Hübner, Christoph; Lukacs, Zoltan; Musante, Luciana; Gill, Esther; Wienker, Thomas F; Ropers, Hans-Hilger; Knierim, Ellen; Schuelke, Markus

2017-02-01

Klüver-Bucy syndrome (KBS) comprises a set of neurobehavioral symptoms with psychic blindness, hypersexuality, disinhibition, hyperorality, and hypermetamorphosis that were originally observed after bilateral lobectomy in Rhesus monkeys. We investigated two siblings with KBS from a consanguineous family by whole-exome sequencing and autozygosity mapping. We detected a homozygous variant in the heparan-α-glucosaminidase-N-acetyltransferase gene (HGSNAT; c.518G>A, p.(G173D), NCBI ClinVar RCV000239404.1), which segregated with the phenotype. Disease-causing variants in this gene are known to be associated with autosomal recessive Mucopolysaccharidosis type IIIC (MPSIIIC, Sanfilippo C). This lysosomal storage disease is due to deficiency of the acetyl-CoA:α-glucosaminidase-N-acetyltransferase, which was shown to be reduced in patient fibroblasts. Our report extends the phenotype associated with MPSIIIC. Besides MPSIIIA and MPSIIIB, due to variants in SGSH and NAGLU, this is the third subtype of Sanfilippo disease to be associated with KBS. MPSIII should be included in the differential diagnosis of young patients with KBS.

Klüver–Bucy syndrome associated with a recessive variant in HGSNAT in two siblings with Mucopolysaccharidosis type IIIC (Sanfilippo C)

Science.gov (United States)

Hu, Hao; Hübner, Christoph; Lukacs, Zoltan; Musante, Luciana; Gill, Esther; Wienker, Thomas F; Ropers, Hans-Hilger; Knierim, Ellen; Schuelke, Markus

2017-01-01

Klüver–Bucy syndrome (KBS) comprises a set of neurobehavioral symptoms with psychic blindness, hypersexuality, disinhibition, hyperorality, and hypermetamorphosis that were originally observed after bilateral lobectomy in Rhesus monkeys. We investigated two siblings with KBS from a consanguineous family by whole-exome sequencing and autozygosity mapping. We detected a homozygous variant in the heparan-α-glucosaminidase-N-acetyltransferase gene (HGSNAT; c.518G>A, p.(G173D), NCBI ClinVar RCV000239404.1), which segregated with the phenotype. Disease-causing variants in this gene are known to be associated with autosomal recessive Mucopolysaccharidosis type IIIC (MPSIIIC, Sanfilippo C). This lysosomal storage disease is due to deficiency of the acetyl-CoA:α-glucosaminidase-N-acetyltransferase, which was shown to be reduced in patient fibroblasts. Our report extends the phenotype associated with MPSIIIC. Besides MPSIIIA and MPSIIIB, due to variants in SGSH and NAGLU, this is the third subtype of Sanfilippo disease to be associated with KBS. MPSIII should be included in the differential diagnosis of young patients with KBS. PMID:27827379

QT interval changes in term pregnant women living at moderately ...

African Journals Online (AJOL)

Objective: This study aimed to compare the QT interval changes in women with term pregnancy living at moderately high altitude (1890 m in Erzurum, Turkey) with those of women living at sea level (31 m in İstanbul, Turkey). Materials and Methods: One‑hundred ten women (n = 55, for each group) with full‑term and single ...

Frequency and clinicopathological correlations of histopathological variants of idiopathic focal segmental glomerulosclerosis in nephrotic adolescents

International Nuclear Information System (INIS)

Shakeel, S.; Mubarak, M.; Kazi, J.I.

2014-01-01

Objective: To determine the frequency and clinicopathological correlations of focal segmental glomerulosclerosis variants in adolescents with idiopathic nephrotic syndrome. Methods: All consecutive adolescents (12 to 18 years) who presented with idiopathic nephrotic syndrome in the period, January 2009 to December 2012, and in whom the histological diagnosis of focal segmental glomerulosclerosis was made on renal biopsies, were included in this prospective study. Their clinical, laboratory and histopathological features at the time of presentation or biopsy were noted from the case files and the biopsy reports. Results: Among 50 adolescents, 34 (68%) were males and 16 (32%) females. The mean age was 15.14+-2.3 years. The mean duration of disease was 6.3+-11.2 months. The mean serum creatinine was 0.96+-0.82 mg/dl. The mean 24-hour urinary protein excretion was 3.8+-0.68 grams. Biopsy indications were steroid-resistant nephritic syndrome in 15 (30%), steroid-dependant nephritic syndrome in 19 (38%) and adolescent nephritic syndrome in 16 (32%) cases. Among the focal segmental glomerulosclerosis variants, 40 (80%) were not otherwise specified, followed by the collapsing variant, which accounted for 8 (16%) cases. The tip and cellular variants, both were found in one (2%) case each. Among the histological features, global glomerulosclerosis was found in 23 (46%) cases, and segmental scarring/collapse in all (100%). A variable degree of tubular atrophy and interstitial fibrosis was noted in 44 (88%) cases. Conclusion: The results from this study indicate that the pattern of focal segmental glomerulosclerosis variants differs markedly in adolescents compared with younger children. (author)

Further delineation of the KBG syndrome phenotype caused by ANKRD11 aberrations

NARCIS (Netherlands)

Ockeloen, Charlotte W.; Willemsen, Marjolein H.; De Munnik, Sonja; Van Bon, Bregje W M; De Leeuw, Nicole; Verrips, Aad; Kant, Sarina G.; Jones, Elizabeth A.; Brunner, Han G.; Van Loon, Rosa L E; Smeets, Eric E J; Van Haelst, Mieke M.; Van Haaften, Gijs; Nordgren, Ann; Malmgren, Helena; Grigelioniene, Giedre; Vermeer, Sascha; Louro, Pedro; Ramos, Lina; Maal, Thomas J J; Van Heumen, Celeste C.; Yntema, Helger G.; Carels, Carine E L; Kleefstra, Tjitske

2015-01-01

Loss-of-function variants in ANKRD11 were identified as the cause of KBG syndrome, an autosomal dominant syndrome with specific dental, neurobehavioural, craniofacial and skeletal anomalies. We present the largest cohort of KBG syndrome cases confirmed by ANKRD11 variants reported so far, consisting

Further delineation of the KBG syndrome phenotype caused by ANKRD11 aberrations

NARCIS (Netherlands)

C. Ockeloen (Charlotte); M.H. Willemsen; S. de Munnik (Sonja); B. van Bon (Bregje); N. de Leeuw (Nicole); A. Verrips (Aad); S.G. Kant (Sarina); E.A. Jones (Elizabeth A.); H.G. Brunner; R.L.E. Van Loon (Rosa); E.E.J. Smeets (Eric E.J.); M.M. van Haelst (Mieke); G. van Haaften (Gijs); A. Nordgren (Ann); H. Malmgren (Helena); G. Grigelioniene (Giedre); S.E. Vermeer (Sarah); P. Louro (Pedro); L. Ramos (Lina); T.J.J. Maal (Thomas J.J.); C.C.M. van Heumen (Céleste); H.G. Yntema; C.E.L. Carels (Carine); T. Kleefstra (Tjitske)

2015-01-01

textabstractLoss-of-function variants in ANKRD11 were identified as the cause of KBG syndrome, an autosomal dominant syndrome with specific dental, neurobehavioural, craniofacial and skeletal anomalies. We present the largest cohort of KBG syndrome cases confirmed by ANKRD11 variants reported so

Assessment of cabozantinib treatment on QT interval in a phase 3 study in medullary thyroid cancer: evaluation of indirect QT effects mediated through treatment-induced changes in serum electrolytes.

Science.gov (United States)

Miles, Dale R; Lacy, Steven A; Wada, David R; Milwee, Steve; Yaron, Yifah; Nguyen, Linh T

2017-08-01

This study evaluated factors impacting QTc interval in a phase 3 trial of cabozantinib in progressive, metastatic, medullary thyroid cancer (MTC). Electrocardiogram (12-lead ECG) measurements were obtained at screening, and at pre-dose, and 2, 4, and 6 h post-dose on Days 1 and 29 in a phase 3 study in patients with MTC treated with cabozantinib (140 mg/day). Central tendency analyses were conducted on baseline-corrected QTc values. Linear and nonlinear mixed-effects models were used to evaluate potential factors affecting the QTc interval, including serum electrolytes, patient demographics, and cabozantinib concentration. Central tendency analysis showed that oral cabozantinib (140 mg/day) produced a 10-15 ms increase in delta-delta Fridericia corrected QT (∆∆QTcF) and delta-delta study-specific corrected QT (∆∆QTcS) on Day 29, but not on Day 1. Further analysis showed that QTcS provided a slightly more accurate QT correction than QTcF. Mixed-effects models evaluating serum electrolytes, age, sex, and cabozantinib concentration showed that decreased serum calcium and potassium could explain the majority of cabozantinib treatment-associated QTcS prolongation observed in this study. Cabozantinib treatment prolongs the ∆∆QTcF interval by 10-15 ms. There was the absence of a strong relationship between cabozantinib concentration and QTcS prolongation. Cabozantinib treatment effects on serum calcium and potassium best explain the QTcS prolongation observed in this study.

Expansion of phenotype and genotypic data in CRB2-related syndrome.

