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  1. Association of a congenital long QT syndrome type 1 with Takotsubo cardiomyopathy.

    PubMed

    El-Battrawy, Ibrahim; Behnes, Michael; Borggrefe, Martin; Akin, Ibrahim

    2016-08-01

    The occurrence of takotsubo cardiomyopathy in a patient with congenital long QT syndrome has rarely been described. This case report discusses the occurrence of a clinically overt takotsubo cardiomyopathy accompanied by congenital long QT syndrome type 1 in a female patient. PMID:27525086

  2. How Is Long QT Syndrome Diagnosed?

    MedlinePlus

    ... page from the NHLBI on Twitter. How Is Long QT Syndrome Diagnosed? Cardiologists diagnose and treat long ... or blood levels of potassium. Types of Inherited Long QT Syndrome If you have inherited LQTS, it ...

  3. Autonomic Control of Heart Rate and of QT Interval Variability Influences Arrhythmic Risk in Long QT Syndrome Type 1

    PubMed Central

    Porta, Alberto; Girardengo, Giulia; Bari, Vlasta; George, Alfred L.; Brink, Paul A.; Goosen, Althea; Crotti, Lia; Schwartz, Peter J.

    2014-01-01

    BACKGROUND A puzzling feature of the long QT syndrome (LQTS) is that family members carrying the same mutation often have divergent symptoms and clinical outcomes. OBJECTIVES We tested the hypothesis that vagal and sympathetic control, as assessed from spectral analysis of spontaneous beat-to-beat variability of RR and QT intervals from standard 24-hour electrocardiogram Holter recordings, can modulate the severity of LQTS type 1 (LQT1) in 46 members of a South-African LQT1 founder population carrying the clinically severe KCNQ1-A341V mutation. METHODS Nonmutation carriers (NMCs, n = 14) were compared with mutation carriers (MCs, n = 32), 22 with and 10 without major symptoms. We assessed the effect of circadian rhythm and of beta-blocker therapy over traditional time and frequency domain RR and QT variability indices. RESULTS The asymptomatic MCs differed significantly from the symptomatic MCs and from NMCs in less vagal control of heart rate and more reactive sympathetic modulation of the QT interval, particularly during daytime when arrhythmia risk for LQT1 patients is greatest. CONCLUSIONS The present data identify an additional factor contributing to the differential arrhythmic risk among LQT1 patients carrying the same mutation. A “normal” autonomic control confers a high risk, whereas patients with higher sympathetic control of the QT interval and reduced vagal control of heart rate are at lower risk. This differential “autonomic make-up,” likely under genetic control, will allow refinement of risk stratification within LQTS families, leading to more targeted management. PMID:25634836

  4. Refined multiscale entropy analysis of heart period and QT interval variabilities in long QT syndrome type-1 patients.

    PubMed

    Bari, Vlasta; Valencia, Jose F; Vallverdu, Montserrat; Girardengo, Giulia; Bassani, Tito; Marchi, Andrea; Calvillo, Laura; Caminal, Pere; Cerutti, Sergio; Brink, Paul A; Crotti, Lia; Schwartz, Peter J; Porta, Alberto

    2013-01-01

    This study assesses complexity of cardiovascular control in patients affected by type-1 variant of long QT (LQT1) syndrome. Complexity was assessed by refined multiscale entropy of heart period (HP) and QT interval variabilities. HP was taken as the time distance between two consecutive R peaks (RR) and QT interval was approximated as the time distance between the R-peak and T-wave apex (RTa) and between R-peak and T-wave end (RTe). RR, RTa and RTe intervals were automatically extracted from 24h Holter recordings and the daytime period was analyzed (from 02:00 to 06:00 PM). Non mutation carrier (NMC) individuals (n=11), utilized as a control group, were taken from the same family line of the mutation carrier (MC) subjects (n=26). We found that, while NMC and MC groups were indistinguishable based on time domain and complexity analyses of RR dynamics, complexity analysis of RTa and RTe variabilities clearly separates the two populations and suggests an impairment in the cardiac control mechanisms acting on the ventricles. PMID:24110995

  5. Response of the QT interval to mental and physical stress in types LQT1 and LQT2 of the long QT syndrome

    PubMed Central

    Paavonen, K; Swan, H; Piippo, K; Hokkanen, L; Laitinen, P; Viitasalo, M; Toivonen, L; Kontula, K

    2001-01-01

    OBJECTIVE—To study and compare the effects of mental and physical stress on long QT syndrome (LQTS) patients.
DESIGN—Case-control study.
MAIN OUTCOME MEASURES—QT intervals were measured from lead V3. Serum potassium and plasma catecholamine concentrations were also monitored.
PATIENTS—16 patients with type 1 LQTS (LQT1), 14 with type 2 LQTS (LQT2), both groups asymptomatic, and 14 healthy control subjects.
INTERVENTIONS—Three types of mental stress tests and a submaximal exercise stress test.
RESULTS—Heart rate responses to mental stress and exercise were similar in all groups. During mental stress, the mean QT interval shortened to a similar extent in controls (-29 ms), LQT1 patients (-34 ms), and LQT2 patients (-30 ms). During exercise, the corresponding QT adaptation to exercise stress was more pronounced (p < 0.01) in healthy controls (-47 ms) than in LQT1 (-38 ms) or LQT2 patients (-38 ms). During exercise changes in serum potassium concentrations were correlated to changes in QT intervals in controls, but not in LQTS patients. LQT1 and LQT2 patients did not differ in serum potassium, catecholamine or heart rate responses to mental or physical stress.
CONCLUSIONS—QT adaptation to mental and exercise stress in healthy people and in patients with LQTS is different. In healthy people QT adaptation is more sensitive to physical than to mental stress while no such diverging pattern was seen in asymptomatic LQTS patients.


Keywords: exercise; long QT syndrome; mental stress; potassium channel PMID:11410559

  6. Congenital long QT syndrome

    PubMed Central

    Crotti, Lia; Celano, Giuseppe; Dagradi, Federica; Schwartz, Peter J

    2008-01-01

    Congenital long QT syndrome (LQTS) is a hereditary cardiac disease characterized by a prolongation of the QT interval at basal ECG and by a high risk of life-threatening arrhythmias. Disease prevalence is estimated at close to 1 in 2,500 live births. The two cardinal manifestations of LQTS are syncopal episodes, that may lead to cardiac arrest and sudden cardiac death, and electrocardiographic abnormalities, including prolongation of the QT interval and T wave abnormalities. The genetic basis of the disease was identified in the mid-nineties and all the LQTS genes identified so far encode cardiac ion channel subunits or proteins involved in modulating ionic currents. Mutations in these genes (KCNQ1, KCNH2, KCNE1, KCNE2, CACNA1c, CAV3, SCN5A, SCN4B) cause the disease by prolonging the duration of the action potential. The most prevalent LQTS variant (LQT1) is caused by mutations in the KCNQ1 gene, with approximately half of the genotyped patients carrying KCNQ1 mutations. Given the characteristic features of LQTS, the typical cases present no diagnostic difficulties for physicians aware of the disease. However, borderline cases are more complex and require the evaluation of various electrocardiographic, clinical, and familial findings, as proposed in specific diagnostic criteria. Additionally, molecular screening is now part of the diagnostic process. Treatment should always begin with β-blockers, unless there are valid contraindications. If the patient has one more syncope despite a full dose β-blockade, left cardiac sympathetic denervation (LCSD) should be performed without hesitation and implantable cardioverter defibrillator (ICD) therapy should be considered with the final decision being based on the individual patient characteristics (age, sex, clinical history, genetic subgroup including mutation-specific features in some cases, presence of ECG signs – including 24-hour Holter recordings – indicating high electrical instability). The prognosis of the

  7. How Is Long QT Syndrome Treated?

    MedlinePlus

    ... page from the NHLBI on Twitter. How Is Long QT Syndrome Treated? The goal of treating long QT syndrome (LQTS) is to prevent life-threatening, ... levels. (For more information, go to "What Causes Long QT Syndrome?" ) Many people who have LQTS also ...

  8. What Are the Signs and Symptoms of Long QT Syndrome?

    MedlinePlus

    ... Twitter. What Are the Signs and Symptoms of Long QT Syndrome? Major Signs and Symptoms If you ... This may cause noisy gasping while sleeping. Silent Long QT Syndrome Sometimes long QT syndrome doesn't ...

  9. A Neonate with Susceptibility to Long QT Syndrome Type 6 who Presented with Ventricular Fibrillation and Sudden Unexpected Infant Death

    PubMed Central

    Sauer, Charles W.; Marc-Aurele, Krishelle L.

    2016-01-01

    Patient: Female, 19-day Final Diagnosis: 19 day old neonate with susceptibility to Long QT syndrome • ventricular fibrillation Symptoms: Cardiac arrest • cardiac arrhythmia • encephalopathy Medication: — Clinical Procedure: Cardioversion Specialty: Pediatrics and Neonatology Objective: Rare disease Background: This is a case of a neonate with susceptibility to long QT syndrome (LQTS) who presented with a sudden unexpected infant death. Experts continue to debate whether universal electrocardiogram (ECG) screening of all newborns is feasible, practical, and cost-effective. Case Report: A 19-day-old neonate was found unresponsive by her mother. ECG showed ventricular fibrillation and a combination of a lidocaine drip plus multiple defibrillations converted the rhythm to normal sinus. Unfortunately, MRI brain imaging showed multiple infarcts and EEG showed burst suppression pattern with frequent seizures; life supportive treatment was stopped and the infant died. Genetic testing revealed two mutations in the KCNE2 gene consistent with susceptibility to LQTS type 6. Conclusions: We believe this case is the first to demonstrate both a precipitating electrocardiographic and genetic cause of death for an infant with LQTS, showing a cause-and-effect relationship between LQTS mutation, ventricular arrhythmia, and death. We wonder whether universal ECG newborn screening to prevent LQTS death could have saved this baby. PMID:27465075

  10. Autonomic modulation and antiarrhythmic therapy in a model of long QT syndrome type 3

    PubMed Central

    Fabritz, Larissa; Damke, Dierk; Emmerich, Markus; Kaufmann, Susann G.; Theis, Kathrin; Blana, Andreas; Fortmüller, Lisa; Laakmann, Sandra; Hermann, Sven; Aleynichenko, Elena; Steinfurt, Johannes; Volkery, Daniela; Riemann, Burkhard; Kirchhefer, Uwe; Franz, Michael R.; Breithardt, Günter; Carmeliet, Edward; Schäfers, Michael; Maier, Sebastian K.G.; Carmeliet, Peter; Kirchhof, Paulus

    2010-01-01

    Aims Clinical observations in patients with long QT syndrome carrying sodium channel mutations (LQT3) suggest that bradycardia caused by parasympathetic stimulation may provoke torsades de pointes (TdP). β-Adrenoceptor blockers appear less effective in LQT3 than in other forms of the disease. Methods and results We studied effects of autonomic modulation on arrhythmias in vivo and in vitro and quantified sympathetic innervation by autoradiography in heterozygous mice with a knock-in deletion (ΔKPQ) in the Scn5a gene coding for the cardiac sodium channel and increased late sodium current (LQT3 mice). Cholinergic stimulation by carbachol provoked bigemini and TdP in freely roaming LQT3 mice. No arrhythmias were provoked by physical stress, mental stress, isoproterenol, or atropine. In isolated, beating hearts, carbachol did not prolong action potentials per se, but caused bradycardia and rate-dependent action potential prolongation. The muscarinic inhibitor AFDX116 prevented effects of carbachol on heart rate and arrhythmias. β-Adrenoceptor stimulation suppressed arrhythmias, shortened rate-corrected action potential duration, increased rate, and minimized difference in late sodium current between genotypes. β-Adrenoceptor density was reduced in LQT3 hearts. Acute β-adrenoceptor blockade by esmolol, propranolol or chronic propranolol in vivo did not suppress arrhythmias. Chronic flecainide pre-treatment prevented arrhythmias (all P < 0.05). Conclusion Cholinergic stimulation provokes arrhythmias in this model of LQT3 by triggering bradycardia. β-Adrenoceptor density is reduced, and β-adrenoceptor blockade does not prevent arrhythmias. Sodium channel blockade and β-adrenoceptor stimulation suppress arrhythmias by shortening repolarization and minimizing difference in late sodium current. PMID:20110334

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

    PubMed

    Fatima, Azra; Ivanyuk, Dina; Herms, Stefan; Heilmann-Heimbach, Stefanie; O'Shea, Orla; Chapman, Charlotte; Izsvák, Zsuszanna; Farr, Martin; Hescheler, Jürgen; Šarić, Tomo

    2016-03-01

    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). PMID:27345990

  12. Genetics Home Reference: short QT syndrome

    MedlinePlus

    ... Information What information about a genetic condition can statistics provide? Why are some genetic conditions more common in particular ethnic groups? Genetic Changes Mutations in the KCNH2 , KCNJ2 , and KCNQ1 genes can cause short QT syndrome . These ...

  13. Short QT Syndrome in Current Clinical Practice.

    PubMed

    Khera, Sahil; Jacobson, Jason T

    2016-01-01

    Short QT syndrome is a rare inherited autosomal dominant cardiac channelopathy associated with malignant ventricular and atrial arrhythmias. A shortened corrected QT interval is a marker for risk of malignant arrhythmias, which are secondary to increased transmural dispersion of repolarization. The underlying gain of function mutations in the potassium channels are most common but genetic testing remains low yield. This review discusses the cellular mechanisms, genetic involvement, clinical presentation, and current recommended management of patients with short QT syndrome relevant to current clinical practice. PMID:26440650

  14. Large-scale Mutational Analysis of Kv11.1 Reveals Molecular Insights into Type 2 Long QT Syndrome

    PubMed Central

    Anderson, Corey L.; Kuzmicki, Catherine E.; Childs, Ryan R.; Hintz, Caleb J.; Delisle, Brian P.; January, Craig T.

    2014-01-01

    It has been suggested that deficient protein trafficking to the cell membrane is the dominant mechanism associated with type 2 Long QT syndrome (LQT2) caused by Kv11.1 potassium channel missense mutations, and that for many mutations the trafficking defect can be corrected pharmacologically. However, this inference was based on expression of a small number of Kv11.1 mutations. We performed a comprehensive analysis of 167 LQT2-linked missense mutations in four Kv11.1 structural domains and found that deficient protein trafficking is the dominant mechanism for all domains except for the distal C-terminus. Also, most pore mutations—in contrast to intracellular domain mutations —were found to have severe dominant-negative effects when co-expressed with wild type subunits. Finally, pharmacological correction of the trafficking defect in homomeric mutant channels was possible for mutations within all structural domains. However, pharmacological correction is dramatically improved for pore mutants when co-expressed with wild type subunits to form heteromeric channels. PMID:25417810

  15. Large-scale mutational analysis of Kv11.1 reveals molecular insights into type 2 long QT syndrome

    NASA Astrophysics Data System (ADS)

    Anderson, Corey L.; Kuzmicki, Catherine E.; Childs, Ryan R.; Hintz, Caleb J.; Delisle, Brian P.; January, Craig T.

    2014-11-01

    It has been suggested that deficient protein trafficking to the cell membrane is the dominant mechanism associated with type 2 Long QT syndrome (LQT2) caused by Kv11.1 potassium channel missense mutations, and that for many mutations the trafficking defect can be corrected pharmacologically. However, this inference was based on expression of a small number of Kv11.1 mutations. We performed a comprehensive analysis of 167 LQT2-linked missense mutations in four Kv11.1 structural domains and found that deficient protein trafficking is the dominant mechanism for all domains except for the distal carboxy-terminus. Also, most pore mutations—in contrast to intracellular domain mutations—were found to have severe dominant-negative effects when co-expressed with wild-type subunits. Finally, pharmacological correction of the trafficking defect in homomeric mutant channels was possible for mutations within all structural domains. However, pharmacological correction is dramatically improved for pore mutants when co-expressed with wild-type subunits to form heteromeric channels.

  16. A Neonate with Susceptibility to Long QT Syndrome Type 6 who Presented with Ventricular Fibrillation and Sudden Unexpected Infant Death.

    PubMed

    Sauer, Charles W; Marc-Aurele, Krishelle L

    2016-01-01

    BACKGROUND This is a case of a neonate with susceptibility to long QT syndrome (LQTS) who presented with a sudden unexpected infant death. Experts continue to debate whether universal electrocardiogram (ECG) screening of all newborns is feasible, practical, and cost-effective. CASE REPORT A 19-day-old neonate was found unresponsive by her mother. ECG showed ventricular fibrillation and a combination of a lidocaine drip plus multiple defibrillations converted the rhythm to normal sinus. Unfortunately, MRI brain imaging showed multiple infarcts and EEG showed burst suppression pattern with frequent seizures; life supportive treatment was stopped and the infant died. Genetic testing revealed two mutations in the KCNE2 gene consistent with susceptibility to LQTS type 6. CONCLUSIONS We believe this case is the first to demonstrate both a precipitating electrocardiographic and genetic cause of death for an infant with LQTS, showing a cause-and-effect relationship between LQTS mutation, ventricular arrhythmia, and death. We wonder whether universal ECG newborn screening to prevent LQTS death could have saved this baby. PMID:27465075

  17. Concealed long QT syndrome and intractable partial epilepsy: a case report.

    PubMed

    Anderson, Jason H; Bos, Johan Martijn; Meyer, Fredric B; Cascino, Gregory D; Ackerman, Michael J

    2012-11-01

    Herein, we describe a patient with concealed type 2 long QT syndrome with concomitant electroencephalogram-documented epilepsy. Although syncope in patients with long QT syndrome is common and often secondary to cerebral hypoxia after a protracted ventricular arrhythmia, this article demonstrates the importance of avoiding "tunnel vision" as patients with long QT syndrome could also have a primary seizure disorder. Identification of the etiology underlying seizurelike activity is paramount in instituting effective therapy. Furthermore, we theorize that abnormal KCHN2-encoded potassium channel repolarization in the brain could result in epilepsy and arrhythmias in long QT syndrome. PMID:23058853

  18. Association of the hERG mutation with long-QT syndrome type 2, syncope and epilepsy

    PubMed Central

    LI, GUOLIANG; SHI, RUI; WU, JINE; HAN, WENQI; ZHANG, AIFENG; CHENG, GONG; XUE, XIAOLIN; SUN, CHAOFENG

    2016-01-01

    Mutations in the human ether-à-go-go-related gene (hERG) are responsible for long-QT syndrome (LQTS) type 2 (LQT2). In the present study, a heterozygous missense mutation (A561V) linked to LQT2, syncope and epilepsy was identified in the S5/pore region of the hERG protein. The mutation, A561V, was prepared and subcloned into hERG-pcDNA3.0. Mutant plasmids were co-transfected into HEK-293 cells, which stably express wild-type (WT) hERG, in order to mimic a heterozygous genotype, and the whole-cell current was recorded using a patch-clamp technique. Confocal microscopy was performed to evaluate the membrane distribution of the hERG channel protein using a green fluorescent protein tagged to the N-terminus of hERG. A561V-hERG decreased the amplitude of the WT-hERG currents in a concentration-dependent manner. In addition, A561V-hERG resulted in alterations to activation, inactivation and recovery from inactivation in the hERG protein channels. Further evaluation of hERG membrane localization indicated that the A561V-hERG mutant protein was unable to travel to the plasma membrane, which resulted in a trafficking-deficient WT-hERG protein. In conclusion, A561V-hERG exerts a potent dominant-negative effect on WT-hERG channels, resulting in decreased hERG currents and impairment of hERG membrane localization. This may partially elucidate the clinical manifestations of LQTS patients who carry the A561V mutation. PMID:26847485

  19. Association of the hERG mutation with long-QT syndrome type 2, syncope and epilepsy.

    PubMed

    Li, Guoliang; Shi, Rui; Wu, Jine; Han, Wenqi; Zhang, Aifeng; Cheng, Gong; Xue, Xiaolin; Sun, Chaofeng

    2016-03-01

    Mutations in the human ether‑à‑go‑go‑related gene (hERG) are responsible for long‑QT syndrome (LQTS) type 2 (LQT2). In the present study, a heterozygous missense mutation (A561V) linked to LQT2, syncope and epilepsy was identified in the S5/pore region of the hERG protein. The mutation, A561V, was prepared and subcloned into hERG‑pcDNA3.0. Mutant plasmids were co‑transfected into HEK‑293 cells, which stably express wild‑type (WT) hERG, in order to mimic a heterozygous genotype, and the whole‑cell current was recorded using a patch‑clamp technique. Confocal microscopy was performed to evaluate the membrane distribution of the hERG channel protein using a green fluorescent protein tagged to the N‑terminus of hERG. A561V‑hERG decreased the amplitude of the WT‑hERG currents in a concentration‑dependent manner. In addition, A561V‑hERG resulted in alterations to activation, inactivation and recovery from inactivation in the hERG protein channels. Further evaluation of hERG membrane localization indicated that the A561V‑hERG mutant protein was unable to travel to the plasma membrane, which resulted in a trafficking‑deficient WT‑hERG protein. In conclusion, A561V‑hERG exerts a potent dominant‑negative effect on WT‑hERG channels, resulting in decreased hERG currents and impairment of hERG membrane localization. This may partially elucidate the clinical manifestations of LQTS patients who carry the A561V mutation. PMID:26847485

  20. The long Q-T syndromes.

    PubMed

    Gordon, N

    1994-01-01

    Loss of consciousness in childhood may be due to cardiovascular causes, and the Long Q-T syndromes can present with seizures. The Romano-Ward syndrome is of autosomal dominant inheritance, and the Jervell and Lange-Nielson syndrome, with associated deafness, of autosomal recessive inheritance. The diagnosis is often delayed, but a careful history can avoid this. The syndromes can appear to be due to an imbalance in the sympathetic nerve to the ventricular myocardium, and precipitating causes such as stress suggest a CNS influence on this. The electrocardiogram can confirm the prolonged Q-T interval, but this is not always present, at least without an exercise test. Treatment with beta-blockers is often successful. If a wrong diagnosis of epilepsy is made a chance may be missed of avoiding sudden death, quite apart from all the medical, and social consequences that can result from such a diagnosis. PMID:8048706

  1. Mouse models of long QT syndrome

    PubMed Central

    Salama, Guy; London, Barry

    2007-01-01

    Congenital long QT syndrome is a rare inherited condition characterized by prolongation of action potential duration (APD) in cardiac myocytes, prolongation of the QT interval on the surface electrocardiogram (ECG), and an increased risk of syncope and sudden death due to ventricular tachyarrhythmias. Mutations of cardiac ion channel genes that affect repolarization cause the majority of the congenital cases. Despite detailed characterizations of the mutated ion channels at the molecular level, a complete understanding of the mechanisms by which individual mutations may lead to arrhythmias and sudden death requires study of the intact heart and its modulation by the autonomic nervous system. Here, we will review studies of molecularly engineered mice with mutations in the genes (a) known to cause long QT syndrome in humans and (b) specific to cardiac repolarization in the mouse. Our goal is to provide the reader with a comprehensive overview of mouse models with long QT syndrome and to emphasize the advantages and limitations of these models. PMID:17038432

  2. KCNQ1 mutations associated with Jervell and Lange-Nielsen syndrome and autosomal recessive Romano-Ward syndrome in India-expanding the spectrum of long QT syndrome type 1.

    PubMed

    Vyas, Bijal; Puri, Ratna D; Namboodiri, Narayanan; Nair, Mohan; Sharma, Deepak; Movva, Sireesha; Saxena, Renu; Bohora, Shomu; Aggarwal, Neeraj; Vora, Amit; Kumar, Jatinder; Singh, Tarandeep; Verma, Ishwar C

    2016-06-01

    Long QT syndrome type 1 (LQT1) is the most common type of all Long QT syndromes (LQTS) and occurs due to mutations in KCNQ1. Biallelic mutations with deafness is called Jervell and Lange-Nielsen syndrome (JLNS) and without deafness is autosomal recessive Romano-Ward syndrome (AR RWS). In this prospective study, we report biallelic mutations in KCNQ1 in Indian patients with LQT1 syndrome. Forty patients with a clinical diagnosis of LQT1 syndrome were referred for molecular testing. Of these, 18 were excluded from the analysis as they did not fulfill the inclusion criteria of broad T wave ECG pattern of the study. Direct sequencing of KCNQ1 was performed in 22 unrelated probands, parents and at-risk family members. Mutations were identified in 17 patients, of which seven had heterozygous mutations and were excluded in this analysis. Biallelic mutations were identified in 10 patients. Five of 10 patients did not have deafness and were categorized as AR RWS, the rest being JLNS. Eight mutations identified in this study have not been reported in the literature and predicted to be pathogenic by in silico analysis. We hypothesize that the homozygous biallelic mutations identified in 67% of families was due to endogamous marriages in the absence of consanguinity. This study presents biallelic gene mutations in KCNQ1 in Asian Indian patients with AR JLNS and RWS. It adds to the scant worldwide literature of mutation studies in AR RWS. © 2016 Wiley Periodicals, Inc. PMID:27041150

  3. The binding site for channel blockers that rescue misprocessed human long QT syndrome type 2 ether-a-gogo-related gene (HERG) mutations.

    PubMed

    Ficker, Eckhard; Obejero-Paz, Carlos A; Zhao, Shuxia; Brown, Arthur M

    2002-02-15

    Mutations in the human ether-a-gogo-related gene (HERG) K(+) channel gene cause chromosome 7-linked long QT syndrome type 2 (LQT2), which is characterized by a prolonged QT interval in the electrocardiogram and an increased susceptibility to life-threatening cardiac arrhythmias. LQT2 mutations produce loss-of-function phenotypes and reduce I(Kr) currents either by the heteromeric assembly of non- or malfunctioning channel subunits with wild type subunits at the cell surface or by retention of misprocessed mutant HERG channels in the endoplasmic reticulum. Misprocessed mutations often encode for channel proteins that are functional upon incorporation into the plasma membrane. As a result the pharmacological correction of folding defects and restoration of protein function are of considerable interest. Here we report that the trafficking-deficient pore mutation HERG G601S was rescued by a series of HERG channel blockers that increased cell surface expression. Rescue by these pharmacological chaperones varied directly with their blocking potency. We used structure-activity relationships and site-directed mutagenesis to define the binding site of the pharmacological chaperones. We found that binding occurred in the inner cavity and correlated with hydrophobicity and cationic charge. Rescue was domain-restricted because the trafficking of two misprocessed mutations in the C terminus, HERG F805C and HERG R823W, was not restored by channel blockers. Our findings represent a first step toward the design of pharmacological chaperones that will rescue HERG K(+) channels without block. PMID:11741928

  4. Drug-Induced Long QT Syndrome

    PubMed Central

    Kannankeril, Prince; Darbar, Dawood

    2010-01-01

    The drug-induced long QT syndrome is a distinct clinical entity that has evolved from an electrophysiologic curiosity to a centerpiece in drug regulation and development. This evolution reflects an increasing recognition that a rare adverse drug effect can profoundly upset the balance between benefit and risk that goes into the prescription of a drug by an individual practitioner as well as the approval of a new drug entity by a regulatory agency. This review will outline how defining the central mechanism, block of the cardiac delayed-rectifier potassium current IKr, has contributed to defining risk in patients and in populations. Models for studying risk, and understanding the way in which clinical risk factors modulate cardiac repolarization at the molecular level are discussed. Finally, the role of genetic variants in modulating risk is described. PMID:21079043

  5. Structure of the Cyclic Nucleotide-Binding Homology Domain of the hERG Channel and Its Insight into Type 2 Long QT Syndrome.

    PubMed

    Li, Yan; Ng, Hui Qi; Li, Qingxin; Kang, CongBao

    2016-01-01

    The human ether-à-go-go related gene (hERG) channel is crucial for the cardiac action potential by contributing to the fast delayed-rectifier potassium current. Mutations in the hERG channel result in type 2 long QT syndrome (LQT2). The hERG channel contains a cyclic nucleotide-binding homology domain (CNBHD) and this domain is required for the channel gating though molecular interactions with the eag domain. Here we present solution structure of the CNBHD of the hERG channel. The structural study reveals that the CNBHD adopts a similar fold to other KCNH channels. It is self-liganded and it contains a short β-strand that blocks the nucleotide-binding pocket in the β-roll. Folding of LQT2-related mutations in this domain was shown to be affected by point mutation. Mutations in this domain can cause protein aggregation in E. coli cells or induce conformational changes. One mutant-R752W showed obvious chemical shift perturbation compared with the wild-type, but it still binds to the eag domain. The helix region from the N-terminal cap domain of the hERG channel showed unspecific interactions with the CNBHD. PMID:27025590

  6. Structure of the Cyclic Nucleotide-Binding Homology Domain of the hERG Channel and Its Insight into Type 2 Long QT Syndrome

    PubMed Central

    Li, Yan; Ng, Hui Qi; Li, Qingxin; Kang, CongBao

    2016-01-01

    The human ether-à-go-go related gene (hERG) channel is crucial for the cardiac action potential by contributing to the fast delayed-rectifier potassium current. Mutations in the hERG channel result in type 2 long QT syndrome (LQT2). The hERG channel contains a cyclic nucleotide-binding homology domain (CNBHD) and this domain is required for the channel gating though molecular interactions with the eag domain. Here we present solution structure of the CNBHD of the hERG channel. The structural study reveals that the CNBHD adopts a similar fold to other KCNH channels. It is self-liganded and it contains a short β-strand that blocks the nucleotide-binding pocket in the β-roll. Folding of LQT2-related mutations in this domain was shown to be affected by point mutation. Mutations in this domain can cause protein aggregation in E. coli cells or induce conformational changes. One mutant-R752W showed obvious chemical shift perturbation compared with the wild-type, but it still binds to the eag domain. The helix region from the N-terminal cap domain of the hERG channel showed unspecific interactions with the CNBHD. PMID:27025590

  7. Single-Channel Characteristics of Wild-Type IKs Channels and Channels formed with Two MinK Mutants that Cause Long QT Syndrome

    PubMed Central

    Sesti, Federico; Goldstein, Steve A.N.

    1998-01-01

    IKs channels are voltage dependent and K+ selective. They influence cardiac action potential duration through their contribution to myocyte repolarization. Assembled from minK and KvLQT1 subunits, IKs channels are notable for a heteromeric ion conduction pathway in which both subunit types contribute to pore formation. This study was undertaken to assess the effects of minK on pore function. We first characterized the properties of wild-type human IKs channels and channels formed only of KvLQT1 subunits. Channels were expressed in Xenopus laevis oocytes or Chinese hamster ovary cells and currents recorded in excised membrane patches or whole-cell mode. Unitary conductance estimates were dependent on bandwidth due to rapid channel “flicker.” At 25 kHz in symmetrical 100-mM KCl, the single-channel conductance of IKs channels was ∼16 pS (corresponding to ∼0.8 pA at 50 mV) as judged by noise-variance analysis; this was fourfold greater than the estimated conductance of homomeric KvLQT1 channels. Mutant IKs channels formed with D76N and S74L minK subunits are associated with long QT syndrome. When compared with wild type, mutant channels showed lower unitary currents and diminished open probabilities with only minor changes in ion permeabilities. Apparently, the mutations altered single-channel currents at a site in the pore distinct from the ion selectivity apparatus. Patients carrying these mutant minK genes are expected to manifest decreased K+ flux through IKs channels due to lowered single-channel conductance and altered gating. PMID:9834138

  8. A short story of the short QT syndrome.

    PubMed

    Maluli, Hayan Al; Meshkov, Arnold B

    2013-01-01

    Short QT syndrome is a recently recognized cause of cardiac rhythm disorders, including sudden cardiac death. Although the syndrome is rare, its potential lethality justifies routinely screening the electrocardiograms of patients with syncope or unexplained atrial or ventricular arrhythmias to look for this diagnosis. This review discusses recent advances in the understanding of the pathogenesis of this syndrome and outlines some of the challenges in establishing the diagnosis. PMID:23288944

  9. hERG quality control and the long QT syndrome.

    PubMed

    Foo, Brian; Williamson, Brittany; Young, Jason C; Lukacs, Gergely; Shrier, Alvin

    2016-05-01

    Long-QT syndrome type-2 (LQT2) is characterized by reduced functional expression of the human ether-à-go-go related (hERG) gene product, resulting in impaired cardiac repolarization and predisposition to fatal arrhythmia. Previous studies have implicated abnormal trafficking of misfolded hERG as the primary mechanism of LQT2, with misfolding being caused by mutations in the hERG gene (inherited) or drug treatment (acquired). More generally, environmental and metabolic stresses present a constant challenge to the folding of proteins, including hERG, and must be countered by robust protein quality control (QC) systems. Disposal of partially unfolded yet functional plasma membrane (PM) proteins by protein QC contributes to the loss-of-function phenotype in various conformational diseases including cystic fibrosis (CF) and long-QT syndrome type-2 (LQT2). The prevalent view has been that the loss of PM expression of hERG is attributed to biosynthetic block by endoplasmic reticulum (ER) QC pathways. However, there is a growing appreciation for protein QC pathways acting at post-ER cellular compartments, which may contribute to conformational disease pathogenesis. This article will provide a background on the structure and cellular trafficking of hERG as well as inherited and acquired LQT2. We will review previous work on hERG ER QC and introduce the more novel view that there is a significant peripheral QC at the PM and peripheral cellular compartments. Particular attention is drawn to the unique role of the peripheral QC system in acquired LQT2. Understanding the QC process and players may provide targets for therapeutic intervention in dealing with LQT2. PMID:26718903

  10. Effects of exercise on heart rate, QT, QTc and QT/QS2 in the Romano-Ward inherited long QT syndrome.

    PubMed

    Vincent, G M; Jaiswal, D; Timothy, K W

    1991-08-15

    Patients with the Romano-Ward inherited long QT syndrome have an incompletely defined cardiac sympathetic system abnormality, and exhibit ventricular arrhythmias during exercise, fear and anxiety. Treadmill and bicycle exercise were used to modulate cardiac autonomic activity in 27 Romano-Ward subjects and 27 normal controls. The heart rate, and the QT, QTc and QT/QS2 (ratio of electrical to mechanical systole) intervals were compared. Subjects with long QT were compared with normals. Those with a long QT interval had the following results: similar resting heart rates; lower rates during moderate (151.6 vs 169.6 beats/min, p = 0.04) and maximal (155.9 vs 182.1 beats/min, p = less than 0.001) exercise; an abnormal QT cycle-length relationship, with failure of the QT to shorten normally with increasing heart rate; an increase in QTc versus a decrease in normals; supine rest QT/QS2 ratio of 1.12 vs 0.93, p = 0.001; and an exercise QT/QS2 that increased by 30%, from 1.12 at rest to 1.45, versus 15%, in normals, from 0.93 to 1.07, p = 0.001. The lower heart rates and excessively prolonged QT/QS2 ratios during exercise further support an abnormality of, or abnormal cardiac response to, sympathetic activity. A QT/QS2 greater than 1.0 at rest, an exercise QT/QS2 ratio greater than 1.17, and an increase in QTc during moderate exercise may be helpful diagnostic findings in patients with borderline long QTc intervals at rest. PMID:1872278

  11. Short QT Syndrome – Review of Diagnosis and Treatment

    PubMed Central

    Schimpf, Rainer; Borggrefe, Martin

    2014-01-01

    Short QT syndrome (SQTS) is an inherited cardiac channelopathy characterised by an abnormally short QT interval and increased risk for atrial and ventricular arrhythmias. Diagnosis is based on the evaluation of symptoms (syncope or cardiac arrest), family history and electrocardiogram (ECG) findings. Mutations of cardiac ion channels responsible for the repolarisation orchestrate electrical heterogeneity during the action potential and provide substrate for triggering and maintaining of tachyarrhythmias. Due to the malignant natural history of SQTS, implantable cardioverter defibrillator (ICD) is the first-line therapy in affected patients. This review summarises current data and addresses the genetic basis and clinical features of SQTS. PMID:26835070

  12. Congenital and drug-induced long-QT syndrome: an update

    PubMed Central

    Wehrens, X.H.T.; Doevendans, P.A.

    2004-01-01

    The congenital long-QT syndrome is a potentially life-threatening condition characterised clinically by prolonged QT intervals, syncope and sudden cardiac death. The abnormally prolonged repolarisation is the result of mutations in genes encoding cardiac ion channels. The diagnosis of long-QT syndrome is based on clinical, electrocardiographic, and genetic criteria. Beta-blocking therapy is important in the treatment of long-QT syndrome, although pacemakers and implantable cardioverter defibrillators (ICD) are useful in certain categories of patients. In the near future, mutation-specific treatment will probably become a novel approach to this potentially lethal syndrome. Drug-induced long-QT syndrome has been associated with silent mutations and common polymorphisms in potassium and sodium channel genes associated with congenital long-QT syndrome. Genetic screening for such mutations and polymorphisms may become an important instrument in preventing drug-induced 'torsades de pointes' arrhythmias in otherwise asymptomatic patients. PMID:25696318

  13. Risk factors for drug-induced long-QT syndrome

    PubMed Central

    Paulussen, A.D.C.; Aerssens, J.