Science.gov (United States)

Lamont, Ryan E; Tan, Wen-Hann; Innes, A Micheil; Parboosingh, Jillian S; Schneidman-Duhovny, Dina; Rajkovic, Aleksandar; Pappas, John; Altschwager, Pablo; DeWard, Stephanie; Fulton, Anne; Gray, Kathryn J; Krall, Max; Mehta, Lakshmi; Rodan, Lance H; Saller, Devereux N; Steele, Deanna; Stein, Deborah; Yatsenko, Svetlana A; Bernier, François P; Slavotinek, Anne M

2016-10-01

Sequence variants in CRB2 cause a syndrome with greatly elevated maternal serum alpha-fetoprotein and amniotic fluid alpha-fetoprotein levels, cerebral ventriculomegaly and renal findings similar to Finnish congenital nephrosis. All reported patients have been homozygotes or compound heterozygotes for sequence variants in the Crumbs, Drosophila, Homolog of, 2 (CRB2) genes. Variants affecting CRB2 function have also been identified in four families with steroid resistant nephrotic syndrome, but without any other known systemic findings. We ascertained five, previously unreported individuals with biallelic variants in CRB2 that were predicted to affect function. We compiled the clinical features of reported cases and reviewed available literature for cases with features suggestive of CRB2-related syndrome in order to better understand the phenotypic and genotypic manifestations. Phenotypic analyses showed that ventriculomegaly was a common clinical manifestation (9/11 confirmed cases), in contrast to the original reports, in which patients were ascertained due to renal disease. Two children had minor eye findings and one was diagnosed with a B-cell lymphoma. Further genetic analysis identified one family with two affected siblings who were both heterozygous for a variant in NPHS2 predicted to affect function and separate families with sequence variants in NPHS4 and BBS7 in addition to the CRB2 variants. Our report expands the clinical phenotype of CRB2-related syndrome and establishes ventriculomegaly and hydrocephalus as frequent manifestations. We found additional sequence variants in genes involved in kidney development and ciliopathies in patients with CRB2-related syndrome, suggesting that these variants may modify the phenotype.

High Resolution ECG for Evaluation of QT Interval Variability during Exposure to Acute Hypoxia

Science.gov (United States)

Zupet, P.; Finderle, Z.; Schlegel, Todd T.; Starc, V.

2010-01-01

Ventricular repolarization instability as quantified by the index of QT interval variability (QTVI) is one of the best predictors for risk of malignant ventricular arrhythmias and sudden cardiac death. Because it is difficult to appropriately monitor early signs of organ dysfunction at high altitude, we investigated whether high resolution advanced ECG (HR-ECG) analysis might be helpful as a non-invasive and easy-to-use tool for evaluating the risk of cardiac arrhythmias during exposure to acute hypoxia. 19 non-acclimatized healthy trained alpinists (age 37, 8 plus or minus 4,7 years) participated in the study. Five-minute high-resolution 12-lead electrocardiograms (ECGs) were recorded (Cardiosoft) in each subject at rest in the supine position breathing room air and then after breathing 12.5% oxygen for 30 min. For beat-to-beat RR and QT variability, the program of Starc was utilized to derive standard time domain measures such as root mean square of the successive interval difference (rMSSD) of RRV and QTV, the corrected QT interval (QTc) and the QTVI in lead II. Changes were evaluated with paired-samples t-test with p-values less than 0.05 considered statistically significant. As expected, the RR interval and its variability both decreased with increasing altitude, with p = 0.000 and p = 0.005, respectively. Significant increases were found in both the rMSSDQT and the QTVI in lead II, with p = 0.002 and p = 0.003, respectively. There was no change in QTc interval length (p = non significant). QT variability parameters may be useful for evaluating changes in ventricular repolarization caused by hypoxia. These changes might be driven by increases in sympathetic nervous system activity at ventricular level.

Revesz syndrome

Directory of Open Access Journals (Sweden)

Dayane Cristine Issaho

2015-04-01

Full Text Available Revesz syndrome is a rare variant of dyskeratosis congenita and is characterized by bilateral exudative retinopathy, alterations in the anterior ocular segment, intrauterine growth retardation, fine sparse hair, reticulate skin pigmentation, bone marrow failure, cerebral calcification, cerebellar hypoplasia and psychomotor retardation. Few patients with this syndrome have been reported, and significant clinical variations exist among patients. This report describes the first Brazilian case of Revesz syndrome and its ocular and clinical features.

Klüver–Bucy syndrome associated with a recessive variant in HGSNAT in two siblings with Mucopolysaccharidosis type IIIC (Sanfilippo C)

OpenAIRE

Hu, Hao; Hübner, Christoph; Lukacs, Zoltan; Musante, Luciana; Gill, Esther; Wienker, Thomas F; Ropers, Hans-Hilger; Knierim, Ellen; Schuelke, Markus

2016-01-01

Klüver–Bucy syndrome (KBS) comprises a set of neurobehavioral symptoms with psychic blindness, hypersexuality, disinhibition, hyperorality, and hypermetamorphosis that were originally observed after bilateral lobectomy in Rhesus monkeys. We investigated two siblings with KBS from a consanguineous family by whole-exome sequencing and autozygosity mapping. We detected a homozygous variant in the heparan-α-glucosaminidase-N-acetyltransferase gene (HGSNAT; c.518G>A, p.(G173D), NCBI ClinVar RCV000...

MIPEP recessive variants cause a syndrome of left ventricular non-compaction, hypotonia, and infantile death

Directory of Open Access Journals (Sweden)

Mohammad K. Eldomery

2016-11-01

Full Text Available Abstract Background Mitochondrial presequence proteases perform fundamental functions as they process about 70 % of all mitochondrial preproteins that are encoded in the nucleus and imported posttranslationally. The mitochondrial intermediate presequence protease MIP/Oct1, which carries out precursor processing, has not yet been established to have a role in human disease. Methods Whole exome sequencing was performed on four unrelated probands with left ventricular non-compaction (LVNC, developmental delay (DD, seizures, and severe hypotonia. Proposed pathogenic variants were confirmed by Sanger sequencing or array comparative genomic hybridization. Functional analysis of the identified MIP variants was performed using the model organism Saccharomyces cerevisiae as the protein and its functions are highly conserved from yeast to human. Results Biallelic single nucleotide variants (SNVs or copy number variants (CNVs in MIPEP, which encodes MIP, were present in all four probands, three of whom had infantile/childhood death. Two patients had compound heterozygous SNVs (p.L582R/p.L71Q and p.E602*/p.L306F and one patient from a consanguineous family had a homozygous SNV (p.K343E. The fourth patient, identified through the GeneMatcher tool, a part of the Matchmaker Exchange Project, was found to have inherited a paternal SNV (p.H512D and a maternal CNV (1.4-Mb deletion of 13q12.12 that includes MIPEP. All amino acids affected in the patients’ missense variants are highly conserved from yeast to human and therefore S. cerevisiae was employed for functional analysis (for p.L71Q, p.L306F, and p.K343E. The mutations p.L339F (human p.L306F and p.K376E (human p.K343E resulted in a severe decrease of Oct1 protease activity and accumulation of non-processed Oct1 substrates and consequently impaired viability under respiratory growth conditions. The p.L83Q (human p.L71Q failed to localize to the mitochondria. Conclusions Our findings reveal for the first

No evidence for pathogenic variants or maternal effect of ZFP57 as the cause of Beckwith-Wiedemann Syndrome

DEFF Research Database (Denmark)

Boonen, Susanne E; Hahnemann, Johanne M D; Mackay, Deborah

2012-01-01

in patients with BWS. We sequenced ZFP57 in 27 BWS probands and in 23 available mothers to test for a maternal effect. We identified three novel, presumably benign sequence variants in ZFP57; thus, we found no evidence for ZFP57 alterations as a major cause in sporadic BWS cases.......Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome, which, in 50-60% of sporadic cases, is caused by hypomethylation of KCNQ1OT1 differentially methylated region (DMR) at chromosome 11p15.5. The underlying defect of this hypomethylation is largely unknown. Recently, recessive mutations...... of the ZFP57 gene were reported in patients with transient neonatal diabetes mellitus type 1, showing hypomethylation at multiple imprinted loci, including KCNQ1OT1 DMR in some. The aim of our study was to determine whether ZFP57 alterations were a genetic cause of the hypomethylation at KCNQ1OT1 DMR...

EPICS-QT based graphical user interface for accelerator control

International Nuclear Information System (INIS)

Basu, A.; Singh, S.K.; Rosily, Sherry; Bhagwat, P.V.

2016-01-01

Particle accelerators and many industrial complex systems, require a robust and efficient control for its proper operation to achieve required beam quality, safety of its sub component and all working personnel. This control is executed via a graphical user interface through which an operator interacts with the accelerator to achieve the desired state of the machine and its output. Experimental Physics and Industrial Control System (EPICS) is a widely used control system framework in the field of accelerator control. It acts as a middle layer between field devices and graphic user interface used by the operator. Field devices can also be made EPICS compliant by using EPICS based software in that. On the other hand Qt is a C++ framework which is widely used for creating very professional looking and user friendly graphical component. In Low Energy High Intensity Proton Accelerator (LEHIPA), which is the first stage of the three stage Accelerator Driven System (ADS) program taken by Bhabha Atomic Research Centre (BARC), it is decided that EPICS will be used for controlling the accelerator and Qt will be used for developing the various Graphic User Interface (GUI) for operation and diagnostics. This paper discuss the work carried out to achieve this goal in LEHIPA

The MECP2 variant c.925C>T (p.Arg309Trp) causes intellectual disability in both males and females without classic features of Rett syndrome

NARCIS (Netherlands)

Schonewolf-Greulich, B.; Tejada, M.I.; Stephens, K.; Hadzsiev, K.; Gauthier, J.; Brondum-Nielsen, K.; Pfundt, R.P.; Ravn, K.; Maortua, H.; Gener, B.; Martinez-Bouzas, C.; Piton, A.; Rouleau, G.; Clayton-Smith, J.; Kleefstra, T.; Bisgaard, A.M.; Tumer, Z.

2016-01-01

Missense MECP2 variants can have various phenotypic effects ranging from a normal phenotype to typical Rett syndrome (RTT). In females, the phenotype can also be influenced by the X-inactivation pattern. In this study, we present detailed clinical descriptions of six patients with a rare base-pair

Short QTc Interval in Males with Klinefelter Syndrome-Influence of CAG Repeat Length, Body Composition, and Testosterone Replacement Therapy

DEFF Research Database (Denmark)

Jørgensen, Inger Norlyk; Skakkebaek, Anne; Andersen, Niels Holmark

2015-01-01

BackgroundKlinefelter syndrome (KS) is a sex chromosomal aneuploidy (47,XXY) affecting 1/660 males. Based on findings in Turner syndrome, we hypothesized that electrocardiogram (ECG) abnormalities would be present in males with KS. ObjectiveTo investigate ECGs in males with KS and compare...... syndrome was determined in participants with a QTc ... interval comparable to controls. No mutations in genes related to short QT syndrome were found. ConclusionWe found short QTc interval in males with KS, with further shortening of the QTc interval by T. These results suggest that genes on the X chromosome could be involved in regulation of the QTc interval...

Integral type operators from normal weighted Bloch spaces to QT,S spaces

Directory of Open Access Journals (Sweden)

Yongyi GU

2016-08-01

Full Text Available Operator theory is an important research content of the analytic function space theory. The discussion of simultaneous operator and function space is an effective way to study operator and function space. Assuming that  is an analytic self map on the unit disk Δ, and the normal weighted bloch space μ-B is a Banach space on the unit disk Δ, defining a composition operator C∶C(f=f on μ-B for all f∈μ-B, integral type operator JhC and CJh are generalized by integral operator and composition operator. The boundeness and compactness of the integral type operator JhC acting from normal weighted Bloch spaces to QT,S spaces are discussed, as well as the boundeness of the integral type operators CJh acting from normal weighted Bloch spaces to QT,S spaces. The related sufficient and necessary conditions are given.

Circadian rhythm in QT interval is preserved in mice deficient of potassium channel interacting protein 2

DEFF Research Database (Denmark)

Gottlieb, Lisa A; Lubberding, Anniek; Larsen, Anders Peter

2017-01-01

Potassium Channel Interacting Protein 2 (KChIP2) is suggested to be responsible for the circadian rhythm in repolarization duration, ventricular arrhythmias, and sudden cardiac death. We investigated the hypothesis that there is no circadian rhythm in QT interval in the absence of KChIP2. Implanted...... cardiac deaths were observed. We find similar diurnal (light:dark) and circadian (darkness) rhythms of RR intervals in WT and KChIP2(-/-) mice. Circadian rhythms in QT100 intervals are present in both groups, but at physiological small amplitudes: 1.6 ± 0.2 and 1.0 ± 0.3 ms in WT and KChIP2......(-/-), respectively (p = 0.15). A diurnal rhythm in QT100 intervals was only found in WT mice. QTmean-RR intervals display clear diurnal and circadian rhythms in both WT and KChIP2(-/-). The amplitude of the circadian rhythm in QTmean-RR is 4.0 ± 0.3 and 3.1 ± 0.5 ms in WT and KChIP2(-/-), respectively (p = 0...

Mechanistic Basis for Type 2 Long QT Syndrome Caused by KCNH2 Mutations that Disrupt Conserved Arginine Residue in the Voltage Sensor

Science.gov (United States)

McBride, Christie M.; Smith, Ashley M.; Smith, Jennifer L.; Reloj, Allison R.; Velasco, Ellyn J.; Powell, Jonathan; Elayi, Claude S.; Bartos, Daniel C.; Burgess, Don E.

2013-01-01

KCNH2 encodes the Kv11.1 channel, which conducts the rapidly activating delayed rectifier K+ current (IKr) in the heart. KCNH2 mutations cause type 2 long QT syndrome (LQT2), which increases the risk for life-threatening ventricular arrhythmias. LQT2 mutations are predicted to prolong the cardiac action potential (AP) by reducing IKr during repolarization. Kv11.1 contains several conserved basic amino acids in the fourth transmembrane segment (S4) of the voltage sensor that are important for normal channel trafficking and gating. This study sought to determine the mechanism(s) by which LQT2 mutations at conserved arginine residues in S4 (R531Q, R531W or R534L) alter Kv11.1 function. Western blot analyses of HEK293 cells transiently expressing R531Q, R531W or R534L suggested that only R534L inhibited Kv11.1 trafficking. Voltage-clamping experiments showed that R531Q or R531W dramatically altered Kv11.1 current (IKv11.1) activation, inactivation, recovery from inactivation and deactivation. Coexpression of wild type (to mimic the patients’ genotypes) mostly corrected the changes in IKv11.1 activation and inactivation, but deactivation kinetics were still faster. Computational simulations using a human ventricular AP model showed that accelerating deactivation rates was sufficient to prolong the AP, but these effects were minimal compared to simply reducing IKr. These are the first data to demonstrate that coexpressing wild type can correct activation and inactivation dysfunction caused by mutations at a critical voltage-sensing residue in Kv11.1. We conclude that some Kv11.1 mutations might accelerate deactivation to cause LQT2 but that the ventricular AP duration is much more sensitive to mutations that decrease IKr. This likely explains why most LQT2 mutations are nonsense or trafficking-deficient. PMID:23546015

Guillain-Barré Syndrome: A Variant Consisting of Facial Diplegia and Paresthesia with Left Facial Hemiplegia Associated with Antibodies to Galactocerebroside and Phosphatidic Acid.

Science.gov (United States)

Nishiguchi, Sho; Branch, Joel; Tsuchiya, Tsubasa; Ito, Ryoji; Kawada, Junya

2017-10-02

BACKGROUND A rare variant of Guillain-Barré syndrome (GBS) consists of facial diplegia and paresthesia, but an even more rare association is with facial hemiplegia, similar to Bell's palsy. This case report is of this rare variant of GBS that was associated with IgG antibodies to galactocerebroside and phosphatidic acid. CASE REPORT A 54-year-old man presented with lower left facial palsy and paresthesia of his extremities, following an upper respiratory tract infection. Physical examination confirmed lower left facial palsy and paresthesia of his extremities with hyporeflexia of his lower limbs and sensory loss of all four extremities. The differential diagnosis was between a variant of GBS and Bell's palsy. Following initial treatment with glucocorticoids followed by intravenous immunoglobulin (IVIG), his sensory abnormalities resolved. Serum IgG antibodies to galactocerebroside and phosphatidic acid were positive in this patient, but not other antibodies to glycolipids or phospholipids were found. Five months following discharge from hospital, his left facial palsy had improved. CONCLUSIONS A case of a rare variant of GBS is presented with facial diplegia and paresthesia and with unilateral facial palsy. This rare variant of GBS may which may mimic Bell's palsy. In this case, IgG antibodies to galactocerebroside and phosphatidic acid were detected.

Double uterus with obstructed hemivagina and ipsilateral renal agenesis: pelvic anatomic variants in 87 cases.

Science.gov (United States)

Fedele, L; Motta, F; Frontino, G; Restelli, E; Bianchi, S

2013-06-01

What are the anatomic variants (and their frequencies) of double uterus, obstructed hemivagina and ipsilateral renal agenesis? Most cases examined (72.4%) were of the classic anatomic variant of the Herlyn-Werner-Wunderlich syndrome (with didelphys uterus, obstructed hemivagina and ipsilateral renal agenesis) but the 27.6% of cases are of a rare variant of the syndrome (with uterus septum or cervical agenesis), showing relevant clinical and surgical implications. The extreme variability of anatomic structures involved in this syndrome (both uterus, cervico-vaginal and renal anomalies) is well known, even if a complete and uniform analysis of all its heterogeneous presentations in a large series is lacking. This is a retrospective study with 87 patients referred to our third level referral center between 1981 and 2011. We analyzed the laparoscopic and chart records of 87 women, who referred to our institute with double uterus, unilateral cervico-vaginal obstruction and ipsilateral renal anomalies. Sixty-three of 87 patients had the more classic variant of didelphys uterus with obstructed hemivagina; 10/87 patients had septate bicollis uterus with obstructed hemivagina; 9/87 patients had bicornuate bicollis uterus with obstructed hemivagina; 4/87 patients had didelphys uterus with unilateral cervical atresia; 1/87 patients had bicornuate uterus with one septate cervix and unilateral obstructed hemivagina. This is a retrospective study with a long enrolling period (30 years). New insights in the anatomic variants of this rare syndrome with their relevant surgical implications.

Cushing’s Syndrome: All variants, detection, and treatment

Science.gov (United States)

Sharma, Susmeeta T.; Nieman, Lynnette K.