    2005-01-01

    Congenital long-QT syndrome (cLQTS) is a ventricular arrhythmia that is characterised by a prolonged QT interval on the surface electro-cardiogram (ECG). Clinical symptoms include sudden loss of consciousness (syncopes), seizures, cardiac arrest and sudden death. The prevalence of this inherited disease is approximately one in 10,000 in Caucasians. Over the last decade, more than 200 different diseases causing mutations have been identified in five genes that encode ion channels involved in the delicate balance of inward and outward K/Ca currents during the cardiac action potential. A prolonged QT interval accompanied by very similar clinical symptoms as in cLQTS can also occur in otherwise healthy individuals after the intake of specific drug(s). This phenomenon is known as 'acquired' or 'drug-induced' long-QT syndrome. Because the clinical symptoms of the two forms are very similar, the question arises whether a common underlying genetic basis also exists. Several studies indicate that only a minority (approximately 10%) of the drug-induced LQTS cases can be explained by a mutation or polymorphism in one of the known LQTS genes. Even though the disease can often at least partially be explained by environmental factors, mutations or polymorphisms in other genes are also expected to be involved, including genes encoding drug-metabolising enzymes, adrenergic receptors, hormone-related genes and mitochondrial genes. This article reviews the current knowledge on risk factors for drug-induced LQTS, with a special emphasis on the role of genetic determinants. ImagesFigure 1AFigure 2Figure 3 PMID:25696450

  14. Anaesthesia Application for Cardiac Denervation in a Patient with Long QT Syndrome and Cardiomyopathy

    PubMed Central

    Karadeniz, Ümit; Demir, Aslı; Koçulu, Rabia

    2016-01-01

    Long QT syndrome is a congenital disorder that is characterized by a prolongation of the QT interval on electrocardiograms and a propensity to ventricular tachyarrhythmias, which may lead to syncope, cardiac arrest or sudden death. Cardiomyopathy and pulmonary hypertension diseases have additional risks in anaesthesia management. In this study, we emphasize on one lung ventilation, pacemaker-implantable cardioverter–defibrillator and the anaesthesia management process in a patient with long QT syndrome, cardiomyopathy and pulmonary hypertension who underwent thoracic sympathectomy. PMID:27366557

  15. Drugs to be avoided in patients with long QT syndrome: Focus on the anaesthesiological management

    PubMed Central

    Fazio, Giovanni; Vernuccio, Federica; Grutta, Giuseppe; Re, Giuseppe Lo

    2013-01-01

    Long QT syndrome incidence is increasing in general population. A careful pre-, peri- and post-operative management is needed for patients with this syndrome because of the risk of Torsades de Pointes and malignant arrhythmias. The available data regarding prevention of lethal Torsades de Pointes during anesthesia in patients with long QT syndrome is scant and conflicting: only case reports and small case series with different outcomes have been published. Actually, there are no definitive guidelines on pre-, peri- and post-operative anesthetic management of congenital long QT syndrome. Our review focuses on anesthetic recommendations for patients diagnosed with congenital long QT syndrome furnishing some key points for preoperative optimization, intraoperative anesthetic agents and postoperative care plan, which could be the best for patients with c-long QT syndrome who undergo surgery. PMID:23675554

  16. Toward Personalized Medicine: Using Cardiomyocytes Differentiated From Urine-Derived Pluripotent Stem Cells to Recapitulate Electrophysiological Characteristics of Type 2 Long QT Syndrome

    PubMed Central

    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

    2015-01-01

    Background 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. Methods and Results 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. Conclusions UhiPS cells from patients carrying ion channel mutations can be used as novel tools to differentiate functional CMs that recapitulate cardiac arrhythmia phenotypes. PMID:26330336

  17. Mechanisms of cardiac arrhythmias and sudden death in transgenic rabbits with long QT syndrome

    PubMed Central

    Brunner, Michael; Peng, Xuwen; Liu, Gong Xin; Ren, Xiao-Qin; Ziv, Ohad; Choi, Bum-Rak; Mathur, Rajesh; Hajjiri, Mohammed; Odening, Katja E.; Steinberg, Eric; Folco, Eduardo J.; Pringa, Ekatherini; Centracchio, Jason; Macharzina, Roland R.; Donahay, Tammy; Schofield, Lorraine; Rana, Naveed; Kirk, Malcolm; Mitchell, Gary F.; Poppas, Athena; Zehender, Manfred; Koren, Gideon

    2008-01-01

    Long QT syndrome (LQTS) is a heritable disease associated with ECG QT interval prolongation, ventricular tachycardia, and sudden cardiac death in young patients. Among genotyped individuals, mutations in genes encoding repolarizing K+ channels (LQT1:KCNQ1; LQT2:KCNH2) are present in approximately 90% of affected individuals. Expression of pore mutants of the human genes KCNQ1 (KvLQT1-Y315S) and KCNH2 (HERG-G628S) in the rabbit heart produced transgenic rabbits with a long QT phenotype. Prolongations of QT intervals and action potential durations were due to the elimination of IKs and IKr currents in cardiomyocytes. LQT2 rabbits showed a high incidence of spontaneous sudden cardiac death (>50% at 1 year) due to polymorphic ventricular tachycardia. Optical mapping revealed increased spatial dispersion of repolarization underlying the arrhythmias. Both transgenes caused downregulation of the remaining complementary IKr and IKs without affecting the steady state levels of the native polypeptides. Thus, the elimination of 1 repolarizing current was associated with downregulation of the reciprocal repolarizing current rather than with the compensatory upregulation observed previously in LQTS mouse models. This suggests that mutant KvLQT1 and HERG interacted with the reciprocal wild-type α subunits of rabbit ERG and KvLQT1, respectively. These results have implications for understanding the nature and heterogeneity of cardiac arrhythmias and sudden cardiac death. PMID:18464931

  18. Women, but not men, have prolonged QT interval if depressed after an acute coronary syndrome

    PubMed Central

    Whang, William; Julien, Howard M.; Higginbotham, Laura; Soto, Ana V.; Broodie, Nisha; Bigger, J. Thomas; Garan, Hasan; Burg, Matthew M.; Davidson, Karina W.

    2012-01-01

    Aims Depression is a mortality risk marker for acute coronary syndrome (ACS) patients. We hypothesized that the QT interval, a predictor for risk of sudden cardiac death, was related to depressive symptoms in ACS. Methods and results We performed an analysis of admission electrocardiograms from hospitalized patients with unstable angina or non-ST elevation myocardial infarction from two prospective observational studies of depression in ACS. Depressive symptoms were assessed with the Beck Depression Inventory (BDI), and depression was defined as BDI score ≥10, compared with <5. Patients with QRS duration ≥120 ms and/or who were prescribed antidepressants were excluded. QT intervals were adjusted for heart rate by two methods. Our analyses included 243 men (40.0% with BDI ≥10) and 139 women (62.0% with BDI ≥ 10). Among women, average QT corrected by Fridericia's method (QTcF) was 435.4 ± 26.6 ms in the depressed group, vs. 408.6 ± 24.3 ms in the non-depressed group (P< 0.01). However, among men, average QTcF was not significantly different between the depressed and non-depressed groups (415.4 ± 23.6 vs. 412.0 ± 25.8 ms, P= 0.29). In multivariable analyses that included hypertension, diabetes, ACS type, left ventricular ejection fraction <0.40, and use of QT-prolonging medication, there was a statistically significant interaction between depressive symptoms and gender (P< 0.001). Conclusions In this ACS sample, prolongation of the QT interval was associated with depressive symptoms in women, but not in men. Further investigation of the mechanism of the relationship between depression and abnormal cardiac repolarization, particularly in women, is warranted to develop treatment strategies. PMID:21798879

  19. Acquired long QT syndrome: a focus for the general pediatrician.

    PubMed

    Marzuillo, Pierluigi; Benettoni, Alessandra; Germani, Claudio; Ferrara, Giovanna; D'Agata, Biancamaria; Barbi, Egidio

    2014-04-01

    Acquired long QT syndrome (LQTS) is a disorder of cardiac repolarization most often due to specific drugs, hypokalemia, or hypomagnesemia that may precipitate torsade de pointes and cause sudden cardiac death. Common presentations of the LQTS are palpitations, presyncope, syncope, cardiac arrest, and seizures. An abnormal 12-lead electrocardiogram obtained while the patient is at rest is the key to diagnosis. The occurrence of drug-induced LQTS is unpredictable in any given individual, but a common observation is that most patients have at least 1 identifiable risk factor in addition to drug exposure. The cornerstone of the management of acquired LQTS includes the identification and discontinuation of any precipitating drug and the correction of metabolic abnormalities, such as hypokalemia or hypomagnesemia. Most of the episodes of torsade de pointes are short-lived and terminate spontaneously. We propose a management protocol that could be useful for the daily practice in the emergency pediatric department to reduce the risk of acquired QT prolongation. PMID:24694881

  20. Drug-induced long QT syndrome increases the risk of drowning.

    PubMed

    Vincenzi, Frank F

    2016-02-01

    There is strong evidence linking inherited long QT syndromes with an increased risk of drowning due to fatal arrhythmias in the water. Drug-induced long QT syndrome (DILQTS) is hypothesized to increase the risk of drowning by similar mechanisms. It is suggested that QT prolongation caused by a drug or drugs, when combined with the autonomic conflict associated with the mammalian dive reflex and/or the cold shock reflex, sets up conditions that may result in a sudden fatal arrhythmia while in water - thus an increased risk of drowning related to a drug-induced prolongation of the QT interval. Many widely used drugs prolong the QT interval thus raising a drug safety issue that needs confirmation or refutation. PMID:26826633

  1. A common antitussive drug, clobutinol, precipitates the long QT syndrome 2.

    PubMed

    Bellocq, Chloé; Wilders, Ronald; Schott, Jean-Jacques; Louérat-Oriou, Bénédicte; Boisseau, Pierre; Le Marec, Hervé; Escande, Denis; Baró, Isabelle

    2004-11-01

    QT prolongation, a classic risk factor for arrhythmias, can result from a mutation in one of the genes governing cardiac repolarization and also can result from the intake of a medication acting as blocker of the cardiac K(+) channel human ether-a-go-go-related gene (HERG). Here, we identified the arrhythmogenic potential of a nonopioid antitussive drug, clobutinol. The deleterious effects of clobutinol were suspected when a young boy, with a diagnosis of congenital long QT syndrome, experienced arrhythmias while being treated with this drug. Using the patch-clamp technique, we showed that clobutinol dose-dependently inhibited the HERG K(+) current with a half-maximum block concentration of 2.9 microM. In the proband, we identified a novel A561P HERG mutation. Two others long QT mutations (A561V and A561T) had been reported previously at the same position. None of the three mutants led to a sizeable current in heterologous expression system. When coexpressed with wild-type (WT) HERG channels, the three Ala561 mutants reduced the trafficking of WT and mutant heteromeric channels, resulting in decreased K(+) current amplitude (dominant-negative effects). In addition, A561P but not A561V and A561T mutants induced a approximately -11 mV shift of the current activation curve and accelerated deactivation, thereby partially counteracting the dominant-negative effects. A561P mutation and clobutinol effects on the human ventricular action potential characteristics were simulated using the Priebe-Beuckelmann model. Our work shows that clobutinol has limited effects on WT action potential but should be classified as a "drug to be avoided by congenital long QT patients" rather than as a "drug with risk of torsades de pointes". PMID:15280442

  2. [Progress in research on defective protein trafficking and functional restoration in HERG-associated long QT syndrome].

    PubMed

    Fang, Peiliang; Lian, Jiangfang

    2016-02-01

    The human ether-a-go-go related gene (HERG) encodes the α -subunit of the rapid component of the delayed rectifier K(+) channel, which is essential for the third repolarization of the action potential of human myocardial cells. Mutations of the HERG gene can cause type II hereditary long QT syndrome (LQT2), characterized by prolongation of the QT interval, abnormal T wave, torsade de pointes, syncope and sudden cardiac death. So far more than 300 HERG mutations have been identified, the majority of which can cause LQT2 due to HERG protein trafficking defect. It has been reported that certain drugs can induce acquired long QT syndrome through directly blocking the pore and/or affecting the HERG trafficking. The trafficking defects and K(+) currents can be restored with low temperature and certain drugs. However, the mechanisms underlying defective trafficking caused by HERG mutations and the inhibition/restoration of HERG trafficking by drugs are still unknown. This review summarizes the current understanding of the molecular mechanisms including HERG trafficking under physiological and pathological conditions, and the effects of drugs on the HERG trafficking, in order to provide theoretical evidence for the diagnosis and treatment of long QT syndrome. PMID:26829745

  3. Of Founder Populations, Long QT Syndrome, and Destiny

    PubMed Central

    Schwartz, Peter J.; Brink, Paul A.

    2009-01-01

    Founder populations, characterized by a single ancestor affected by LQTS and by a large number of individuals and families all related to the ancestor and thereby carrying the same disease-causing mutation, represent the ideal human model to study the role of “modifier genes” in the long QT syndrome (LQTS). This chapter reviews some of the fundamental concepts related to founder populations and provides the necessary historic background to understand why so many can be found in South Africa. The focus then moves onto a specific LQT1 founder population, carrier of the A341V mutation, that has been extensively studied during the last 10 years and has provided a significant number of previously unforeseen information. These novel findings range from an unusually high clinical severity not explained by the electrophysiological characteristics of the mutation, to the importance of the tonic and reflex control of heart rate for risk stratification, to the identification of the first modifier genes for the clinical severity of LQTS. PMID:19880070

  4. Long QT Syndrome: An Emerging Role for Inflammation and Immunity

    PubMed Central

    Lazzerini, Pietro Enea; Capecchi, Pier Leopoldo; Laghi-Pasini, Franco

    2015-01-01

    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 or 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. PMID:26798623

  5. Genotype–phenotype correlation in long QT syndrome families

    PubMed Central

    Qureshi, Sameera Fatima; Ali, Altaf; Venkateshwari, Ananthapur; Rao, Hygriv; Jayakrishnan, M.P.; Narasimhan, Calambur; Shenthar, Jayaprakash; Thangaraj, Kumarasamy; Nallari, Pratibha

    2015-01-01

    Heterogeneity in clinical manifestations is a well-known feature in Long QT Syndrome (LQTS). The extent of this phenomenon became evident in families wherein both symptomatic and asymptomatic family members are reported. The study hence warrants genetic testing and/or screening of family members of LQTS probands for risk stratification and prediction. Of the 46 families screened, 18 probands revealed novel variations/compound heterozygosity in the gene/s screened. Families 1–4 revealed probands carrying novel variations in KCNQ1 gene along with compound heterozygosity of risk genotypes of the SCN5A, KCNE1 and NPPA gene/s polymorphisms screened. It was also observed that families- 5, 6 and 7 were typical cases of “anticipation” in which both mother and child were diagnosed with congenital LQTS (cLQTS). Families- 16 and 17 represented aLQTS probands with variations in IKs and INa encoding genes. First degree relatives (FDRs) carrying the same haplotype as the proband were also identified which may help in predictive testing and management of LQTS. Most of the probands exhibiting a family history were found to be genetic compounds which clearly points to the role of cardiac genes and their modifiers in a recessive fashion in LQTS manifestation.

  6. Evidence of genetic heterogeneity in the long QT syndrome

    SciTech Connect

    Keating, M. )

    1993-06-25

    thee long QT syndrome (LQT) is a familial predisposition to sudden death from cardiac arrhythmias. M. Keating et al. performed linkage analysis in a large Utah family and found that th disease was closely linked to the Harvey ras-1 (H-ras-1) locus on chromosome 11. With the use of the probe pTBB-2 at the H-ras-1 oncogene, a logarithm of the likelihood ratio for linkage (lod score) of +16.44 was obtained by Keating et al. In a subsequent study, tight linkage of LQT to the H-ras-1 locus was found in six other small LQT families. The combined lod score from these two studies was +21.65 at a recombination fraction of 0. This tight linkage suggests that mutations at the H-ras-1 locus or at a closely linked locus resulted in LQT in the families studied. In view of the clinical heterogeneity and possible genetic heterogeneity in this syndrome, we analyzed a large Jewish family with a history of LQT. This family, whose origin is the island of Jerba near Tunic and whose members reside in Israel, is probably the largest family with LQT outside the United States. It comprises 131 individuals, of whom 28 have been affected. Clinical and electrocardiographic data collected over 7 years were available for 92 family members and blood samples for genetic analysis were available for 74. This analysis, together with that of Keating et al., provides evidence for genetic heterogeneity in the determination of the LQT.

  7. In Utero Diagnosis of Long QT Syndrome by Magnetocardiography

    PubMed Central

    Cuneo, Bettina F.; Strasburger, Janette F.; Yu, Suhong; Horigome, Hitoshi; Hosono, Takayoshi; Kandori, Akihiko; Wakai, Ronald T.

    2013-01-01

    Background The electrophysiology of long QT syndrome (LQTS) in utero is virtually unstudied. Our goal here was to evaluate the efficacy of fetal magnetocardiography (fMCG) for diagnosis and prognosis of fetuses at risk of LQTS. Methods and Results We reviewed the pre/postnatal medical records of 30 fetuses referred for fMCG due to a family history of LQTS (n=17); neonatal/childhood sudden cardiac death (n=3) and/or presentation of prenatal LQTS rhythms (n=12): 2° AVB, ventricular tachycardia, heart rate < 3rd percentile. We evaluated heart rate and reactivity, cardiac time intervals, T-wave characteristics, and initiation/termination of Torsade de Pointes (TdP), and compared these with neonatal ECG findings. After birth, subjects were tested for LQTS mutations. Based on accepted clinical criteria, 21 subjects (70%; 9 KCNQ1, 5 KCNH2, 2 SCN5A, 2 other, 3 untested) had LQTS. Using a threshold of QTc= 490 ms, fMCG accurately identified LQTS fetuses with 89% (24/27) sensitivity and 89% (8/9) specificity in 36 sessions. Four fetuses (2 KCNH2 and 2 SCN5A), all with QTc ≥ 620 ms, had frequent episodes of TdP, which were present 22–79% of the time. While some episodes initiated with a long-short sequence, most initiations showed QRS aberrancy and a notable lack of pause dependency. T-wave alternans was strongly associated with severe LQTS phenotype. Conclusions QTc prolongation (≥490 ms) assessed by fMCG accurately identified LQTS in utero; extreme QTc prolongation (≥620 ms) predicted TdP. FMCG can play a critical role in the diagnosis and management of fetuses at risk of LQTS. PMID:24218437

  8. Quality of Life of Pediatric Patients With Long QT Syndrome.

    PubMed

    Czosek, Richard J; Kaltman, Jonathan R; Cassedy, Amy E; Shah, Maully J; Vetter, Victoria L; Tanel, Ronn E; Wernovksy, Gil; Wray, Jo; Marino, Bradley S

    2016-02-15

    Children with long QT syndrome (LQTS) live with the risk of sudden death, activity restrictions, and the need for daily medications. We sought to evaluate the quality of life (QOL), self-perception, and behavior of patients with LQTS as perceived by both patients and their parents and identify predictors of lower QOL. QOL (Pediatric QOL Inventory [PedsQL] and Pediatric Cardiac Quality of Life Inventory [PCQLI]), self-perception, and behavioral inventories were completed by patients with LQTS and their parents. Comparison of PedsQL scores was made to published data for healthy children using t tests, and PCQLI scores were compared with those of patients with differing complexity of congenital heart disease. Mixed modeling was used for multivariable analysis. Sixty-one patients with LQTS were evaluated (age 13.6 ± 3.0 years; male 49%). Compared with healthy children, the PedsQL Total, Psychosocial, and Physical Health Summary scores were significantly lower for patients with LQTS and parent proxy reports (p ≤0.001). In general, PCQLI scores of patients with LQTS and parents were similar to those of patients with tetralogy of Fallot (p ≥0.2), lower than those of patients with bicuspid aortic valve (p ≤0.02), and higher than those of patients with single ventricle (p ≤0.03). Lower patient and parent PCQLI scores were associated with internalizing problems. For parents, the presence of a cardiac device and medication side effects were additionally associated with lower PCQLI scores. In conclusion, patients with LQTS and their parents report lower QOL than normal children secondary to physical and psychosocial factors. Increasing focus on the psychological well-being of these patients is needed in an effort to improve their QOL. PMID:26721659

  9. The impact of recent advances in genetics in understanding disease mechanisms underlying the long QT syndromes.

    PubMed

    Harmer, Stephen C; Tinker, Andrew

    2016-07-01

    Long QT syndrome refers to a characteristic abnormality of the electrocardiogram and it is associated with a form of ventricular tachycardia known as torsade-de-pointes and sudden arrhythmic death. It can occur as part of a hereditary syndrome or can be acquired usually because of drug administration. Here we review recent genetic, molecular and cellular discoveries and outline how they have furthered our understanding of this disease. Specifically we focus on compound mutations, genome wide association studies of QT interval, modifier genes and the therapeutic implications of this recent work. PMID:26910742

  10. Sex differences in the mechanisms underlying long QT syndrome.

    PubMed

    Salama, Guy; Bett, Glenna C L

    2014-09-01

    Sexual dimorphism is a well-established phenomenon, but its degree varies tremendously among species. Since the early days of Einthoven's development of the three-lead galvanometer ECG, we have known there are marked differences in QT intervals of men and women. It required over a century to appreciate the profound implications of sex-based electrophysiological differences in QT interval on the panoply of sex differences with respect to arrhythmia risk, drug sensitivity, and treatment modalities. Little is known about the fundamental mechanism responsible for sex differences in electrical substrate of the human heart, in large part due to the lack of tissue availability. Animal models are an important research tool, but species differences in the sexual dimorphism of the QT interval, the ionic currents underlying the cardiac repolarization, and effects of sex steroids make it difficult to interpolate animal to human sex differences. In addition, in some species, different strains of the same animal model yield conflicting data. Each model has its strengths, such as ease of genetic manipulation in mice or size in dogs. However, many animals do not reproduce the sexual dimorphism of QT seen in humans. To match sex linked prolongation of QT interval and arrhythmogenic phenotype, the current data suggest that the rabbit may be best suited to provide insight into sex differences in humans. In the future, emerging technologies such as induced pluripotent stem cell derived cardiac myocyte systems may offer the opportunity to study sex differences in a controlled hormonal situation in the context of a sex specific human model system. PMID:24973386

  11. Effects of L-type Ca2+ channel antagonism on ventricular arrhythmogenesis in murine hearts containing a modification in the Scn5a gene modelling human long QT syndrome 3.

    PubMed

    Thomas, Glyn; Gurung, Iman S; Killeen, Matthew J; Hakim, Parvez; Goddard, Catharine A; Mahaut-Smith, Martyn P; Colledge, William H; Grace, Andrew A; Huang, Christopher L-H

    2007-01-01

    Ventricular arrhythmogenesis in long QT 3 syndrome (LQT3) involves both triggered activity and re-entrant excitation arising from delayed ventricular repolarization. Effects of specific L-type Ca2+ channel antagonism were explored in a gain-of-function murine LQT3 model produced by a DeltaKPQ 1505-1507 deletion in the SCN5A gene. Monophasic action potentials (MAPs) were recorded from epicardial and endocardial surfaces of intact, Langendorff-perfused Scn5a+/Delta hearts. In untreated Scn5a+/Delta hearts, epicardial action potential duration at 90% repolarization (APD90) was 60.0 +/- 0.9 ms compared with 46.9 +/- 1.6 ms in untreated wild-type (WT) hearts (P < 0.05; n = 5). The corresponding endocardial APD(90) values were 52.0 +/- 0.7 ms and 53.7 +/- 1.6 ms in Scn5a+/Delta and WT hearts, respectively (P > 0.05; n = 5). Epicardial early afterdepolarizations (EADs), often accompanied by spontaneous ventricular tachycardia (VT), occurred in 100% of MAPs from Scn5a+/Delta but not in any WT hearts (n = 10). However, EAD occurrence was reduced to 62 +/- 7.1%, 44 +/- 9.7%, 10 +/- 10% and 0% of MAPs following perfusion with 10 nm, 100 nm, 300 nm and 1 mum nifedipine, respectively (P < 0.05; n = 5), giving an effective IC50 concentration of 79.3 nm. Programmed electrical stimulation (PES) induced VT in all five Scn5a+/Delta hearts (n = 5) but not in any WT hearts (n = 5). However, repeat PES induced VT in 3, 2, 2 and 0 out of 5 Scn5a+/Delta hearts following perfusion with 10 nm, 100 nm, 300 nm and 1 mum nifedipine, respectively. Patch clamp studies in isolated ventricular myocytes from Scn5a+/Delta and WT hearts confirmed that nifedipine (300 nm) completely suppressed the inward Ca2+ current but had no effect on inward Na+ currents. No significant effects were seen on epicardial APD90, endocardial APD90 or ventricular effective refractory period in Scn5a+/Delta and WT hearts following perfusion with nifedipine at 1 nm, 10 nm, 100 nm, 300 nm and 1 microm nifedipine

  12. SCN4B-Encoded Sodium Channel β4 Subunit in Congenital Long-QT Syndrome

    PubMed Central

    Medeiros-Domingo, Argelia; Kaku, Toshihiko; Tester, David J.; Iturralde-Torres, Pedro; Itty, Ajit; Ye, Bin; Valdivia, Carmen; Ueda, Kazuo; Canizales-Quinteros, Samuel; Tusié-Luna, Maria Teresa; Makielski, Jonathan C.; Ackerman, Michael J.

    2012-01-01

    Background Congenital long-QT syndrome (LQTS) is potentially lethal secondary to malignant ventricular arrhythmias and is caused predominantly by mutations in genes that encode cardiac ion channels. Nearly 25% of patients remain without a genetic diagnosis, and genes that encode cardiac channel regulatory proteins represent attractive candidates. Voltage-gated sodium channels have a pore-forming α-subunit associated with 1 or more auxiliary β-subunits. Four different β-subunits have been described. All are detectable in cardiac tissue, but none have yet been linked to any heritable arrhythmia syndrome. Methods and Results We present a case of a 21-month-old Mexican-mestizo female with intermittent 2:1 atrioventricular block and a corrected QT interval of 712 ms. Comprehensive open reading frame/splice mutational analysis of the 9 established LQTS-susceptibility genes proved negative, and complete mutational analysis of the 4 Navβ-subunits revealed a L179F (C535T) missense mutation in SCN4B that cosegregated properly throughout a 3-generation pedigree and was absent in 800 reference alleles. After this discovery, SCN4B was analyzed in 262 genotype-negative LQTS patients (96% white), but no further mutations were found. L179F was engineered by site-directed mutagenesis and heterologously expressed in HEK293 cells that contained the stably expressed SCN5A-encoded sodium channel α-subunit (hNaV1.5). Compared with the wild-type, L179F-β4 caused an 8-fold (compared with SCN5A alone) and 3-fold (compared with SCN5A + WT-β4) increase in late sodium current consistent with the molecular/electrophysiological phenotype previously shown for LQTS-associated mutations. Conclusions We provide the seminal report of SCN4B-encoded Navβ4 as a novel LQT3-susceptibility gene. PMID:17592081

  13. Effects of cardioactive drugs on human induced pluripotent stem cell derived long QT syndrome cardiomyocytes.

    PubMed

    Kuusela, Jukka; Kujala, Ville J; Kiviaho, Anna; Ojala, Marisa; Swan, Heikki; Kontula, Kimmo; Aalto-Setälä, Katriina

    2016-01-01

    Human induced pluripotent stem cells (hiPSC) have enabled a major step forward in pathophysiologic studies of inherited diseases and may also prove to be valuable in in vitro drug testing. Long QT syndrome (LQTS), characterized by prolonged cardiac repolarization and risk of sudden death, may be inherited or result from adverse drug effects. Using a microelectrode array platform, we investigated the effects of six different drugs on the electrophysiological characteristics of human embryonic stem cell-derived cardiomyocytes as well as hiPSC-derived cardiomyocytes from control subjects and from patients with type 1 (LQT1) and type 2 (LQT2) of LQTS. At baseline the repolarization time was significantly longer in LQTS cells compared to controls. Isoprenaline increased the beating rate of all cell lines by 10-73 % but did not show any arrhythmic effects in any cell type. Different QT-interval prolonging drugs caused prolongation of cardiac repolarization by 3-13 % (cisapride), 10-20 % (erythromycin), 8-23 % (sotalol), 16-42 % (quinidine) and 12-27 % (E-4031), but we did not find any systematic differences in sensitivity between the control, LQT1 and LQT2 cell lines. Sotalol, quinidine and E-4031 also caused arrhythmic beats and beating arrests in some cases. In summary, the drug effects on these patient-specific cardiomyocytes appear to recapitulate clinical observations and provide further evidence that these cells can be applied for in vitro drug testing to probe their vulnerability to arrhythmia. PMID:27026928

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

    PubMed Central

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

    2013-01-01

    Aims 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. Methods and results Prospective web-use statistical analysis combined with online surveys were employed. Our main outcome measure was the percentage of Long QT syndrome patients and Brugada syndrome patients reporting refraining or discontinuation of possible unsafe drugs. QTdrugs.org has received >3 100 000 visitors from 180 countries. Most visitors originated from the Americas (87%), as compared with Europe (7%), Asia (3%), Oceania (2%), and Africa (1%). The QTdrugs.org survey yielded 340 respondents: 34% were patients and 50% medical professionals. Of the patients, 79% reported that they refrained from, and 61% reported discontinuing drugs due to the website. The website was very much appreciated by 65% of the respondents and 30% found it rather helpful. The BrugadaDrugs.org received >48 000 visitors from 154 countries. Most visitors originated from Europe (46%) and the Americas (39%), but less from Asia (10%), Oceania (4%), and Africa (<1%). The BrugadaDrugs.org survey yielded 178 respondents: 68% were patients and 21% medical professionals. Of the patients, 72% reported refraining from, and 48% discontinuing drugs due to the website. The website was very much appreciated by 72% of the respondents and 25% found it rather helpful. Conclusion These websites are extensively used, they promote drug awareness, and they help patients to avoid possible pro-arrhythmic drugs. Visitors find the websites valuable but should note their limitations. PMID:23533266

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

    NASA Astrophysics Data System (ADS)

    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.

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

    NASA Astrophysics Data System (ADS)

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

    2004-05-01

    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.

  17. Update on the Diagnosis and Management of Familial Long QT Syndrome.

    PubMed

    Waddell-Smith, Kathryn E; Skinner, Jonathan R

    2016-08-01

    This update was reviewed by the CSANZ Continuing Education and Recertification Committee and ratified by the CSANZ board in August 2015. Since the CSANZ 2011 guidelines, adjunctive clinical tests have proven useful in the diagnosis of LQTS and are discussed in this update. Understanding of the diagnostic and risk stratifying role of LQTS genetics is also discussed. At least 14 LQTS genes are now thought to be responsible for the disease. High-risk individuals may have multiple mutations, large gene rearrangements, C-loop mutations in KCNQ1, transmembrane mutations in KCNH2, or have certain gene modifiers present, particularly NOS1AP polymorphisms. In regards to treatment, nadolol is preferred, particularly for long QT type 2, and short acting metoprolol should not be used. Thoracoscopic left cardiac sympathectomy is valuable in those who cannot adhere to beta blocker therapy, particularly in long QT type 1. Indications for ICD therapies have been refined; and a primary indication for ICD in post-pubertal females with long QT type 2 and a very long QT interval is emerging. PMID:27262388

  18. Reduced Uptake of Family Screening in Genotype-Negative Versus Genotype-Positive Long QT Syndrome.

    PubMed

    Hanninen, Mikael; Klein, George J; Laksman, Zachary; Conacher, Susan S; Skanes, Allan C; Yee, Raymond; Gula, Lorne J; Leong-Sit, Peter; Manlucu, Jaimie; Krahn, Andrew D

    2015-08-01

    The acceptance and yield of family screening in genotype-negative long QT syndrome (LQTS) remains incompletely characterized. In this study of family screening for phenotype-definite Long QT Syndrome (LQTS, Schwartz score ≥3.5), probands at a regional Inherited Cardiac Arrhythmia clinic were reviewed. All LQTS patients were offered education by a qualified genetic counselor, along with materials for family screening including electronic and paper correspondence to provide to family members. Thirty-eight qualifying probands were identified and 20 of these had family members who participated in cascade screening. The acceptance of screening was found to be lower among families without a known pathogenic mutation (33 vs. 77 %, p = 0.02). A total of 52 relatives were screened; fewer relatives were screened per index case when the proband was genotype-negative (1.7 vs. 3.1, p = 0.02). The clinical yield of screening appeared to be similar irrespective of gene testing results (38 vs. 33 %, p = 0.69). Additional efforts to promote family screening among gene-negative long QT families may be warranted. PMID:25273952

  19. Genotype- and Phenotype-Guided Management of Congenital Long QT Syndrome

    PubMed Central

    Giudicessi, John R.; Ackerman, Michael J.