2010-01-01

Synopsis Cushing’s syndrome is caused by prolonged exposure to excess glucocorticoids. Diagnosis of Cushing’s syndrome involves a step-wise approach and establishing the cause can be challenging in some cases. Hypertension is present in about 80% of patients with Cushing’s syndrome and can lead to significant morbidity and mortality. Several pathogenic mechanisms have been proposed for glucocorticoid-induced hypertension including a functional mineralocorticoid excess state, up-regulation of the renin angiotensin system and deleterious effects of cortisol on the vasculature. Surgical excision of the cause of excess glucocorticoids remains the optimal treatment for Cushing’s syndrome. Anti-glucocorticoid and antihypertensive agents and steroidogenesis inhibitors can be used as adjunctive treatment modalities in preparation for surgery, and in cases where surgery is contraindicated or has not led to cure. PMID:21565673

Heterozygous RTEL1 variants in bone marrow failure and myeloid neoplasms.

Science.gov (United States)

Marsh, Judith C W; Gutierrez-Rodrigues, Fernanda; Cooper, James; Jiang, Jie; Gandhi, Shreyans; Kajigaya, Sachiko; Feng, Xingmin; Ibanez, Maria Del Pilar F; Donaires, Flávia S; Lopes da Silva, João P; Li, Zejuan; Das, Soma; Ibanez, Maria; Smith, Alexander E; Lea, Nicholas; Best, Steven; Ireland, Robin; Kulasekararaj, Austin G; McLornan, Donal P; Pagliuca, Anthony; Callebaut, Isabelle; Young, Neal S; Calado, Rodrigo T; Townsley, Danielle M; Mufti, Ghulam J

2018-01-09

Biallelic germline mutations in RTEL1 (regulator of telomere elongation helicase 1) result in pathologic telomere erosion and cause dyskeratosis congenita. However, the role of RTEL1 mutations in other bone marrow failure (BMF) syndromes and myeloid neoplasms, and the contribution of monoallelic RTEL1 mutations to disease development are not well defined. We screened 516 patients for germline mutations in telomere-associated genes by next-generation sequencing in 2 independent cohorts; one constituting unselected patients with idiopathic BMF, unexplained cytopenia, or myeloid neoplasms (n = 457) and a second cohort comprising selected patients on the basis of the suspicion of constitutional/familial BMF (n = 59). Twenty-three RTEL1 variants were identified in 27 unrelated patients from both cohorts: 7 variants were likely pathogenic, 13 were of uncertain significance, and 3 were likely benign. Likely pathogenic RTEL1 variants were identified in 9 unrelated patients (7 heterozygous and 2 biallelic). Most patients were suspected to have constitutional BMF, which included aplastic anemia (AA), unexplained cytopenia, hypoplastic myelodysplastic syndrome, and macrocytosis with hypocellular bone marrow. In the other 18 patients, RTEL1 variants were likely benign or of uncertain significance. Telomeres were short in 21 patients (78%), and 3' telomeric overhangs were significantly eroded in 4. In summary, heterozygous RTEL1 variants were associated with marrow failure, and telomere length measurement alone may not identify patients with telomere dysfunction carrying RTEL1 variants. Pathogenicity assessment of heterozygous RTEL1 variants relied on a combination of clinical, computational, and functional data required to avoid misinterpretation of common variants.

X-Linked and Autosomal Recessive Alport Syndrome

DEFF Research Database (Denmark)

Savige, Judith; Storey, Helen; Il Cheong, Hae

2016-01-01

Alport syndrome results from mutations in the COL4A5 (X-linked) or COL4A3/COL4A4 (recessive) genes. This study examined 754 previously- unpublished variants in these genes from individuals referred for genetic testing in 12 accredited diagnostic laboratories worldwide, in addition to all published...... COL4A5, COL4A3 and COL4A4 variants in the LOVD databases. It also determined genotype-phenotype correlations for variants where clinical data were available. Individuals were referred for genetic testing where Alport syndrome was suspected clinically or on biopsy (renal failure, hearing loss...

Fatal cardiac arrhythmia and long-QT syndrome in a new form of congenital generalized lipodystrophy with muscle rippling (CGL4 due to PTRF-CAVIN mutations.

Directory of Open Access Journals (Sweden)

Anna Rajab

2010-03-01

Full Text Available We investigated eight families with a novel subtype of congenital generalized lipodystrophy (CGL4 of whom five members had died from sudden cardiac death during their teenage years. ECG studies revealed features of long-QT syndrome, bradycardia, as well as supraventricular and ventricular tachycardias. Further symptoms comprised myopathy with muscle rippling, skeletal as well as smooth-muscle hypertrophy, leading to impaired gastrointestinal motility and hypertrophic pyloric stenosis in some children. Additionally, we found impaired bone formation with osteopenia, osteoporosis, and atlanto-axial instability. Homozygosity mapping located the gene within 2 Mbp on chromosome 17. Prioritization of 74 candidate genes with GeneDistiller for high expression in muscle and adipocytes suggested PTRF-CAVIN (Polymerase I and transcript release factor/Cavin as the most probable candidate leading to the detection of homozygous mutations (c.160delG, c.362dupT. PTRF-CAVIN is essential for caveolae biogenesis. These cholesterol-rich plasmalemmal vesicles are involved in signal-transduction and vesicular trafficking and reside primarily on adipocytes, myocytes, and osteoblasts. Absence of PTRF-CAVIN did not influence abundance of its binding partner caveolin-1 and caveolin-3. In patient fibroblasts, however, caveolin-1 failed to localize toward the cell surface and electron microscopy revealed reduction of caveolae to less than 3%. Transfection of full-length PTRF-CAVIN reestablished the presence of caveolae. The loss of caveolae was confirmed by Atomic Force Microscopy (AFM in combination with fluorescent imaging. PTRF-CAVIN deficiency thus presents the phenotypic spectrum caused by a quintessential lack of functional caveolae.

Co-existence of Blau syndrome and NAID? Diagnostic challenges associated with presence of multiple pathogenic variants in NOD2 gene: a case report.

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Dziedzic, Magdalena; Marjańska, Agata; Bąbol-Pokora, Katarzyna; Urbańczyk, Anna; Grześk, Elżbieta; Młynarski, Wojciech; Kołtan, Sylwia

2017-07-27

Pediatric autoinflammatory diseases are rare and still poorly understood conditions resulting from defective genetic control of innate immune system, inter alia from anomalies of NOD2 gene. The product of this gene is Nod2 protein, taking part in maintenance of immune homeostasis. Clinical form of resultant autoinflammatory condition depends on NOD2 genotype; usually patients with NOD2 defects present with Blau syndrome, NOD2-associated autoinflammatory disease (NAID) or Crohn's disease. We present the case of a 7-year-old girl with co-existing symptoms of two rare diseases, Blau syndrome and NAID. Overlapping manifestations of two syndromes raised a significant diagnostic challenge, until next-generation molecular test (NGS) identified presence of three pathogenic variants of NOD2 gene: P268S, IVS8 +158 , 1007 fs, and established the ultimate diagnosis. Presence of multiple genetical abnormalities resulted in an ambiguous clinical presentation with overlapping symptoms of Blau syndrome and NAID. Final diagnosis of autoinflammatory disease opened new therapeutic possibilities, including the use of biological treatments.

[Approach to diagnosis and management of myeloproliferative neoplasm variants].

Science.gov (United States)

Mitsumori, Toru; Kirito, Keita

2015-08-01

Myeloproliferative neoplasm (MPN) variants are defined as relatively uncommon myeloid neoplasms which do not meet the criteria for either classical MPN or myelodysplastic syndrome. Due to the lack of specific markers, it has been challenging to accurately diagnose these malignant diseases. Recent studies have revealed new genetic abnormalities in MPN variants. These research advances are anticipated to open new approaches to not only achieving accurate diagnosis but also novel therapeutic options for these diseases.

Collapsing variant of focal segmental glomerulosclerosis in children = Variante colapsante de la glomeruloesclerosis focal y segmentaria en niños

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Jonh Fredy Nieto Ríos

2013-10-01

Full Text Available Focal segmental glomerulosclerosis (FSGS collapsing variant refers to a renal lesion that may be idiopathic or associated to some factors, characterized by glomerular collapse leading to cortico-resistant nephrotic syndrome and chronic progressive renal failure. This glomerulopathy has been scarcely studied in children, but in this age group most cases are idiopathic. In this paper we present a report of 6 cases of collapsing variant of FSGS in children no associated to HIV, which were resistant to immunosuppressive management and with a high mortality

In Silico Systems Biology Analysis of Variants of Uncertain Significance in Lynch Syndrome Supports the Prioritization of Functional Molecular Validation.

Science.gov (United States)

Borras, Ester; Chang, Kyle; Pande, Mala; Cuddy, Amanda; Bosch, Jennifer L; Bannon, Sarah A; Mork, Maureen E; Rodriguez-Bigas, Miguel A; Taggart, Melissa W; Lynch, Patrick M; You, Y Nancy; Vilar, Eduardo

2017-10-01

Lynch syndrome (LS) is a genetic condition secondary to germline alterations in the DNA mismatch repair (MMR) genes with 30% of changes being variants of uncertain significance (VUS). Our aim was to perform an in silico reclassification of VUS from a large single institutional cohort that will help prioritizing functional validation. A total of 54 VUS were detected with 33 (61%) novel variants. We integrated family history, pathology, and genetic information along with supporting evidence from eight different in silico tools at the RNA and protein level. Our assessment allowed us to reclassify 54% (29/54) of the VUS as probably damaging, 13% (7/54) as possibly damaging, and 28% (15/54) as probably neutral. There are more than 1,000 VUS reported in MMR genes and our approach facilitates the prioritization of further functional efforts to assess the pathogenicity to those classified as probably damaging. Cancer Prev Res; 10(10); 580-7. ©2017 AACR . ©2017 American Association for Cancer Research.