    2014-01-01

    Congenital Long QT syndrome (LQTS) is a genetically heterogeneous collection of heritable disorders of myocardial repolarization linked by their shared clinical phenotype of QT prolongation on electrocardiogram and an increased risk of potentially life-threatening cardiac arrhythmias. At the molecular level, mutations in 15 distinct LQTS-susceptibility genes that encode ion channel pore-forming α-subunits and accessory/auxiliary subunits central to the electromechanical function of the heart have been implicated in its pathogenesis. Over the past two decades, our evolving understanding of the electrophysiological mechanisms by which specific genetic substrates perturb the cardiac action potential has translated into vastly improved approaches to the diagnosis, risk stratification, and treatment of patients with LQTS. In this Review, we detail how our understanding of the molecular underpinnings of LQTS has yielded numerous clinically meaningful genotype-phenotype correlations and how these insights have translated into genotype- and phenotype-guided approaches to the clinical management of LQTS. PMID:24093767

  20. Sevoflurane-associated torsade de pointes in a patient with congenital long QT syndrome genotype 2.

    PubMed

    Kumakura, Mika; Hara, Koji; Sata, Takeyoshi

    2016-09-01

    Although patients with congenital long QT syndrome (c-LQTS) are considered to be at high risk for anesthesia, few reports describe c-LQTS genotype-specific considerations for anesthesia. We describe a case of torsade de pointes (TdP) caused by sevoflurane in a patient with c-LQTS genotype 2 (LQT2). A 39-year-old woman diagnosed with c-LQTS was scheduled for an elective therapeutic abortion. Immediately after starting the operation, the patient developed TdP. Since pulseless ventricular tachycardia was sustained despite intravenous injection of lidocaine, defibrillation was performed. Analysis of the electrocardiogram revealed that the corrected QT interval before anesthesia was 530 ms and 2.0% sevoflurane markedly prolonged the corrected QT interval to 693 ms. Postoperative studies revealed a mutation in the KCNH2 gene. Anesthesiologists should note that patients with LQT2 could be more susceptible to volatile anesthetics than are those with other major genotypes. Genotype-specific management of anesthesia may reduce the risk of developing TdP during the perioperative period. PMID:27555138

  1. Reconstitution of defective protein trafficking rescues Long-QT syndrome in zebrafish.

    PubMed

    Meder, Benjamin; Scholz, Eberhard P; Hassel, David; Wolff, Christoph; Just, Steffen; Berger, Ina M; Patzel, Eva; Karle, Christoph; Katus, Hugo A; Rottbauer, Wolfgang

    2011-05-01

    Inherited cardiac arrhythmias are caused by genetic defects in ion channels and associated proteins. Mutations in these channels often do not affect their biophysical properties, but rather interfere with their trafficking to the cell membrane. Accordingly, strategies that could reroute the mutated channels to the membrane should be sufficient to restore the electrical properties of the affected cells, thereby suppressing the underlying arrhythmia. We identified here both, embryonic and adult zebrafish breakdance (bre) as a valuable model for human Long-QT syndrome. Electrocardiograms of adult homozygous bre mutants exhibit significant QT prolongation caused by delayed repolarization of the ventricle. We further show that the bre mutation (zERG(I59S)) disrupts ERG protein trafficking, thereby reducing the amount of active potassium channels on the cell membrane. Interestingly, improvement of channel trafficking by cisapride or dimethylsulfoxid is sufficient to reconstitute ERG channels on the cell membrane in a manner that suffices to suppress the Long-QT induced arrhythmia in breakdance mutant zebrafish. In summary, we show for the first time that therapeutic intervention can cure protein trafficking defects and the associated cardiac arrhythmia in vivo. PMID:21458413

  2. Fluvoxamine by itself has potential to directly induce long QT syndrome at supra-therapeutic concentrations.

    PubMed

    Yamazaki-Hashimoto, Yukiko; Nakamura, Yuji; Ohara, Hiroshi; Cao, Xin; Kitahara, Ken; Izumi-Nakaseko, Hiroko; Ando, Kentaro; Yamazaki, Hiroshi; Ikeda, Takanori; Yamazaki, Junichi; Sugiyama, Atsushi

    2015-02-01

    Fluvoxamine is one of the typical selective serotonin-reuptake inhibitors. While its combined use with QT-prolonging drugs has been contraindicated because of the increase in plasma concentrations of such drugs, information is still limited whether fluvoxamine by itself may directly prolong the QT interval. We examined electropharmacological effects of fluvoxamine together with its pharmacokinetic profile by using the halothane-anesthetized dogs (n = 4). Fluvoxamine was intravenously administered in three escalating doses of 0.1, 1 and 10 mg/kg over 10 min with a pause of 20 min between the doses. The low dose provided therapeutic plasma drug concentration, whereas the middle and high doses attained approximately 10 and 100 times of the therapeutic ones, respectively. Supra-therapeutic concentration of fluvoxamine exerted the negative chronotropic, inotropic and hypotensive effects; and suppressed the atrioventricular nodal and intraventricular conductions, indicating inhibitory actions on Ca2+ and Na+ channels, whereas it delayed the repolarization in a reverse use-dependent manner, reflecting characteristics of rapidly activating delayed rectifier K+ current channel-blocking property. Fluvoxamine prolonged the terminal repolarization phase at 100 times higher concentration than the therapeutic, indicating its proarrhythmic potential. Thus, fluvoxamine by itself has potential to directly induce long QT syndrome at supra-therapeutic concentrations. PMID:25560394

  3. Electrophysiologic Substrate in Congenital Long QT Syndrome: Noninvasive Mapping with Electrocardiographic Imaging (ECGI)

    PubMed Central

    Desouza, Kavit A.; Abraham, Robert L.; Strom, Maria; Sacher, Frederic; Van Hare, George F.; Haïssaguerre, Michel; Roden, Dan M.; Rudy, Yoram

    2014-01-01

    Background Congenital Long QT syndrome (LQTS) is an arrhythmogenic disorder that causes syncope and sudden death. While its genetic basis has become well-understood, the mechanisms whereby mutations translate to arrhythmia susceptibility in the in situ human heart have not been fully defined. We used noninvasive ECG imaging (ECGI) to map the cardiac electrophysiologic substrate and examine whether LQTS patients display regional heterogeneities in repolarization, a substrate which promotes arrhythmogenesis. Methods and Results 25 subjects (9 LQT1, 9 LQT2, 5 LQT3 and 2 LQT5) with genotype and phenotype positive LQTS underwent ECGI. Seven normal subjects provided control. Epicardial maps of activation, recovery times (RT), Activation-recovery intervals (ARI) and repolarization dispersion were constructed. Activation was normal in all patients. However, RT and ARI were prolonged relative to control, indicating delayed repolarization and abnormally long APD (312 ± 30 ms vs. 235 ± 21 ms in control). ARI prolongation was spatially heterogeneous, with repolarization gradients much steeper than control (119 ± 19 ms/cm vs. 2.0 ± 2.0 ms/cm). There was variability in steepness and distribution of repolarization gradients between and within LQTS types. Repolarization gradients were steeper in symptomatic patients (130 ± 27 ms/cm in 12 symptomatic patients vs. 98 ± 19 ms/cm in 13 asymptomatic patients; P < 0.05). Conclusions LQTS patients display regions with steep repolarization dispersion caused by localized APD prolongation. This defines a substrate for reentrant arrhythmias, not detectable by surface ECG. Steeper dispersion in symptomatic patients suggests a possible role for ECGI in risk stratification. PMID:25294783

  4. Genetically induced dysfunctions of Kir2.1 channels: implications for short QT3 syndrome and autism–epilepsy phenotype

    PubMed Central

    Ambrosini, Elena; Sicca, Federico; Brignone, Maria S.; D'Adamo, Maria C.; Napolitano, Carlo; Servettini, Ilenio; Moro, Francesca; Ruan, Yanfei; Guglielmi, Luca; Pieroni, Stefania; Servillo, Giuseppe; Lanciotti, Angela; Valvo, Giulia; Catacuzzeno, Luigi; Franciolini, Fabio; Molinari, Paola; Marchese, Maria; Grottesi, Alessandro; Guerrini, Renzo; Santorelli, Filippo M.; Priori, Silvia; Pessia, Mauro

    2014-01-01

    Short QT3 syndrome (SQT3S) is a cardiac disorder characterized by a high risk of mortality and associated with mutations in Kir2.1 (KCNJ2) channels. The molecular mechanisms leading to channel dysfunction, cardiac rhythm disturbances and neurodevelopmental disorders, potentially associated with SQT3S, remain incompletely understood. Here, we report on monozygotic twins displaying a short QT interval on electrocardiogram recordings and autism–epilepsy phenotype. Genetic screening identified a novel KCNJ2 variant in Kir2.1 that (i) enhanced the channel's surface expression and stability at the plasma membrane, (ii) reduced protein ubiquitylation and degradation, (iii) altered protein compartmentalization in lipid rafts by targeting more channels to cholesterol-poor domains and (iv) reduced interactions with caveolin 2. Importantly, our study reveals novel physiological mechanisms concerning wild-type Kir2.1 channel processing by the cell, such as binding to both caveolin 1 and 2, protein degradation through the ubiquitin–proteasome pathway; in addition, it uncovers a potential multifunctional site that controls Kir2.1 surface expression, protein half-life and partitioning to lipid rafts. The reported mechanisms emerge as crucial also for proper astrocyte function, suggesting the need for a neuropsychiatric evaluation in patients with SQT3S and offering new opportunities for disease management. PMID:24794859

  5. Pharmacological approach to the treatment of long and short QT syndromes.

    PubMed

    Patel, Chinmay; Antzelevitch, Charles

    2008-04-01

    Inherited channelopathies have received increasing attention in recent years. The past decade has witnessed impressive progress in our understanding of the molecular and cellular basis of arrhythmogenesis associated with inherited channelopathies. An imbalance in ionic forces induced by these channelopathies affects the duration of ventricular repolarization and amplifies the intrinsic electrical heterogeneity of the myocardium, creating an arrhythmogenic milieu. Today, many of the channelopathies have been linked to mutations in specific genes encoding either components of ion channels or membrane or regulatory proteins. Many of the channelopathies are genetically heterogeneous with a variable degree of expression of the disease. Defining the molecular basis of channelopathies can have a profound impact on patient management, particularly in cases in which genotype-specific pharmacotherapy is available. The long QT syndrome (LQTS) is one of the first identified and most studied channelopathies where abnormal prolongation of ventricular repolarization predisposes an individual to life threatening ventricular arrhythmia called Torsade de Pointes. On the other hand of the spectrum, molecular defects favoring premature repolarization lead to Short QT syndrome (SQTS), a recently described inherited channelopathy. Both of these channelopathies are associated with a high risk of sudden cardiac death due to malignant ventricular arrhythmia. Whereas pharmacological therapy is first line treatment for LQTS, defibrillators are considered as primary treatment for SQTS. This review provides a comprehensive review of the molecular genetics, clinical features, genotype-phenotype correlations and genotype-specific approach to pharmacotherapy of these two mirror-image channelopathies, SQTS and LQTS. PMID:18378319

  6. Primary Carnitine Deficiency Presents Atypically with Long QT Syndrome: A Case Report.

    PubMed

    De Biase, Irene; Champaigne, Neena Lorenzana; Schroer, Richard; Pollard, Laura Malinda; Longo, Nicola; Wood, Tim

    2012-01-01

    Primary carnitine deficiency (PCD) is an autosomal recessive disorder of fatty acid oxidation caused by mutations in the SLC22A5 gene encoding for the carnitine transporter OCTN2. Carnitine uptake deficiency results in renal carnitine wasting and low plasma levels. PCD usually presents early in life either with acute metabolic crisis or as progressive cardiomyopathy that responds to carnitine supplementation. PCD inclusion in the newborn screening (NBS) programs has led to the identification of asymptomatic adult patients ascertained because of a positive NBS in their offspring. We extensively reviewed the literature and found that 15 of 42 adult published cases (35.7%) were symptomatic. Cardiac arrhythmias were present in five patients (12%). Here, we report the ascertainment and long-term follow-up of the first case of PCD presenting with long QT syndrome. The patient presented in her early twenties with a syncopal episode caused by ventricular tachycardia, and a prolonged QT interval. Arrhythmias were poorly controlled by pharmacologic therapy and a defibrillator was installed. Syncopal episodes escalated during her first pregnancy. A positive NBS in the patient's child suggested a carnitine uptake deficiency, which was confirmed by reduced carnitine transporter activity and by molecular testing. After starting carnitine supplementation, no further syncopal episodes have occurred and the QT interval returned to normal. As precaution, a low-dose metoprolol therapy and the defibrillator are still in place. Although rare, PCD should be ruled out as a cause of cardiac arrhythmias since oral carnitine supplementation is readily available and efficient. PMID:23430858

  7. An interdomain KCNH2 mutation produces an intermediate long QT syndrome

    PubMed Central

    Osterbur, Marika L.; Zheng, Renjian; Marion, Robert; Walsh, Christine; McDonald, Thomas V.

    2015-01-01

    Hereditary Long QT Syndrome is caused by deleterious mutation in one of several genetic loci, including locus LQT2 that contains the KCNH2 gene (or hERG), causing faulty cardiac repolarization. Here, we describe and characterize a novel mutation, p.Asp219Val in the hERG channel, identified in an 11 year old male with syncope and prolonged QT interval. Genetic sequencing showed a non-synonymous variation in KCNH2 (c.656A>T: amino acid p.Asp219Val). p.Asp219Val resides in a region of the channel predicted to be unstructured and flexible, located between the PAS (Per-Arnt-Sim) domain and its interaction sites in the transmembrane domain. The p.Asp219Val hERG channel produced K+ current that activated with modest changes in voltage dependence. Mutant channels were also slower to inactivate, recovered from inactivation more readily and demonstrated a significantly accelerated deactivation rate compared to the slow deactivation of WT channels. The intermediate nature of the biophysical perturbation is consistent with the degree of severity in the clinical phenotype. The findings of this study demonstrate a previously unknown role of the proximal N-terminus in deactivation and support the hypothesis that the proximal N-terminal domain is essential in maintaining slow hERG deactivation. PMID:25914329

  8. Short QT syndrome presenting as syncope: how short is too short?

    PubMed

    Portugal, Guilherme; Martins Oliveira, Mário; Silva Cunha, Pedro; Ferreira, Filipa; Lousinha, Ana; Fiarresga, António; Nogueira da Silva, Manuel; Cruz Ferreira, Rui

    2014-10-01

    We report the case of a 52-year-old man who presented to our emergency department (ED) after three episodes of syncope in the seven hours before admission. During his stay in the ED he had recurrent ventricular tachycardia (VT) requiring external electrical cardioversion. A 12-lead electrocardiogram (ECG) showed a short QT (SQT) interval (270 ms, QTc 327 ms), with frequent R-on-T extrasystoles triggering sustained polymorphic VT. After exclusion of other precipitating causes, the patient was diagnosed as having SQT syndrome (SQTS) according to the Gollob criteria. To our knowledge, this is the first known documentation of an SQT-caused arrhythmic episode on a 12-lead ECG, as well as the first reported case of SQTS in Portugal. The patient received an implantable cardioverter-defibrillator and was discharged. At a follow-up assessment 14 months later he was symptom-free, interrogation of the device showed no arrhythmic events, and the ECG showed a QT interval of 320 ms (QTc 347 ms). PMID:25442000

  9. We Only Find What We Look For: Fetal Heart Rate and the Diagnosis of Long QT Syndrome

    PubMed Central

    Cuneo, Bettina F.; Strasburger, Janette F.

    2015-01-01

    Long QT syndrome (LQTS), an inherited channelopathy, is a common cause of arrhythmic death in infants, children and young adults. Although many LQTS genes have been identified, most (~75%) of LQTS mutations are found in KCNQ1, KCNH2 or SCN5A. In most cases, treatment for LQTS is successful and modifies the risk of life-threatening arrhythmias; thus, making the correct diagnosis is important. The diagnosis of LQTS is made by the measurement of a prolonged QT interval on the standard ECG; family history or characteristic arrhythmia features are used to strengthen the diagnosis and genetic testing confirms the diagnosis. PMID:26286300

  10. Identification of Genetic Alterations, as Causative Genetic Defects in Long QT Syndrome, Using Next Generation Sequencing Technology

    PubMed Central

    Mademont-Soler, Irene; Allegue, Catarina; Cesar, Sergi; Ferrer-Costa, Carles; Coll, Monica; Mates, Jesus; Iglesias, Anna; Brugada, Josep; Brugada, Ramon

    2014-01-01

    Background Long QT Syndrome is an inherited channelopathy leading to sudden cardiac death due to ventricular arrhythmias. Despite that several genes have been associated with the disease, nearly 20% of cases remain without an identified genetic cause. Other genetic alterations such as copy number variations have been recently related to Long QT Syndrome. Our aim was to take advantage of current genetic technologies in a family affected by Long QT Syndrome in order to identify the cause of the disease. Methods Complete clinical evaluation was performed in all family members. In the index case, a Next Generation Sequencing custom-built panel, including 55 sudden cardiac death-related genes, was used both for detection of sequence and copy number variants. Next Generation Sequencing variants were confirmed by Sanger method. Copy number variations variants were confirmed by Multiplex Ligation dependent Probe Amplification method and at the mRNA level. Confirmed variants and copy number variations identified in the index case were also analyzed in relatives. Results In the index case, Next Generation Sequencing revealed a novel variant in TTN and a large deletion in KCNQ1, involving exons 7 and 8. Both variants were confirmed by alternative techniques. The mother and the brother of the index case were also affected by Long QT Syndrome, and family cosegregation was observed for the KCNQ1 deletion, but not for the TTN variant. Conclusions Next Generation Sequencing technology allows a comprehensive genetic analysis of arrhythmogenic diseases. We report a copy number variation identified using Next Generation Sequencing analysis in Long QT Syndrome. Clinical and familiar correlation is crucial to elucidate the role of genetic variants identified to distinguish the pathogenic ones from genetic noise. PMID:25494010

  11. Atrial Fibrillation and Long QT Syndrome Presenting in a 12-Year-Old Girl.

    PubMed

    Knoche, Jonathan W; Orland, Kate M; January, Craig T; Maginot, Kathleen R

    2012-01-01

    Atrial fibrillation (AF) is rare in the pediatric population; however, there is increasing recognition that AF can be inherited. Long QT syndrome (LQTS), likewise, can be both acquired and inherited with mutations leading to abnormalities in cardiac ion channel function. Mutations in KCNQ1 are the most common cause of LQTS. Although rare, mutations in KCNQ1 also can cause familial AF. This report describes a child with a KCNQ1 missense mutation who uniquely expresses concomitant AF and LQTS. Due to the potential for increased morbidity and mortality, young patients who present with AF and a family history suggestive of inherited arrhythmias should trigger further investigation for LQTS and subsequent familial genetic counseling. PMID:23193492

  12. Atrial Fibrillation and Long QT Syndrome Presenting in a 12-Year-Old Girl

    PubMed Central

    Knoche, Jonathan W.; Orland, Kate M.; January, Craig T.; Maginot, Kathleen R.

    2012-01-01

    Atrial fibrillation (AF) is rare in the pediatric population; however, there is increasing recognition that AF can be inherited. Long QT syndrome (LQTS), likewise, can be both acquired and inherited with mutations leading to abnormalities in cardiac ion channel function. Mutations in KCNQ1 are the most common cause of LQTS. Although rare, mutations in KCNQ1 also can cause familial AF. This report describes a child with a KCNQ1 missense mutation who uniquely expresses concomitant AF and LQTS. Due to the potential for increased morbidity and mortality, young patients who present with AF and a family history suggestive of inherited arrhythmias should trigger further investigation for LQTS and subsequent familial genetic counseling. PMID:23193492

  13. α1-Syntrophin Variant Identified in Drug-Induced Long QT Syndrome Increases Late Sodium Current

    PubMed Central

    Choi, Jong-Il; Wang, Chaojian; Thomas, Matthew J.; Pitt, Geoffrey S.

    2016-01-01

    Drug-induced long-QT syndrome (diLQTS) is often due to drug block of IKr, especially in genetically susceptible patients with subclinical mutations in the IKr-encoding KCHN2. Few variants in the cardiac NaV1.5 Na+ channel complex have been associated with diLQTS. We tested whether a novel SNTA1 (α1-syntrophin) variant (p.E409Q) found in a patient with diLQTS increases late sodium current (INa-L), thereby providing a disease mechanism. Electrophysiological studies were performed in HEK293T cells co-expressing human NaV1.5/nNOS/PMCA4b with either wild type (WT) or SNTA1 variants (A390V-previously reported in congenital LQTS; and E409Q); and in adult rat ventricular cardiomyocytes infected with SNTA1 expressing adenoviruses (WT or one of the two SNTA1 variants). In HEK293T cells and in cardiomyocytes, there was no significant difference in the peak INa densities among the SNTA1 WT and variants. However, both variants increased INa-L (% of peak current) in HEK293T cells (0.58±0.10 in WT vs. 0.90±0.11 in A390V, p = 0.048; vs. 0.88±0.07 in E409Q, p = 0.023). In cardiomyocytes, INa-L was significantly increased by E409Q, but not by A390V compared to WT (0.49±0.14 in WT vs.0.94±0.23 in A390V, p = 0.099; vs. 1.12±0.24 in E409Q, p = 0.019). We demonstrated that a novel SNTA1 variant is likely causative for diLQTS by augmenting INa-L. These data suggest that variants within the NaV1.5-interacting α1-syntrophin are a potential mechanism for diLQTS, thereby expanding the concept that variants within congenital LQTS loci can cause diLQTS. PMID:27028743

  14. Malignant Perinatal Variant of Long-QT Syndrome Caused by a Profoundly Dysfunctional Cardiac Sodium Channel

    PubMed Central

    Wang, Dao W.; Crotti, Lia; Shimizu, Wataru; Pedrazzini, Matteo; Cantu', Francesco; De Filippo, Paolo; Kishiki, Kanako; Miyazaki, Aya; Ikeda, Tomoaki; Schwartz, Peter J.; George, Alfred L.

    2009-01-01

    Background Inherited cardiac arrhythmia susceptibility contributes to sudden death during infancy and may contribute to perinatal and neonatal mortality, but the molecular basis of this risk and the relationship to genetic disorders presenting later in life is unclear. We studied the functional and pharmacological properties of a novel de novo cardiac sodium channel gene (SCN5A) mutation associated with an extremely severe perinatal presentation of long-QT syndrome in unrelated probands of different ethnicity. Methods and Results Two subjects exhibiting severe fetal and perinatal ventricular arrhythmias were screened for SCN5A mutations and the functional properties of a novel missense mutation (G1631D) were determined by whole-cell patch clamp recording. In vitro electrophysiological studies revealed a profound defect in sodium channel function characterized by ~10-fold slowing of inactivation, increased persistent current, slowing of recovery from inactivation, depolarized voltage dependence of activation and inactivation. Single channel recordings demonstrated increased frequency of late openings, prolonged mean open time and increased latency to first opening for the mutant. Subjects carrying this mutation responded clinically to the combination of mexiletine with propranolol and survived. Pharmacologically, the mutant exhibited 2-fold greater tonic and use-dependent mexiletine block than wildtype channels. The mutant also exhibited enhanced tonic (2.4-fold) and use-dependent block (~5-fold) by propranolol, and we observed additive effects of the two drugs on the mutant. Conclusions Our study demonstrates the molecular basis for a malignant perinatal presentation of long-QT syndrome, illustrates novel functional and pharmacological properties of SCN5A-G1631D which caused the disorder, and reveals therapeutic benefits of propranolol block of mutant sodium channels in this setting. PMID:19808432

  15. In silico screening of the impact of hERG channel kinetic abnormalities on channel block and susceptibility to acquired long QT syndrome.

    PubMed

    Romero, Lucia; Trenor, Beatriz; Yang, Pei-Chi; Saiz, Javier; Clancy, Colleen E

    2015-10-01

    Accurate diagnosis of predisposition to long QT syndrome is crucial for reducing the risk of cardiac arrhythmias. In recent years, drug-induced provocative tests have proved useful to unmask some latent mutations linked to cardiac arrhythmias. In this study we expanded this concept by developing a prototype for a computational provocative screening test to reveal genetic predisposition to acquired long-QT syndrome (aLQTS). We developed a computational approach to reveal the pharmacological properties of I(Kr) blocking drugs that are most likely to cause aLQTS in the setting of subtle alterations in I(Kr) channel gating that would be expected to result from benign genetic variants.Weused themodel to predict themost potentially lethal combinations of kinetic anomalies and drug properties. In doing so, we also implicitly predicted ideal inverse therapeutic properties of K channel openers that would be expected to remedy a specific defect. We systematically performed “in silico mutagenesis” by altering discrete kinetic transition rates of the Fink et al. Markov model of human I(Kr) channels, corresponding to activation, inactivation, deactivation and recovery from inactivation of I(Kr) channels. We then screened and identified the properties of I(Kr) blockers that caused acquired long QT and therefore unmasked mutant phenotypes formild,moderate and severe variants. Mutant I(Kr) channels were incorporated into the O'Hara et al. human ventricular action potential (AP) model and subjected to simulated application of a wide variety of I(Kr)-drug interactions in order to identify the characteristics that selectively exacerbate the AP duration (APD) differences between wild-type and I(Kr) mutated cells. Our results show that drugs with disparate affinities to conformation states of the I(Kr) channel are key to amplify variants underlying susceptibility to acquired long QT syndrome, an effect that is especially pronounced at slow frequencies. Finally, we developed a

  16. In silico screening of the impact of hERG channel kinetic abnormalities on channel block and susceptibility to acquired long QT syndrome

    PubMed Central

    Romero, Lucia; Trenor, Beatriz; Yang, Pei-Chi; Saiz, Javier; Clancy, Colleen E.

    2016-01-01

    Accurate diagnosis of predisposition to long QT syndrome is crucial for reducing the risk of cardiac arrhythmias. In recent years, drug-induced provocative tests have proved useful to unmask some latent mutations linked to cardiac arrhythmias. In this study we expanded this concept by developing a prototype for a computational provocative screening test to reveal genetic predisposition to acquired long-QT syndrome (aLQTS). We developed a computational approach to reveal the pharmacological properties of IKr blocking drugs that are most likely to cause aLQTS in the setting of subtle alterations in IKr channel gating that would be expected to result from benign genetic variants. We used the model to predict the most potentially lethal combinations of kinetic anomalies and drug properties. In doing so, we also implicitly predicted ideal inverse therapeutic properties of K channel openers that would be expected to remedy a specific defect. We systematically performed “in silico mutagenesis” by altering discrete kinetic transition rates of the Fink et al. Markov model of human IKr channels, corresponding to activation, inactivation, deactivation and recovery from inactivation of IKr channels. We then screened and identified the properties of IKr blockers that caused acquired long QT and therefore unmasked mutant phenotypes for mild, moderate and severe variants. Mutant IKr channels were incorporated into the O'Hara et al. human ventricular action potential (AP) model and subjected to simulated application of a wide variety of IKr–drug interactions in order to identify the characteristics that selectively exacerbate the AP duration (APD) differences between wild-type and IKr mutated cells. Our results show that drugs with disparate affinities to conformation states of the IKr channel are key to amplify variants underlying susceptibility to acquired long QT syndrome, an effect that is especially pronounced at slow frequencies. Finally, we developed a mathematical

  17. In silico screening of the impact of hERG channel kinetic abnormalities on channel block and susceptibility to acquired long QT syndrome.

    PubMed

    Romero, Lucia; Trenor, Beatriz; Yang, Pei-Chi; Saiz, Javier; Clancy, Colleen E

    2014-07-01

    Accurate diagnosis of predisposition to long QT syndrome is crucial for reducing the risk of cardiac arrhythmias. In recent years, drug-induced provocative tests have proved useful to unmask some latent mutations linked to cardiac arrhythmias. In this study we expanded this concept by developing a prototype for a computational provocative screening test to reveal genetic predisposition to acquired long-QT syndrome (aLQTS). We developed a computational approach to reveal the pharmacological properties of IKr blocking drugs that are most likely to cause aLQTS in the setting of subtle alterations in IKr channel gating that would be expected to result from benign genetic variants. We used the model to predict the most potentially lethal combinations of kinetic anomalies and drug properties. In doing so, we also implicitly predicted ideal inverse therapeutic properties of K channel openers that would be expected to remedy a specific defect. We systematically performed "in silico mutagenesis" by altering discrete kinetic transition rates of the Fink et al. Markov model of human IKr channels, corresponding to activation, inactivation, deactivation and recovery from inactivation of IKr channels. We then screened and identified the properties of IKr blockers that caused acquired long QT and therefore unmasked mutant phenotypes for mild, moderate and severe variants. Mutant IKr channels were incorporated into the O'Hara et al. human ventricular action potential (AP) model and subjected to simulated application of a wide variety of IKr-drug interactions in order to identify the characteristics that selectively exacerbate the AP duration (APD) differences between wild-type and IKr mutated cells. Our results show that drugs with disparate affinities to conformation states of the IKr channel are key to amplify variants underlying susceptibility to acquired long QT syndrome, an effect that is especially pronounced at slow frequencies. Finally, we developed a mathematical

  18. In silico screening of the impact of hERG channel kinetic abnormalities on channel block and susceptibility to acquired long QT syndrome

    PubMed Central

    Romero, Lucia; Trenor, Beatriz; Yang, Pei-Chi; Saiz, Javier; Clancy, Colleen E.

    2014-01-01

    Accurate diagnosis of predisposition to long QT syndrome is crucial for reducing the risk of cardiac arrhythmias. In recent years, drug-induced provocative tests have proved useful to unmask some latent mutations linked to cardiac arrhythmias. In this study we expanded this concept by developing a prototype for a computational provocative screening test to reveal genetic predisposition to acquired Long-QT Syndrome (aLTQS). We developed a computational approach to reveal the pharmacological properties of IKr blocking drugs that are most likely to cause aLQTS in the setting of subtle alterations in IKr channel gating that would be expected to result from benign genetic variants. We used the model to predict the most potentially lethal combinations of kinetic anomalies and drug properties. In doing so, we also implicitly predicted ideal inverse therapeutic properties of K channel openers that would be expected to remedy a specific defect. We systematically performed “in silico mutagenesis” by altering discrete kinetic transition rates of the Fink et al. Markov model of human IKr channels, corresponding to activation, inactivation, deactivation and recovery from inactivation of IKr channels. We then screened and identified the properties of IKr blockers that caused acquired Long QT and therefore unmasked mutant phenotypes for mild, moderate and severe variants. Mutant IKr channels were incorporated into the O’Hara et al. human ventricular action potential (AP) model and subjected to simulated application of a wide variety of IKr-drug interactions in order to identify the characteristics that selectively exacerbate the AP duration (APD) differences between wild-type and IKr mutated cells. Our results show that drugs with disparate affinities to conformation states of the IKr channel are key to amplify variants underlying susceptibility to acquired Long QT Syndrome, an effect that is especially pronounced at slow frequencies. Finally, we developed a mathematical

  19. Genetic analysis, in silico prediction, and family segregation in long QT syndrome.

    PubMed

    Riuró, Helena; Campuzano, Oscar; Berne, Paola; Arbelo, Elena; Iglesias, Anna; Pérez-Serra, Alexandra; Coll-Vidal, Mònica; Partemi, Sara; Mademont-Soler, Irene; Picó, Ferran; Allegue, Catarina; Oliva, Antonio; Gerstenfeld, Edward; Sarquella-Brugada, Georgia; Castro-Urda, Víctor; Fernández-Lozano, Ignacio; Mont, Lluís; Brugada, Josep; Scornik, Fabiana S; Brugada, Ramon

    2015-01-01

    The heritable cardiovascular disorder long QT syndrome (LQTS), characterized by prolongation of the QT interval on electrocardiogram, carries a high risk of sudden cardiac death. We sought to add new data to the existing knowledge of genetic mutations contributing to LQTS to both expand our understanding of its genetic basis and assess the value of genetic testing in clinical decision-making. Direct sequencing of the five major contributing genes, KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2, was performed in a cohort of 115 non-related LQTS patients. Pathogenicity of the variants was analyzed using family segregation, allele frequency from public databases, conservation analysis, and Condel and Provean in silico predictors. Phenotype-genotype correlations were analyzed statistically. Sequencing identified 36 previously described and 18 novel mutations. In 51.3% of the index cases, mutations were found, mostly in KCNQ1, KCNH2, and SCN5A; 5.2% of cases had multiple mutations. Pathogenicity analysis revealed 39 mutations as likely pathogenic, 12 as VUS, and 3 as non-pathogenic. Clinical analysis revealed that 75.6% of patients with QTc≥500 ms were genetically confirmed. Our results support the use of genetic testing of KCNQ1, KCNH2, and SCN5A as part of the diagnosis of LQTS and to help identify relatives at risk of SCD. Further, the genetic tools appear more valuable as disease severity increases. However, the identification of genetic variations in the clinical investigation of single patients using bioinformatic tools can produce erroneous conclusions regarding pathogenicity. Therefore segregation studies are key to determining causality. PMID:24667783

  20. Genetic analysis, in silico prediction, and family segregation in long QT syndrome

    PubMed Central

    Riuró, Helena; Campuzano, Oscar; Berne, Paola; Arbelo, Elena; Iglesias, Anna; Pérez-Serra, Alexandra; Coll-Vidal, Mònica; Partemi, Sara; Mademont-Soler, Irene; Picó, Ferran; Allegue, Catarina; Oliva, Antonio; Gerstenfeld, Edward; Sarquella-Brugada, Georgia; Castro-Urda, Víctor; Fernández-Lozano, Ignacio; Mont, Lluís; Brugada, Josep; Scornik, Fabiana S; Brugada, Ramon

    2015-01-01

    The heritable cardiovascular disorder long QT syndrome (LQTS), characterized by prolongation of the QT interval on electrocardiogram, carries a high risk of sudden cardiac death. We sought to add new data to the existing knowledge of genetic mutations contributing to LQTS to both expand our understanding of its genetic basis and assess the value of genetic testing in clinical decision-making. Direct sequencing of the five major contributing genes, KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2, was performed in a cohort of 115 non-related LQTS patients. Pathogenicity of the variants was analyzed using family segregation, allele frequency from public databases, conservation analysis, and Condel and Provean in silico predictors. Phenotype-genotype correlations were analyzed statistically. Sequencing identified 36 previously described and 18 novel mutations. In 51.3% of the index cases, mutations were found, mostly in KCNQ1, KCNH2, and SCN5A; 5.2% of cases had multiple mutations. Pathogenicity analysis revealed 39 mutations as likely pathogenic, 12 as VUS, and 3 as non-pathogenic. Clinical analysis revealed that 75.6% of patients with QTc≥500 ms were genetically confirmed. Our results support the use of genetic testing of KCNQ1, KCNH2, and SCN5A as part of the diagnosis of LQTS and to help identify relatives at risk of SCD. Further, the genetic tools appear more valuable as disease severity increases. However, the identification of genetic variations in the clinical investigation of single patients using bioinformatic tools can produce erroneous conclusions regarding pathogenicity. Therefore segregation studies are key to determining causality. PMID:24667783

  1. The canine Purkinje fiber: an in vitro model system for acquired long QT syndrome and drug-induced arrhythmogenesis.

    PubMed

    Gintant, G A; Limberis, J T; McDermott, J S; Wegner, C D; Cox, B F

    2001-05-01

    Torsade de pointes is a rare but potentially fatal ventricular arrhythmia associated with drug-induced delayed repolarization and prolongation of the QT interval. To determine if the arrhythmogenic potential of noncardiac drugs can be assessed in vitro, we evaluated the effects of 12 drugs on the action potential duration (APD) of cardiac Purkinje fibers and compared results with clinical observations. APD changes in canine and porcine fibers were evaluated under physiologic conditions (37 degrees C, [K+]0 = 4 mM) using standard microelectrode techniques. Six of seven drugs associated with QT prolongation or torsade de pointes in man (cisapride, erythromycin, grepafloxacin, moxifloxacin, sertindole, and sotalol) affected concentration-dependent prolongation of the APD in canine fibers during slow stimulation (2-s basic cycle length), attaining greater than 15% prolongation at high concentrations (> or = 10-fold clinically encountered plasma levels). Each of five drugs not linked clinically to QT prolongation and torsade de pointes (azithromycin, enalaprilat, fluoxetine, indomethacin, and pinacidil) failed to attain 15% prolongation, with fluoxetine, indomethacin, and pinacidil abbreviating the APD. Drugs eliciting the greatest prolongation also demonstrated prominent reverse rate-dependent effects. The antihistamine terfenadine (linked to dose-dependent QT prolongation and torsade de pointes clinically) only minimally prolonged the APD in canine and porcine fibers (and exerted no effect on midmyocardial fibers from left ventricular free wall) at supratherapeutic concentrations. On the basis of concentration-dependent APD prolongation and reverse rate-dependent effects, this Purkinje fiber model detects six of seven drugs linked clinically to acquired long QT syndrome and torsade de pointes, and clears each of five drugs not associated with repolarization abnormalities (overall 92% accuracy), validating the utility of this Purkinje fiber model in the preclinical

  2. Localization of Romano-Ward long QT syndrome gene, LQTI, to the interval between tyrosine hydroxylase (TH) and D11S1349

    SciTech Connect

    Russell, M.W. |; Hulse, J.E.; Campbell, R.M.

    1995-08-01

    The Romano-Ward long-QT syndrome (RWLQTS) is an autosomal dominant disorder that is characterized by heritable prolongation of the QT interval, syncope, and sudden death. Identification of the gene responsible for this syndrome may aid the diagnosis, management, and treatment of patients with this disease. Furthermore, it may lead to improved understanding of and therapy for other sympathetic-dependent ventricular arrhythmias. 20 refs., 1 fig., 1 tab.

  3. Impact of Gene Patents and Licensing Practices on Access to Genetic Testing for Long QT Syndrome

    PubMed Central

    Angrist, Misha; Chandrasekharan, Subhashini; Heaney, Christopher; Cook-Deegan, Robert

    2010-01-01

    Genetic testing for Long QT syndrome (LQTS) exemplifies patenting and exclusive licensing with different outcomes at different times. Exclusive licensing from the University of Utah changed the business model from sole provider to two US providers of LQTS testing. LQTS is associated with mutations in many genes, ten of which are now tested by two competing firms in the United States, PGxHealth and GeneDx. Until 2009, PGxHealth was sole provider, based largely on exclusive rights to patents from the University of Utah and other academic institutions. University of Utah patents were initially licensed to DNA Sciences, whose patent rights were acquired by Gennaissance, and then by Clinical Data, Inc., which owns PGxHealth. In 2002, DNA Sciences “cleared the market” by sending cease and desist patent enforcement letters to university and reference laboratories offering LQTS genetic testing. There was no test on the market for a one- to two-year period. From 2005-2008, most LQTS-related patents were controlled by Clinical Data, Inc., and its subsidiary PGxHealth. BioReference Laboratories, Inc., secured countervailing exclusive patent rights starting in 2006, also from the University of Utah, and broke the PGxHealth monopoly in early 2009, creating a duopoly for genetic testing in the United States, and expanding the number of genes for which commercial testing is available from five to ten. PMID:20393304

  4. Mapping of a Gene for Long QT Syndrome to Chromosome 4q25-27

    PubMed Central

    Schott, Jean-Jacques; Charpentier, Flavien; Peltier, Sophie; Foley, Patrick; Drouin, Emmanuel; Bouhour, Jean-Brieuc; Donnelly, Patricia; Vergnaud, Gilles; Bachner, Lucien; Moisan, Jean-Paul; Le Marec, Hervé; Pascal, Olivier

    1995-01-01

    Long QT syndrome (LQTS) is a heterogeneous inherited disorder causing syncope and sudden death from ventricular arrhythmias. A first locus for this disorder was mapped to chromosome 11p15.5. However, locus heterogeneity has been demonstrated in several families, and two other loci have recently been located on chromosomes 7q35-36 and 3p21-24. We used linkage analysis to map the locus in a 65-member family in which LQTS was associated with more marked sinus bradycardia than usual, leading to sinus node dysfunction. Linkage to chromosome 11p15.5, 7q35-36, or 3p21-24 was excluded. Positive linkage was obtained for markers located on chromosome 4q25-27. A maximal LOD score of 7.05 was found for marker D4S402. The identification of a fourth locus for LQTS confirms its genetic heterogeneity. Locus 4q25-27 is associated with a peculiar phenotype within the LQTS entity. PMID:7485162

  5. Mapping of a gene for long QT syndrome to chromosome 4q25-27

    SciTech Connect

    Schott, J.J.; Charpentier, F.; Peltier, S.

    1995-11-01

    Long QT syndrome (LQTS) is a heterogeneous inherited disorder causing syncope and sudden death from ventricular arrhythmias. A first locus for this disorder was mapped to chromosome 11p15.5. However, locus heterogeneity has been demonstrated in several families, and two other loci have recently been located on chromosomes 7q35-36 and 3p21-24. We used linkage analysis to map the locus in a 65-member family in which LQTS was associated with more marked sinus bradycardia than usual, leading to sinus node dysfunction. Linkage to chromosome 11p15.5, 7q35-36, or 3p21-24 was excluded. Positive linkage was obtained for markers located on chromosome 4q25-27. A maximal LOD score of 7.05 was found for marker D4S402. The identification of a fourth locus for LQTS confirms its genetic heterogeneity. Locus 4q25-27 is associated with a peculiar phenotype within the LQTS entity. 42 refs., 4 figs., 3 tabs.

  6. Novel missense mutation in the cyclic nucleotide-binding domain of HERG causes long QT syndrome

    SciTech Connect

    Satler, C.A.; Walsh, E.P.; Vesely, M.R.

    1996-10-02

    Autosomal-dominant long QT syndrome (LQT) is an inherited disorder, predisposing affected individuals to sudden death from tachyarrhythmias. To identify the gene(s) responsible for LQT, we identified and characterized an LQT family consisting of 48 individuals. DNA was screened with 150 microsatellite polymorphic markers encompassing approximately 70% of the genome. We found evidence for linkage of the LQT phenotype to chromosome 7(q35-36). Marker D7S636 yielded a maximum lod score of 6.93 at a recombination fraction ({theta}) of 0.00. Haplotype analysis further localized the LQT gene within a 6-2-cM interval. HERG encodes a potassium channel which has been mapped to this region. Single-strand conformational polymorphism analyses demonstrated aberrant bands that were unique to all affected individuals. DNA sequencing of the aberrant bands demonstrated a G to A substitution in all affected patients; this point mutation results in the substitution of a highly conserved valine residue with a methionine (V822M) in the cyclic nucleotide-binding domain of this potassium channel. The cosegregation of this distinct mutation with LQT demonstrates that HERG is the LQT gene in this pedigree. Furthermore, the location and character of this mutation suggests that the cyclic nucleotide-binding domain of the potassium channel encoded by HERG plays an important role in normal cardiac repolarization and may decrease susceptibility to ventricular tachyarrhythmias. 38 refs., 7 figs., 2 tabs.

  7. Molecular Diagnosis of Long-QT syndrome at 10 Days of Life by Rapid Whole Genome Sequencing

    PubMed Central

    Priest, James R.; Ceresnak, Scott R.; Dewey, Frederick E.; Malloy-Walton, Lindsey E.; Dunn, Kyla; Grove, Megan E.; Perez, Marco V.; Maeda, Katsuhide; Dubin, Anne M.; Ashley, Euan A.

    2014-01-01

    Background The advent of clinical next generation sequencing is rapidly changing the landscape of rare disease medicine. Molecular diagnosis of long QT syndrome (LQTS) can impact clinical management, including risk stratification and selection of pharmacotherapy based on the type of ion channel affected, but results from current gene panel testing requires 4 to 16 weeks before return to clinicians. Objective A term female infant presented with 2:1 atrioventricular block and ventricular arrhythmias consistent with perinatal LQTS, requiring aggressive treatment including epicardial pacemaker, and cardioverter-defibrillator implantation and sympathectomy on day of life two. We sought to provide a rapid molecular diagnosis for optimization of treatment strategies. Methods We performed CLIA-certified rapid whole genome sequencing (WGS) with a speed-optimized bioinformatics platform to achieve molecular diagnosis at 10 days of life. Results We detected a known pathogenic variant in KCNH2 that was demonstrated to be paternally inherited by followup genotyping. The unbiased assessment of the entire catalog of human genes provided by whole genome sequencing revealed a maternally inherited variant of unknown significance in a novel gene. Conclusions Rapid clinical WGS provides faster and more comprehensive diagnostic information by 10 days of life than standard gene-panel testing. In selected clinical scenarios such as perinatal LQTS, rapid WGS may be able to provide more timely and clinically actionable information than a standard commercial test. PMID:24973560

  8. Late sodium current block for drug-induced long QT syndrome: Results from a prospective clinical trial.

    PubMed

    Johannesen, L; Vicente, J; Mason, J W; Erato, C; Sanabria, C; Waite-Labott, K; Hong, M; Lin, J; Guo, P; Mutlib, A; Wang, J; Crumb, W J; Blinova, K; Chan, D; Stohlman, J; Florian, J; Ugander, M; Stockbridge, N; Strauss, D G

    2016-02-01

    Drug-induced long QT syndrome has resulted in many drugs being withdrawn from the market. At the same time, the current regulatory paradigm for screening new drugs causing long QT syndrome is preventing drugs from reaching the market, sometimes inappropriately. In this study, we report the results of a first-of-a-kind clinical trial studying late sodium (mexiletine and lidocaine) and calcium (diltiazem) current blocking drugs to counteract the effects of hERG potassium channel blocking drugs (dofetilide and moxifloxacin). We demonstrate that both mexiletine and lidocaine substantially reduce heart-rate corrected QT (QTc) prolongation from dofetilide by 20 ms. Furthermore, all QTc shortening occurs in the heart-rate corrected J-Tpeak (J-Tpeak c) interval, the biomarker we identified as a sign of late sodium current block. This clinical trial demonstrates that late sodium blocking drugs can substantially reduce QTc prolongation from hERG potassium channel block and assessment of J-Tpeak c may add value beyond only assessing QTc. PMID:26259627

  9. Long QT, Syndactyly, Joint Contractures, Stroke and Novel CACNA1C Mutation: Expanding the Spectrum of Timothy Syndrome

    PubMed Central

    Gillis, Jane; Burashnikov, Elena; Antzelevitch, Charles; Blaser, Susan; Gross, Gil; Turner, Lesley; Babul-Hirji, Riyana; Chitayat, David

    2011-01-01

    Timothy syndrome (TS) is described as an autosomal dominant condition with the constellation of features including prolonged QT interval, hand and foot abnormalities and mental retardation or autism. Splawski et al. [2004] previously described two phenotypes associated with TS distinguished by two unique and different mutations within the CACNA1C gene. We report on a newborn who presented with prolonged QT interval and associated polymorphic ventricular tachycardia, dysmorphic facial features, syndactyly of the hands and feet and joint contractures, suggestive of TS. He developed a stroke, subsequent intractable seizures and was found to have cortical blindness and later profound developmental delay. Initial targeted mutation analysis did not identify either of the previously described TS associated mutations; however, full gene sequencing detected a novel CACNA1C gene mutation (p.Ala1473Gly). The clinical and genetic findings in our case expand both the clinical and molecular knowledge of TS. PMID:22106044

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

    PubMed Central

    Adeniran, Ismail; Hancox, Jules C.; Zhang, Henggui

    2013-01-01

    Introduction: Genetic forms of the Short QT Syndrome (SQTS) arise due to cardiac ion channel mutations leading to accelerated ventricular repolarization, arrhythmias and sudden cardiac death. Results from experimental and simulation studies suggest that changes to refractoriness and tissue vulnerability produce a substrate favorable 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 [Ca2+]i 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, at a stimulation frequency of 1Hz, the SQTS mutations produced dramatic reductions in the amplitude of [Ca2+]i 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 modeling 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. PMID

  11. Exome Analyses of Long QT Syndrome Reveal Candidate Pathogenic Mutations in Calmodulin-Interacting Genes.

    PubMed

    Shigemizu, Daichi; Aiba, Takeshi; Nakagawa, Hidewaki; Ozaki, Kouichi; Miya, Fuyuki; Satake, Wataru; Toda, Tatsushi; Miyamoto, Yoshihiro; Fujimoto, Akihiro; Suzuki, Yutaka; Kubo, Michiaki; Tsunoda, Tatsuhiko; Shimizu, Wataru; Tanaka, Toshihiro

    2015-01-01

    Long QT syndrome (LQTS) is an arrhythmogenic disorder that can lead to sudden death. To date, mutations in 15 LQTS-susceptibility genes have been implicated. However, the genetic cause for approximately 20% of LQTS patients remains elusive. Here, we performed whole-exome sequencing analyses on 59 LQTS and 61 unaffected individuals in 35 families and 138 unrelated LQTS cases, after genetic screening of known LQTS genes. Our systematic analysis of familial cases and subsequent verification by Sanger sequencing identified 92 candidate mutations in 88 genes for 23 of the 35 families (65.7%): these included eleven de novo, five recessive (two homozygous and three compound heterozygous) and seventy-three dominant mutations. Although no novel commonly mutated gene was identified other than known LQTS genes, protein-protein interaction (PPI) network analyses revealed ten new pathogenic candidates that directly or indirectly interact with proteins encoded by known LQTS genes. Furthermore, candidate gene based association studies using an independent set of 138 unrelated LQTS cases and 587 controls identified an additional novel candidate. Together, mutations in these new candidates and known genes explained 37.1% of the LQTS families (13 in 35). Moreover, half of the newly identified candidates directly interact with calmodulin (5 in 11; comparison with all genes; p=0.042). Subsequent variant analysis in the independent set of 138 cases identified 16 variants in the 11 genes, of which 14 were in calmodulin-interacting genes (87.5%). These results suggest an important role of calmodulin and its interacting proteins in the pathogenesis of LQTS. PMID:26132555

  12. The long QT syndrome: a transatlantic clinical approach to diagnosis and therapy.

    PubMed

    Schwartz, Peter J; Ackerman, Michael J

    2013-10-01

    The mind-boggling progress in the understanding of the molecular mechanisms underlying the long QT syndrome (LQTS) has been the subject of many articles and reviews. Still, when it comes to the management of the patients affected by this life-threatening disorder, too many errors still take place, both in the diagnostic process and in the therapeutic choices. The price of these errors is paid by the patients and their families. This review is not directed to the relatively small number of LQTS experts who know what to do. It does not deal with genetics, with epidemiology, or with the well-known clinical manifestations. We have focused solely on the approach to diagnosis and therapy and we have directed this review to the average clinical cardiologist who, in his/her practice, sees occasionally patients affected or suspected to be affected by LQTS; the cardiologist who may know enough to manage them but not enough to be completely confident on his/her most critical choices. We have provided our personal views without making any attempt to blend differences whenever present. On most issues we agree fully but where we do not, we make it clear to the reader by indicating who is thinking what. The result may be unconventional, but it mirrors the challenges, often severe, that we all face in managing and protecting these patients from sudden death while also helping them live and thrive despite their diagnosis. We trust that this unabashed presentation of our clinical approach will be useful for both cardiologists and patients. PMID:23509228

  13. Cellular mechanisms of ventricular arrhythmias in a mouse model of Timothy syndrome (long QT syndrome 8).

    PubMed

    Drum, Benjamin M L; Dixon, Rose E; Yuan, Can; Cheng, Edward P; Santana, Luis F

    2014-01-01

    Ca(2+) flux through l-type CaV1.2 channels shapes the waveform of the ventricular action potential (AP) and is essential for excitation-contraction (EC) coupling. Timothy syndrome (TS) is a disease caused by a gain-of-function mutation in the CaV1.2 channel (CaV1.2-TS) that decreases inactivation of the channel, which increases Ca(2+) influx, prolongs APs, and causes lethal arrhythmias. Although many details of the CaV1.2-TS channels are known, the cellular mechanisms by which they induce arrhythmogenic changes in intracellular Ca(2+) remain unclear. We found that expression of CaV1.2-TS channels increased sarcolemmal Ca(2+) "leak" in resting TS ventricular myocytes. This resulted in higher diastolic [Ca(2+)]i in TS ventricular myocytes compared to WT. Accordingly, TS myocytes had higher sarcoplasmic reticulum (SR) Ca(2+) load and Ca(2+) spark activity, larger amplitude [Ca(2+)]i transients, and augmented frequency of Ca(2+) waves. The large SR Ca(2+) release in TS myocytes had a profound effect on the kinetics of CaV1.2 current in these cells, increasing the rate of inactivation to a high, persistent level. This limited the amount of influx during EC coupling in TS myocytes. The relationship between the level of expression of CaV1.2-TS channels and the probability of Ca(2+) wave occurrence was non-linear, suggesting that even low levels of these channels were sufficient to induce maximal changes in [Ca(2+)]i. Depolarization of WT cardiomyocytes with a TS AP waveform increased, but did not equalize [Ca(2+)]i, compared to depolarization of TS myocytes with the same waveform. We propose that CaV1.2-TS channels increase [Ca(2+)] in the cytosol and the SR, creating a Ca(2+)overloaded state that increases the probability of arrhythmogenic spontaneous SR Ca(2+) release. PMID:24215710

  14. Synchronous Systolic Subcellular Ca2+-Elevations Underlie Ventricular Arrhythmia in Drug-Induced Long QT Type 2

    PubMed Central

    Kim, Jong J.; Němec, Jan; Li, Qiao; Salama, Guy

    2015-01-01

    Background Repolarization-delay is a common clinical problem which can promote ventricular arrhythmias. In myocytes, abnormal sarcoplasmic reticulum Ca2+-release is proposed as the mechanism that causes early afterdepolarizations, the cellular equivalent of ectopic-activity in drug-induced long QT syndrome. A crucial missing link is how such a stochastic process can overcome the source-sink mismatch to depolarize sufficient ventricular tissue to initiate arrhythmias. Methods and Results Optical maps of action potentials (APs) and Ca2+-transients (CaT) from Langendorff rabbit hearts were measured at low (150×150 μm2/pixel) and high (1.5×1.5 μm2/pixel) resolution before and during arrhythmias. Drug-induced long QT type 2, elicited with dofetilide inhibition, produced spontaneous Ca2+-elevations during diastole and systole, before the onset of arrhythmias. Diastolic Ca2+− waves appeared randomly, propagated within individual myocytes, were out-of-phase with adjacent myocytes and often died-out. Systolic secondary Ca2+− elevations were synchronous within individual myocytes, appeared 188±30ms after the AP-upstroke, occurred during high cytosolic-Ca2+ (40–60% of peak-CaT), appeared first in small islands (0.5×0.5 mm2) that enlarged and spread throughout the epicardium. Synchronous systolic Ca2+-elevations preceded voltage-depolarizations (9.2±5ms, n=5) and produced pronounced Spatial Heterogeneities of CaT-durations and AP-durations. Early afterdepolarizations originating from sites with the steepest gradients of membrane-potential propagated and initiated arrhythmias. Interestingly, more complex subcellular Ca2+-dynamics (multiple chaotic Ca2+-waves) occurred during arrhythmias. K201, a ryanodine receptor stabilizer, eliminated Ca2+-elevations and arrhythmias. Conclusions The results indicate that systolic and diastolic Ca2+-elevations emanate from sarcoplasmic reticulum Ca2+-release and systolic Ca2+-elevations are synchronous because of high cytosolic

  15. Potassium Channel Block and Novel Autoimmune-Associated Long QT Syndrome.

    PubMed

    Boutjdir, Mohamed; Lazzerini, Pietro Enea; Capecchi, Pier Leopoldo; Laghi-Pasini, Franco; El-Sherif, Nabil

    2016-06-01

    This article reviews advances in the pathogenesis of anti-SSA/Ro antibody-induced corrected QT (QTc) prolongation in patients with autoimmune diseases; particularly connective tissue disease (CTD). Evidence shows that anti-SSA/Ro antibody-positive patients with CTD show QTc prolongation and complex ventricular arrhythmias. Molecular and functional data provide evidence that the human ether-a-go-go-related gene potassium channel conducting the rapidly activating delayed rectifier potassium current is directly inhibited by anti-SSA/Ro antibodies, resulting in action potential duration prolongation leading to QT interval lengthening. Routine electrocardiogram screening in anti-SSA/Ro antibody-positive patients and counseling for patients with other QTc prolonging risk factors is recommended. PMID:27261828

  16. Buprenorphine as a safe alternative to methadone in a patient with acquired long QT syndrome: a case report.

    PubMed

    de Jong, I M; de Ruiter, G S

    2013-05-01

    A 52-year-old man with a medical history of intravenous drug abuse was admitted to our hospital with syncope due to torsades de pointes (TdP). Two days earlier, he had used methadone. The electrocardiogram showed a prolonged corrected QT interval (QTc) of 600 ms. Continuous telemetry observation showed multiple episodes of TdP. The patient was diagnosed with bradyarrhythmia-induced TdP with acquired long QT syndrome resulting from methadone use. The QTc normalised within 2 weeks after discontinuation of the methadone. In this case of a patient with opioid dependency, there is a reasonable risk of repeated methadone use. Therefore, implantable cardioverter defibrillator or pacemaker implantation is justified but risky because of possible infections when using intravenous drugs. Given the high mortality rates seen in untreated illicit opioid users, this patient needs an alternative pharmacological treatment. Buprenorphine is an opiate-receptor agonist associated with less QTc prolongation. The patient was referred to a rehab clinic and treated with an oral combination of buprenorphine and naloxone (Suboxone). During this therapy, his QTc remained normal. PMID:22020456

  17. Electro-mechanical dysfunction in long QT syndrome: Role for arrhythmogenic risk prediction and modulation by sex and sex hormones.

    PubMed

    Lang, C N; Menza, M; Jochem, S; Franke, G; Perez Feliz, S; Brunner, M; Koren, G; Zehender, M; Bugger, H; Jung, B A; Foell, D; Bode, C; Odening, K E

    2016-01-01

    Long QT syndrome (LQTS) is a congenital arrhythmogenic channelopathy characterized by impaired cardiac repolarization. Increasing evidence supports the notion that LQTS is not purely an "electrical" disease but rather an "electro-mechanical" disease with regionally heterogeneously impaired electrical and mechanical cardiac function. In the first part, this article reviews current knowledge on electro-mechanical (dys)function in LQTS, clinical consequences of the observed electro-mechanical dysfunction, and potential underlying mechanisms. Since several novel imaging techniques - Strain Echocardiography (SE) and Magnetic Resonance Tissue Phase Mapping (TPM) - are applied in clinical and experimental settings to assess the (regional) mechanical function, advantages of these non-invasive techniques and their feasibility in the clinical routine are particularly highlighted. The second part provides novel insights into sex differences and sex hormone effects on electro-mechanical cardiac function in a transgenic LQT2 rabbit model. Here we demonstrate that female LQT2 rabbits exhibit a prolonged time to diastolic peak - as marker for contraction duration and early relaxation - compared to males. Chronic estradiol-treatment enhances these differences in time to diastolic peak even more and additionally increases the risk for ventricular arrhythmia. Importantly, time to diastolic peak is particularly prolonged in rabbits exhibiting ventricular arrhythmia - regardless of hormone treatment - contrasting with a lack of differences in QT duration between symptomatic and asymptomatic LQT2 rabbits. This indicates the potential added value of the assessment of mechanical dysfunction in future risk stratification of LQTS patients. PMID:26718598

  18. Fetal ventricular tachycardia secondary to long QT syndrome treated with maternal intravenous magnesium: case report and review of the literature.

    PubMed

    Simpson, J M; Maxwell, D; Rosenthal, E; Gill, H

    2009-10-01

    Ventricular tachycardia is a very rare fetal arrhythmia accounting for fewer than 2% of fetal tachycardias. We describe a fetus presenting at 30 weeks' gestation with ventricular tachycardia at a rate of 220 beats per min and fetal hydrops. The tachycardia was unresponsive to flecainide but was controlled within 12 h by an intravenous infusion of magnesium to the mother. Despite rapid control of the arrhythmia the fetus developed severe periventricular leukomalacia before birth for which a poor neurological prognosis was given. The baby was delivered preterm at 32 weeks' gestation and died on the sixth day after birth. Long QT syndrome was identified postnatally on the electrocardiogram, and was confirmed by genetic testing which showed a mutation in the KCNH2 gene (p.T613M). PMID:19731233

  19. Case ascertainment and estimated incidence of drug-induced long-QT syndrome: study in Southwest France

    PubMed Central

    Molokhia, Mariam; Pathak, Atul; Lapeyre-Mestre, Maryse; Caturla, Laetitia; Montastruc, Jean Louis; McKeigue, Paul

    2008-01-01

    AIMS The aim of this study was to investigate the incidence and reporting rate of drug-induced long-QT syndrome (LQTS) in France [defined by evidence of torsades de pointes (TdP), QT prolongation and exposure to a relevant drug] and to assess feasibility of case collection for drug-induced LQTS. METHODS A retrospective population-based study was carried out in Southwest France in five institutions: three main hospitals, one private clinic and one cardiac emergency unit, searched from 1 January 1999 to 1 January 2005 (population coverage of 614 000). The study population consisted of 861 cases with International Classification of Diseases-10 diagnostic codes for ventricular tachycardia (I147.2), ventricular fibrillation (I149.0) and sudden cardiac death (I146.1) from hospital discharge summaries, supplemented by cases reported to national or regional pharmacovigilance systems, and voluntary reporting by physicians, validated according to internationally defined criteria for drug-induced LQTS. RESULTS Of 861 patients coded with arrhythmias or sudden cardiac death, there were 40 confirmed surviving acquired cases of drug-induced LQTS. We estimated that the incidence of those who survive to reach hospital drug-induced LQTS is approximately 10.9 per million annually in France (95% confidence interval 7.8, 14.8). CONCLUSIONS Many cases of drug-induced LQTS may not survive before they reach hospital, as the reporting rate for drug-induced LQTS identified through the cardiology records and also reported to pharmacovigilance systems for the Midi-Pyrenees area is 3/40 (7.5%). Using the methods outlined it is possible to assemble cases to study genetic susceptibility to drug-induced LQTS and adapt these methods more widely. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Drug-induced long-QT syndrome (LQTS) is a potentially fatal condition that has led to a number of postmarketing withdrawals in recent years. However, many cases may not survive long enough to reach hospital, and

  20. Calcium oscillations and T-wave lability precede ventricular arrhythmias in acquired long QT type 2

    PubMed Central

    Němec, Jan; Kim, Jong J.; Gabris, Beth; Salama, Guy

    2010-01-01

    Background Alternans of intracellular Ca2+ (Cai) underlies T-wave alternans, a predictor of cardiac arrhythmias. A related phenomenon, T-Wave Lability (TWL), precedes Torsade de Pointes (TdP) in patients and animal models with impaired repolarization. However, the role of Cai in TWL remains unexplored. Methods Action potentials (APs) and Cai transients, (CaTs) were mapped optically from paced Langendorff female rabbit hearts (n=8) at 1.2s cycle length, after AV node ablation. Hearts were perfused with normal Tyrode's solution then with dofetilide (0.5 μM) and reduced [K+] (2 mM) and [Mg2+] (0.5 mM) to elicit long QT type 2 (LQT2). Lability of EKG, voltage and Cai signals were evaluated during regular paced rhythm, before and after dofetilide perfusion. Results In LQT2, lability of Cai, voltage and EKG signals increased during paced rhythm, before the appearance of early afterdepolarizations (EADs). LQT2 resulted in AP prolongation and multiple (1-3) additional Cai upstrokes, while APs remained monophasic. When EADs appeared, Cai rose before voltage upstrokes at the origins of propagating EADs. Interventions (i.e. ryanodine and thapsigargin, n=3 or low [Ca]o and nifedipine, n=4) that suppressed Cai oscillations also abolished EADs. Conclusions In LQT2, Cai oscillations (CaiO) precede EADs by minutes, indicating that they result from spontaneous sarcoplasmic reticulum Ca2+ release rather than spontaneous ICaL reactivation. CaiO likely produce oscillations of Na/Ca exchange current, INCX. Depolarizing INCX during the AP plateau contributes to the generation of EADs by re-activating Ca2+-channels that have recovered from inactivation. TWL reflects CaTs and APs lability that occur before EADs and TdP. PMID:20599524

  1. Subject identification via ECG fiducial-based systems: influence of the type of QT interval correction.

    PubMed

    Gargiulo, Francesco; Fratini, Antonio; Sansone, Mario; Sansone, Carlo

    2015-10-01

    Electrocardiography (ECG) has been recently proposed as biometric trait for identification purposes. Intra-individual variations of ECG might affect identification performance. These variations are mainly due to Heart Rate Variability (HRV). In particular, HRV causes changes in the QT intervals along the ECG waveforms. This work is aimed at analysing the influence of seven QT interval correction methods (based on population models) on the performance of ECG-fiducial-based identification systems. In addition, we have also considered the influence of training set size, classifier, classifier ensemble as well as the number of consecutive heartbeats in a majority voting scheme. The ECG signals used in this study were collected from thirty-nine subjects within the Physionet open access database. Public domain software was used for fiducial points detection. Results suggested that QT correction is indeed required to improve the performance. However, there is no clear choice among the seven explored approaches for QT correction (identification rate between 0.97 and 0.99). MultiLayer Perceptron and Support Vector Machine seemed to have better generalization capabilities, in terms of classification performance, with respect to Decision Tree-based classifiers. No such strong influence of the training-set size and the number of consecutive heartbeats has been observed on the majority voting scheme. PMID:26143963

  2. Some legal, social, and ethical issues related to the genetic testing revolution, as exemplified in the long QT syndrome.

    PubMed

    Liebman, J

    2001-01-01

    Molecular Biology is revolutionizing medicine. There are a number of conditions, particularly exemplified by the long QT syndrome, where there is no structural abnormality but where a subset of patients is prone to sudden death. The issues of appropriate care are very complex, because there is tremendous overlap between patients with prolongation of the QT who remain asymptomatic and those with prolongation who are very symptomatic. Furthermore, even those who are prone to have one of the abnormal genes, may be asymptomatic. A large literature has developed, from both legal and ethical aspects, related to the fact that in genetic disease per se, not only is the person at risk, but so are many members of his or her family. A large literature has also developed as to which should be prime, the patient's privacy or the responsibility to make sure the entire family is knowledgeable and perhaps tested. At the present moment our care is based upon the fact that the precise identification of the gene is not yet available on a routine basis. This of course, may soon change. But we will still have difficult decisions to make. Obviously, we have a responsibility as physicians to be as precise as our discipline allows, but we have a responsibility to be flexible. Relief of anxiety, as an example, has to be a prime issue. This is certainly the case now when any information related to infants with potential sudden death is still incomplete. We must not approach the care of the patient in such a way that protection of the physician may interfere with appropriate care. The discussion necessarily includes a variety of aspects. PMID:11781954

  3. Re-evaluating the efficacy of β-adrenergic agonists and antagonists in long QT-3 syndrome through computational modelling

    PubMed Central

    Ahrens-Nicklas, Rebecca C.; Clancy, Colleen E.; Christini, David J.

    2009-01-01

    Aims Long QT syndrome (LQTS) is a heterogeneous collection of inherited cardiac ion channelopathies characterized by a prolonged electrocardiogram QT interval and increased risk of sudden cardiac death. β-Adrenergic blockers are the mainstay of treatment for LQTS. While their efficacy has been demonstrated in LQTS patients harbouring potassium channel mutations, studies of β-blockers in subtype 3 (LQT3), which is caused by sodium channel mutations, have produced ambiguous results. In this modelling study, we explore the effects of β-adrenergic drugs on the LQT3 phenotype. Methods and results In order to investigate the effects of β-adrenergic activity and to identify sources of ambiguity in earlier studies, we developed a computational model incorporating the effects of β-agonists and β-blockers into an LQT3 mutant guinea pig ventricular myocyte model. β-Activation suppressed two arrhythmogenic phenomena, transmural dispersion of repolarization and early after depolarizations, in a dose-dependent manner. However, the ability of β-activation to prevent cardiac conduction block was pacing-rate-dependent. Low-dose β-blockade by propranolol reversed the beneficial effects of β-activation, while high dose (which has off-target sodium channel effects) decreased arrhythmia susceptibility. Conclusion These results demonstrate that β-activation may be protective in LQT3 and help to reconcile seemingly conflicting results from different experimental models. They also highlight the need for well-controlled clinical investigations re-evaluating the use of β-blockers in LQT3 patients. PMID:19264765

  4. Long QT Syndrome Leading to Multiple Cardiac Arrests After Posaconazole Administration in an Immune-Compromised Patient with Sepsis: An Unusual Case Report

    PubMed Central

    Panos, George; Velissaris, Dimitrios; Karamouzos, Vasilios; Matzaroglou, Charalampos; Tyllianakis, Minos

    2016-01-01

    Patient: Female, 26 Final Diagnosis: Sepsis • drug induced long QT syndrome Symptoms: Cardiac arrest • cardiac arrhythmia • fever • Qt prolongation Medication: Posaconazole Clinical Procedure: Pacemaker insertion Specialty: Infectious Diseases Objective: Rare disease Background: We present the case of a septic patient with severe immunodeficiency, who developed QT interval prolongation followed by episodes of lethal cardiac arrhythmia. Cardiac events occurred after posaconazole administration, incriminating posaconazole use, alone or in combination with voriconazole, as the culpable agent. Case Report: A 26-year-old female patient underwent orthopedic surgery to remove ectopic calcifications in her left hip joint. On the first post-operative day she became septic due to a surgical wound infection. Despite being treated according to the therapeutic protocols for sepsis, no clinical improvement was noticed and further assessment revealed an underlying immunodeficiency. Considering the underlying immunodeficiency and to that point poor clinical response, an antifungal agent was added to the antibiotic regiment. Following discontinuation of multiple antifungal agents due to adverse effects, posaconazole was administered. Posaconazole oral intake was followed by episodes of bradycardia and QT interval prolongation. The patient suffered continuous incidents of cardiac arrest due to polymorphic ventricular tachycardia (torsades des pointes) that degenerated to lethal ventricular fibrillation. Posaconazole was immediately discontinued and a temporary pacemaker was installed. The patient finally recovered without any neurological deficit, and was discharged in a good clinical status. Conclusions: Close cardiac monitoring is recommended in cases where posaconazole administration is combined with coexisting risk factors, as they may lead to severe ECG abnormalities and cardiac arrhythmias such as long QT interval syndrome and torsades de pointes. Posaconazole

  5. Importance of QT interval in clinical practice.

    PubMed

    Ambhore, Anand; Teo, Swee-Guan; Bin Omar, Abdul Razakjr; Poh, Kian-Keong

    2014-12-01

    Long QT interval is an important finding that is often missed by electrocardiogram interpreters. Long QT syndrome (inherited and acquired) is a potentially lethal cardiac channelopathy that is frequently mistaken for epilepsy. We present a case of long QT syndrome with multiple cardiac arrests presenting as syncope and seizures. The long QTc interval was aggravated by hypomagnesaemia and drugs, including clarithromycin and levofloxacin. Multiple drugs can cause prolongation of the QT interval, and all physicians should bear this in mind when prescribing these drugs. PMID:25630313

  6. Isogenic human pluripotent stem cell pairs reveal the role of a KCNH2 mutation in long-QT syndrome

    PubMed Central

    Bellin, Milena; Casini, Simona; Davis, Richard P; D'Aniello, Cristina; Haas, Jessica; Ward-van Oostwaard, Dorien; Tertoolen, Leon G J; Jung, Christian B; Elliott, David A; Welling, Andrea; Laugwitz, Karl-Ludwig; Moretti, Alessandra; Mummery, Christine L

    2013-01-01

    Patient-specific induced pluripotent stem cells (iPSCs) will assist research on genetic cardiac maladies if the disease phenotype is recapitulated in vitro. However, genetic background variations may confound disease traits, especially for disorders with incomplete penetrance, such as long-QT syndromes (LQTS). To study the LQT2-associated c.A2987T (N996I) KCNH2 mutation under genetically defined conditions, we derived iPSCs from a patient carrying this mutation and corrected it. Furthermore, we introduced the same point mutation in human embryonic stem cells (hESCs), generating two genetically distinct isogenic pairs of LQTS and control lines. Correction of the mutation normalized the current (IKr) conducted by the HERG channel and the action potential (AP) duration in iPSC-derived cardiomyocytes (CMs). Introduction of the same mutation reduced IKr and prolonged the AP duration in hESC-derived CMs. Further characterization of N996I-HERG pathogenesis revealed a trafficking defect. Our results demonstrated that the c.A2987T KCNH2 mutation is the primary cause of the LQTS phenotype. Precise genetic modification of pluripotent stem cells provided a physiologically and functionally relevant human cellular context to reveal the pathogenic mechanism underlying this specific disease phenotype. PMID:24213244

  7. Identification of a KCNQ1 Polymorphism Acting as a Protective Modifier against Arrhythmic Risk in Long QT Syndrome

    PubMed Central

    Duchatelet, Sabine; Crotti, Lia; Peat, Rachel A.; Denjoy, Isabelle; Itoh, Hideki; Berthet, Myriam; Ohno, Seiko; Fressart, Véronique; Monti, Maria Cristina; Crocamo, Cristina; Pedrazzini, Matteo; Dagradi, Federica; Vicentini, Alessandro; Klug, Didier; Brink, Paul A.; Goosen, Althea; Swan, Heikki; Toivonen, Lauri; Lahtinen, Annukka M.; Kontula, Kimmo; Shimizu, Wataru; Horie, Minoru; George, Alfred L.; Trégouët, David-Alexandre; Guicheney, Pascale; Schwartz, Peter J.

    2013-01-01

    Background Long-QT Syndrome (LQTS) is characterized by such striking clinical heterogeneity, that even among family members carrying the same mutation, clinical outcome can range between sudden death to no symptoms. We investigated the role of genetic variants as modifiers of risk for cardiac events in LQTS patients. Methods and Results In a matched case-control study including 112 LQTS patient duos from France, Italy and Japan, 25 polymorphisms were genotyped based on either their association with QTc duration in healthy populations or on their role in adrenergic responses. The duos were composed of two relatives harboring the same heterozygous KCNQ1 or KCNH2 mutation; one with cardiac events and one asymptomatic and untreated. The findings were then validated in two independent founder populations totaling 174 symptomatic and 162 asymptomatic LQTS patients, and a meta-analysis was performed. The KCNQ1 rs2074238 T-allele was significantly associated with a decreased risk of symptoms 0.34 [0.19 – 0.61] (p<0.0002) and with shorter QTc (p<0.0001) in the combined discovery and replication cohorts. Conclusions We provide evidence that the KCNQ1 rs2074238 polymorphism is an independent risk modifier with the minor T-allele conferring protection against cardiac events in LQTS patients. This finding is a step toward a novel approach for risk stratification in LQTS patients. PMID:23856471

  8. Genetic variants for long QT syndrome among infants and children from a statewide newborn hearing screening program cohort

    PubMed Central

    Chang, Ruey-Kang R.; Lan, Yueh-Tze; Silka, Michael J.; Morrow, Hallie; Kwong, Alan; Smith-Lang, Janna; Wallerstein, Robert; Lin, Henry J.

    2014-01-01

    Objectives Autosomal recessive long QT syndrome (LQTS), or Jervell and Lange-Nielsen syndrome (JLNS), can be associated with sensorineural hearing loss (SNHL). We aimed to explore newborn hearing screening combined with ECGs for early JLNS detection. Study design We conducted California statewide, prospective ECG screening of children ≤6 years of age with unilateral or bilateral, severe or profound, sensorineural or mixed hearing loss. Families were identified through newborn hearing screening and interviewed about medical and family histories. Twelve-lead ECGs were obtained. Those with positive histories or QTc intervals ≥450 ms had repeat ECGs. DNA sequencing of 12 LQTS genes was performed for repeat QTc intervals ≥450 ms. Results We screened 707 subjects by ECGs (number screened/number of responses = 91%; number of responses/number of families who were mailed invitations = 54%). Of these, 73 had repeat ECGs, and 19 underwent gene testing. No subject had homozygous or compound heterozygous LQTS mutations, as in JLNS. However, 3 individuals (with QTc intervals of 472, 457, and 456 ms, respectively) were heterozygous for variants that cause truncation or missplicing: 2 in KCNQ1 (c.1343dupC or p.Glu449Argfs*14; c.1590+1G>A or p.Glu530sp) and 1 in SCN5A (c.5872C>T or p.Arg1958*). Conclusions In contrast to reports of JLNS in up to 4% of children with SNHL, we found no examples of JLNS. Because the 3 variants identified were unrelated to hearing, they likely represent the prevalence of potential LQTS mutations in the general population. Further studies are needed to define consequences of such mutations and assess the overall prevalence. PMID:24388587

  9. Phenotype of Children with QT Prolongation Identified Using an Institution-Wide QT Alert System.

    PubMed

    Anderson, Heather N; Bos, J Martijn; Haugaa, Kristina H; Morlan, Bruce W; Tarrell, Robert F; Caraballo, Pedro J; Ackerman, Michael J

    2015-10-01

    QT prolongation is an independent risk factor for cardiovascular mortality in adults. However, there is little information available on pediatric patients with QT prolongation and their outcomes. Herein, we evaluated the prevalence of QT prolongation in pediatric patients identified by an institution-wide QT alert system, and the spectrum of their phenotype. Patients with documented QT prolongation on an ECG obtained between November 2010 and June 2011 were included. There were 1303 pediatric ECGs, and 68 children had electrographically isolated QT prolongation. Comprehensive review of medical records was performed with particular attention to QT-prolonging clinical, laboratory, and medication data, which were summarized into a pro-QTc score. Overall, 68 (5 %) pediatric patients had isolated QT prolongation. The mean age of this pediatric cohort was 9 ± 6 years, and the average QTc was 494 ± 42 ms. All children had 1 or more QT-prolonging risk factor(s), most commonly QT-prolonging medications. One patient was identified with congenital long QT syndrome (LQTS), which was not previously diagnosed. In one-year follow-up, only one pediatric death (non-cardiac) occurred (1.5 %). Potentially QT-offending/pro-arrhythmic medications were changed in 80 % of pediatric patients after the physician received the QT alert. Children with QT prolongation had very low mortality and minimal polypharmacy. Still, medications and other modifiable conditions were the most common causes of QT prolongation. Children with a prolonged QTc should be evaluated for modifiable QT-prolonging factors. However, if no risk factors are present or the QTc does not attenuate after risk factor modification/removal, the child should be evaluated for congenital LQTS. PMID:25845942

  10. [Excessive energy drink consumption caused marked QT prolongation. Case report].