Catastrophic antiphospholipid syndrome in leprosy | Chewoolkar ...

African Journals Online (AJOL)

Catastrophic antiphospholipid syndrome is an acute and life threatening variant of antiphospholipid syndrome with a high mortality rate. Many infections are known to be accompanied by the thrombotic manifestations of this syndrome. We came across a patient of leprosy who developed bowel ischaemia secondary to ...

The QT dispersion and QTc dispersion in patients presenting with acute neurological events and its impact on early prognosis

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Kailash Kumar Rahar

2016-01-01

Full Text Available Aims: To find out and investigate whether the QT dispersion and QTc dispersion is related to type and prognosis of the acute stroke in patients presenting within 24 h of the onset of stroke. Settings and Design: This was a observational study conducted at Mahatma Gandhi Hospital, Dr. SN. Medical College, Jodhpur, during January 2014 to January 2015. Subjects and Methods: The patients presented within 24 h of onset of acute stroke (hemorrhagic, infarction, or transient ischemic event were included in the study. The stroke was confirmed by computed tomography scan and magnetic resonance imaging. Patients with (i altered sensorium because of metabolic, infective, seizures, trauma, or tumor; (ii prior history of cardiovascular disease, electrocardiographic abnormalities' because of dyselectrolytemia; and (iii and patients who were on drugs (antiarrhythmic drugs, antipsychotic drugs, erythromycin, theophylline, etc., which known to cause electrocardiogram changes, were excluded from the study. National Institute of Health Stroke Score (NIHSS was calculated at the time of admission and Modified Rankin Scale (MRS at the time of discharge. Fifty age- and sex-matched healthy controls included. Statistical Analysis Used: Student's t-test, ANOVA, and area under curve for sensitivity and specificity for the test. Results: We included 52 patients (male/female: 27/25 and 50 controls (26/24. The mean age of patients was 63.17 ± 08.90 years. Of total patients, infarct was found in 32 (61.53%, hemorrhage in 18 (34.61%, transient ischemic attack (TIA in 1 (1.9%, and subarachnoid hemorrhage in 1 (1.9% patient. The QT dispersion and QTc dispersion were significantly higher in cases as compare to controls. (87.30 ± 24.42 vs. 49.60 ± 08.79 ms; P < 0.001 and (97.53 ± 27.36 vs. 56.28 ± 09.86 ms; P < 0.001. Among various types of stroke, the mean QT dispersion and QTc dispersion were maximum and significantly higher in hemorrhagic stroke as compared to infarct and

Potassium dynamics are attenuated in hyperkalemia and a determinant of QT adaptation in exercising hemodialysis patients

DEFF Research Database (Denmark)

Tran, Cao Thach; Bundgaard, Henning; Ladefoged, Søren Daustrand

2013-01-01

Disturbances in plasma potassium concentration (pK) are well known risk factors for the development of cardiac arrhythmia. The aims of the present study were to evaluate the effect of hemodialysis on exercise pK dynamics and QT hysteresis, and whether QT hysteresis is associated with the p......K decrease following exercise. Twenty-two end-stage renal disease patients exercised on a cycle ergometer with incremental work load before and after hemodialysis. ECG was recorded and pK was measured during exercise and recovery. During exercise, pK increased from 5.1 ± 0.2 to 6.1 ± 0.2 mM (mean ± SE; P...

TAFRO Syndrome.

Science.gov (United States)

Igawa, Takuro; Sato, Yasuharu

2018-02-01

TAFRO syndrome is a newly recognized variant of idiopathic multicentric Castleman disease (iMCD) that involves a constellation of syndromes: thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O). Thrombocytopenia and severe anasarca accompanied by relatively low serum immunoglobulin levels are characteristic clinical findings of TAFRO syndrome that are not present in iMCD-not otherwise specified (iMCD-NOS). Lymph node biopsy is recommended to exclude other diseases and to diagnose TAFRO syndrome, which reveals characteristic histopathological findings similar to hyaline vascular-type CD. TAFRO syndrome follows a more aggressive course, compared with iMCD-NOS, and there is no standard treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

QT Prolongation due to Graves’ Disease

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Zain Kulairi

2017-01-01

Full Text Available Hyperthyroidism is a highly prevalent disease affecting over 4 million people in the US. The disease is associated with many cardiac complications including atrial fibrillation and also less commonly with ventricular tachycardia and fibrillation. Many cardiac pathologies have been extensively studied; however, the relationship between hyperthyroidism and rate of ventricular repolarization manifesting as a prolonged QTc interval is not well known. Prolonged QTc interval regardless of thyroid status is a risk factor for cardiovascular mortality and life-threatening ventricular arrhythmia. The mechanism regarding the prolongation of the QT interval in a hyperthyroid patient has not been extensively investigated although its clinical implications are relevant. Herein, we describe a case of prolonged QTc in a patient who presented with signs of hyperthyroidism that was corrected with return to euthyroid status.

Visualizing Mutation-Specific Differences in the Trafficking-Deficient Phenotype of Kv11.1 Proteins Linked to Long QT Syndrome Type 2.

Science.gov (United States)

Hall, Allison R; Anderson, Corey L; Smith, Jennifer L; Mirshahi, Tooraj; Elayi, Claude S; January, Craig T; Delisle, Brian P

2018-01-01

KCNH2 encodes the Kv11.1 α-subunit that underlies the rapidly activating delayed-rectifier K + current in the heart. Loss-of-function KCNH2 mutations cause long QT syndrome type 2 (LQT2), and most LQT2-linked missense mutations inhibit the trafficking of Kv11.1 channel protein to the cell surface membrane. Several trafficking-deficient LQT2 mutations (e.g., G601S) generate Kv11.1 proteins that are sequestered in a microtubule-dependent quality control (QC) compartment in the transitional endoplasmic reticulum (ER). We tested the hypothesis that the QC mechanisms that regulate LQT2-linked Kv11.1 protein trafficking are mutation-specific. Confocal imaging analyses of HEK293 cells stably expressing the trafficking-deficient LQT2 mutation F805C showed that, unlike G601S-Kv11.1 protein, F805C-Kv11.1 protein was concentrated in several transitional ER subcompartments. The microtubule depolymerizing drug nocodazole differentially affected G601S- and F805C-Kv11.1 protein immunostaining. Nocodazole caused G601S-Kv11.1 protein to distribute into peripheral reticular structures, and it increased the diffuse immunostaining of F805C-Kv11.1 protein around the transitional ER subcompartments. Proteasome inhibition also affected the immunostaining of G601S- and F805C-Kv11.1 protein differently. Incubating cells in MG132 minimally impacted G601S-Kv11.1 immunostaining, but it dramatically increased the diffuse immunostaining of F805C-Kv11.1 protein in the transitional ER. Similar results were seen after incubating cells in the proteasome inhibitor lactacystin. Differences in the cellular distribution of G601S-Kv11.1 and F805C-Kv11.1 protein persisted in transfected human inducible pluripotent stem cell derived cardiomyocytes. These are the first data to visually demonstrate mutation-specific differences in the trafficking-deficient LQT2 phenotype, and this study has identified a novel way to categorize trafficking-deficient LQT2 mutations based on differences in intracellular

Clinical spectrum of KIAA2022 pathogenic variants in males: Case report of two boys with kiaa2022 pathogenic variants and review of the literature.

Science.gov (United States)

Lorenzo, Melissa; Stolte-Dijkstra, Irene; van Rheenen, Patrick; Smith, Ronald Garth; Scheers, Tom; Walia, Jagdeep S

2018-04-25

KIAA2022 is an X-linked intellectual disability (XLID) syndrome affecting males more severely than females. Few males with KIAA2022 variants and XLID have been reported. We present a clinical report of two unrelated males, with two nonsense KIAA2022 pathogenic variants, with profound intellectual disabilities, limited language development, strikingly similar autistic behavior, delay in motor milestones, and postnatal growth restriction. Patient 1, 19-years-old, has long ears, deeply set eyes with keratoconus, strabismus, a narrow forehead, anteverted nares, café-au-lait spots, macroglossia, thick vermilion of the upper and lower lips, and prognathism. He has gastroesophageal reflux, constipation with delayed rectosigmoid colonic transit time, difficulty regulating temperature, several musculoskeletal issues, and a history of one grand mal seizure. Patient 2, 10-years-old, has mild dysmorphic features, therapy resistant vomiting with diminished motility of the stomach, mild constipation, cortical visual impairment with intermittent strabismus, axial hypotonia, difficulty regulating temperature, and cutaneous mastocytosis. Genetic testing identified KIAA2022 variant c.652C > T(p.Arg218*) in Patient 1, and a novel nonsense de novo variant c.2707G > T(p.Glu903*) in Patient 2. We also summarized features of all reported males with KIAA2022 variants to date. This report not only adds knowledge of a novel pathogenic variant to the KIAA2022 variant database, but also likely extends the spectrum by describing novel dysmorphic features and medical conditions including macroglossia, café-au-lait spots, keratoconus, severe cutaneous mastocytosis, and motility problems of the GI tract, which may help physicians involved in the care of patients with this syndrome. Lastly, we describe the power of social media in bringing families with rare medical conditions together. © 2018 Wiley Periodicals, Inc.

Hypoglycaemia and QT interval prolongation in type 1 diabetes - bridging the gap between clamp studies and spontaneous episodes

DEFF Research Database (Denmark)

Christensen, Toke F.; Cichosz, Simon Lebech; Tarnow, Lise

2014-01-01

AIMS: We propose a study design with controlled hypoglycaemia induced by subcutaneous injection of insulin and matched control episodes to bridge the gap between clamp studies and studies of spontaneous hypoglycaemia. The observed prolongation of the heart rate corrected QT interval (QTc) during...... hypoglycaemia varies greatly between studies. METHODS: We studied ten adults with type 1 diabetes (age 41±15years) without cardiovascular disease or neuropathy. Single-blinded hypoglycaemia was induced by a subcutaneous insulin bolus followed by a control episode on two occasions separated by 4weeks. QT...

A case of oral-facial-digital syndrome with overlapping manifestations of type V and type VI: a possible new OFD syndrome

International Nuclear Information System (INIS)

Chung Wongyiu; Chung Laupo

1999-01-01

We report a child with clinical and radiological manifestations characteristic of both V'aradi syndrome (oral-facial-digital syndrome type VI) and Thurston syndrome (oral-facial-digital syndrome type V). The findings have not been reported previously, and we believe that it represents a new variant. (orig.)

Differences in antimicrobial susceptibility of pigmented and unpigmented colonial variants of Mycobacterium avium.

Science.gov (United States)

Stormer, R S; Falkinham, J O

1989-01-01

Unpigmented colonial variants were isolated from pigmented Mycobacterium avium isolates recovered from patients with acquired immunodeficiency syndrome and the environment. The variants were interconvertible: the rate of transition from unpigmented to pigmented type was 4.0 x 10(-5) variants per cell per generation. The unpigmented variants were more tolerant to antibiotics, especially beta-lactams, and Cd2+ and Cu2+ salts than were their pigmented parents. Both pigmented and unpigmented variants of the strains produced beta-lactamase, although beta-lactamase did not appear to be a determinant of beta-lactam susceptibility. Pigmented variants grew more rapidly in a number of commonly used mycobacterial media, were more hydrophobic, and had higher carotenoid contents than their unpigmented segregants. PMID:2808669

Germline Variants in Targeted Tumor Sequencing Using Matched Normal DNA.

Science.gov (United States)

Schrader, Kasmintan A; Cheng, Donavan T; Joseph, Vijai; Prasad, Meera; Walsh, Michael; Zehir, Ahmet; Ni, Ai; Thomas, Tinu; Benayed, Ryma; Ashraf, Asad; Lincoln, Annie; Arcila, Maria; Stadler, Zsofia; Solit, David; Hyman, David M; Hyman, David; Zhang, Liying; Klimstra, David; Ladanyi, Marc; Offit, Kenneth; Berger, Michael; Robson, Mark

2016-01-01

Tumor genetic sequencing identifies potentially targetable genetic alterations with therapeutic implications. Analysis has concentrated on detecting tumor-specific variants, but recognition of germline variants may prove valuable as well. To estimate the burden of germline variants identified through routine clinical tumor sequencing. Patients with advanced cancer diagnoses eligible for studies of targeted agents at Memorial Sloan Kettering Cancer Center are offered tumor-normal sequencing with MSK-IMPACT, a 341-gene panel. We surveyed the germline variants seen in 187 overlapping genes with Mendelian disease associations in 1566 patients who had undergone tumor profiling between March and October 2014. The number of presumed pathogenic germline variants (PPGVs) and variants of uncertain significance per person in 187 genes associated with single-gene disorders and the proportions of individuals with PPGVs in clinically relevant gene subsets, in genes consistent with known tumor phenotypes, and in genes with evidence of second somatic hits in their tumors. The mean age of the 1566 patients was 58 years, and 54% were women. Presumed pathogenic germline variants in known Mendelian disease-associated genes were identified in 246 of 1566 patients (15.7%; 95% CI, 14.0%-17.6%), including 198 individuals with mutations in genes associated with cancer susceptibility. Germline findings in cancer susceptibility genes were concordant with the individual's cancer type in only 81 of 198 cases (40.9%; 95% CI, 34.3%-47.9%). In individuals with PPGVs retained in the tumor, somatic alteration of the other allele was seen in 39 of 182 cases (21.4%; 95% CI, 16.1%-28.0%), of which 13 cases did not show a known correlation of the germline mutation and a known syndrome. Mutations in non-cancer-related Mendelian disease genes were seen in 55 of 1566 cases (3.5%; 95% CI, 27.1%-45.4%). Almost every individual had more than 1 variant of uncertain significance (1565 of 1566 patients; 99

Noninvasive cardiac activation imaging of ventricular arrhythmias during drug-induced QT prolongation in the rabbit heart.

Science.gov (United States)

Han, Chengzong; Pogwizd, Steven M; Killingsworth, Cheryl R; Zhou, Zhaoye; He, Bin

2013-10-01

Imaging myocardial activation from noninvasive body surface potentials promises to aid in both cardiovascular research and clinical medicine. To investigate the ability of a noninvasive 3-dimensional cardiac electrical imaging technique for characterizing the activation patterns of dynamically changing ventricular arrhythmias during drug-induced QT prolongation in rabbits. Simultaneous body surface potential mapping and 3-dimensional intracardiac mapping were performed in a closed-chest condition in 8 rabbits. Data analysis was performed on premature ventricular complexes, couplets, and torsades de pointes (TdP) induced during intravenous administration of clofilium and phenylephrine with combinations of various infusion rates. The drug infusion led to a significant increase in the QT interval (from 175 ± 7 to 274 ± 31 ms) and rate-corrected QT interval (from 183 ± 5 to 262 ± 21 ms) during the first dose cycle. All the ectopic beats initiated by a focal activation pattern. The initial beat of TdPs arose at the focal site, whereas the subsequent beats were due to focal activity from different sites or 2 competing focal sites. The imaged results captured the dynamic shift of activation patterns and were in good correlation with the simultaneous measurements, with a correlation coefficient of 0.65 ± 0.02 averaged over 111 ectopic beats. Sites of initial activation were localized to be ~5 mm from the directly measured initiation sites. The 3-dimensional cardiac electrical imaging technique could localize the origin of activation and image activation sequence of TdP during QT prolongation induced by clofilium and phenylephrine in rabbits. It offers the potential to noninvasively investigate the proarrhythmic effects of drug infusion and assess the mechanisms of arrhythmias on a beat-to-beat basis. © 2013 Heart Rhythm Society. All rights reserved.

Long QT Syndrome

Science.gov (United States)

... medical center. Support from family and friends also can help relieve stress and anxiety. Let your loved ones know how you feel and what they can do to help you. Some people learn they have LQTS because ...

Are ECG monitoring recommendations before prescription of QT-prolonging drugs applied in daily practice?

DEFF Research Database (Denmark)

Warnier, Miriam Jacoba; Rutten, Frans Hendrik; Souverein, Patrick Cyriel

2015-01-01

PURPOSE: Monitoring of the QT duration by electrocardiography (ECG) prior to treatment is frequently recommended in the label of QT-prolonging drugs. It is, however, unknown how often general practitioners in daily clinical practice are adhering to these risk-minimization measures. We assessed...... the frequency of ECG measurements in patients where haloperidol was initiated in primary care. METHODS: Patients (≥18 years) with a first prescription of haloperidol in the UK Clinical Practice Research Datalink (2009-2013) were included. The proportion of ECGs made was determined in two blocks of 4 weeks......: during the exposure period when haloperidol was initiated, and during the control period, 1 year before. Conditional logistic regression analysis was applied to calculate the relative risk of having an ECG in the exposure period compared with the control period. Subgroup analyses were performed to assess...

Analysis of Relationship between Levofloxacin and Corrected QT Prolongation Using a Clinical Data Warehouse.

Science.gov (United States)

Park, Man Young; Kim, Eun Yeob; Lee, Young Ho; Kim, Woojae; Kim, Ku Sang; Sheen, Seung Soo; Lim, Hong Seok; Park, Rae Woong

2011-03-01

The aim of this study was to examine whether or not levofloxacin has any relationship with QT prolongation in a real clinical setting by analyzing a clinical data warehouse of data collected from different hospital information systems. Electronic prescription data and medical charts from 3 different hospitals spanning the past 9 years were reviewed, and a clinical data warehouse was constructed. Patients who were both administrated levofloxacin and given electrocardiograms (ECG) were selected. The correlations between various patient characteristics, concomitant drugs, corrected QT (QTc) prolongation, and the interval difference in QTc before and after levofloxacin administration were analyzed. A total of 2,176 patients from 3 different hospitals were included in the study. QTc prolongation was found in 364 patients (16.7%). The study revealed that age (OR 1.026, p data seem to be essential to adverse drug reaction surveillance in future.

QT-interval effects of methadone, levomethadyl, and buprenorphine in a randomized trial.