    PubMed

    Tomcsányi, János; Jávor, Kinga

    2015-10-25

    The authors report a case of a 22-year-old man with atypical chest pain after consumption of six energy drinks (1.5 liter containing 470 mg coffein) with vodka. On admission ECG showed marked QT/QTc prolongation (QT/QTc, 520/580 msec). Next day the QT/QTc returned to fully normal (QT/QTc, 360/430 msec). It was assumed that the patient had a silent long QT syndrome and that high dose of highly caffeinated energy drink triggered the (paradoxical) prolonged QT/QTc. The authors conclude that excessive energy drink intake with alcohol or during physical exercise should be avoided. PMID:26477618

  11. The link between abnormal calcium handling and electrical instability in acquired long QT syndrome - Does calcium precipitate arrhythmic storms?

    PubMed

    Němec, Jan; Kim, Jong J; Salama, Guy

    2016-01-01

    Release of Ca(2+) ions from sarcoplasmic reticulum (SR) into myocyte cytoplasm and their binding to troponin C is the final signal form myocardial contraction. Synchronous contraction of ventricular myocytes is necessary for efficient cardiac pumping function. This requires both shuttling of Ca(2+) between SR and cytoplasm in individual myocytes, and organ-level synchronization of this process by means of electrical coupling among ventricular myocytes. Abnormal Ca(2+) release from SR causes arrhythmias in the setting of CPVT (catecholaminergic polymorphic ventricular tachycardia) and digoxin toxicity. Recent optical mapping data indicate that abnormal Ca(2+) handling causes arrhythmias in models of both repolarization impairment and profound bradycardia. The mechanisms involve dynamic spatial heterogeneity of myocardial Ca(2+) handling preceding arrhythmia onset, cell-synchronous systolic secondary Ca(2+) elevation (SSCE), as well as more complex abnormalities of intracellular Ca(2+) handling detected by subcellular optical mapping in Langendorff-perfused hearts. The regional heterogeneities in Ca(2+) handling cause action potential (AP) heterogeneities through sodium-calcium exchange (NCX) activation and eventually overwhelm electrical coupling of the tissue. Divergent Ca(2+) dynamics among different myocardial regions leads to temporal instability of AP duration and - on the patient level - in T wave lability. Although T-wave alternans has been linked to cardiac arrhythmias, non-alternans lability is observed in pre-clinical models of the long QT syndrome (LQTS) and CPVT, and in LQTS patients. Analysis of T wave lability may provide a real-time window on the abnormal Ca(2+) dynamics causing specific arrhythmias such as Torsade de Pointes (TdP). PMID:26631594

  12. Asymmetry of parental origin in long QT syndrome: preferential maternal transmission of KCNQ1 variants linked to channel dysfunction.

    PubMed

    Itoh, Hideki; Berthet, Myriam; Fressart, Véronique; Denjoy, Isabelle; Maugenre, Svetlana; Klug, Didier; Mizusawa, Yuka; Makiyama, Takeru; Hofman, Nynke; Stallmeyer, Birgit; Zumhagen, Sven; Shimizu, Wataru; Wilde, Arthur A M; Schulze-Bahr, Eric; Horie, Minoru; Tezenas du Montcel, Sophie; Guicheney, Pascale

    2016-08-01

    Transmission distortion of disease-causing alleles in long QT syndrome (LQTS) has been reported, suggesting a potential role of KCNQ1 and KCNH2 in reproduction. This study sought to investigate parental transmission in LQTS families according to ethnicity, gene loci (LQT1-3: KCNQ1, KCNH2, and SCN5A) or severity of channel dysfunction. We studied 3782 genotyped members from 679 European and Japanese LQTS families (2748 carriers). We determined grandparental and parental origins of variant alleles in 1903 children and 624 grandchildren, and the grandparental origin of normal alleles in healthy children from 44 three-generation control families. LQTS alleles were more of maternal than paternal origin (61 vs 39%, P<0.001). The ratio of maternally transmitted alleles in LQT1 (66%) was higher than in LQT2 (56%, P<0.001) and LQT3 (57%, P=0.03). Unlike the Mendelian distribution of grandparental alleles seen in control families, variant grandparental LQT1 and LQT2 alleles in grandchildren showed an excess of maternally transmitted grandmother alleles. For LQT1, maternal transmission differs according to the variant level of dysfunction with 68% of maternal transmission for dominant negative or unknown functional consequence variants vs 58% for non-dominant negative and variants leading to haploinsufficiency, P<0.01; however, for LQT2 or LQT3 this association was not significant. An excess of disease-causing alleles of maternal origin, most pronounced in LQT1, was consistently found across ethnic groups. This observation does not seem to be linked to an imbalance in transmission of the LQTS subtype-specific grandparental allele, but to the potential degree of potassium channel dysfunction. PMID:26669661

  13. Improved Clinical Risk Stratification in Patients with Long QT Syndrome? Novel Insights from Multi-Channel ECGs

    PubMed Central

    Samol, Alexander; Gönes, Mehmet; Zumhagen, Sven; Bruns, Hans-Jürgen; Paul, Matthias; Vahlhaus, Christian; Waltenberger, Johannes; Schulze-Bahr, Eric; Eckardt, Lars; Mönnig, Gerold

    2016-01-01

    Background We investigated whether multichannel ECG-recordings are useful to risk-stratify patients with congenital long-QT syndrome (LQTS) for risk of sudden cardiac death under optimized medical treatment. Methods In 34 LQTS-patients (11 male; age 31±13 years, QTc 478±51ms; LQT1 n = 8, LQT2 n = 15) we performed a standard 12-channel ECG and a 120-channel body surface potential mapping. The occurrence of clinical events (CE; syncope, torsade de pointes (TdP), sudden cardiac arrest (SCA)) was documented and correlated with different ECG-parameters in all lead positions. Results Seven patients developed TdP, four survived SCA and 12 experienced syncope. 12/34 had at least one CE. CE was associated with a longer QTc-interval (519±43ms vs. 458±42ms; p = 0.001), a lower T-wave integral (TWI) on the left upper chest (-1.2±74.4mV*ms vs. 63.0±29.7mV*ms; p = 0.001), a lower range of T-wave amplitude (TWA) in the region of chest lead V8 (0.10±0.08mV vs. 0.18±0.07mV; p = 0.008) and a longer T-peak-T-end time (TpTe) in lead V1 (98±23ms vs. 78±26ms; p = 0.04). Receiver-operating-characteristic (ROC) analyses revealed a sensitivity of 96% and a specificity of 75% (area under curve (AUC) 0.89±0.06, p = 0.001) at a cut-off value of 26.8mV*ms for prediction of CE by TWI, a sensitivity of 86% and a specificity of 83% at a cut-off value of 0.11mV (AUC 0.83±0.09, p = 0.002) for prediction of CE by TWA and a sensitivity of 83% and a specificity of 73% at a cut-off value of 87ms (AUC 0.80±0.07, p = 0.005) for prediction of CE by TpTe. Conclusions Occurrence of CE in LQTS-patients seems to be associated with a prolonged, low-amplitude T-wave. PMID:27379800

  14. Role of Sarcoplasmic Reticulum Calcium in Development of Secondary Calcium Rise and Early Afterdepolarizations in Long QT Syndrome Rabbit Model

    PubMed Central

    Chang, Po-Cheng; Wo, Hung-Ta; Lee, Hui-Ling; Lin, Shien-Fong; Wen, Ming-Shien; Chu, Yen; Yeh, San-Jou; Chou, Chung-Chuan

    2015-01-01

    Background L-type calcium current reactivation plays an important role in development of early afterdepolarizations (EADs) and torsades de pointes (TdP). Secondary intracellular calcium (Cai) rise is associated with initiation of EADs. Objective To test whether inhibition of sarcoplasmic reticulum (SR) Ca2+ cycling suppresses secondary Cai rise and genesis of EADs. Methods Langendorff perfusion and dual voltage and Cai optical mapping were conducted in 10 rabbit hearts. Atrioventricular block (AVB) was created by radiofrequency ablation. After baseline studies, E4031, SR Ca2+ cycling inhibitors (ryanodine plus thapsigargin) and nifedipine were then administrated subsequently, and the protocols were repeated. Results At baseline, there was no spontaneous or pacing-induced TdP. After E4031 administration, action potential duration (APD) was significantly prolonged and the amplitude of secondary Cai rise was enhanced, and 7 (70%) rabbits developed spontaneous or pacing-induced TdP. In the presence of ryanodine plus thapsigargin, TdP inducibility was significantly reduced (2 hearts, 20%, p = 0.03). Although APD was significantly prolonged (from 298 ± 30 ms to 457 ± 75 ms at pacing cycle length of 1000 m, p = 0.007) by ryanodine plus thapsigargin, the secondary Cai rise was suppressed (from 8.8 ± 2.6% to 1.2 ± 0.9%, p = 0.02). Nifedipine inhibited TdP inducibility in all rabbit hearts. Conclusion In this AVB and long QT rabbit model, inhibition of SR Ca2+ cycyling reduces the inducibility of TdP. The mechanism might be suppression of secondary Cai rise and genesis of EADs. PMID:25875599

  15. Prolonged Tp-e Interval, Tp-e/QT Ratio and Tp-e/QTc Ratio in Patients with Type 2 Diabetes Mellitus

    PubMed Central

    Kiliçaslan, Fethi; Alis, Metin; Yiginer, Omer; Uzun, Mehmet

    2016-01-01

    Background Type 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. Methods Forty-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. Results Mean 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. Conclusion Tp-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. PMID:26676332

  16. Drug-induced long QT syndrome: hERG K+ channel block and disruption of protein trafficking by fluoxetine and norfluoxetine

    PubMed Central

    Rajamani, S; Eckhardt, L L; Valdivia, C R; Klemens, C A; Gillman, B M; Anderson, C L; Holzem, K M; Delisle, B P; Anson, B D; Makielski, J C; January, C T

    2006-01-01

    Background and purpose: Fluoxetine (Prozac®) is a widely prescribed drug in adults and children, and it has an active metabolite, norfluoxetine, with a prolonged elimination time. Although uncommon, Prozac causes QT interval prolongation and arrhythmias; a patient who took an overdose of Prozac exhibited a prolonged QT interval (QTc 625 msec). We looked for possible mechanisms underlying this clinical finding by analysing the effects of fluoxetine and norfluoxetine on ion channels in vitro. Experimental approach: We studied the effects of fluoxetine and norfluoxetine on the electrophysiology and cellular trafficking of hERG K+ and SCN5A Na+ channels heterologously expressed in HEK293 cells. Key results: Voltage clamp analyses employing square pulse or ventricular action potential waveform protocols showed that fluoxetine and norfluoxetine caused direct, concentration-dependent, block of hERG current (IhERG). Biochemical studies showed that both compounds also caused concentration-dependent reductions in the trafficking of hERG channel protein into the cell surface membrane. Fluoxetine had no effect on SCN5A channel or HEK293 cell endogenous current. Mutations in the hERG channel drug binding domain reduced fluoxetine block of IhERG but did not alter fluoxetine's effect on hERG channel protein trafficking. Conclusions and implications: Our findings show that both fluoxetine and norfluoxetine at similar concentrations selectively reduce IhERG by two mechanisms, (1) direct channel block, and (2) indirectly by disrupting channel protein trafficking. These two effects are not mediated by a single drug binding site. Our findings add complexity to understanding the mechanisms that cause drug-induced long QT syndrome. PMID:16967046

  17. Long QT Syndrome Leading to Multiple Cardiac Arrests After Posaconazole Administration in an Immune-Compromised Patient with Sepsis: An Unusual Case Report.

    PubMed

    Panos, George; Velissaris, Dimitrios; Karamouzos, Vasilios; Matzaroglou, Charalampos; Tylianakis, Minos

    2016-01-01

    BACKGROUND We present the case of a septic patient with severe immunodeficiency, who developed QT interval prolongation followed by episodes of lethal cardiac arrhythmia. Cardiac events occurred after posaconazole administration, incriminating posaconazole use, alone or in combination with voriconazole, as the culpable agent. CASE REPORT A 26-year-old female patient underwent orthopedic surgery to remove ectopic calcifications in her left hip joint. On the first post-operative day she became septic due to a surgical wound infection. Despite being treated according to the therapeutic protocols for sepsis, no clinical improvement was noticed and further assessment revealed an underlying immunodeficiency. Considering the underlying immunodeficiency and to that point poor clinical response, an antifungal agent was added to the antibiotic regiment. Following discontinuation of multiple antifungal agents due to adverse effects, posaconazole was administered. Posaconazole oral intake was followed by episodes of bradycardia and QT interval prolongation. The patient suffered continuous incidents of cardiac arrest due to polymorphic ventricular tachycardia (torsades des pointes) that degenerated to lethal ventricular fibrillation. Posaconazole was immediately discontinued and a temporary pacemaker was installed. The patient finally recovered without any neurological deficit, and was discharged in a good clinical status. CONCLUSIONS Close cardiac monitoring is recommended in cases where posaconazole administration is combined with coexisting risk factors, as they may lead to severe ECG abnormalities and cardiac arrhythmias such as long QT interval syndrome and torsades de pointes. Posaconazole interactions with medications metabolized via the CYP3A4 pathway should be considered an additional risk factor for lethal cardiac incidents. PMID:27125217

  18. Long QT Syndrome

    MedlinePlus

    ... distinct electrical waves: P, Q, R, S, and T. EKG The image shows the standard setup for an EKG. In figure A, a normal heart rhythm recording ... B, a patient lies in a bed with EKG electrodes attached to his chest, upper arms, and ...

  19. Genetics Home Reference: otopalatodigital syndrome type 2

    MedlinePlus

    ... Conditions otopalatodigital syndrome type 2 otopalatodigital syndrome type 2 Enable Javascript to view the expand/collapse boxes. ... Open All Close All Description Otopalatodigital syndrome type 2 is a disorder involving abnormalities in skeletal development ...

  20. Genetics Home Reference: otopalatodigital syndrome type 1

    MedlinePlus

    ... Conditions otopalatodigital syndrome type 1 otopalatodigital syndrome type 1 Enable Javascript to view the expand/collapse boxes. ... Open All Close All Description Otopalatodigital syndrome type 1 is a disorder primarily involving abnormalities in skeletal ...

  1. Drug- and non-drug-associated QT interval prolongation

    PubMed Central

    van Noord, Charlotte; Eijgelsheim, Mark; Stricker, Bruno H Ch

    2010-01-01

    Sudden cardiac death is among the most common causes of cardiovascular death in developed countries. The majority of sudden cardiac deaths are caused by acute ventricular arrhythmia following repolarization disturbances. An important risk factor for repolarization disturbances is use of QT prolonging drugs, probably partly explained by gene–drug interactions. In this review, we will summarize QT interval physiology, known risk factors for QT prolongation, including drugs and the contribution of pharmacogenetics. The long QT syndrome can be congenital or acquired. The congenital long QT syndrome is caused by mutations in ion channel subunits or regulatory protein coding genes and is a rare monogenic disorder with a mendelian pattern of inheritance. Apart from that, several common genetic variants that are associated with QT interval duration have been identified. Acquired QT prolongation is more prevalent than the congenital form. Several risk factors have been identified with use of QT prolonging drugs as the most frequent cause. Most drugs that prolong the QT interval act by blocking hERG-encoded potassium channels, although some drugs mainly modify sodium channels. Both pharmacodynamic as well as pharmacokinetic mechanisms may be responsible for QT prolongation. Pharmacokinetic interactions often involve drugs that are metabolized by cytochrome P450 enzymes. Pharmacodynamic gene–drug interactions are due to genetic variants that potentiate the QT prolonging effect of drugs. QT prolongation, often due to use of QT prolonging drugs, is a major public health issue. Recently, common genetic variants associated with QT prolongation have been identified. Few pharmacogenetic studies have been performed to establish the genetic background of acquired QT prolongation but additional studies in this newly developing field are warranted. PMID:20642543

  2. A Framework of Knowledge Integration and Discovery for Supporting Pharmacogenomics Target Predication of Adverse Drug Events: A Case Study of Drug-Induced Long QT Syndrome

    PubMed Central

    Jiang, Guoqian; Wang, Chen; Zhu, Qian; Chute, Christopher G.

    2013-01-01

    Knowledge-driven text mining is becoming an important research area for identifying pharmacogenomics target genes. However, few of such studies have been focused on the pharmacogenomics targets of adverse drug events (ADEs). The objective of the present study is to build a framework of knowledge integration and discovery that aims to support pharmacogenomics target predication of ADEs. We integrate a semantically annotated literature corpus Semantic MEDLINE with a semantically coded ADE knowledgebase known as ADEpedia using a semantic web based framework. We developed a knowledge discovery approach combining a network analysis of a protein-protein interaction (PPI) network and a gene functional classification approach. We performed a case study of drug-induced long QT syndrome for demonstrating the usefulness of the framework in predicting potential pharmacogenomics targets of ADEs. PMID:24303306

  3. Mild Beckwith-Wiedemann and severe long-QT syndrome due to deletion of the imprinting center 2 on chromosome 11p.

    PubMed

    Gurrieri, Fiorella; Zollino, Marcella; Oliva, Antonio; Pascali, Vincenzo; Orteschi, Daniela; Pietrobono, Roberta; Camporeale, Antonella; Coll Vidal, Monica; Partemi, Sara; Brugada, Ramon; Bellocci, Fulvio; Neri, Giovanni

    2013-09-01

    We report on a young woman admitted to our Cardiology Unit because of an episode of cardiac arrest related to a long-QT syndrome (LQTS). This manifestation was part of a broader phenotype, which was recognized as a mild form of Beckwith-Wiedemann syndrome (BWS). Molecular analysis confirmed the diagnosis of BWS owing to a maternally inherited deletion of the centromeric imprinting center, or ICR2, an extremely rare genetic mechanism in BWS. The deletion interval (198 kb) also included exons 11-16 of the KCNQ1 gene, known to be responsible for LQTS at locus LQT1. No concomitant mutations were found in any other of the known LQT genes. The proposita's mother carries the same deletion in her paternal chromosome and shows manifestations of the Silver-Russell syndrome (SRS). This report describes the smallest BWS-causing ICR2 deletion and provides the first evidence that a paternal deletion of ICR2 leads to a SRS-like phenotype. In addition, our observation strongly suggests that in cases of LQTS due to mutation of the KCNQ1 gene (LQT1), an accurate clinical genetic evaluation should be done in order to program the most appropriate genetic tests. PMID:23511928

  4. Intravenous Administration of Apomorphine Does NOT Induce Long QT Syndrome: Experimental Evidence from In Vivo Canine Models.

    PubMed

    Watanabe, Yudai; Nakamura, Yuji; Cao, Xin; Ohara, Hiroshi; Yamazaki, Yukiko; Murayama, Norie; Sugiyama, Yosuke; Izumi-Nakaseko, Hiroko; Ando, Kentaro; Yamazaki, Hiroshi; Sugiyama, Atsushi

    2015-06-01

    Apomorphine is a non-selective dopamine D1/D2 receptor agonist, which has been used for patients with Parkinson's disease and reported to induce QT interval prolongation and cardiac arrest. To clarify their causal link, we assessed the cardiovascular and pharmacokinetic profile of apomorphine with the halothane-anaesthetized canine model (n = 4), whereas pro-arrhythmic potential of apomorphine was analysed with the chronic atrioventricular block canine model (n = 4). In the halothane-anaesthetized model, 0.01 mg/kg, i.v. of apomorphine hydrochloride over 10 min., providing about 10 times of its therapeutic concentration, increased the heart rate and ventricular contraction; 0.1 mg/kg over 10 min., providing about 100 times of the therapeutic, prolonged the ventricular effective refractory period; and 1 mg/kg over 10 min., providing about 1000 times of the therapeutic, decreased the ventricular contraction, mean blood pressure and cardiac output together with the intraventricular conduction delay and prolongation of the effective refractory period, whereas the left ventricular end-diastolic pressure, atrioventricular nodal conduction or ventricular repolarization were hardly affected. Meanwhile, in the atrioventricular block model, 1 mg/kg, i.v. of apomorphine hydrochloride over 10 min. neither prolonged the QT interval nor induced torsade de pointes. These results suggest that apomorphine may possess a wide margin of cardiovascular safety contrary to our expectations. PMID:25370785

  5. Measurement and interpretation of electrocardiographic QT intervals in murine hearts.

    PubMed

    Zhang, Yanmin; Wu, JingJing; King, James H; Huang, Christopher L-H; Fraser, James A

    2014-06-01

    Alterations in ECG QT intervals correlate with the risk of potentially fatal arrhythmias, for which transgenic murine hearts are becoming increasingly useful experimental models. However, QT intervals are poorly defined in murine ECGs. As a consequence, several different techniques have been used to measure murine QT intervals. The present work develops a consistent measure of the murine QT interval that correlates with changes in the duration of ventricular myocyte action potentials (APs). Volume-conducted ECGs were compared with simultaneously recorded APs, obtained using floating intracellular microelectrodes in Langendorff-perfused mouse hearts. QT intervals were measured from the onset of the QRS complex. The interval, Q-APR90, measured to the time at 90% AP recovery, was compared with two measures of the QT interval. QT1 was measured to the recovery of the ECG trace to the isoelectric baseline for entirely positive T-waves or to the trough of any negative T-wave undershoot. QT2-used extensively in previous studies-was measured to the return of any ECG trough to the isoelectric baseline. QT1, but not QT2, closely correlated with changes in Q-APR90. These findings were confirmed over a range of pacing rates, in low K(+) concentration solutions, and in Scn5a+/ΔKPQ hearts used to model human long QT syndrome. Application of this method in whole anesthetized mice similarly demonstrated a prolonged corrected QT (QTc) in Scn5a+/ΔKPQ hearts. We therefore describe a robust method for the determination of QT and QTc intervals that correlate with the duration of ventricular myocyte APs in murine hearts. PMID:24705556

  6. Electrocardiogram in Andersen-Tawil Syndrome. New Electrocardiographic Criteria for Diagnosis of Type-1 Andersen-Tawil Syndrome

    PubMed Central

    Kukla, Piotr; Biernacka, Elżbieta K; Baranchuk, Adrian; Jastrzębski, Marek; Jagodzińska, Michalina

    2014-01-01

    Andersen - Tawil syndrome (ATS) is an autosomal - dominant or sporadic disorder characterized by ventricular arrhythmias, periodic paralysis, and distinctive facial and skeletal dysmorphism. Mutations in KCNJ2, which encodes the α-subunit of the potassium channel Kir2.1, were identified in patients with ATS. This genotype has been designated as type-1 ATS (ATS1). KCNJ2 mutations are detectable in up to 60 % of patients with ATS. Cardiac manifestations of ATS include frequent premature ventricular contractions (PVC), Q-U interval prolongation, prominent U-waves, and a special type of polymorphic ventricular tachycardia (PMVT) called bidirectional ventricular tachycardia (BiVT). The presence of frequent PVCs at rest are helpful in distinguishing ATS from typical catecholaminergic polymorphic ventricular tachycardia (CPVT). In typical CPVT, rapid PMVT and BiVT usually manifest during or after exercising. Additionally, CPVT or torsade de pointes in LQTS are faster, very symptomatic causing syncope or often deteriorate into VF resulting in sudden cardiac death. PVCs at rest are quite frequent in ATS1 patients, however, in LQTS patients, PVCs and asymptomatic VT are uncommon which also contributes to differentiating them. The article describes the new electrocardiographic criteria proposed for diagnosis of type-1 Andersen-Tawil syndrome. A differential diagnosis between Andersen-Tawil syndrome, the catecholamine polymorphic ventiruclar tachycardia and long QT syndrome is depicted. Special attention is paid on the repolarization abnormalities, QT interval and the pathologic U wave. In this article, we aim to provide five new electrocardiographic clues for the diagnosis of ATS1. PMID:24827800

  7. Nicorandil normalizes prolonged repolarisation in the first transgenic rabbit model with Long-QT syndrome 1 both in vitro and in vivo

    PubMed Central

    Biermann, Jürgen; Wu, Kezhong; Odening, Katja E.; Asbach, Stefan; Koren, Gideon; Peng, Xuwen; Zehender, Manfred; Bode, Christoph; Brunner, Michael

    2010-01-01

    Transgenic rabbits expressing loss-of-function pore mutants of the human gene KCNQ1 (KvLQT1-Y315S) have a Long QT-Syndrome 1 (LQT1) phenotype. We evaluated for the first time the effect of nicorandil, an opener of ATP-sensitive potassium channels, and of isoproterenol on cardiac action potential duration and heart rate dependent dispersion of repolarisation in transgenic LQT1 rabbits. In vivo LQT1 and littermate control were subjected to transvenous electrophysiological studies; in vitro monophasic action potentials were recorded from explanted Langendorff-perfused hearts. In vivo ventricular effective refractory periods (VERP) at the right ventricular base were significantly prolonged in LQT1 as compared to littermate control, resulting in a more pronounced VERP dispersion in LQT1. This difference in VERP dispersion between LQT1 and littermate control disappeared after infusion of nicorandil. In vitro, mean action potential durations (APD75 and APD90) of LQT1 were significantly prolonged compared to littermate control at baseline. Nicorandil decreased APD75 and APD90 in LQT1 and littermate control at all stimulated heart rates. After adding nicorandil, the APD90 at all hearts rates and the APD75 at high heart rates were no longer different. Dispersion of repolarisation (ΔAPD75 and ΔAPD90) was heart rate dependently decreased after nicorandil at all tested stimulation cycle lengths only in LQT1. We demonstrated phenotypic differences of LQT1 and littermate control in vivo and in vitro. Nicorandil 20 μmol/l improved repolarisation abnormalities and heterogeneities in transgenic LQT1 rabbits. PMID:20959120

  8. Electrocardiographic screening for hypertrophic cardiomyopathy and long QT syndrome: the drivers of cost-effectiveness for the prevention of sudden cardiac death.

    PubMed

    Anderson, Brett R; McElligott, Sean; Polsky, Daniel; Vetter, Victoria L

    2014-02-01

    It is universally recognized that the prevention of sudden cardiac death (SCD) in youth is an important public health initiative. The best approach remains uncertain. Many European and Asian countries support the use of electrocardiograms (ECGs). In the United States, this is highly controversial. Many debate its cost-effectiveness. We designed a comprehensive economic model of two of the most prevalent causes of SCD identifiable by ECG, hypertrophic cardiomyopathy (HCM) and long QT syndrome (LQTS), to determine the drivers of uncertainty in the estimate of cost-effectiveness. We compared the cost-effectiveness of screening with history and physical examination (H&P) plus ECG to the current United States standard, H&P alone, for the detection and treatment of HCM and LQTS. We used a Markov model on a theoretical cohort of healthy 12-year-olds over a 70-year time horizon from a societal perspective, employing extensive univariable and probabilistic sensitivity analyses, to determine drivers of costs and effectiveness. The incremental cost-effectiveness of adding ECGs to H&Ps was $41,400/life-year saved. The model was highly sensitive to the effect of identification and treatment of previously undiagnosed individuals with HCM; however, it was insensitive to many variables commonly assumed to be significant, including the costs of ECGs, echocardiograms, and genetic testing, as well as the sensitivity and specificity of ECGs. No LQTS-related parameters were significant. This study suggests that the key to determining the cost-effectiveness of ECG screening in the United States lies in developing a better understanding of disease progression in the previously undiagnosed HCM population. PMID:24005901

  9. Atrial and ventricular lead insulation defects with resulting inappropriate shocks and end-of-life of the ICD pulse generator in a young bodybuilder with congenital long-QT-syndrome.

    PubMed

    Diez, Claudius; Hofmann, Hans-Stefan; Börgermann, Jochen

    2009-01-01

    We report on a 19-year-old male with a congenital Long-QT syndrome who was admitted to our hospital because of insulation defects of both atrial and ventricular ICD leads resulting in inappropriate delivered shocks and a non-responding pulse generator during telemetrical evaluation. The insulation defects led to multiple arc marks within the ICD pocket and there was a short circuit between denuded leads and the electrically active pulse generator. The high current flow generated sufficient heat to damage several circuits of the generator. A new ICD system was implanted successfully and the postoperative course has been remained uneventful for almost 6 years. PMID:18776999

  10. Mucopolysaccharidosis type II, Hunter's syndrome.

    PubMed

    Tylki-Szymańska, Anna

    2014-09-01

    Hunter syndrome is caused by deficiency of the lysososmal enzyme iduronate-2-sulphatase that cleaves O-linked sulphate moieties from dermatan sulphate and heparan sulphate and leads to accumulation of GAGs. The disease is a X-linked condition affecting males and rarely females, clinically divided into severe (2/3) and attenuated types. Children with severe form, diagnosed at 12-36 months, have coarse facial feature, short stature, joint stiffness, short neck, broad chest, large head circumference, watery diarrhea, skeletal changes, progressive and profound mental retardation, retinal degeneration' hearing loss, cardiomyopathy, valvular involvement, with progressive thickening and stiffening of the valve leaflets leading to mitral and aortic regurgitation and stenosis . Recurrent and prolonged rhinitis with persistent nasal discharge are the first symptoms of airway disease that manifests itself as noisy breathing and later sleep apnea. Some patients develop ivory-colored skin lesions on the upper back and sides of the upper arms, pathogenomic of Hunter syndrome. The scalp hair becomes coarse, straight and bristly. Inguinal and umbilical hernias occur caused by the disturbed structure of connective tissue and increased liver and spleen volume. Patients with attenuated form have normal intelligence and a milder phenotype. Physical features diagnosed later are similar but less pronounced but progress to severe disease. Sceening is by quantitative assessment of urinary GAGs excretion. Qualitative assessment of GAG by electrophoresis can distinguish the type of mucopolysaccharidosis. Definitive diagnosis is based on enzyme activity assay in leukocytes, fibroblasts or plasma. Molecular testing is recommended mainly for genetic counseling and carrier detection. Limited experience of Haematopoietic stem cell therapy in MPS II showed progressive neurodegeneration. Recombinant 125 Idursulfase, is indicated for long-term treatment. The response appears to depend on the

  11. Genetics Home Reference: autoimmune polyglandular syndrome, type 1

    MedlinePlus

    ... polyglandular syndrome, type 1 autoimmune polyglandular syndrome, type 1 Enable Javascript to view the expand/collapse boxes. ... All Close All Description Autoimmune polyglandular syndrome, type 1 is an inherited condition that affects many of ...

  12. Living with Long QT Syndrome

    MedlinePlus

    ... or go into cardiac arrest. Tell them to call 9–1–1 right away if you faint. Consider asking a family member and/or coworker to learn cardiopulmonary resuscitation (CPR) in case your heart stops beating. You also may want to keep an automated external defibrillator (AED) with you at home or ...

  13. Kenny-Caffey syndrome type 1

    PubMed Central

    El Jabbour, Tony; Aboursheid, Tarek; Keifo, Mohammad Baraa; Maksoud, Ismael; Alasmar, Diana

    2014-01-01

    Kenny-Caffey syndrome type 1 is a rare hereditary skeletal disorder. We present here a documented case of a 7-month-old girl with the characteristic symptoms of growth retardation, dysmorphic features, and hypoparathyroidism. PMID:24982829

  14. Sinus bradycardia, junctional rhythm, and low-rate atrial fibrillation in Short QT syndrome during 20 years of follow-up: three faces of the same genetic problem.

    PubMed

    Righi, Daniela; Silvetti, Massimo S; Drago, Fabrizio

    2016-03-01

    We describe the case of an asymptomatic girl with sinus bradycardia and short QT interval at birth, junctional bradycardia in infancy requiring single-chamber pacemaker, atrial fibrillation in adolescence, and V141M mutation in the KCNQ1 gene. Atrial fibrillation recurred and became unresponsive to electrical or anti-arrhythmic therapy. During 20 years of follow-up, a progressive evolution from sinus node dysfunction to low-rate atrial fibrillation was observed. PMID:26279191

  15. hERG1a N-terminal eag domain-containing polypeptides regulate homomeric hERG1b and heteromeric hERG1a/hERG1b channels: a possible mechanism for long QT syndrome.

    PubMed

    Trudeau, Matthew C; Leung, Lisa M; Roti, Elon Roti; Robertson, Gail A

    2011-12-01

    Human ether-á-go-go-related gene (hERG) potassium channels are critical for cardiac action potential repolarization. Cardiac hERG channels comprise two primary isoforms: hERG1a, which has a regulatory N-terminal Per-Arnt-Sim (PAS) domain, and hERG1b, which does not. Isolated, PAS-containing hERG1a N-terminal regions (NTRs) directly regulate NTR-deleted hERG1a channels; however, it is unclear whether hERG1b isoforms contain sufficient machinery to support regulation by hERG1a NTRs. To test this, we constructed a series of PAS domain-containing hERG1a NTRs (encoding amino acids 1-181, 1-228, 1-319, and 1-365). The NTRs were also predicted to form from truncation mutations that were linked to type 2 long QT syndrome (LQTS), a cardiac arrhythmia disorder associated with mutations in the hERG gene. All of the hERG1a NTRs markedly regulated heteromeric hERG1a/hERG1b channels and homomeric hERG1b channels by decreasing the magnitude of the current-voltage relationship and slowing the kinetics of channel closing (deactivation). In contrast, NTRs did not measurably regulate hERG1a channels. A short NTR (encoding amino acids 1-135) composed primarily of the PAS domain was sufficient to regulate hERG1b. These results suggest that isolated hERG1a NTRs directly interact with hERG1b subunits. Our results demonstrate that deactivation is faster in hERG1a/hERG1b channels compared to hERG1a channels because of fewer PAS domains, not because of an inhibitory effect of the unique hERG1b NTR. A decrease in outward current density of hERG1a/hERG1b channels by hERG1a NTRs may be a mechanism for LQTS. PMID:22124116

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

    PubMed Central

    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.; zu Schwabedissen, Henriette Meyer; 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.; consortium, HRGEN; 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.; Fabiola Del, Greco M.; 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.; Leach, Irene Mateo; 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; 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; 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 a genome-wide association and replication study in up to 100,000 individuals we identified 35 common variant QT interval loci, that collectively explain ∼8-10% of QT variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 novel QT loci in 298 unrelated LQTS probands identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode for proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies novel candidate genes for ventricular arrhythmias, LQTS,and SCD. PMID:24952745

  17. Fluconazole-Induced Type 1 Kounis Syndrome.

    PubMed

    Singh Mahal, Hardeep

    2016-01-01

    The administration of fluconazole is commonly used in both inpatient and outpatient settings for the management of candidiasis infection. Although it is associated with a relatively safe side effect profile, some patients experience adverse effects associated with increased morbidity. We describe 1 such patient, a 42-year-old woman with a history of severe eczema who developed fluconazole-induced type 1 Kounis syndrome. Review of literature indicates that this as the first case reported of fluconazole-induced type 1 Kounis syndrome. PMID:26938747

  18. Rare case of orofaciodigital syndrome type I

    PubMed Central

    Singh, Abhishek Bahadur; Girhotra, Manish; Goel, Medha; Bhatia, Shilpee

    2013-01-01

    Orofaciodigital syndrome (OFDS) is a group of congenital anomalies which affects the face, oral structures and digits. There are nine subtypes with different modes of inheritance. OFDS type I is an X-linked dominant trait with lethality in the vast majority of affected males. We report a case of OFDS type I in an Indian girl at the age of seven who had most of the typical features of OFDS type I and nephrocalcinosis. PMID:23417374

  19. QT dispersion in adult hypertensives.

    PubMed Central

    Sani, Isa Muhammad; Solomon, Danbauchi Sulei; Imhogene, Oyati Albert; Ahmad, Alhassan Muhammad; Bala, Garko Sani

    2006-01-01

    Increased QT dispersion is associated with sudden cardiac death in congestive cardiac failure, hypertrophic cardiomyopathy and following myocardial infarction. Patients with hypertension--in particular, those with left ventricular hypertrophy (LVH)--are also at greater risk of sudden cardiac death. We examined whether QT dispersion, which is easily obtained from a routine ECG, correlates with LVH. One-hundred untreated patients with systemic hypertension and 78 normotensives had QT dispersion measured manually from a surface 12-lead electrocardiogram and two-dimensional echocardiography performed to measure interventricular septal thickness, posterior wall thickness and left ventricular internal diameter. Office blood pressure was also recorded. Multivariate analysis demonstrated significant relationships between QT dispersion and office systolic blood pressure, and left ventricular mass index. Manual measurement of QT dispersion might be a simple, noninvasive screening procedure to identify those hypertensives at greatest risk of sudden cardiac death in a third-world country. PMID:16623077

  20. Pronounced Effects of HERG-Blockers E-4031 and Erythromycin on APD, Spatial APD Dispersion and Triangulation in Transgenic Long-QT Type 1 Rabbits

    PubMed Central

    Franke, Gerlind; Perez Feliz, Stefanie; Hartmann, Maximilian; Koren, Gideon; Zehender, Manfred; Bode, Christoph; Brunner, Michael; Odening, Katja E.