Science.gov (United States)

Wedam, Erich F; Bigelow, George E; Johnson, Rolley E; Nuzzo, Paul A; Haigney, Mark C P

2007-12-10

Levomethadyl acetate, methadone hydrochloride, and buprenorphine hydrochloride are equally effective treatments for opioid dependence. Each blocks the human ether-a-go-go-related gene (hERG)-associated channel in vitro and represents a risk for QT prolongation. To compare the effects of 3 known hERG-associated channel blockers on the corrected QT (QTc), we conducted a randomized, controlled trial of opioid-addicted subjects. We analyzed 12-lead electrocardiograms collected at baseline and every 4 weeks from 165 opioid-addicted participants in a 17-week randomized double-blind clinical trial of equally effective doses of levomethadyl, methadone, and buprenorphine at a major referral center. Analyses were limited to the 154 patients with a normal baseline QTc = (QT/ radical R-R) who had at least 1 subsequent in-treatment electrocardiogram. Patients were randomized to receive treatment with levomethadyl, methadone, or buprenorphine (hereinafter, levomethadyl, methadone, and buprenorphine groups, respectively). The prespecified end points were a QTc greater than 470 milliseconds in men (or >490 milliseconds in women), or an increase from baseline in QTc greater than 60 milliseconds. Baseline QTc was similar in the 3 groups. The levomethadyl and methadone groups were significantly more likely to manifest a QTc greater than 470 or 490 milliseconds (28% for the levomethadyl group vs 23% for the methadone group vs 0% for the buprenorphine group; P methadone group [odds ratio, 8.4; 95% confidence interval, 1.9-36.4]) compared with the buprenorphine group (2% of subjects; P methadone remained fixed over at least 8 weeks, the QTc continued to increase progressively over time (P = .08 for the levomethadyl group, P = .01 for the methadone group). Buprenorphine is associated with less QTc prolongation than levomethadyl or methadone and may be a safe alternative.

A Nested Case-Control Study of Luteinizing Hormone Variants and Risk of Breast Cancer

Science.gov (United States)

1999-10-01

study has addressed the relationship of the presence of the variant LH to clinical and hormonal parameters among women with polycystic ovaries as...compared to healthy subjects (6). In this study, the variant was appreciably more frequent in obese women with polycystic ovaries than in normal women...immunological LH- 13-subunit variant in a UK population of healthy women and women with polycystic ovary syndrome. Clin Endocrinol. 1995; 43:297-303

Visi—A VTK- and QT-Based Open-Source Project for Scientific Data Visualization

Science.gov (United States)

Li, Yiming; Chen, Cheng-Kai

2009-03-01

In this paper, we present an open-source project, Visi for high-dimensional engineering and scientific data visualization. Visi is with state-of-the-art interactive user interface and graphics kernels based upon Qt (a cross-platform GUI toolkit) and VTK (an object-oriented visualization library). For an initialization of Visi, a preliminary window will be activated by Qt, and the kernel of VTK is simultaneously embedded into the window, where the graphics resources are allocated. Representation of visualization is through an interactive interface so that the data will be rendered according to user's preference. The developed framework possesses high flexibility and extensibility for advanced functions (e.g., object combination, etc) and further applications. Application of Visi to data visualization in various fields, such as protein structure in bioinformatics, 3D semiconductor transistor, and interconnect of very-large scale integration (VLSI) layout is also illustrated to show the performance of Visi. The developed open-source project is available in our project website on the internet [1].

The MLH1 c.1852_1853delinsGC (p.K618A variant in colorectal cancer: genetic association study in 18,723 individuals.

Directory of Open Access Journals (Sweden)

Anna Abulí

Full Text Available Colorectal cancer is one of the most frequent neoplasms and an important cause of mortality in the developed world. Mendelian syndromes account for about 5% of the total burden of CRC, being Lynch syndrome and familial adenomatous polyposis the most common forms. Lynch syndrome tumors develop mainly as a consequence of defective DNA mismatch repair associated with germline mutations in MLH1, MSH2, MSH6 and PMS2. A significant proportion of variants identified by screening these genes correspond to missense or noncoding changes without a clear pathogenic consequence, and they are designated as "variants of uncertain significance", being the c.1852_1853delinsGC (p.K618A variant in the MLH1 gene a clear example. The implication of this variant as a low-penetrance risk variant for CRC was assessed in the present study by performing a case-control study within a large cohort from the COGENT consortium-COST Action BM1206 including 18,723 individuals (8,055 colorectal cancer cases and 10,668 controls and a case-only genotype-phenotype correlation with several clinical and pathological characteristics restricted to the Epicolon cohort. Our results showed no involvement of this variant as a low-penetrance variant for colorectal cancer genetic susceptibility and no association with any clinical and pathological characteristics including family history for this neoplasm or Lynch syndrome.

The clinical factors′ prediction of increased intradialytic qt dispersion on the electrocardiograms of chronic hemodialysis patients

Directory of Open Access Journals (Sweden)

Dina Oktavia

2013-01-01

Full Text Available Ventricular arrhythmias and sudden death are common in patients on maintenance hemodialysis (HD. The increase in QT dispersion (QTd on the electrocardiogram (ECG reflects increased tendency for ventricular repolarization that predisposes to arrhythmias. The purpose of the study was to identify the clinical factors that may predict the increased intradialytic QTd and to assess differences in QTd before and after HD. Each of 61 chronic HD patients underwent 12-lead ECG and blood pressure (BP measurement before and every 1 h during a single HD session. The QT intervals were corrected for heart rate using Bazett′s formula. Intradialytic QTd increased in 30 (49% patients. There was no correlation between the increased QTd and the clinical factors including hypertension, pulse pressure, intradialytic hypotension, left ventricular hypertrophy, old myocardial infarct, diabetes mellitus, and nutritional status. The means of QT interval and QTd increased after HD session (from 382 ± 29 to 444 ± 26 ms, P <0.05; and from 74 ± 21 to 114 ± 53 ms, respectively, P <0.05. We conclude that the increased intradialytic QTd could not be predicted by any of the clinical factors evaluated in this study. There was significant difference in the means of QTd before and after HD session.

Bi-allelic Alterations in AEBP1 Lead to Defective Collagen Assembly and Connective Tissue Structure Resulting in a Variant of Ehlers-Danlos Syndrome

KAUST Repository

Blackburn, Patrick R.; Xu, Zhi; Tumelty, Kathleen E.; Zhao, Rose W.; Monis, William J.; Harris, Kimberly G.; Gass, Jennifer M.; Cousin, Margot A.; Boczek, Nicole J.; Mitkov, Mario V.; Cappel, Mark A.; Francomano, Clair A.; Parisi, Joseph E.; Klee, Eric W.; Faqeih, Eissa; Alkuraya, Fowzan S.; Layne, Matthew D.; McDonnell, Nazli B.; Atwal, Paldeep S.

2018-01-01

AEBP1 encodes the aortic carboxypeptidase-like protein (ACLP) that associates with collagens in the extracellular matrix (ECM) and has several roles in development, tissue repair, and fibrosis. ACLP is expressed in bone, the vasculature, and dermal tissues and is involved in fibroblast proliferation and mesenchymal stem cell differentiation into collagen-producing cells. Aebp1 mice have abnormal, delayed wound repair correlating with defects in fibroblast proliferation. In this study, we describe four individuals from three unrelated families that presented with a unique constellation of clinical findings including joint laxity, redundant and hyperextensible skin, poor wound healing with abnormal scarring, osteoporosis, and other features reminiscent of Ehlers-Danlos syndrome (EDS). Analysis of skin biopsies revealed decreased dermal collagen with abnormal collagen fibrils that were ragged in appearance. Exome sequencing revealed compound heterozygous variants in AEBP1 (c.1470delC [p.Asn490_Met495delins(40)] and c.1743C>A [p.Cys581]) in the first individual, a homozygous variant (c.1320_1326del [p.Arg440Serfs3]) in the second individual, and a homozygous splice site variant (c.1630+1G>A) in two siblings from the third family. We show that ACLP enhances collagen polymerization and binds to several fibrillar collagens via its discoidin domain. These studies support the conclusion that biallelic pathogenic variants in AEBP1 are the cause of this autosomal-recessive EDS subtype.

Bi-allelic Alterations in AEBP1 Lead to Defective Collagen Assembly and Connective Tissue Structure Resulting in a Variant of Ehlers-Danlos Syndrome

KAUST Repository

Blackburn, Patrick R.

2018-03-29

AEBP1 encodes the aortic carboxypeptidase-like protein (ACLP) that associates with collagens in the extracellular matrix (ECM) and has several roles in development, tissue repair, and fibrosis. ACLP is expressed in bone, the vasculature, and dermal tissues and is involved in fibroblast proliferation and mesenchymal stem cell differentiation into collagen-producing cells. Aebp1 mice have abnormal, delayed wound repair correlating with defects in fibroblast proliferation. In this study, we describe four individuals from three unrelated families that presented with a unique constellation of clinical findings including joint laxity, redundant and hyperextensible skin, poor wound healing with abnormal scarring, osteoporosis, and other features reminiscent of Ehlers-Danlos syndrome (EDS). Analysis of skin biopsies revealed decreased dermal collagen with abnormal collagen fibrils that were ragged in appearance. Exome sequencing revealed compound heterozygous variants in AEBP1 (c.1470delC [p.Asn490_Met495delins(40)] and c.1743C>A [p.Cys581]) in the first individual, a homozygous variant (c.1320_1326del [p.Arg440Serfs3]) in the second individual, and a homozygous splice site variant (c.1630+1G>A) in two siblings from the third family. We show that ACLP enhances collagen polymerization and binds to several fibrillar collagens via its discoidin domain. These studies support the conclusion that biallelic pathogenic variants in AEBP1 are the cause of this autosomal-recessive EDS subtype.