    2014-01-01

    Background Prolongation of action potential duration (APD), increased spatial APD dispersion, and triangulation are major factors promoting drug-induced ventricular arrhythmia. Preclinical identification of HERG/IKr-blocking drugs and their pro-arrhythmic potential, however, remains a challenge. We hypothesize that transgenic long-QT type 1 (LQT1) rabbits lacking repolarizing IKs current may help to sensitively detect HERG/IKr-blocking properties of drugs. Methods Hearts of adult female transgenic LQT1 and wild type littermate control (LMC) rabbits were Langendorff-perfused with increasing concentrations of HERG/IKr-blockers E-4031 (0.001–0.1 µM, n = 9/7) or erythromycin (1–300 µM, n = 9/7) and APD, APD dispersion, and triangulation were analyzed. Results At baseline, APD was longer in LQT1 than in LMC rabbits in LV apex and RV mid. Erythromycin and E-4031 prolonged APD in LQT1 and LMC rabbits in all positions. However, erythromycin-induced percentaged APD prolongation related to baseline (%APD) was more pronounced in LQT1 at LV base-lateral and RV mid positions (100 µM, LQT1, +40.6±9.7% vs. LMC, +24.1±10.0%, p<0.05) and E-4031-induced %APD prolongation was more pronounced in LQT1 at LV base-lateral (0.01 µM, LQT1, +29.6±10.6% vs. LMC, +19.1±3.8%, p<0.05) and LV base-septal positions. Moreover, erythromycin significantly increased spatial APD dispersion only in LQT1 and increased triangulation only in LQT1 in LV base-septal and RV mid positions. Similarly, E-4031 increased triangulation only in LQT1 in LV apex and base-septal positions. Conclusions E-4031 and erythromycin prolonged APD and increased triangulation more pronouncedly in LQT1 than in LMC rabbits. Moreover, erythromycin increased APD dispersion only in LQT1, indicating that transgenic LQT1 rabbits could serve as sensitive model to detect HERG/IKr-blocking properties of drugs. PMID:25244401

  1. [Waardenburg syndrome type I: case report].

    PubMed

    Silva, Patricia Capua Vieira da; Rangel, Paula; Couto Jr, Abelardo

    2011-01-01

    Waardenburg syndrome (WS) type I is a non-progressive auditory-pigmentary disorder comprising congenital sensorineural hearing loss and pigmentary disturbances of the iris, hair, and skin, along with dystopia canthorum (lateral displacement of the inner canthi). Affected individuals may have higher risk of: neural tube defects, cleft lip and palate, limb abnormalities, and Hirschsprung disease. The diagnosis is clinical and should be considered if the individual has two major or one major plus two minor criteria. PAX3 is the only known gene associated to the syndrome. Nevertheless, its use is mostly for genetic counseling. Regarding different diagnosis, we may list: other causes of non-progressive auditory-pigmentary disorder comprising congenital sensorineural hearing loss, other types of Waardenburg syndrome, piebaldism, albinism, vitiligo and Teitz syndrome. This paper presents a case of an eleven year old boy with deafness and ophthalmologic alterations, based on his files and exams. It reinforced the importance of the ophthalmologist contributing for the diagnosis of this rare systemic disease, as it includes some ophthalmologic alterations. We remind that the early diagnosis allows adequate stimulation for the hearing loss, as well as preventive measures in case of pregnant women affected by genetic counseling. PMID:21915450

  2. Antimicrobial agents-associated with QT interval prolongation.

    PubMed

    Bril, Fernando; Gonzalez, Claudio Daniel; Di Girolamo, Guillermo

    2010-01-01

    QT interval prolongation is one of the most important causes of withdrawal of drugs from the market, due to its association with Torsades de Pointes (TdP), a potentially fatal arrhythmia. Although many antimicrobial drugs are capable of inducing this type of arrhythmia, the importance of this effect is usually underestimated. Macrolides, quinolones, azoles, pentamidine, protease inhibitors, antimalarial drugs and cotrimoxazole are the anti-infective agents more frequently associated with this adverse effect. Despite the fact that the risk of QT prolongation and TdP under single antimicrobial therapy is low, these drugs are so extensively used that sporadic cases of this arrhythmia are reported. Moreover, antimicrobial drugs are susceptible to pharmacokinetic and pharmacodynamic interactions with other drugs, which may increase the risk of this arrhythmia. Therefore, physicians must be familiar with not only the antimicrobial drugs capable of producing QT interval prolongation, but also their potential interactions. In addition, patient's specific risk factors of prolonging QT interval or producing TdP must be taken into account. This article reviews the role of anti-infective drugs in QT prolongation, focusing on QT prolongation mechanisms, potential drug interactions, and patients' predisposing factors to this arrhythmia. PMID:20210724

  3. Waardenburg Syndrome type 1: A case report.

    PubMed

    Demirci, Gulsen Tukenmez; Atıs, Guldehan; Altunay, Ilknur Kıvanc

    2011-01-01

    Waardenburg Syndrome (WS) is a rare hereditary disorder that is characterized by the clinical manifestations of oculocutaneous anomalies of pigmentation, congenital deafness, dystopia canthorum, and broad nasal root. It demonstrates both genetically and clinically heterogenous characteristics. In this article, we report an 11-month-old boy with WS1, one of four clinicat types of WS. He exhibited white forelock, hypopigmented macules and patches, heterochromia irides, and dystopia canthorum. PMID:22136859

  4. QT interval in anorexia nervosa.

    PubMed Central

    Cooke, R A; Chambers, J B; Singh, R; Todd, G J; Smeeton, N C; Treasure, J; Treasure, T

    1994-01-01

    OBJECTIVES--To determine the incidence of a long QT interval as a marker for sudden death in patients with anorexia nervosa and to assess the effect of refeeding. To define a long QT interval by linear regression analysis and estimation of the upper limit of the confidence interval (95% CI) and to compare this with the commonly used Bazett rate correction formula. DESIGN--Prospective case control study. SETTING--Tertiary referral unit for eating disorders. SUBJECTS--41 consecutive patients with anorexia nervosa admitted over an 18 month period. 28 age and sex matched normal controls. MAIN OUTCOME MEASURES--maximum QT interval measured on 12 lead electrocardiograms. RESULTS--43.6% of the variability in the QT interval was explained by heart rate alone (p < 0.00001) and group analysis contributed a further 5.9% (p = 0.004). In 6 (15%) patients the QT interval was above the upper limit of the 95% CI for the prediction based on the control equation (NS). Two patients died suddenly; both had a QT interval at or above the upper limit of the 95% CI. In patients who reached their target weights the QT interval was significantly shorter (median 9.8 ms; p = 0.04) relative to the upper limit of the 60% CI of the control regression line, which best discriminated between patients and controls. The median Bazett rate corrected QT interval (QTc) in patients and controls was 435 v 405 ms.s-1/2 (p = 0.0004), and before and after refeeding it was 435 v 432 ms.s1/2 (NS). In 14(34%) patients and three (11%) controls the QTc was > 440 ms.s-1/2 (p = 0.053). CONCLUSIONS--The QT interval was longer in patients with anorexia nervosa than in age and sex matched controls, and there was a significant tendency to reversion to normal after refeeding. The Bazett rate correction formula overestimated the number of patients with QT prolongation and also did not show an improvement with refeeding. PMID:8068473

  5. Congenital Nephrotic Syndrome – Finish Type

    PubMed Central

    Spahiu, Lidvana; Merovci, Besart; Jashari, Haki; Këpuska, Arbnore Batalli; Rugova, Blerta Elezi

    2016-01-01

    Introduction: Identification of the NPHS1 gene, which encodes nephrin, was followed by many studies demonstrating its mutation as a frequent cause of congenital nephrotic syndrome (CNS). While this gene is found in 98% of Finnish children with this syndrome, non-Finnish cases have lower level of incidence ranging from 39 to 80%. Case report: This report describes the clinical presentation of a two-week-old neonate who presented with periorbital and lower extremities edema, abdominal distention, heavy proteinuria, serum hypoproteinemia and failure to thrive. Genetic analysis revealed NHPS1 gene mutation leading to CNS-Finnish type diagnosis. Conclusion: Through this case we want to create awareness about diagnosis and treatment challenges in developing countries for rare congenital diseases. PMID:27594755

  6. Cardiorenal Syndrome Type 4: A Review

    PubMed Central

    Clementi, Anna; Virzì, Grazia Maria; Goh, Ching Yan; Cruz, Dinna N.; Granata, Antonio; Vescovo, Girogio; Ronco, Claudio

    2013-01-01

    There is a bidirectional and complex relationship between the heart and kidneys. This interaction is physical, chemical as well as biological and is also reflected in a strong connection between renal and cardiovascular diseases. Cardiorenal syndrome type 4 (CRS type 4) is characterized by primary chronic kidney disease (CKD) leading to an impairment of cardiac function, with ventricular hypertrophy, diastolic dysfunction, and/or increased risk of adverse cardiovascular events. The incidence of CKD is increasing, and CRS type 4 is becoming a major public health problem associated with a high morbidity and mortality. In this study, we briefly review the epidemiology and pathophysiology of CRS type 4, the role of biomarkers in its early identification, and its management. PMID:23946725

  7. Targeted therapy for hereditary cancer syndromes: neurofibromatosis type 1, neurofibromatosis type 2, and Gorlin syndrome.

    PubMed

    Agarwal, Rishi; Liebe, Sarah; Turski, Michelle L; Vidwans, Smruti J; Janku, Filip; Garrido-Laguna, Ignacio; Munoz, Javier; Schwab, Richard; Rodon, Jordi; Kurzrock, Razelle; Subbiah, Vivek

    2014-12-01

    Hereditary cancer syndromes are well known in the oncology community, typically affecting children, adolescents, and young adults and thereby resulting in great cumulative morbidity and mortality. These syndromes often lag behind their de novo counterparts in the development of approved novel treatment options due to their rarity in the general population. Recent work has allowed the identification of molecular aberrations and associated targeted therapies that may effectively treat these conditions. In this review, we seek to characterize some of the involved aberrations and associated targeted therapies for several germline malignancies, including neurofibromatosis types 1 and 2, and Gorlin syndrome. Though patients with hereditary cancer syndromes may be too rare to effectively include in large clinical trials, by understanding the pathophysiology of these diseases, clinicians can attain insights into the use of targeted therapies in their own practice when treating affected individuals. PMID:25549703

  8. Iatrogenic QT Abnormalities and Fatal Arrhythmias: Mechanisms and Clinical Significance

    PubMed Central

    Cubeddu, Luigi X

    2009-01-01

    Severe and occasionally fatal arrhythmias, commonly presenting as Torsade de Pointes [TdP] have been reported with Class III-antiarrhythmics, but also with non-antiarrhythmic drugs. Most cases result from an action on K+ channels encoded by the HERG gene responsible for the IKr repolarizing current, leading to a long QT and repolarization abnormalities. The hydrophobic central cavity of the HERG-K+ channels, allows a large number of structurally unrelated drugs to bind and cause direct channel inhibition. Some examples are dofetilide, quinidine, sotalol, erythromycin, grepafloxacin, cisapride, dolasetron, thioridazine, haloperidol, droperidol and pimozide. Other drugs achieve channel inhibition indirectly by impairing channel traffic from the endoplasmic reticulum to the cell membrane, decreasing channel membrane density (pentamidine, geldalamicin, arsenic trioxide, digoxin, and probucol). Whereas, ketoconazole, fluoxetine and norfluoxetine induce both direct channel inhibition and impaired channel trafficking. Congenital long QT syndrome, subclinical ion-channel mutations, subjects and relatives of subjects with previous history of drug-induced long QT or TdP, dual drug effects on cardiac repolarization [long QT plus increased QT dispersion], increased transmural dispersion of repolarization and T wave abnormalities, use of high doses, metabolism inhibitors and/or combinations of QT prolonging drugs, hypokalemia, structural cardiac disease, sympathomimetics, bradycardia, women and older age, have been shown to increase the risk for developing drug-induced TdP. Because most of these reactions are preventable, careful evaluation of risk factors and increased knowledge of drugs use associated with repolarization abnormalities is strongly recommended. Future genetic testing and development of practical and simple provocation tests are in route to prevent iatrogenic TdP. PMID:20676275

  9. Nephrocalcinosis as adult presentation of Bartter syndrome type II.

    PubMed

    Huang, L; Luiken, G P M; van Riemsdijk, I C; Petrij, F; Zandbergen, A A M; Dees, A

    2014-02-01

    Bartter syndrome consists a group of rare autosomal-recessive renal tubulopathies characterised by renal salt wasting, hypokalaemic metabolic alkalosis, hypercalciuria and hyperreninaemic hyperaldosteronism. It is classified into five types. Mutations in the KCNJ1 gene (classified as type II) usually cause the neonatal form of Bartter syndrome. We describe an adult patient with a homozygous KCNJ1 mutation resulting in a remarkably mild phenotype of neonatal type Bartter syndrome. PMID:24659592

  10. hERG channel function: beyond long QT

    PubMed Central

    Babcock, Joseph J; Li, Min

    2013-01-01

    To date, research on the human ether-a-go-go related gene (hERG) has focused on this potassium channel's role in cardiac repolarization and Long QT Syndrome (LQTS). However, growing evidence implicates hERG in a diversity of physiologic and pathological processes. Here we discuss these other functions of hERG, particularly their impact on diseases beyond cardiac arrhythmia. PMID:23459091

  11. Epidemiology of paediatric metabolic syndrome and type 2 diabetes mellitus.

    PubMed

    De Ferranti, Sarah D; Osganian, Stavroula K

    2007-12-01

    The epidemic in childhood obesity is a driving force behind the increase in paediatric metabolic syndrome, a collection of abnormalities that is associated in adults with increased risk for cardiovascular disease and type 2 diabetes mellitus. Although there is no clear consensus about the paediatric definition for metabolic syndrome, the prevalence of this syndrome is clearly rising. Children with metabolic syndrome are at increased risk for metabolic syndrome in adulthood. A late consequence of metabolic syndrome is type 2 diabetes, which increasingly affects adolescents. The rise in metabolic syndrome and type 2 diabetes in children is almost sure to lead to an increase in associated complications in young adulthood, including early cardiovascular disease. This epidemic will bear fruit in forthcoming decades, putting further stress on the healthcare system and probably leading to increased morbidity and a shorter lifespan for future generations. PMID:18158698

  12. Autoimmune polyglandular syndrome type 3 with anorexia.

    PubMed

    Kahara, Toshio; Wakakuri, Hitomi; Takatsuji, Juri; Motoo, Iori; Shima, Kosuke R; Ishikura, Kazuhide; Usuda, Rika; Noda, Yatsugi

    2012-01-01

    A 71-year-old man with diabetes mellitus visited our hospital with complaints of anorexia and weight loss (12 kg/3 months). He had megaloblastic anemia, cobalamin level was low, and autoantibody to intrinsic factor was positive. He was treated with intramuscular cyanocobalamin, and he was able to consume meals. GAD autoantibody and ICA were positive, and he was diagnosed with slowly progressive type 1 diabetes mellitus (SPIDDM). Thyroid autoantibodies were positive. According to these findings, he was diagnosed with autoimmune polyglandular syndrome type 3 with SPIDDM, pernicious anemia, and Hashimoto's thyroiditis. Extended periods of cobalamin deficiency can cause serious complications such as ataxia and dementia, and these complications may not be reversible if replacement therapy with cobalamin is delayed. Although type 1 diabetes mellitus with coexisting pernicious anemia is very rare in Japan, physicians should consider the possibility of pernicious anemia when patients with diabetes mellitus have cryptogenic anorexia with the finding of significant macrocytosis (MCV > 100 fL). PMID:23304573

  13. Histopathological types in adult nephrotic syndrome.

    PubMed

    Yusuf, Md Ghulam; Das, Bidhu Bhushan; Shaha, Amaresh Chandra; Hossain, Md Zakir

    2016-01-01

    In Bangladesh, there are very few studies about biopsy proven adult Nephrotic syndrome (NS) with histological types and their clinical findings. To determine the histological types of glomerulonephritis (GN) in adult NS and correlate them with the clinical presentations and biochemical parameters, we studied 100 biopsies in 87 patients who underwent ultrasonography- guided renal biopsy in Rangpur Medical College and Hospital from July 2010 to June 2012. The mean age of the patients was 32.8 ± 13.2 years; male was preponderance (72.4%) and most of the patients (67.8%) came from rural areas. Membranoproliferative GN (MPGN) was the most common underlying cause that was found in 32 (36.8%) patients followed by mesangial prolife- rative GN in 27 (31%) patients, membranous GN in 16 (18.4%) cases, minimal change disease in four (4.6%) patients, diffuse proliferative GN in four (4.6%) patients, focal segmental GN, and focal proliferative GN in two (2.4%) patients each. High proteinuria level was found in minimal change disease, which was 7.59 ± 0.24 g/24 h (mean ± standard deviation). The most common symptoms were oliguria (92%) and edema (86.2%) followed by hematuria (dark urine) (72.4%) and hypertension (35.6%). MPGN was the most common histological type of adult NS in Rangpur. PMID:27215253

  14. Waardenburg syndrome type 2: an orthodontic perspective.

    PubMed

    Şuhani, Raluca Diana; Şuhani, Mihai Flaviu; Muntean, Alexandrina; Mesaroş, Michaela Florica; Badea, Mîndra Eugenia

    2015-01-01

    Waardenburg syndrome is a rare form of neurocristopathy. It is a disorder in the development of neural crest cells, caused by an altered cellular migration during the embryonic phase. That alteration causes an association of different abnormalities such as pigmentary disturbances of the hair, iris, skin, stria vascularis of the cochlea, dystopia canthorum and sensorineural hearing loss. We report a case of a 14-year-old Romanian male, with a family history of Waardenburg syndrome (mother) and Usher syndrome (father - congenitally sensorineural hearing loss and retinal degeneration). The case particularities are: the correlation between malocclusion and Waardenburg syndrome due to hypoplastic alae nasi and also factors that produced hearing loss, which could be Waardenburg syndrome, Usher syndrome or the presence of the connexin 26 (W24X) gene mutation. PMID:26429191

  15. Cholesterol and Alzheimer Type Dementia among Adults with Down Syndrome

    ERIC Educational Resources Information Center

    Buckley, Frank

    2008-01-01

    This article reports a summary of research by Warren Zigman and colleagues investigating the link between cholesterol levels and Alzheimer type dementia among adults with Down syndrome. Warren Zigman and colleagues followed 123 adults with Down syndrome between May 1998 and April 2006. The participants were aged between 41 and 78 years at the…

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

    PubMed

    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

    2014-08-01

    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 a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD. PMID:24952745

  17. The risk for type B aortic dissection in Marfan syndrome.

    PubMed

    Setacci, C; Galzerano, G; Setacci, F; Mazzitelli, G; de Donato, G; Ricci, C

    2015-12-01

    Marfan syndrome is the most prevalent connective tissue disorder, with an autosomal dominant inheritance with variable penetrance. This paper aims to summarize epidemiology and treatment for type B dissection in Marfan patients. PMID:26350976

  18. Sudden cardiac arrest during anesthesia in a 30-month-old boy with syndactyly: a case of genetically proven Timothy syndrome.

    PubMed

    An, Hyo Soon; Choi, Eun Young; Kwon, Bo Sang; Kim, Gi Beom; Bae, Eun Jung; Noh, Chung Il; Choi, Jung Yun; Park, Sung Sup

    2013-05-01

    Timothy syndrome, long QT syndrome type 8, is highly malignant with ventricular tachyarrhythmia. A 30-month-old boy had sudden cardiac arrest during anesthesia induction before plastic surgery for bilateral cutaneous syndactyly. After successful resuscitation, prolonged QT interval (QTc, 0.58-0.60 sec) and T-wave alternans were found in his electrocardiogram. Starting β-blocker to prevent further tachycardia and collapse event, then there were no more arrhythmic events. The genes KCNQ1, KCNH2, KCNE1 and 2, and SCN5A were negative for long QT syndrome. The mutation p.Gly406Arg was confirmed in CACNA1C, which maintains L-type calcium channel depolarization in the heart and other systems. PMID:23678275

  19. Gait Strategy in Patients with Ehlers-Danlos Syndrome Hypermobility Type and Down Syndrome

    ERIC Educational Resources Information Center

    Rigoldi, Chiara; Galli, Manuela; Cimolin, Veronica; Camerota, Filippo; Celletti, Claudia; Tenore, Nunzio; Albertini, Giorgio

    2012-01-01

    People suffering from Ehlers-Danlos syndrome (EDS) hypermobility type present a severe ligament laxity that results in difficulties in muscle force transmission. The same condition is present in people suffering from Down syndrome (DS) even if their clumsy movements are due to cerebral and cognitive impairments. The aim of this study was to…

  20. Type VI Aplasia Cutis Congenita: Bart's Syndrome

    PubMed Central

    Kulalı, Ferit; Bas, Ahmet Yagmur; Kale, Yusuf; Celik, Istemi Han; Demirel, Nihal; Apaydın, Sema

    2015-01-01

    Bart's syndrome is characterized by aplasia cutis congenita and epidermolysis bullosa. We present the case of a newborn male who developed blisters on the mucous membranes and the skin following congenital localized absence of skin. Bart's syndrome (BS) is diagnosed clinically based on the disorder's unique signs and symptoms but histologic evaluation of the skin can help to confirm the final diagnosis. The patient was managed conservatively with topical antibacterial ointment and wet gauze dressing. Periodic follow-up examinations showed complete healing. We emphasized that it is important to use relatively simple methods for optimal healing without the need for complex surgical interventions. PMID:26609453

  1. QT Dispersion after Thrombolytic Therapy

    PubMed Central

    Oni Heris, Saeed; Rahimi, Behzad; Faridaalaee, Gholamreza; Hajahmadi, Mojgan; Sayyadi, Hojjat; Naghipour, Bahman

    2014-01-01

    Background: QT dispersion (QTd) is equal to longer QTc minus shorter QTc measured by 12-lead electrocardiogram (ECG). QTd reflects inhomogeneity in repolarization of ventricular myocardium and because of easy and fast measurement of QTd, it can be used to predict high-risk patients for dysrhythmia after Acute Myocardial Infarction (AMI). Objectives: This study aimed to assess the effect of thrombolytic therapy on QTd before and 1 hour and 4 days after beginning of thrombolytic therapy. Patients and Methods: The patients with chest pain and ST Elevated Myocardial Infarction (STEMI) that underwent thrombolytic therapy were enrolled into this study. Streptokinase was the thrombolytic agent in all the patients. Standard 12-lead (ECG) was evaluated before beginning of thrombolytic therapy (QTd 1) and 1 hour (QTd2) and 4 days (QTd3) after thrombolytic therapy. First, ECG was magnified × 10 for exact calculation of QT and QTd. After all, the variables were compared using one–way analysis of variance (ANOVA). Besides, P ≤ 0.05 was considered as statistically significant. Results: This study was conducted on 160 patients. The results revealed no significant differences among QTd 1, QTd 2, and QTd 3 (P > 0.05). At inferior AMI, however, a significant difference was observed among QTd1, QTd2, and QTd3 (P = 0.031). Conclusions: Thrombolytic therapy had no significant effects on QTd. Thus, thrombolytic therapy does not increase the risk of arrhythmia. PMID:25614860

  2. Nevus comedonicus in oral-facial-digital syndrome type 1: a new finding or overlapping syndromes?

    PubMed

    Baker, Lauren A; Agim, Nnenna G

    2014-01-01

    We report a patient with oral-facial-digital syndrome type 1 (OFDS1) who exhibited features overlapping those of nevus comedonicus syndrome, an unusual presentation that may potentially represent a new variant of OFDS1. OFDS1 and nevus comedonicus syndrome represent two rare syndromes with numerous overlapping features that have yet to be described in relation to one another. The features present in our patient led us to propose the possibility of a new variant of OFDS1 in which nevus comedonicus represents a cutaneous manifestation of the syndrome. Knowledge of this potential relationship is important for identification and management of the syndromes' accompanying manifestations in affected patients and may offer further insight into crossroads of pathogenesis. PMID:24517846

  3. Oral Contraceptive Use and the ECG: Evidence of an Adverse QT Effect on Corrected QT Interval

    PubMed Central

    Sedlak, Tara; Shufelt, Chrisandra; Iribarren, Carlos; Lyon, Liisa L; Merz, C. Noel Bairey

    2013-01-01

    Background A prolonged corrected QT (QTc) interval is a marker for an increased risk of sudden cardiac death. We evaluated the relationship between oral contraceptive (OC) use, type of OC, and QTc interval. Methods We identified 410,782 ECGs performed at Northern California Kaiser Permanente on female patients between 15–53 years from January, 1995 to June, 2008. QT was corrected for heart rate using log-linear regression. OC generation (first, second and third) was classified by increasing progestin androgenic potency, while the fourth generation was classified as anti-androgenic. Results Among 410,782 women, 8.4% were on OC. In multivariate analysis after correction for comorbidities, there was an independent shortening effect of OCs overall (slope = −0.5ms; SE = 0.12, p<0.0002). Users of first and second generation progestins had a significantly shorter QTc than non-users (p<0.0001), while users of fourth generation had a significantly longer QTc than non-users (slope = 3.6ms, SE = 0.35, p<0.0001). Conclusion Overall, OC use has a shortening effect on the QTc. Shorter QTc is seen with first and second generation OC while fourth generation OC use has a lengthening effect on the QTc. Careful examination of adverse event rates in fourth generation OC users is needed. PMID:23879279

  4. Burning mouth syndrome due to herpes simplex virus type 1.

    PubMed

    Nagel, Maria A; Choe, Alexander; Traktinskiy, Igor; Gilden, Don

    2015-01-01

    Burning mouth syndrome is characterised by chronic orofacial burning pain. No dental or medical cause has been found. We present a case of burning mouth syndrome of 6 months duration in a healthy 65-year-old woman, which was associated with high copy numbers of herpes simplex virus type 1 (HSV-1) DNA in the saliva. Her pain resolved completely after antiviral treatment with a corresponding absence of salivary HSV-1 DNA 4 weeks and 6 months later. PMID:25833911

  5. Cardio-renal syndrome type 5: epidemiology, pathophysiology, and treatment.

    PubMed

    Soni, Sachin S; Ronco, Claudio; Pophale, Rupesh; Bhansali, Ashish S; Nagarik, Amit P; Barnela, Shriganesh R; Saboo, Sonali S; Raman, Anuradha

    2012-01-01

    The cardio-renal syndromes (CRS) recently were defined systematically as disorders of the heart or kidney whereby dysfunction of one organ leads to dysfunction of another. Five types of CRS are defined. The first four types describe acute or chronic cardio-renal or renocardiac syndromes. Type 5 CRS refers to secondary cardio-renal syndrome or cardio-renal involvement in systemic conditions. It is a clinical and pathophysiological entity to describe the concomitant presence of renal and cardiovascular dysfunction. Type 5 CRS can be acute or chronic and it does not strictly satisfy the definition of CRS. However, it encompasses many conditions in which combined heart and kidney dysfunction is observed. Because this entity has been described only recently there is limited information about the epidemiology, clinical course, and treatment of this condition. PMID:22365162

  6. Risk assessment of drug-induced QT prolongation

    PubMed Central

    Isbister, Geoffrey K

    2015-01-01

    SUMMARY Drugs can cause prolongation of the QT interval, alone or in combination, potentially leading to fatal arrhythmias such as torsades de pointes. When prescribing drugs that prolong the QT interval, the balance of benefit versus harm should always be considered. Readouts from automated ECG machines are unreliable. The QT interval should be measured manually. Changes in heart rate influence the absolute QT interval. Heart rate correction formulae are inaccurate, particularly for fast and slow heart rates. The QT nomogram, a plot of QT interval versus heart rate, can be used as a risk assessment tool to detect an abnormal QT interval. PMID:26648606

  7. Type 2 leprosy reaction with Sweet's syndrome-like presentation*

    PubMed Central

    Chiaratti, Francielle Chiavelli; Daxbacher, Egon Luiz Rodrigues; Neumann, Antonielle Borges Faria; Jeunon, Thiago

    2016-01-01

    Leprosy is a chronic disease characterized by manifestations in the peripheral nerves and skin. The course of the disease may be interrupted by acute phenomena called reactions. This article reports a peculiar case of type 2 leprosy reaction with Sweet's syndrome-like features as the first clinical manifestation of leprosy, resulting in a delay in the diagnosis due to unusual clinical presentation. The patient had clinical and histopathological features reminiscent of Sweet's syndrome associated with clusters of vacuolated histiocytes containing acid-fast bacilli isolated or forming globi. Herein, it is discussed how to recognize type 2 leprosy reaction with Sweet's syndrome features, the differential diagnosis with type 1 leprosy reaction and the treatment options. When this kind of reaction is the first clinical presentation of leprosy, the correct diagnosis might be not suspected clinically, and established only with histopathologic evaluation. PMID:27438203

  8. Evidence for a fourth locus in Usher syndrome type I.

    PubMed Central

    Gerber, S; Larget-Piet, D; Rozet, J M; Bonneau, D; Mathieu, M; Der Kaloustian, V; Munnich, A; Kaplan, J

    1996-01-01

    Usher syndrome type I (US1) is an autosomal recessive condition in which three different genes have been already localised (USH1A, USH1B, and USH1C on chromosomes 14q32, 11q13, and 11p15 respectively). The genetic heterogeneity of US1 has been confirmed in a previous study by linkage analysis of 20 French pedigrees. Here, we report the genetic exclusion of the three previously reported loci in two large multiplex families of Moroccan and Pakistani origin, suggesting the existence of at least a fourth locus in Usher syndrome type I. PMID:8825055

  9. Mammary-type myofibroblastoma with the nephrotic syndrome

    PubMed Central

    Vankawala, Preksha; Kuperman, Michael B.; Mennel, Robert G.

    2016-01-01

    We describe a 23-year-old white man who presented with anasarca and a new periumbilical mass. He had preserved kidney function and laboratory findings consistent with nephrotic syndrome, including 9.7 g/day albuminuria. Serum serologies were positive for anti-SSa and anti-SSb and low complements but were negative for antinuclear antibody. Pathologic findings of the abdominal mass showed a mammary-type myofibroblastoma. A kidney biopsy revealed a diffuse proliferative and membranous immune-mediated glomerulonephritis with 10% interstitial fibrosis. This is a novel case of mammary-type myofibroblastoma associated with nephrotic syndrome mimicking a proliferative lupus pattern. PMID:27365885

  10. Complex regional pain syndrome after thromboendarterectomy: which type is it?

    PubMed

    Baillet, Georges; Planchon, Claude Alain; Tamgac, Feyzi; Thomassin, Martine; Foult, Jean-Marc

    2002-09-01

    The authors describe a complex regional pain syndrome (CRPS) and discuss its type according to the presence or absence of nerve injury. A patient underwent thromboendarterectomy of the right popliteal artery. Subsequently, right lower limb reflex sympathetic dystrophy developed, which was confirmed by scintigraphy and responded well to calcitonin treatment. Typing according to the new classification of CRPS type I or II with possible nerve injury is discussed, and a short review of the literature is included. PMID:12192276

  11. Use of in vitro methods to predict QT prolongation

    SciTech Connect

    Hammond, T.G. . E-mail: tim.hammond@astrazeneca.com; Pollard, C.E.

    2005-09-01

    The inhibition of the hERG-encoded potassium channel can lead to prolongation of the cardiac action potential-manifested as a prolongation of the QT interval on the ECG. Although QT interval prolongation is not dangerous per se, in a small percentage of cases, it is associated with a potentially fatal arrhythmia: Torsades de Pointes (TdP). This channel type is pharmacologically promiscuous, so many compounds have caused QT interval prolongation in man and this has led to drugs being withdrawn from the market following evidence of TdP. From a drug discovery perspective, focusing as early as possible on screening out hERG activity is important. Retrospective analysis of hERG potency versus clinical incidence of TdP suggests provisional safety margins that could be used as target values by medicinal chemists. Large safety margins will not always be possible; however, and in such circumstances, if the risk-benefit ratio still favours developing the compound, a pre-clinical assessment of the likelihood that any QT interval prolongation will or will not lead to TdP in man may be important. An isolated rabbit heart model of arrhythmia shows promise in this respect, based on a comparison of clinical data with that obtained from this assay. Specific regulatory guidance on this topic is still in the draft form but the pre-clinical document (ICH S7B) contains a largely useful perspective on how an integrated risk assessment could be formed using in vitro and in vivo assays. The role of this document is evolving however, since the draft clinical guideline (E14) suggests that irrespective of the pre-clinical data, a thorough clinical ECG study will be required at some point during development.

  12. Ehlers-danlos syndrome-hypermobility type and hemorrhoids.

    PubMed

    Plackett, Timothy P; Kwon, Edward; Gagliano, Ronald A; Oh, Robert C

    2014-01-01

    Ehlers-Danlos syndrome-hypermobility type (EDS-HT) is a connective tissue disorder associated with chronic musculoskeletal pain. The diagnosis is based on simple clinical examination, although it is easily overlooked. Herein we present a case of EDS-HT associated with hemorrhoids and suggest that there may be an association between the two conditions. PMID:24839575

  13. Free flap transfer for complex regional pain syndrome type II

    PubMed Central

    Matsuda, Ken; Kikuchi, Mamoru; Murase, Tsuyoshi; Hosokawa, Ko; Shibata, Minoru

    2014-01-01

    Abstract A patient with complex regional pain syndrome type II was successfully treated using free anterolateral thigh flap transfer with digital nerve coaptation to the cutaneous nerve of the flap. Release of the scarred tissue and soft tissue coverage with targeted sensory nerve coaptation were useful in relieving severe pain.

  14. Bilateral Horner's syndrome in cluster type headaches.

    PubMed

    Khurana, R K

    1993-09-01

    A patient with cluster type headaches demonstrated bilateral and alternating ocular sympathetic dysfunction during a spontaneous as well as a nitroglycerin-induced attack. Biochemical evaluation revealed postganglionic pupillary dysfunction on the symptomatic side and preganglionic pupillary dysfunction contralaterally. These findings defy a simple explanation regarding a central or peripheral origin of the oculocephalic sympathetic dysfunction. PMID:8262788

  15. Management of pregnancy in Crigler Najjar syndrome type 2

    PubMed Central

    Chaubal, Alisha Nitin; Patel, Ruchir; Choksi, Dhaval; Shah, Kaivan; Ingle, Meghraj; Sawant, Prabha

    2016-01-01

    Crigler Najjar syndrome is associated with indirect hyperbilirubinemia due to a deficiency of enzyme Uridine Di Phospho Glucoronosyl Transferase (UDPGT). Presented here is a case of a female in the first trimester of pregnancy, who was diagnosed to have type 2 Crigler Najjar syndrome. We also discuss the management of this rare disease especially in pregnancy. Unconjugated bilirubin can cross the placental barrier causing neurological damage in the newborn. Patient was carefully monitored during pregnancy and treatment with phenobarbitone in low doses was adjusted such that the serum bilirubin levels were below 10 mg/dL. Crigler Najjar syndrome being rare needs to be diagnosed early in pregnancy to avoid adverse fetal outcomes. Phenobarbitone being an inducer of enzyme UDPGT is used as the first line of treatment and is not teratogenic in the low doses used. Treatment protocol followed was on the basis of previous reported cases and successful perinatal outcome was achieved. PMID:27099654

  16. Adult presentation of Bartter syndrome type IV with erythrocytosis

    PubMed Central

    Heilberg, Ita Pfeferman; Tótoli, Cláudia; Calado, Joaquim Tomaz

    2015-01-01

    Abstract Bartter syndrome comprises a group of rare autosomal-recessive salt-losing disorders with distinct phenotypes, but one unifying pathophysiology consisting of severe reductions of sodium reabsorption caused by mutations in five genes expressed in the thick ascending limb of Henle, coupled with increased urinary excretion of potassium and hydrogen, which leads to hypokalemic alkalosis. Bartter syndrome type IV, caused by loss-of-function mutations in barttin, a subunit of chloride channel CLC-Kb expressed in the kidney and inner ear, usually occurs in the antenatal-neonatal period. We report an unusual case of late onset presentation of Bartter syndrome IV and mild phenotype in a 20 years-old man who had hypokalemia, deafness, secondary hyperparathyroidism and erythrocytosis. PMID:26537508

  17. A 24-HOUR AMBULATORY ECG MONITORING IN ASSESSMENT OF QT INTERVAL DURATION AND DISPERSION IN ROWERS WITH PHYSIOLOGICAL MYOCARDIAL HYPERTROPHY

    PubMed Central

    Kim, Z.F.; Bilalova, R.R.; Tsibulkin, N.A.; Almetova, R.R.; Mudarisova, R.R.; Ahmetov, I.I.