CAPSAICIN SUPPLEMENTATION FAILS TO MODULATE AUTONOMIC AND CARDIAC ELECTROPHYSIOLOGIC ACTIVITY DURING EXERCISE IN THE OBESE: WITH VARIANTS OF UCP2 AND UCP3 POLYMORPHISM

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Ki Ok Shin

2008-09-01

Full Text Available We investigated the effects of capsaicin supplementation (150mg on alterations of autonomic nervous system (ANS activity associated with adverse effects of cardiac depolarization-repolarization intervals during aerobic exercise in obese humans. Nine obese males (26.1 ± 1.5 yrs volunteered between study designed. The cardiac ANS activities evaluated by means of heart rate variability of power spectral analysis and cardiac QT interval were continuously measured during 5-min rest and 30-min exercise at 50% of maximal ventilation threshold (50%VTmax on stationary ergometer with placebo (CON or capsaicin (CAP oral administration chosen at random. The uncoupling protein (UCP 2 and UCP 3 genetic variants of the subjects were analyzed by noninvasive genotyping method from collecting buccal mucosa cells. The results indicated that there were no significant differences in cardiac ANS activities during rest and exercise between CON and CAP trials. Although no significant difference, A/A allele of UCP2 polymorphism showed a reduced sympathetic nervous system (SNS index activity compared to G/G + G/A allele during exercise intervention in our subjects. On the other hand, the data on cardiac QT interval showed no significant difference, indicating that oral administration of capsaicin did not cause any adverse effect on cardiac depolarization-repolarization. In conclusion, our results suggest that capsaicin supplementation 1 h before exercise intervention has no effect on cardiac ANS activities and cardiac electrical stability during exercise in obese individuals. Further studies should also consider genetic variants for exercise efficacy against obesity

New age- and sex-specific criteria for QT prolongation based on rate correction formulas that minimize bias at the upper normal limits.

Science.gov (United States)

Rautaharju, Pentti M; Mason, Jay W; Akiyama, Toshio

2014-07-01

Existing formulas for rate-corrected QT (QTc) commonly fail to properly adjust the upper normal limits which are more critical than the mean QTc for evaluation of prolonged QT. Age- and sex-related differences in QTc are also often overlooked. Our goal was to establish criteria for prolonged QTc using formulas that minimize QTc bias at the upper normal limits. Strict criteria were used in selecting a study group of 57,595 persons aged 5 to 89 years (54% women) and to exclude electrocardiograms (ECG) with possible disease-associated changes. Two QT rate adjustment formulas were identified which both minimized rate-dependency in the 98 th percentile limits: QTcmod, based on an electrophysiological model (QTcMod = QTx(120 + HR)/180)), and QTcLogLin, a power function of the RR interval with exponents 0.37 for men and 0.38 for women. QTc shortened in men during adolescence and QTcMod became 13 ms shorter than in women at age 20-29 years. The sex difference was maintained through adulthood although decreasing with age. The criteria established for prolonged QTc were: Age < 40 years, men 430 ms, women 440 ms; Age 40 to 69, men 440 ms, women 450 ms; Age ≥ 70 years, men 455 ms, and women 460 ms. Sex difference in QTc originates from shortened QT in adolescent males. Upper normal limits for QTc vary substantially by age and sex, and it is essential to use age- and sex-specific criteria for evaluation of QT prolongation. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Mechanistic basis for type 2 long QT syndrome caused by KCNH2 mutations that disrupt conserved arginine residues in the voltage sensor.

Science.gov (United States)

McBride, Christie M; Smith, Ashley M; Smith, Jennifer L; Reloj, Allison R; Velasco, Ellyn J; Powell, Jonathan; Elayi, Claude S; Bartos, Daniel C; Burgess, Don E; Delisle, Brian P

2013-05-01

KCNH2 encodes the Kv11.1 channel, which conducts the rapidly activating delayed rectifier K+ current (I Kr) in the heart. KCNH2 mutations cause type 2 long QT syndrome (LQT2), which increases the risk for life-threatening ventricular arrhythmias. LQT2 mutations are predicted to prolong the cardiac action potential (AP) by reducing I Kr during repolarization. Kv11.1 contains several conserved basic amino acids in the fourth transmembrane segment (S4) of the voltage sensor that are important for normal channel trafficking and gating. This study sought to determine the mechanism(s) by which LQT2 mutations at conserved arginine residues in S4 (R531Q, R531W or R534L) alter Kv11.1 function. Western blot analyses of HEK293 cells transiently expressing R531Q, R531W or R534L suggested that only R534L inhibited Kv11.1 trafficking. Voltage-clamping experiments showed that R531Q or R531W dramatically altered Kv11.1 current (I Kv11.1) activation, inactivation, recovery from inactivation and deactivation. Coexpression of wild type (to mimic the patients' genotypes) mostly corrected the changes in I Kv11.1 activation and inactivation, but deactivation kinetics were still faster. Computational simulations using a human ventricular AP model showed that accelerating deactivation rates was sufficient to prolong the AP, but these effects were minimal compared to simply reducing I Kr. These are the first data to demonstrate that coexpressing wild type can correct activation and inactivation dysfunction caused by mutations at a critical voltage-sensing residue in Kv11.1. We conclude that some Kv11.1 mutations might accelerate deactivation to cause LQT2 but that the ventricular AP duration is much more sensitive to mutations that decrease I Kr. This likely explains why most LQT2 mutations are nonsense or trafficking-deficient.

The Role of KCNQ1 Mutations and Maternal Beta Blocker Use During Pregnancy in the Growth of Children With Long QT Syndrome

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Heta Huttunen

2018-04-01

Full Text Available ObjectiveTwo missense mutations in KCNQ1, an imprinted gene that encodes the alpha subunit of the voltage-gated potassium channel Kv7.1, cause autosomal dominant growth hormone deficiency and maternally inherited gingival fibromatosis. We evaluated endocrine features, birth size, and subsequent somatic growth of patients with long QT syndrome 1 (LQT1 due to loss-of-function mutations in KCNQ1.DesignMedical records of 104 patients with LQT1 in a single tertiary care center between 1995 and 2015 were retrospectively reviewed.MethodsClinical and endocrine data of the LQT1 patients were included in the analyses.ResultsAt birth, patients with a maternally inherited mutation (n = 52 were shorter than those with paternal inheritance of the mutation (n = 29 (birth length, −0.70 ± 1.1 SDS vs. −0.2 ± 1.0 SDS, P < 0.05. Further analyses showed, however, that only newborns (n = 19 of mothers who had received beta blockers during pregnancy were shorter and lighter at birth than those with paternal inheritance of the mutation (n = 29 (−0.89 ± 1.0 SDS vs. −0.20 ± 1.0 SDS, P < 0.05; and 3,173 ± 469 vs. 3,515 ± 466 g, P < 0.05. Maternal beta blocker treatment during the pregnancy was also associated with lower cord blood TSH levels (P = 0.011 and significant catch-up growth during the first year of life (Δ0.08 SDS/month, P = 0.004. Later, childhood growth of the patients was unremarkable.ConclusionLoss-of-function mutations in KCNQ1 are not associated with abnormalities in growth, whereas maternal beta blocker use during pregnancy seems to modify prenatal growth of LQT1 patients—a phenomenon followed by catch-up growth after birth.

Autosomal dominant syndrome resembling Coffin-Siris syndrome.

Science.gov (United States)

Flynn, Maureen A; Milunsky, Jeff M

2006-06-15

Coffin-Siris syndrome is a multiple congenital anomaly/mental retardation syndrome with phenotypic variability [OMIM 135900]. The diagnosis is based solely on clinical findings, as there is currently no molecular, biochemical, or cytogenetic analysis available to confirm a diagnosis. Although typically described as an autosomal recessive disorder, autosomal dominant inheritance has also been infrequently reported. We describe a mother and her two daughters who all have features that resemble Coffin-Siris syndrome. However, this is not a completely convincing diagnosis given that hypertelorism is not a feature of Coffin-Siris syndrome and the family is relatively mildly affected. Yet, this family provides further evidence of an autosomal dominant mode of inheritance for a likely variant of Coffin-Siris syndrome (at least in some families). In addition, Sibling 1 had premature thelarche. She is the second reported individual within the spectrum of Coffin-Siris syndrome to have premature thelarche, indicating that it may be a rare clinical feature. Copyright 2006 Wiley-Liss, Inc.

Cardiac Channelopathies and Sudden Death: Recent Clinical and Genetic Advances

OpenAIRE

Fernández Falgueras, Anna; Sarquella Brugada, Georgia; Brugada Terradellas, Josep; Brugada, Ramon; Campuzano Larrea, Oscar

2017-01-01

Sudden cardiac death poses a unique challenge to clinicians because it may be the only symptom of an inherited heart condition. Indeed, inherited heart diseases can cause sudden cardiac death in older and younger individuals. Two groups of familial diseases are responsible for sudden cardiac death: cardiomyopathies (mainly hypertrophic cardiomyopathy, dilated cardiomyopathy, and arrhythmogenic cardiomyopathy) and channelopathies (mainly long QT syndrome, Brugada syndrome, short QT syndrome, a...

Genetics of migraine and related syndromes

NARCIS (Netherlands)

Stam, Anine Henrike

2014-01-01

In this dissertation clinical genetic investigations on migraine, related syndromes and comorbid conditions are described. The first migraine syndrome studied is Familial Hemiplegic Migraine (FHM), a monogenic migraine variant. The clinical spectrum of FHM1-3 and the relation with closely related

Antenatal Bartter's syndrome with sensorineural deafness

OpenAIRE

Bhamkar, R. P.; Gajendragadkar, A.

2009-01-01

Bartter's syndrome is a group of inherited, salt-losing tubulopathies presenting as metabolic alkalosis with normotensive hyperreninemia and hyperaldosteronism. We report here the first case of a neonate with bilateral, sensorineural deafness, a variant of antenatal Bartter's syndrome from an Indian community.

Sudden cardiac death in children and adolescents (excluding Sudden Infant Death Syndrome

Directory of Open Access Journals (Sweden)

Gajewski Kelly