    2013-01-01

    Myocardial hypertrophy (MH) due to cardiac pathology is characterized by an increase in QT interval duration and dispersion, while the findings for exercise-induced myocardial hypertrophy are contradictory. The majority of published research findings have not explored this relationship, but there have only been a few conducted studies using 24-hour ECG monitoring. The aim of the study was to determine the QT interval duration and dispersion in short-term and 24-hour ECG in endurance athletes with myocardial hypertrophy and without it. Methods: A total of 26 well-trained rowers underwent a resting 12-lead ECG, 24-hour ECG monitoring and echocardiography. Results: Athletes with MH (n = 7) at rest did not show any increase in QTc interval duration and dispersion, or mean and maximal QTc duration in Holter monitoring compared to athletes without MH (n = 19). Left ventricular mass was not significantly correlated with any QTc characteristics. Furthermore, athletes with MH had significantly longer mean QT (P = 0.01) and maximal QT (P = 0.018) intervals in Holter monitoring and higher 24-hour heart rate variability indexes due to stronger vagal effects. Conclusions: The present study demonstrated that athlete's heart syndrome with myocardial hypertrophy as a benign phenomenon does not lead to an increase in QT interval duration, or increases in maximal and mean duration in a 24-hour ECG. An increase in QT interval duration in athletes may have an autonomic nature. PMID:24744494

  18. Genetics Home Reference: Romano-Ward syndrome

    MedlinePlus

    ... lead to fainting (syncope) or cardiac arrest and sudden death. Related Information What does it mean if a ... list from the University of Kansas Medical Center Sudden Arrhythmia Death Syndromes (SADS) Foundation: Long QT Syndrome GeneReviews (1 ...

  19. Occurrence of Parkinson's syndrome in type I Gaucher disease.

    PubMed

    Neudorfer, O; Giladi, N; Elstein, D; Abrahamov, A; Turezkite, T; Aghai, E; Reches, A; Bembi, B; Zimran, A

    1996-09-01

    Gaucher disease, the most prevalent glycolipid storage disorder, is classically subdivided into types according to the presence or absence of neurological involvement. Type I has hitherto been considered non-neuronopathic. We present six cases and a review of the literature of Parkinsonian symptoms in type I Gaucher disease patients. The hallmark of this atypical Parkinsonian syndrome is a relatively severe clinical course with early appearance of neurological signs in the 4th to 6th decade of life, aggressive progression of the signs and refractoriness to conventional anti-Parkinson therapy. We discuss the implications of these findings in the light of enzyme replacement therapy for Gaucher disease. PMID:8917744

  20. Combining QT and small-x resummations

    NASA Astrophysics Data System (ADS)

    Marzani, Simone

    2016-03-01

    We analyze transverse momentum (QT) resummation of a colorless final state, e.g. Higgs production in gluon fusion or the production of a lepton pair via the Drell-Yan mechanism, in the limit where the invariant mass of the final state is much less than the center-of-mass energy, i.e. Q2≪s . We show how the traditional resummation of logarithms of QT/Q can be supplemented with the resummation of the leading logarithmic contributions at small x =Q2/s and we compute the necessary ingredients to perform such joint resummation.

  1. Hypoglycaemia and QT interval prolongation: Detection by simultaneous Holter and continuous glucose monitoring.

    PubMed

    Lee, Angela S; Brooks, Belinda A; Simmons, Lisa; Kilborn, Michael J; Wong, Jencia; Twigg, Stephen M; Yue, Dennis K

    2016-03-01

    This study using simultaneous Holter and continuous glucose monitoring demonstrates that prolongation of QT interval can occur with hypoglycaemia in an ambulatory setting in people with type 1 and type 2 diabetes treated with insulin. This highlights the potential proarrhythmic harms associated with hypoglycaemia. PMID:26803354

  2. DRESS syndrome associated with type 2 diabetes in a child

    PubMed Central

    Erdem, Semiha Bahceci; Bag, Ozlem; Karkiner, Canan Sule Unsal; Korkmaz, Huseyin Anil; Can, Demet

    2016-01-01

    Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is an uncommon, life-threatening drug reaction. The basic findings are skin rash, multiorgan involvement, and eosinophilia. Most of the aromatic anticonvulsants, such as phenytoin, phenobarbital and carbamazepine can induce DRESS. Herein we report a 14-year-old patient with DRESS syndrome related to carbamazepine use. The patient presented with signs of involvement of the skin, lungs, liver, and microscopic hematuria. Carbamazepine treatment was discontinued; antihistamines and steroids were started. Hyperglycemia, commencing on the first dose of the steroid given, persisted even after the discontinuation of steroids and improvement of other signs. There were no signs of pancreatitis or type 1 diabetes clinically in laboratory tests. Her blood glucose levels were regulated at first with insulin and later with metformin. Within 1 year of follow-up, still regulated with oral antidiabetics, she has been diagnosed with type 2 diabetes. Formerly, long-term sequelae related to “drug rash with eosinophilia and systemic symptoms syndrome” such as hepatic and renal failure, type 1 diabetes mellitus, Grave's disease, autoimmune hemolytic anemia, and lupus have also been reported. However, up to date, no cases with type 2 diabetes have been reported as long-term sequelae. To our knowledge, this is the first case in the literature presenting with type 2 diabetes as long-term sequelae. PMID:26862317

  3. Polyglandular autoimmune syndrome type I among Iranian Jews.

    PubMed Central

    Zlotogora, J; Shapiro, M S

    1992-01-01

    Polyglandular autoimmune syndrome (PAS) has been well characterised and the accepted criteria for diagnosis are the presence of at least two of the three major components: hypoparathyroidism (HPT), candidiasis, and adrenal insufficiency (AI). HPT may, however, be the only manifestation of the syndrome. Iranian Jews, having a high rate of consanguinity, appear to be a community in which PAS type I is frequent. We report on 19 families of patients with HPT from the Iranian Jewish community assuming that they are in fact affected with PAS type I. In the 19 families, 23 patients were affected, including 11 males and 12 females. All the patients but one had HPT (96%), and most were diagnosed by the age of 20 years (91%). AI was diagnosed in five of our patients; in all cases but one it appeared after HPT. Mild oral candidiasis was present in four patients and six of the patients (three males and three females) had hypogonadism. Other features of the syndrome found in some of our patients were pernicious anaemia, hypothyroidism, and alopecia. The disease is autosomal recessive and the calculated prevalence among the Iranian Jews is 1:6500 to 1:9000. The disease is also found with a very high incidence among Finns. A comparison of the symptoms between the two groups showed clinical differences including the relative rarity of candidiasis and absence of keratopathy among the Iranian Jews. PMID:1453436

  4. Acrocephalopolysyndactyly type II--Carpenter syndrome: clinical spectrum and an attempt at unification with Goodman and Summit syndromes.

    PubMed

    Cohen, D M; Green, J G; Miller, J; Gorlin, R J; Reed, J A

    1987-10-01

    Carpenter syndrome (ACPS type II) was first described by Carpenter in 1901. The syndrome consists of acrocephaly, soft tissue syndactyly, brachy- or agenesis mesophalangy of the hands and feet, preaxial polydactyly, congenital heart disease, mental retardation, hypogenitalism, obesity, and umbilical hernia. Here we review the literature on Carpenter syndrome and add 2 affected sibs with marked intrafamilial variability. This review showed that 2 reported variations of Carpenter syndrome, Goodman and Summitt syndromes, actually fall within the clinical spectrum of this disorder. This confirms earlier suggestions of Gorlin (personal communication 1982) and Hall et al [Am J Med Genet 5:423-434, 1980]. PMID:3322002

  5. QT dynamics during treatment with sertindole

    PubMed Central

    Wang, Fan; Graff, Claus; Kanters, Jørgen K.

    2015-01-01

    Objectives: Sertindole is a nonsedating atypical antipsychotic drug with low propensity to cause extrapyramidal side effects but it has been associated with a 20 ms QTc prolongation and increased risk of cardiac events. It is uncertain whether this drug-induced increase in cardiac risk might also 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 (SD 8) versus 80 bpm (SD 10), p = 0.3 or heart rate variability (SDNN) 127 (SD 40) versus 115 ms (SD 45), p = 0.4. Conclusion: Sertindole was associated with 19 ms QTc prolongation and an increased ratio of QT variability to heart rate variability. Both measures may contribute to the increased cardiovascular mortality found with sertindole. PMID:25653828

  6. Respiratory complications of Ehlers-Danlos syndrome type IV.

    PubMed

    Hatake, Katsuhiko; Morimura, Yoshifumi; Kudo, Risa; Kawashima, Wataru; Kasuda, Shogo; Kuniyasu, Hiroki

    2013-01-01

    We describe a case of Ehlers-Danlos syndrome (EDS) type IV in a male in early half in his twenties, who experienced recurrent and eventually fatal pulmonary hemorrhage. EDS type IV is a rare disorder of type III collagen synthesis that is characterized by unusual facies, thin translucent skin with a venous vascular pattern, easy bruising, and hypermobility of the small joints. Autopsy findings showed hypermobility of the joints and distensibility of the skin. Microscopically, the abdominal skin showed substantially decreased dermal thickness. Moreover, the reticular dermis showed fine collagen bundles and large interstitial spaces compared with the skin from a normal control that showed large collagen bundles. Individual elastic fibers were also thicker than those observed in the skin of a normal control. The thoracic aorta showed thin adventitia and a relative increase in elastic fibers. The parenchyma of both the lungs showed markedly diffuse hemorrhage with hemosiderin-laden alveolar macrophages or old thrombi and organized thrombi in the small bronchi. Furthermore, both sections of the lung showed multiple fibrous nodules containing benign metaplastic bone. Vascular wall disruption and tearing of the vessel walls in the lung parenchyma were also observed. We concluded that EDS type IV led to the patient's death because of pulmonary hemorrhage. Because this syndrome resulted in the patient's death from arterial and bowel rupture, it is important to consider EDS as a potential cause of sudden death. PMID:22940417

  7. Jervell and Lange-Nielsen Syndrome (Long QT Syndrome).

    ERIC Educational Resources Information Center

    Hulbert, T. P.

    1994-01-01

    Clinical features, pathogenetic hypotheses, and symptoms of the cardio-auditory or surdo-cardiac disorder first reported by Jervell and Lange-Nielsen are described, and methods of diagnosis and treatment are presented, to alert teachers and other professionals to potentially life-threatening symptoms they may observe when working with deaf and…

  8. An Enhancer Polymorphism at the Cardiomyocyte Intercalated Disc Protein NOS1AP Locus Is a Major Regulator of the QT Interval

    PubMed Central

    Kapoor, Ashish; Sekar, Rajesh B.; Hansen, Nancy F.; Fox-Talbot, Karen; Morley, Michael; Pihur, Vasyl; Chatterjee, Sumantra; Brandimarto, Jeffrey; Moravec, Christine S.; Pulit, Sara L.; Pfeufer, Arne; Mullikin, Jim; Ross, Mark; Green, Eric D.; Bentley, David; Newton-Cheh, Christopher; Boerwinkle, Eric; Tomaselli, Gordon F.; Cappola, Thomas P.; Arking, Dan E.; Halushka, Marc K.; Chakravarti, Aravinda

    2014-01-01

    QT interval variation is assumed to arise from variation in repolarization as evidenced from rare Na- and K-channel mutations in Mendelian QT prolongation syndromes. However, in the general population, common noncoding variants at a chromosome 1q locus are the most common genetic regulators of QT interval variation. In this study, we use multiple human genetic, molecular genetic, and cellular assays to identify a functional variant underlying trait association: a noncoding polymorphism (rs7539120) that maps within an enhancer of NOS1AP and affects cardiac function by increasing NOS1AP transcript expression. We further localized NOS1AP to cardiomyocyte intercalated discs (IDs) and demonstrate that overexpression of NOS1AP in cardiomyocytes leads to altered cellular electrophysiology. We advance the hypothesis that NOS1AP affects cardiac electrical conductance and coupling and thereby regulates the QT interval through propagation defects. As further evidence of an important role for propagation variation affecting QT interval in humans, we show that common polymorphisms mapping near a specific set of 170 genes encoding ID proteins are significantly enriched for association with the QT interval, as compared to genome-wide markers. These results suggest that focused studies of proteins within the cardiomyocyte ID are likely to provide insights into QT prolongation and its associated disorders. PMID:24857694

  9. Griscelli syndrome type 2: A rare and fatal syndrome in a South Indian boy.

    PubMed

    Rajyalakshmi, R; Chakrapani, R N B

    2016-01-01

    Griscelli syndrome (GS) is a rare autosomal recessive disorder caused by mutation in the MYO5A (GS1), RAB27A (GS2), and MLPH (GS3) genes, characterized by a common feature, partial albinism. The common variant of three, GS type 2, in addition, shows primary immunodeficiency which leads to recurrent infections and hemophagocytic lymphohistiocytosis. We, herewith, describe a case of GS type 2, in a 4-year-old male child who presented with chronic and recurrent fever, lymphadenopathy, hepatosplenomegaly, and secondary neurological deterioration; highlighting the cytological and histopathological features of lymph nodes. Hair shaft examination of the child confirmed the diagnosis. PMID:26960655

  10. Ehlers-Danlos Syndrome Type IV with Bilateral Pneumothorax.

    PubMed

    Nakagawa, Hiroaki; Wada, Hiroshi; Hajiro, Takashi; Nagao, Taishi; Ogawa, Emiko; Hatamochi, Atsushi; Tanaka, Toshihiro; Nakano, Yasutaka

    2015-01-01

    A 17-year-old teen was hospitalized with bilateral pneumothorax. After the bilateral lungs were expanded using catheter tubes, he fully recovered and he was discharged from our hospital. He had a history of colon perforation. Ehlers-Danlos syndrome (EDS) was suspected due to the combination of colon perforation and pneumothorax, and EDS type IV was confirmed after a genetic study identified a c.1511g>a mutation in the COL3A1 gene. This is the first report of bilateral pneumothorax caused by EDS type IV. Clinicians should consider EDS type IV in the differential diagnosis for bilateral pneumothorax in conjunction with distinct previous histories and radiological findings. PMID:26666608

  11. Advances in the Pathogenesis of Cardiorenal Syndrome Type 3

    PubMed Central

    Clementi, Anna; Virzì, Grazia Maria; Brocca, Alessandra; de Cal, Massimo; Pastori, Silvia; Clementi, Maurizio; Granata, Antonio; Vescovo, Giorgio; Ronco, Claudio

    2015-01-01

    Cardiorenal syndrome (CRS) type 3 is a subclassification of the CRS whereby an episode of acute kidney injury (AKI) leads to the development of acute cardiac injury or dysfunction. In general, there is limited understanding of the pathophysiologic mechanisms involved in CRS type 3. An episode of AKI may have effects that depend on the severity and duration of AKI and that both directly and indirectly predispose to an acute cardiac event. Experimental data suggest that cardiac dysfunction may be related to immune system activation, inflammatory mediators release, oxidative stress, and cellular apoptosis which are well documented in the setting of AKI. Moreover, significant derangements, such as fluid and electrolyte imbalance, metabolic acidosis, and uremia, which are typical features of acute kidney injury, may impair cardiac function. In this review, we will focus on multiple factors possibly involved in the pathogenesis issues regarding CRS type 3. PMID:25821551

  12. Clinical findings in obligate carriers of type I Usher syndrome

    SciTech Connect

    Wagenaar, M.; Rahe, B. ter; Aarem, A. van; Huygen, P.; Admiraal, R.

    1995-11-20

    Seventeen obligate carriers from nine families with autosomal recessive Usher syndrome type I underwent otological, audiological, vestibular, and ophthalmological examination in order to identify possible manifestations of heterozygosity. Linkage studies were performed and six families showed linkage to chromosome region 11q13.5 while 3 families have so far failed to show linkage to the candidate regions. Eight obligate carriers had an abnormal puretone audiogram. Two different audiometric patterns could be distinguished when hearing loss was corrected for age and sex. Four carriers (24%) had significant sensorineural hearing loss (SNHL) which increased at higher frequencies. The other 13 carriers had SNHL of about 10 dB at 0.25 and 0.5 kHz, but less at higher frequencies. Vestibular findings were generally normal. Electrooculography demonstrated a significant lower mean light peak/dark trough ratio in Usher type I carriers compared to normal control individuals. The methods used in this study were found not to be specific enough to clinically identify carriers of Usher type I syndrome. Nevertheless it is remarkable that a number of obligate carriers showed significant audiological and ophthalmological abnormalities. 29 refs., 1 fig., 3 tabs.

  13. Type 1 diabetes and polyglandular autoimmune syndrome: A review

    PubMed Central

    Hansen, Martin P; Matheis, Nina; Kahaly, George J

    2015-01-01

    Type 1 diabetes (T1D) is an autoimmune disorder caused by inflammatory destruction of the pancreatic tissue. The etiopathogenesis and characteristics of the pathologic process of pancreatic destruction are well described. In addition, the putative susceptibility genes for T1D as a monoglandular disease and the relation to polyglandular autoimmune syndrome (PAS) have also been well explored. The incidence of T1D has steadily increased in most parts of the world, especially in industrialized nations. T1D is frequently associated with autoimmune endocrine and non-endocrine diseases and patients with T1D are at a higher risk for developing several glandular autoimmune diseases. Familial clustering is observed, which suggests that there is a genetic predisposition. Various hypotheses pertaining to viral- and bacterial-induced pancreatic autoimmunity have been proposed, however a definitive delineation of the autoimmune pathomechanism is still lacking. In patients with PAS, pancreatic and endocrine autoantigens either colocalize on one antigen-presenting cell or are expressed on two/various target cells sharing a common amino acid, which facilitates binding to and activation of T cells. The most prevalent PAS phenotype is the adult type 3 variant or PAS type III, which encompasses T1D and autoimmune thyroid disease. This review discusses the findings of recent studies showing noticeable differences in the genetic background and clinical phenotype of T1D either as an isolated autoimmune endocrinopathy or within the scope of polyglandular autoimmune syndrome. PMID:25685279

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

    PubMed

    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

  15. Paradoxical hypertension and salt wasting in Type II Bartter syndrome.

    PubMed

    Chan, Winnie Kwai-Yu; To, Ka Fai; Tong, Joanna H M; Law, Chi Wai

    2012-06-01

    Ante/neonatal Bartter syndrome (BS) is a rare hereditary disorder. It is characterized by renal salt wasting, hypokalaemic metabolic alkalosis, high renin and aldosterone but normal blood pressure. We report a low birth weight newborn baby who presented with repeated apnoea shortly after birth as well as hyponatraemia, hypochloraemia, hyperkalaemia and metabolic acidosis. Her biochemical features mimicked pseudohypoaldosteronism but with initial hypertension, which had not been described in BS. Her subsequent genetic study confirmed two novel heterozygous mutations in the Exon 5 of KCNJ1 compatible with Type II BS. PMID:26069767

  16. Skeletal abnormalities of tricho-rhino-phalangeal syndrome type I.

    PubMed

    de Barros, Guilherme Monteiro; Kakehasi, Adriana Maria

    2016-01-01

    The tricho-rhino-phalangeal syndrome (TRPS) type I is a rare genetic disorder related to the TRPS1 gene mutation in chromosome 8, characterized by craniofacial abnormalities and disturbances in formation and maturation of bone matrix. The hallmarks are sparse and brittle hair, tendency to premature baldness, bulbous nose called pear-shaped, long and flat filter and low ear implantation. The most noticeable skeletal changes are clinodactyly, phalangeal epiphyses of the hands appearing as cone-shaped, short stature and hip joint malformations. We report a case of a teenager boy diagnosed with TRPS and referred for rheumatologic evaluation due to joint complaints. PMID:27267340

  17. Difficulty eating and significant weight loss in joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type.

    PubMed

    Baeza-Velasco, Carolina; Van den Bossche, Thomas; Grossin, Daniel; Hamonet, Claude

    2016-06-01

    Joint Hypermobility Syndrome, also known as Ehlers-Danlos Syndrome Hypermobility Type (JHS/EDS-HT), is a heritable disorder of connective tissue, common but poorly known by the medical community. Although generalized joint hypermobility and fragility of tissues have been described as core features, recent research highlights the multisystemic nature of JHS/EDS-HT, which presents with a wide range of articular and extra-articular symptoms. Among these, gastrointestinal problems, temporomandibular disorders, and smell and taste abnormalities are common among those affected, having significant implications for eating. The present work reviews the literature linking JHS/EDS-HT and eating problems. Two illustrative case reports, in which JHS/EDS-HT manifestations contribute to developing and maintaining disturbed eating behaviors and significant weight loss, are presented. PMID:26506923

  18. A neurodystrophic syndrome resembling carbohydrate-deficient glycoprotein syndrome type III.

    PubMed

    Stibler, H; Gylje, H; Uller, A

    1999-04-01

    A 10-month old girl is described with a serum transferrin isoform abnormality of the same kind as in two previously reported girls with carbohydrate-deficient glycoprotein syndrome type III. This patient presented with joint abnormalities and rapidly developing hypsarrhythmia, hypotonia, psychomotor delay and growth retardation. Fingers, toes, nails and local skin were dysmorphic. She had pale optic discs, thoracic syringomyelia and frontal lobe atrophy at three months. The CDT value in serum was greatly elevated. Several carbohydrate-deficient isoforms were found in transferrin (four), alpha1-antitrypsin (three), antithrombin (two) and thyroxine-binding globulin (four). Mutations in the CDGS 1-gene were excluded. The CDGS III glycoprotein abnormality most probably represents a distinct disorder of glycoprotein metabolism, and needs to be considered in unclear hypsarrhythmia with developmental delay. Dysmorphic features may be added to this syndrome. PMID:10401691

  19. Anisometropic amblyopia in a case of type 2 Waardenburg syndrome.

    PubMed

    Akal, Ali; Göncü, Tugba; Boyaci, Nurefsan; Yılmaz, Ömer Faruk

    2013-01-01

    This study presents a case of an 8-year-old boy with iris heterochromia and anisometropic amblyopia who was diagnosed with Waardenburg syndrome (WS) type 2. An ophthalmic examination revealed iris heterochromia and anisometropic amblyopia in our patient. In the systemic examination, a white forelock and vitiligo on the arms and body were observed and neurosensory hearing loss was revealed, for which the patient used hearing aids. Identification and typing of patients with WS is crucial to address neurosensory hearing loss, glaucoma and fundus changes. While it might be challenging to communicate with a patient with speech and hearing problems, visual acuity should be examined carefully and probable amblyopia should be identified. Anterior segment changes and signs of glaucoma should also be evaluated in detail. PMID:24351514

  20. Ehlers-Danlos Syndrome Type IV: A Case Report.

    PubMed

    Soo-Hoo, Sarah; Porten, Brandon R; Engstrom, Bjorn I; Skeik, Nedaa

    2016-04-01

    Ehlers-Danlos syndrome (EDS) encompasses a group of rare genetic connective tissue disorders. The vascular type (type IV) poses the most serious risk to patients. Diagnosis is usually difficult, especially if patients lack a family history. Life-threatening vascular emergency such as dissection or rupture can be the first presenting symptom. Management of the disease can pose a clinical challenge due to the emergency of presentation, tissue friability, and lack of clear management recommendations. We report a unique case of a 40-year-old man who presented with a ruptured celiac artery and a strong family history of EDS. This case highlights the difficulties and complications associated with treating this uncommon and serious disease. PMID:26975607

  1. Genetics Home Reference: Jervell and Lange-Nielsen syndrome

    MedlinePlus

    ... heartbeats increase the risk of fainting (syncope) and sudden death. Related Information What does it mean if a ... list from the University of Kansas Medical Center Sudden Arrhythmia Death Syndromes (SADS) Foundation: Long QT Syndrome GeneReviews (1 ...

  2. Generalized joint hypermobility, joint hypermobility syndrome and Ehlers-Danlos syndrome, hypermobility type.

    PubMed

    Castori, Marco; Colombi, Marina

    2015-03-01

    This issue of the American Journal of Medical Genetics Seminar Series Part C is dedicated to generalized joint hypermobility (gJHM), joint hypermobility syndrome (JHS), and Ehlers-Danlos syndrome, hypermobility type (EDS-HT). gJHM is the best known clinical manifestation of inherited defects of the connective tissue. On the other side, JHS and EDS-HT are actually considered one and the same from a clinical perspective by most practitioners and researchers (i.e., JHS/EDS-HT), and their molecular basis remains unknown. For decades, "non-syndromic" gJHM and JHS/EDS-HT have been thought to be simple clinical curiosities or an asset for the "affected" individual. In recent years, the attention on these partially overlapping phenotypes has increased, as they are now recognized risk factors for a series of non-communicable diseases and long-term disabilities. This series consists of 10 papers focused on three main topics, namely (i) assessment and differential diagnosis of children and adults with gJHM, (ii) systematic presentation of selected key non-articular manifestations of JHS/EDS-HT and actual perception of physiotherapy as the best therapeutic resource for this condition, and (iii) exploration of the available knowledge relating "congenital laxity of tissues" to various dysfunctions of the nervous system during development and adulthood. The contributors hope that this collection raises attention to this fascinating field of knowledge, which seems to have ramifications in virtually all medical disciplines. PMID:25821089

  3. Relationship between fatigue and gait abnormality in joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type.

    PubMed

    Celletti, Claudia; Galli, Manuela; Cimolin, Veronica; Castori, Marco; Albertini, Giorgio; Camerota, Filippo

    2012-01-01

    Ehlers-Danlos syndrome (EDS) is a clinically and genetically heterogeneous group of inherited connective tissue disorders characterised by joint hypermobility, skin hyperextensibility and tissue fragility. It has recently been shown that muscle weakness occurs frequently in EDS, and that fatigue is a common and clinically important symptom. The aim of this study was to investigate the relationship between fatigue severity and the gait pattern using 3D Gait Analysis (GA). Eleven individuals with Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome Hypermobility type (JHS/EDS-HT) were investigated using muscle strength measured with standardised questionnaire measuring fatigue (Fatigue Severity Scale, FSS) and quantitative 3D GA. Our data showed that FSS value well correlated with the peak of vertical component of ground reaction force (r=-0.66, p<0.05). The negative correlation gives evidence that the higher the fatigue is the more reduced force is during gait. Our results showed that the ground reaction force has been applied as a functional evaluation score for detecting pathology in gait of JHS/EDS-HT participants and the found correlation between vertical force and fatigue demonstrated that muscle fatigue may be associated with a loss of proprioceptive acuity in lower limb muscles. PMID:22819599

  4. Mutations in PIEZO2 Cause Gordon Syndrome, Marden-Walker Syndrome, and Distal Arthrogryposis Type 5

    PubMed Central

    McMillin, Margaret J.; Beck, Anita E.; Chong, Jessica X.; Shively, Kathryn M.; Buckingham, Kati J.; Gildersleeve, Heidi I.S.; Aracena, Mariana I.; Aylsworth, Arthur S.; Bitoun, Pierre; Carey, John C.; Clericuzio, Carol L.; Crow, Yanick J.; Curry, Cynthia J.; Devriendt, Koenraad; Everman, David B.; Fryer, Alan; Gibson, Kate; Giovannucci Uzielli, Maria Luisa; Graham, John M.; Hall, Judith G.; Hecht, Jacqueline T.; Heidenreich, Randall A.; Hurst, Jane A.; Irani, Sarosh; Krapels, Ingrid P.C.; Leroy, Jules G.; Mowat, David; Plant, Gordon T.; Robertson, Stephen P.; Schorry, Elizabeth K.; Scott, Richard H.; Seaver, Laurie H.; Sherr, Elliott; Splitt, Miranda; Stewart, Helen; Stumpel, Constance; Temel, Sehime G.; Weaver, David D.; Whiteford, Margo; Williams, Marc S.; Tabor, Holly K.; Smith, Joshua D.; Shendure, Jay; Nickerson, Deborah A.; Bamshad, Michael J.

    2014-01-01

    Gordon syndrome (GS), or distal arthrogryposis type 3, is a rare, autosomal-dominant disorder characterized by cleft palate and congenital contractures of the hands and feet. Exome sequencing of five GS-affected families identified mutations in piezo-type mechanosensitive ion channel component 2 (PIEZO2) in each family. Sanger sequencing revealed PIEZO2 mutations in five of seven additional families studied (for a total of 10/12 [83%] individuals), and nine families had an identical c.8057G>A (p.Arg2686His) mutation. The phenotype of GS overlaps with distal arthrogryposis type 5 (DA5) and Marden-Walker syndrome (MWS). Using molecular inversion probes for targeted sequencing to screen PIEZO2, we found mutations in 24/29 (82%) DA5-affected families and one of two MWS-affected families. The presence of cleft palate was significantly associated with c.8057G>A (Fisher’s exact test, adjusted p value < 0.0001). Collectively, although GS, DA5, and MWS have traditionally been considered separate disorders, our findings indicate that they are etiologically related and perhaps represent variable expressivity of the same condition. PMID:24726473

  5. Chronic pain in hypermobility syndrome and Ehlers–Danlos syndrome (hypermobility type): it is a challenge

    PubMed Central

    Scheper, Mark C; de Vries, Janneke E; Verbunt, Jeanine; Engelbert, Raoul HH

    2015-01-01

    Generalized joint hypermobility (GJH) is highly prevalent among patients diagnosed with chronic pain. When GJH is accompanied by pain in ≥4 joints over a period ≥3 months in the absence of other conditions that cause chronic pain, the hypermobility syndrome (HMS) may be diagnosed. In addition, GJH is also a clinical sign that is frequently present in hereditary diseases of the connective tissue, such as the Marfan syndrome, osteogenesis imperfecta, and the Ehlers–Danlos syndrome. However, within the Ehlers–Danlos spectrum, a similar subcategory of patients having similar clinical features as HMS but lacking a specific genetic profile was identified: Ehlers–Danlos syndrome hypermobility type (EDS-HT). Researchers and clinicians have struggled for decades with the highly diverse clinical presentation within the HMS and EDS-HT phenotypes (Challenge 1) and the lack of understanding of the pathological mechanisms that underlie the development of pain and its persistence (Challenge 2). In addition, within the HMS/EDS-HT phenotype, there is a high prevalence of psychosocial factors, which again presents a difficult issue that needs to be addressed (Challenge 3). Despite recent scientific advances, many obstacles for clinical care and research still remain. To gain further insight into the phenotype of HMS/EDS-HT and its mechanisms, clearer descriptions of these populations should be made available. Future research and clinical care should revise and create consensus on the diagnostic criteria for HMS/EDS-HT (Solution 1), account for clinical heterogeneity by the classification of subtypes within the HMS/EDS-HT spectrum (Solution 2), and create a clinical core set (Solution 3). PMID:26316810

  6. Chronic pain in hypermobility syndrome and Ehlers-Danlos syndrome (hypermobility type): it is a challenge.

    PubMed

    Scheper, Mark C; de Vries, Janneke E; Verbunt, Jeanine; Engelbert, Raoul Hh

    2015-01-01

    Generalized joint hypermobility (GJH) is highly prevalent among patients diagnosed with chronic pain. When GJH is accompanied by pain in ≥4 joints over a period ≥3 months in the absence of other conditions that cause chronic pain, the hypermobility syndrome (HMS) may be diagnosed. In addition, GJH is also a clinical sign that is frequently present in hereditary diseases of the connective tissue, such as the Marfan syndrome, osteogenesis imperfecta, and the Ehlers-Danlos syndrome. However, within the Ehlers-Danlos spectrum, a similar subcategory of patients having similar clinical features as HMS but lacking a specific genetic profile was identified: Ehlers-Danlos syndrome hypermobility type (EDS-HT). Researchers and clinicians have struggled for decades with the highly diverse clinical presentation within the HMS and EDS-HT phenotypes (Challenge 1) and the lack of understanding of the pathological mechanisms that underlie the development of pain and its persistence (Challenge 2). In addition, within the HMS/EDS-HT phenotype, there is a high prevalence of psychosocial factors, which again presents a difficult issue that needs to be addressed (Challenge 3). Despite recent scientific advances, many obstacles for clinical care and research still remain. To gain further insight into the phenotype of HMS/EDS-HT and its mechanisms, clearer descriptions of these populations should be made available. Future research and clinical care should revise and create consensus on the diagnostic criteria for HMS/EDS-HT (Solution 1), account for clinical heterogeneity by the classification of subtypes within the HMS/EDS-HT spectrum (Solution 2), and create a clinical core set (Solution 3). PMID:26316810

  7. Drug-induced QT interval prolongation: mechanisms and clinical management

    PubMed Central

    Nachimuthu, Senthil; Assar, Manish D.

    2012-01-01

    The prolonged QT interval is both widely seen and associated with the potentially deadly rhythm, Torsades de Pointes (TdP). While it can occur spontaneously in the congenital form, there is a wide array of drugs that have been implicated in the prolongation of the QT interval. Some of these drugs have either been restricted or withdrawn from the market due to the increased incidence of fatal polymorphic ventricular tachycardia. The list of drugs that cause QT prolongation continues to grow, and an updated list of specific drugs that prolong the QT interval can be found at www.qtdrugs.org. This review focuses on the mechanism of drug-induced QT prolongation, risk factors for TdP, culprit drugs, prevention and monitoring of prolonged drug-induced QT prolongation and treatment strategies. PMID:25083239

  8. Drug-induced QT interval prolongation: does ethnicity of the thorough QT study population matter?

    PubMed Central

    Shah, Rashmi R

    2013-01-01

    Inter-ethnic differences in drug responses have been well documented. Drug-induced QT interval prolongation is a major safety concern and therefore, regulatory authorities recommend a clinical thorough QT study (TQT) to investigate new drugs for their QT-prolonging potential. A positive study, determined by breach of a preset regulatory threshold, significantly influences late phase clinical trials by requiring intense ECG monitoring. A few studies that are currently available, although not statistically conclusive at present, question the assumption that ethnicity of the study population may not influence the outcome of a TQT study. Collective consideration of available pharmacogenetic and clinical information suggests that there may be inter-ethnic differences in QT-prolonging effects of drugs and that Caucasians may be more sensitive than other populations. The information also suggest s that (a) these differences may depend on the QT-prolonging potency of the drug and (b) exposure–response (E–R) analysis may be more sensitive than simple changes in QTc interval in unmasking this difference. If the QT response in Caucasians is generally found to be more intense than in non-Caucasians, there may be significant regulatory implications for domestic acceptance of data from a TQT study conducted in foreign populations. However, each drug will warrant an individual consideration when extrapolating the results of a TQT studyfrom one ethnic population to another and the ultimate clinical relevance of any difference. Further adequately designed and powered studies, investigating the pharmacologic properties and E–R relationships of additional drugs with different potencies, are needed in Caucasians, Oriental/Asian and African populations before firm conclusions can be drawn. PMID:22882246

  9. Targeted Exon Sequencing in Usher Syndrome Type I

    PubMed Central

    Bujakowska, Kinga M.; Consugar, Mark; Place, Emily; Harper, Shyana; Lena, Jaclyn; Taub, Daniel G.; White, Joseph; Navarro-Gomez, Daniel; Weigel DiFranco, Carol; Farkas, Michael H.; Gai, Xiaowu; Berson, Eliot L.; Pierce, Eric A.

    2014-01-01

    Purpose. Patients with Usher syndrome type I (USH1) have retinitis pigmentosa, profound congenital hearing loss, and vestibular ataxia. This syndrome is currently thought to be associated with at least six genes, which are encoded by over 180 exons. Here, we present the use of state-of-the-art techniques in the molecular diagnosis of a cohort of 47 USH1 probands. Methods. The cohort was studied with selective exon capture and next-generation sequencing of currently known inherited retinal degeneration genes, comparative genomic hybridization, and Sanger sequencing of new USH1 exons identified by human retinal transcriptome analysis. Results. With this approach, we were able to genetically solve 14 of the 47 probands by confirming the biallelic inheritance of mutations. We detected two likely pathogenic variants in an additional 19 patients, for whom family members were not available for cosegregation analysis to confirm biallelic inheritance. Ten patients, in addition to primary disease–causing mutations, carried rare likely pathogenic USH1 alleles or variants in other genes associated with deaf-blindness, which may influence disease phenotype. Twenty-one of the identified mutations were novel among the 33 definite or likely solved patients. Here, we also present a clinical description of the studied cohort at their initial visits. Conclusions. We found a remarkable genetic heterogeneity in the studied USH1 cohort with multiplicity of mutations, of which many were novel. No obvious influence of genotype on phenotype was found, possibly due to small sample sizes of the genotypes under study. PMID:25468891

  10. [Otoneurologic symptoms associated with Arnold-Chiari syndrome type I].

    PubMed

    Urban, Irena; Namysłowski, Grzegorz; Morawski, Krzysztof; Wojtacha, Maciej

    2004-01-01

    This study presents two cases of Arnold-Chiari malformation type I. In a 26-year old man, right side deafness and left side sensorineural hearing loss at high frequencies occurred. Another patient, a 48-year old man also complained of sensorineural hearing loss and dizziness, that appeared a year and half ago. In addition, this patient had episodes of vertigo with nausea and vomit that occurred about one year before main symptoms. In both patients ENT examinations were performed as well as an audiological diagnostic battery including tonal- and impedance-audiometry, auditory brainstem responses, distortion product otoacoustic emissions and electroencephalography. Magnetic resonance imaging (MRI) showed pathological changes in the cerebello-pontine angle region that allowed diagnosing Arnold-Chiari malformation in both cases. Additionally, angio-MRI performed in patient with right side deafness revealed cochleovestibular nerve compression syndrome on the same side. Presumably, both anomalies occurring simultaneously in this patient might be responsible for deafness in the right ear, instead of mild or moderate hearing loss and tinnitus usually expected according to the literature. The paper presented two cases of Arnold-Chiari malformation with co-existing cochleovestibular nerve compression syndrome in one case. The importance of both audiological diagnostic battery and MRI in diagnostic procedures of this malformation has been demonstrated. PMID:15307473

  11. Acute Type A Aortic Dissection Missed as Acute Coronary Syndrome

    PubMed Central

    Ansari-Ramandi, Mohammad Mostafa; Firoozi, Ata

    2016-01-01

    Although the aortic dissection is not common, its outcome is frequently fatal, and many patients with aortic dissection die before referral to the hospital or any diagnostic testing. The symptoms of aortic dissection can be similar to myocardial ischemia. A 66-year-old male was referred to our hospital with suspicion of aortic dissection after echocardiography done for evaluating his high blood pressure. He had symptoms of acute coronary syndrome two years before and had done coronary angiography. On presentation to our hospital he had a high blood pressure. On reviewing his past medical history and examining, in the film of coronary angiography, the dissection flap in ascending aorta was identified. Although type A aortic dissection is a catastrophic condition with high mortality and requires prompt surgical treatment but in some cases it may be misdiagnosed as acute coronary syndrome. Sometimes against its high mortality when left untreated, patients survive and are diagnosed later in life incidentally. So it is of great importance to have great clinical suspicion for aortic dissection in patients referring to the hospital with chest pain and the predisposing factors. PMID:27437290

  12. Hermansky-Pudlak syndrome type 4 with interstitial pneumonia.

    PubMed

    Sakata, Yoshihiko; Kawamura, Kodai; Ichikado, Kazuya; Suga, Moritaka; Yoshioka, Masakazu

    2013-01-01

    Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by oculocutaneous albinism, bleeding tendency, and lysosomal accumulation of ceroid-like material, with occasional development of interstitial pneumonia (IP). Nine genetically distinct subtypes of HPS are known in humans; IP develops primarily in types 1 and 4. Most reported cases of HPS with IP are type 1, and there are no published reports of type 4 in Japanese individuals. A 58-year-old man with congenital oculocutaneous albinism and progressive dyspnea for 1 month was admitted to our hospital. We administered high-dose corticosteroids on the basis of a diagnosis of acute exacerbation of interstitial pneumonia. Respiratory symptoms and the findings of high-resolution computed tomography (CT) showed improvement. He was diagnosed with HPS type 4 with interstitial pneumonia on the basis of gene analysis. He has been receiving pirfenidone for 1 year and his condition is stable. This is the first report on the use of pirfenidone for HPS with IP caused by a novel mutation in the HPS4 gene. We conclude that HPS should be suspected in patients with albinism and interstitial pneumonia. High-dose corticosteroid treatment may be useful in cases of acute exacerbation of interstitial pneumonia due to HPS-4, and pirfenidone may be useful and well tolerated in patients with HPS-4. PMID:26029628

  13. Creation of a knowledge management system for QT analyses.

    PubMed

    Tornøe, Christoffer W; Garnett, Christine E; Wang, Yaning; Florian, Jeffry; Li, Michael; Gobburu, Jogarao V

    2011-07-01

    An increasing number of thorough QT (TQT) reports are being submitted to the US Food and Drug Administration's interdisciplinary review team for QT (IRT-QT), requiring time-intensive quantitative analyses by a multidisciplinary review team within 45 days. This calls for systematic learning to guide future trials and policies by standardizing and automating the QT analyses to improve review efficiency, provide consistent advice, and enable pooled data analyses to answer key regulatory questions. The QT interval represents the time from initiation of ventricular depolarization to completion of ventricular repolarization recorded by electrocardiograph (ECG) and is used in the proarrhythmic risk assessment. The developed QT knowledge management system is implemented in the R package "QT." Data from 11 crossover TQT studies including time-matched ECGs and pharmacokinetic measurements following single doses of 400 to 1200 mg moxifloxacin were used for the QT analysis example. The automated workflow was divided into 3 components (data management, analysis, and archival). The generated data sets, scripts, tables, and graphs are automatically stored in a queryable repository and summarized in an analysis report. More than 100 TQT studies have been analyzed using the system since 2007. This has dramatically reduced the time needed to review TQT studies and has made the IRT-QT reviews consistent across reviewers. Furthermore, the system enables leveraging prior knowledge through pooled data analyses to answer policy-related questions and to understand the various effects that influence study results. PMID:20978278

  14. Ehlers-Danlos Syndrome Type VIIC: A Mexican Case Report.

    PubMed

    Rincón-Sánchez, Ana Rosa; Arce, Irma Elia; Tostado-Rabago, Enrique Alejandro; Vargas, Alberto; Padilla-Gómez, Luis Alfredo; Bolaños, Alejandro; Barrios-Guyot, Selenne; Anguiano-Alvarez, Víctor Manuel; Ledezma-Rodríguez, Víctor Chistian; Islas-Carbajal, María Cristina; Rivas-Estilla, Ana María; Feria-Velasco, Alfredo; Dávalos, Nory Omayra

    2012-01-01

    Ehlers-Danlos syndrome (EDS) is a heterogeneous group of heritable connective tissue disorders whose primary clinical features include soft and extensible skin, articular hypermobility and tissue fragility. EDS type VIIC or 'human dermatosparaxis' is an autosomal recessive disease characterized by severe skin fragility and sagging redundant skin (major criteria) with a soft, doughy texture, easy bruising, premature rupture of fetal membranes and large hernias (minor criteria). Dermatosparaxis (meaning 'tearing of skin'), which has been described in several non-human species, is a disorder of the connective tissue resulting from a deficiency of the enzyme that cleaves the registration peptide off the N-terminal end of collagen after it has been secreted from fibroblasts. We describe a Mexican case from consanguineous parents with all the phenotypical characteristics previously described, plus skeletal abnormalities. PMID:22787447

  15. Acquired hemophilia complicated by cardiorenal syndrome type 3

    PubMed Central

    Sharma, Rakesh; Dash, Sananta Kumar; Chawla, Rajesh; Kansal, Sudha; Agrawal, Devender Kumar; Dua, Harsh

    2013-01-01

    Development of autoantibodies against coagulation factor VIII (FVIII) leads to a rare condition defined as acquired hemophilia (AH). If not diagnosed and treated early, AH may be associated with high mortality and morbidity. A 65-year-old woman presented with history of macrohematuria, acute renal failure, cardiogenic shock, and acute respiratory failure. Blood investigation revealed azotemia, prolonged activated partial thromboplastin time (aPTT), coagulation FVIII level of <1%, and presence of FVIII inhibitor. Echocardiography showed global hypokinesia and ultrasonography and computed tomography (CT) revealed bilateral hydroureteronephrosis. The final diagnosis was acquired hemophilia A, complicated by acute obstructive renal failure and cardiorenal syndrome (CRS) type 3. Patient was managed with mechanical ventilation, heparin-free hemodialysis, negative fluid balance, recombinant activated factor VII, and prednisolone. Hematuria was relieved, renal function improved, and cardiac function showed improvement on repeat echocardiography. Patient was discharged on prednisolone with subsequent follow ups. PMID:24501492

  16. Hypnosis for postpolio syndrome & Type-A behavior.

    PubMed

    Hammond, D C

    1991-07-01

    Many of the hundreds of thousands of survivors of polio are now developing postpolio syndrome. Symptoms include progressive muscle weakness, fatigue, decreased endurance, joint and muscle pain, weight gain, respiratory difficulties, and sleep disturbance, often precipitated or exacerbated by a Type-A Personality pattern. A postpolio patient with Type-A Personality was taught self-hypnosis as a vital component of treatment. Pre-post testing included the Profile of Mood States, the State-Trait Anxiety Inventory, the State-Trait Anger Inventory, and the Personal Orientation Inventory; the patient's spouse was interviewed during the follow-up. At the 6-month follow-up, improvements were documented in pain level, depression, self-regard, self-acceptance, capacity for intimate contact, time competence (living in the present), confusion, anxiety, insomnia, and in trait and state anger. Only a mild improvement occurred in fatigue, and no improvement was found in weight control. Follow-up at 12 months confirmed the maintenance of improvements. Self-hypnosis training may prove extremely helpful for postpolio patients and may prove helpful in modifying central characteristics of Type-A Personality. PMID:1951142

  17. Gastrointestinal and nutritional issues in joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type.

    PubMed

    Castori, Marco; Morlino, Silvia; Pascolini, Giulia; Blundo, Carlo; Grammatico, Paola

    2015-03-01

    Gastrointestinal involvement is a well known complication of Ehlers-Danlos syndromes (EDSs), mainly in form of abdominal emergencies due to intestinal/abdominal vessels rupture in vascular EDS. In the last decade, a growing number of works investigated the relationship between a wide spectrum of chronic gastrointestinal complaints and various EDS forms, among which the hypermobility type (a.k.a. joint hypermobility syndrome; JHS/EDS-HT) was the most studied. The emerging findings depict a major role for gastrointestinal involvement in the health status and, consequently, management of JHS/EDS-HT patients. Nevertheless, fragmentation of knowledge limits its impact on practice within the boundaries of highly specialized clinics. In this paper, literature review on gastrointestinal manifestations in JHS/EDS-HT was carried out and identified papers categorized as (i) case-control/cohort studies associating (apparently non-syndromic) joint hypermobility and gastrointestinal involvement, (ii) case-control/cohort studies associating JHS/EDS-HT and gastrointestinal involvement, (iii) case reports/series on various gastrointestinal complications in (presumed) JHS/EDS-HT, and (iv) studies reporting gastrointestinal features in heterogeneous EDS patients' cohorts. Gastrointestinal manifestations of JHS/EDS-HT were organized and discussed in two categories, including structural anomalies (i.e., abdominal/diaphragmatic hernias, internal organ/pelvic prolapses, intestinal intussusceptions) and functional features (i.e., dysphagia, gastro-esophageal reflux, dyspepsia, recurrent abdominal pain, constipation/diarrhea), with emphasis on practice and future implications. In the second part of this paper, a summary of possible nutritional interventions in JHS/EDS-HT was presented. Supplementation strategies were borrowed from data available for general population with minor modifications in the light of recent discoveries in the pathogenesis of selected JHS/EDS-HT features. PMID

  18. Neurodevelopmental attributes of joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type: Update and perspectives.

    PubMed

    Ghibellini, Giulia; Brancati, Francesco; Castori, Marco

    2015-03-01

    In the last decade, increasing attention has been devoted to the extra-articular and extra-cutaneous manifestations of joint hypermobility syndrome, also termed Ehlers-Danlos syndrome, hypermobility type (i.e., JHS/EDS-HT). Despite the fact that the current diagnostic criteria for both disorders remain focused on joint hypermobility, musculoskeletal pain and skin changes, medical practice and research have started investigating a wide spectrum of visceral, neurological and developmental complications, which represent major burdens for affected individuals. In particular, children with generalized joint hypermobility often present with various neurodevelopmental issues and can be referred for neurological consultation. It is common that investigations in these patients yield negative or inconsistent results, eventually leading to the exclusion of any structural neurological or muscle disorder. In the context of specialized clinics for connective tissue disorders, a clear relationship between generalized joint hypermobility and a characteristic neurodevelopmental profile affecting coordination is emerging. The clinical features of these patients tend to overlap with those of developmental coordination disorder and can be associated with learning and other disabilities. Physical and psychological consequences of these additional difficulties add to the chief manifestations of the pre-existing connective tissue disorder, affecting the well-being and development of children and their families. In this review, particular attention is devoted to the nature of the link between joint hypermobility, coordination difficulties and neurodevelopmental issues in children. Presumed pathogenesis and management issues are explored in order to attract more attention on this association and nurture future clinical research. PMID:25654988

  19. Gait strategy in patients with Ehlers-Danlos syndrome hypermobility type and Down syndrome.

    PubMed

    Rigoldi, Chiara; Galli, Manuela; Cimolin, Veronica; Camerota, Filippo; Celletti, Claudia; Tenore, Nunzio; Albertini, Giorgio

    2012-01-01

    People suffering from Ehlers-Danlos syndrome (EDS) hypermobility type present a severe ligament laxity that results in difficulties in muscle force transmission. The same condition is present in people suffering from Down syndrome (DS) even if their clumsy movements are due to cerebral and cognitive impairments. The aim of this study was to quantify the gait patterns of subjects with EDS and with DS using Gait Analysis (GA). We quantified the gait strategy in 12 EDS individuals and in 16 participants with DS. Both pathological groups were compared to 20 age-matched healthy controls in terms of kinematics and kinetics. Results showed that DS individuals are characterized by a more compromised gait pattern than EDS participants, even if both groups are characterized by joint hypermobility. All the patients showed significant decreased of ankle stiffness probably due to congenital hypotonia and ligament laxity, while different values of hip stiffness. These findings help to elucidate the complex biomechanical changes due to joint hypermobility and may have a major role in the multidimensional evaluation and tailored management of these patients. PMID:22522202

  20. Joint hypermobility syndrome (a.k.a. Ehlers-Danlos Syndrome, Hypermobility Type): an updated critique.

    PubMed

    Castori, M

    2013-02-01

    Joint hypermobility syndrome, alternatively termed Ehlers-Danlos syndrome hypermobility type (JHS/EDS-HT), is likely the most common, though the least recognized heritable connective tissue disorder. While its leading clinical features typically affect joints, recent evidence indicates a wider spectrum of satellite symptoms/dysfunctions, involving practically all major systems and organs. Accordingly, clinical research on JHS/EDS-HT is moving from rheumatology and clinical genetics to other disciplines, including neurology, clinical psychology, ophthalmology, cardiology and gynecology/obstetrics. As the skin is one of the most commonly affected and, surely, the easiest to assess body part in heritable connective tissue disorders, it is expected that also the dermatologist should be trained to recognize this condition. In this review, JHS/EDS-HT is presented and discussed in separate sections dedicated to all major aspects of diagnosis, differential diagnosis, clinical features, natural history and principles of management. Particular attention is posed on the role of epidermal, dermal and mucosal assessment in JHS/EDS-HT is order to rise the attention to a series of too neglected, though quite common manifestations of this condition. Management principles are presented with a multidisciplinary approach in mind, covering pharmacologic, physical and occupational therapy, surgical, and nutriceutical aspects, as well as general lifestyle recommendations. Connections with organs and systems other than joints and skin are also discussed. PMID:23407074

  1. Realtime Multichannel System for Beat to Beat QT Interval Variability

    NASA Technical Reports Server (NTRS)

    Starc, Vito; Schlegel, Todd T.

    2006-01-01

    The measurement of beat-to-beat QT interval variability (QTV) shows clinical promise for identifying several types of cardiac pathology. However, until now, there has been no device capable of displaying, in real time on a beattobeat basis, changes in QTV in all 12 conventional leads in a continuously monitored patient. While several software programs have been designed to analyze QTV, heretofore, such programs have all involved only a few channels (at most) and/or have required laborious user interaction or offline calculations and postprocessing, limiting their clinical utility. This paper describes a PC-based ECG software program that in real time, acquires, analyzes and displays QTV and also PQ interval variability (PQV) in each of the eight independent channels that constitute the 12lead conventional ECG. The system also processes certain related signals that are derived from singular value decomposition and that help to reduce the overall effects of noise on the realtime QTV and PQV results.

  2. Four treatment strategies for complex regional pain syndrome type 1.

    PubMed

    Lee, Sang Ki; Yang, Dae Suk; Lee, Jae Won; Choy, Won Sik

    2012-06-01

    Complex regional pain syndrome (CRPS) poses a dilemma for many clinicians due to its unknown etiology and largely unsuccessful treatment modalities. The purpose of this study was to compare the clinical results of 4 treatment modalities for CRPS type 1. A total of 59 patients were divided into 4 groups based on treatment modality: group A, an oral nonsteroidal anti-inflammatory drug (NSAID) (n=10); group B, oral gabapentin (n=12); group C, intravenous (IV) 10% mannitol and steroid (n=11); group D, a combination of IV 20% mannitol and steroid with oral gabapentin (n=26). The patients remained under medical supervision after discharge and were evaluated either once a month or once every 2 months until final follow-up at a mean of 8 months. Patients in group A showed improvement in pain level, finger range of motion, swelling, and grip strength, without statistical significance (P=.076, P=.062, P=.312, and P=.804, respectively). Patients in group B showed significant improvement in pain level (P<.001), and patients in group C showed improvement in pain, finger range of motion, and swelling (P=.127), which rendered functional impairment unchanged. In comparison, patients in group D showed recovery of grip strength and improvement in pain level, finger range of motion, and (P<.001, P=.016, P=.031, and P=.047, respectively). Based on these results, a protocol including a combination of IV 20% mannitol and steroid with oral gabapentin is an acceptable and effective treatment for CRPS type 1. PMID:22691654

  3. The Complex QT/RR Relationship in Mice

    PubMed Central

    Roussel, Julien; Champeroux, Pascal; Roy, Jérôme; Richard, Sylvain; Fauconnier, Jérémy; Le Guennec, Jean-Yves; Thireau, Jérôme

    2016-01-01

    The QT interval reflects the time between the depolarization of ventricles until their repolarization and is usually used as a predictive marker for the occurrence of arrhythmias. This parameter varies with the heart rate, expressed as the RR interval (time between two successive ventricular depolarizations). To calculate the QT independently of the RR, correction formulae are currently used. In mice, the QT-RR relationship as such has never been studied in conscious animals, and correction formulas are mainly empirical. In the present paper we studied how QT varies when the RR changes physiologically (comparison of nocturnal and diurnal periods) or after dosing mice with tachycardic agents (norepinephrine or nitroprusside). Our results show that there is significant variability of QT and RR in a given condition, resulting in the need to average at least 200 consecutive complexes to accurately compare the QT. Even following this method, no obvious shortening of the QT was observed with increased heart rate, regardless of whether or not this change occurs abruptly. In conclusion, the relationship between QT and RR in mice is weak, which renders the use of correction formulae inappropriate and misleading in this species. PMID:27138175

  4. QT dispersion in elderly athletes with left ventricular hypertrophy.

    PubMed

    Galetta, F; Franzoni, F; Santoro, G; Prattichizzo, F; Femia, F R; Pastine, F; Pentimone, F

    2003-05-01

    The purpose of this study was to examine the QT dispersion in elderly endurance athletes with left ventricular (LV) hypertrophy. Sixteen athletes (males, mean age 67.6 +/- 4.5 years) with mild to moderate LV hypertrophy, were compared with 16 age-matched hypertensive patients with similar degree of LV hypertrophy and 16 age-matched healthy sedentary controls. All the participants underwent echocardiogram and 12-lead electrocardiogram. QT dispersion was defined as the difference between maximum and minimum QT intervals in the different leads. QT dispersion was corrected (QTc) for heart rate according to Bazett's formula. The results showed in athletes and hypertensive patients comparable LV mass (258.2 +/- 14.2 vs. 262.4 +/- 16.8 g, ns), which was significantly higher than that of controls (p < 0.001). Trained subjects had QT dispersion (38.6 +/- 10.2 ms) and QTc dispersion (39.4 +/- 11.3 ms) significantly lower than hypertensive patients (QT dispersion: 68.4 +/- 11.4 ms; QTc dispersion: 72.2 +/- 8.4, p < 0.001) and comparable with controls (QT dispersion: 44.3 +/- 8.4 ms; QTc dispersion: 46.2 +/- 6.2 ms, ns). In conclusion, in elderly athletes training-induced myocardial hypertrophy was characterized by a QT dispersion significantly lower than hypertensive myocardial hypertrophy. This could provide a simple and inexpensive screening method for differentiating physiologic from pathologic myocardial hypertrophy in elderly subjects. PMID:12784163

  5. QT prolongation and torsades de pointes with psychotropic agents

    PubMed Central

    Desai, Nagaraj; Venkatesh, Chilkunda Raviprakash; Kumar, Shambu Sunil

    2015-01-01

    The unexpected and catastrophic cardiovascular effects of psychotropic drugs are well described albeit uncommon. The list of drugs which have been associated with prolonging QT interval and hence potentially causing Torsades de pointes is exhaustive. The insight into the plausible mechanisms are largely unclear. However, the practical implications of anticipating and recognizing QT prolongation cannot be overemphasized. PMID:26600587

  6. Hearing dysfunction in heterozygous Mitf(Mi-wh) /+ mice, a model for Waardenburg syndrome type 2 and Tietz syndrome.

    PubMed

    Ni, Christina; Zhang, Deming; Beyer, Lisa A; Halsey, Karin E; Fukui, Hideto; Raphael, Yehoash; Dolan, David F; Hornyak, Thomas J

    2013-01-01

    The human deafness-pigmentation syndromes, Waardenburg syndrome (WS) type 2a, and Tietz syndrome are characterized by profound deafness but only partial cutaneous pigmentary abnormalities. Both syndromes are caused by mutations in MITF. To illuminate differences between cutaneous and otic melanocytes in these syndromes, their development and survival in heterozygous Microphthalmia-White (Mitf(Mi-wh) /+) mice were studied and hearing function of these mice characterized. Mitf(Mi-wh) /+ mice have a profound hearing deficit, characterized by elevated auditory brainstem response thresholds, reduced distortion product otoacoustic emissions, absent endocochlear potential, loss of outer hair cells, and stria vascularis abnormalities. Mitf(Mi-wh) /+ embryos have fewer melanoblasts during embryonic development than their wild-type littermates. Although cochlear melanocytes are present at birth, they disappear from the Mitf(Mi-wh) /+ cochlea between P1 and P7. These findings may provide insight into the mechanism of melanocyte and hearing loss in human deafness-pigmentation syndromes such as WS and Tietz syndrome and illustrate differences between otic and follicular melanocytes. PMID:23020089

  7. Rules for distinguishing toxicants that cause type I and type II narcosis syndromes.

    PubMed

    Veith, G D; Broderius, S J

    1990-07-01

    Narcosis is a nonspecific reversible state of arrested activity of protoplasmic structures caused by a wide variety of organic chemicals. The vast majority of industrial organic chemicals can be characterized by a baseline structure-toxicity relationship as developed for diverse aquatic organisms, using only the n-octanol/water partition coefficient as a descriptor. There are, however, many apparent narcotic chemicals that are more toxic than baseline narcosis predicts. Some of these chemicals have been distinguished as polar narcotics. Joint toxic theory and isobole diagrams were used to show that chemicals strictly additive with phenol were generally more toxic than predicted by narcosis I models and characterized by a different mode of action called narcosis II syndrome. This type of toxicity is exemplified by certain amides, amines, phenols, and nitrogen heterocycles. Evidence is provided that suggests that narcosis II syndrome may result from the presence of a strong hydrogen bonding group on the molecule, and narcosis I syndrome results from hydrophobic bonding of the chemical to enzymes and/or membranes. This shift in toxic action is apparently indistinguishable for narcotic chemicals with log P greater than about 2.7. General rules for selecting the appropriate models are proposed. PMID:2269227

  8. Rules for distinguishing toxicants that cause type I and type II narcosis syndromes

    SciTech Connect

    Veith, G.D.; Broderius, S.J. )

    1990-07-01

    Narcosis is a nonspecific reversible state of arrested activity of protoplasmic structures caused by a wide variety of organic chemicals. The vast majority of industrial organic chemicals can be characterized by a baseline structure-toxicity relationship as developed for diverse aquatic organisms, using only the n-octanol/water partition coefficient as a descriptor. There are, however, many apparent narcotic chemicals that are more toxic than baseline narcosis predicts. Some of these chemicals have been distinguished as polar narcotics. Joint toxic theory and isobole diagrams were used to show that chemicals strictly additive with phenol were generally more toxic than predicted by narcosis I models and characterized by a different mode of action called narcosis II syndrome. This type of toxicity is exemplified by certain amides, amines, phenols, and nitrogen heterocycles. Evidence is provided that suggests that narcosis II syndrome may result from the presence of a strong hydrogen bonding group on the molecule, and narcosis I syndrome results from hydrophobic bonding of the chemical to enzymes and/or membranes. This shift in toxic action is apparently indistinguishable for narcotic chemicals with log P greater than about 2.7. General rules for selecting the appropriate models are proposed.

  9. Analysis of HLA and disease susceptibility: Chromosome 6 genes and sex influence long-QT phenotype

    SciTech Connect

    Weitkamp, L.R.; Moss, A.J.; Hall, W.J.; Robinson, J.L.; Guttormsen, S.A.; Lewis, R.A.; MacCluer, J.W.; Schwartz, P.J.; Locati, E.H.; Tzivoni, D.

    1994-12-01

    The long-QT (LQT) syndrome is a genetically complex disorder that is characterized by syncope and fatal ventricular arrhythmias. LQT syndrome, as defined by a prolonged electrocardiographic QT interval, has a higher incidence in females than in males and does not exhibit Mendelian transmission patterns in all families. Among those families that are nearly consistent with Mendelian transmission, linkage between a locus for LQT syndrome and the H-ras-1 locus on the short arm of chromosome 11 has been reported in some families but not in others. Earlier analyses suggesting that LQT syndrome might be caused by a gene in the HLA region of chromosome 6 were not confirmed by standard linkage analyses. Here, we present an analysis of HLA haplotype sharing among affected pedigree members, showing an excess of haplotype sharing in a previously published Japanese pedigree and possibly also in 15 families of European descent. The haplotypes shared by affected individuals derive from both affected and unaffected parents. In an analysis of independent (unrelated) HLA haplotypes, we also found a nonrandom distribution of HLA-DR genes in LQT syndrome patients compared with controls, suggesting an association between the LQT phenotype and specific HLA-DR genes. Our data indicate that DR2 has a protective effect and, particularly in males, that DR7 may increase susceptibility to the LQT syndrome. Thus, LQT syndrome may be influenced by genes on chromosomes 11 and 6, possibly with a sex-specific effect. These results provide a model for an effect of HLA-region genes inherited from either parent on the expression of an illness that may be determined principally by alleles at loci not linked to HLA.

  10. Genetic heterogeneity of usher syndrome type 1 in French families

    SciTech Connect

    Larget-Piet, D.; Gerber, S.; Rozet, J.M. ); Bonneau, D. ); Marc, S.; Weissenbach, J. ); Ghazi, I.; Dufier, J.L. ); David, A. ); Bitoun, P. )

    1994-05-01

    Usher syndrome type 1 (US1) is an autosomal recessive disease characterized by profound congenital hearing impairment with unintelligible speech, early retinitis pigmentosa, and constant vestibular dysfunction. Three localizations have been described in US1: USH1A, 14q32; USH1B, 11q13.5; and USH1C, 11p15. Studying a series of 33 affected individuals belonging to 20 US1 pedigrees of French ancestry, the authors found that none of the three localizations accounted for all US1 families in the series. However, when the sample was split into two groups according to the geographic origin of the probands' grandparents, they were able to confirm the presence of a gene for US1 on chromosome 14q32 (USH1A) in 9 families originating from the Poitou region in Western France. Moreover, they refined the genetic mapping of USH1A by showing that the disease gene maps to the D14S13 locus, within the genetic interval defined by loci D14S78 and D14S250 (location score in log base 10 = 4.90). Consistent with this, nonsignificant lod score values for linkage to either USH1B or USH1C were found in this group. With regard to US1 families of other geographic origin (Normandy and Northern France, 11 families), nonsignificant lod scores for linkage to chromosome 11q13.5 were observed. However, the HOMOG test suggested that USH1B might account for the disease in 9/11 families in the series (families 10-19), the latter two families possibly being accounted for by USH1C (maximum likelihood for heterogeneity = 7.91 in lnL; heterogeneity versus homogeneity, P = 0.01; heterogeneity versus nonlinkage, P < 0.01). The present study supports the view that Usher syndrome type 1 is a genetically heterogeneous condition that is caused by at least three genes and possibly many more. 16 refs., 4 figs., 3 tabs.

  11. Prevalence of metabolic syndrome in type 2 diabetes mellitus patients

    PubMed Central

    Nsiah, Kwabena; Shang, V Owusua; Boateng, K Agyenim; Mensah, FO

    2015-01-01

    Background: The diabetic condition is influenced by several factors, some of which can accelerate the disease's progression to various complications that aggravate the morbidity. Aims: This study aimed at determining the prevalence of metabolic syndrome (MetS) and its individual components and the most critical predictive risk factors of MetS in type 2 diabetic patients. Materials and Methods: This cross-sectional study involved 150 type 2 diabetes mellitus patients and was conducted at the Diabetes Centre of the Komfo Anokye Teaching Hospital in Kumasi, the Ashanti Region of Ghana, from February, 2013 to April, 2013. The study involved the use of a questionnaire to obtain some information on the diabetics, undertaking anthropometric measurements, as well as collecting blood samples for the measurement of some biochemical parameters; fasting blood glucose and lipid profile. MetS was defined according to the National Cholesterol Education Program/Adult Treatment Panel III criteria. Results: The prevalence of MetS was 58% in the studied Ghanaian population. Hypertension was the commonest risk factor (60%), followed by central obesity (48.67%) and dyslipidemia (37%). Female type 2 diabetics had a higher prevalence of MetS, and carried more components than their male counterparts. Regression analysis showed three factors; femininity, high body mass index and low educational status were the most critical predictive risk factors of MetS, according to this study. Conclusion: With hypertension being the commonest component, future cardiovascular disease prevention strategies should focus attention on its management and prevention, through education. PMID:26097823

  12. Partially dominant mutant channel defect corresponding with intermediate Long-QT2 phenotype

    PubMed Central

    Krishnan, Yamini; Zheng, Renjian; Walsh, Christine; Tang, YingYing; McDonald, Thomas V.

    2011-01-01

    Background The hereditary Long QT Syndrome (LQTS) is a common cardiac disorder where ventricular repolarization is delayed, abnormally prolonging the QTc interval on ECG. LQTS is linked to various genetic loci including the KCNH2 (HERG) gene that encodes the α–subunit of the cardiac potassium channel that carries IKr. Here we report and characterize a novel pathologic missense mutation, G816V HERG, in a patient with sudden cardiac death. Methods Autopsy-derived tissue sample was used for DNA extraction and sequencing from an unexpected sudden death victim. The G816V HERG mutation was studied using heterologous expression in mammalian cell culture, whole cell patch clamp, confocal immunofluorescence, and immunochemical analyses. Results The mutant G816V HERG channel has reduced protein expression and shows a trafficking defective phenotype that is incapable of carrying current when expressed at physiological temperatures. The mutant channel showed reduced cell surface localization compared to wild-type HERG (WT HERG) but the mutant and wild-type subunits are capable of interacting. Expression studies at reduced temperatures enabled partial rescue of the trafficking defect with appearance of potassium currents albeit with reduced current density and altered voltage-dependent activation. Lastly, we examined a potential role for hypokalemia as a contributory factor to the patient’s lethal arrhythmia by possible low-potassium induced degradation of WT HERG and haplo-insufficiency of G816V HERG. Conclusion The G816V mutation in HERG causes a trafficking defect which acts in a partially dominant-negative manner. This intermediate severity defect agrees with the mild clinical presentation in other family members harboring the same mutation. Possible hypokalemia in the proband induced WT HERG degradation combined with haplo-insufficiency may have further compromised repolarization reserve and contributed to the lethal arrhythmia. PMID:21951015

  13. Evidence based guidelines for complex regional pain syndrome type 1

    PubMed Central

    2010-01-01

    Background Treatment of complex regional pain syndrome type I (CRPS-I) is subject to discussion. The purpose of this study was to develop multidisciplinary guidelines for treatment of CRPS-I. Method A multidisciplinary task force graded literature evaluating treatment effects for CRPS-I according to their strength of evidence, published between 1980 to June 2005. Treatment recommendations based on the literature findings were formulated and formally approved by all Dutch professional associations involved in CRPS-I treatment. Results For pain treatment, the WHO analgesic ladder is advised with the exception of strong opioids. For neuropathic pain, anticonvulsants and tricyclic antidepressants may be considered. For inflammatory symptoms, free-radical scavengers (dimethylsulphoxide or acetylcysteine) are advised. To promote peripheral blood flow, vasodilatory medication may be considered. Percutaneous sympathetic blockades may be used to increase blood flow in case vasodilatory medication has insufficient effect. To decrease functional limitations, standardised physiotherapy and occupational therapy are advised. To prevent the occurrence of CRPS-I after wrist fractures, vitamin C is recommended. Adequate perioperative analgesia, limitation of operating time, limited use of tourniquet, and use of regional anaesthetic techniques are recommended for secondary prevention of CRPS-I. Conclusions Based on the literature identified and the extent of evidence found for therapeutic interventions for CRPS-I, we conclude that further research is needed into each of the therapeutic modalities discussed in the guidelines. PMID:20356382

  14. Risk of Restless Legs Syndrome Following Tension-Type Headache

    PubMed Central

    Yang, Fu-Chi; Lin, Te-Yu; Chen, Hsuan-Ju; Lee, Jiunn-Tay; Lin, Chun-Chieh; Kao, Chia-Hung

    2015-01-01

    Abstract Migraine and restless legs syndrome (RLS) appear to be associated, but the relationship between tension-type headache (TTH) and RLS is unknown. This nationwide, population-based, retrospective cohort study explored the potential association between TTH and RLS. We identified 15,504 patients with newly diagnosed TTH from 2000 to 2007 and 62,016 individuals without TTH who were selected by frequency matched based on sex, age, and the index year. The study participants were followed until diagnosed with RLS, withdrawal from the NHI program, or the end of 2011. Cox proportional hazard models were used to identify risk factors for RLS in TTH patients. After adjusting for sex, age, comorbidity, and medications, TTH was significantly associated with an increased risk of RLS (hazard ratio [HR] = 1.57, 95% confidence interval [CI] = 1.22–2.02). The risk was most prominent in patients aged 20 to 39 years in the TTH group, which exhibited a 2.60-fold higher risk (95% confidence interval = 1.53–4.42) of RLS compared with the non-TTH group. The TTH group had a higher risk of RLS than that of the non-TTH group regardless of sex. Tension-type headache appears to be associated with an increased risk of developing RLS. This similarity to migraines may indicate that headache and RLS have a coincident pathophysiological mechanism, a possibility requiring further study. Clinicians should be more attentive to RLS as a possible comorbidity in patients with TTH. PMID:26579827

  15. Crooked fingers and sparse hair: an interesting case of trichorhinophalangeal syndrome type 1.

    PubMed

    Narayanan, Ramakrishna; Chennareddy, Srinivasa

    2015-01-01

    Trichorhinophalangeal syndrome type 1 is a rare skeletal dysplasia of autosomal-dominant inheritance due to defects in the TRPS-1 gene. The syndrome is characterised by sparse slow-growing hair, a bulbous pear-shaped nose, cone-shaped epiphyses and deformities of the interphalangeal joints resembling those in rheumatoid arthritis. We present a case of trichorhinophalangeal syndrome in a 23-year-old man who presented with symmetrical painless progressive deformity of the fingers in both hands. PMID:25628322

  16. Mucopolysaccharidosis type I Hurler-Scheie syndrome: A rare case report.

    PubMed

    Tatapudi, Ramesh; Gunashekhar, M; Raju, P Suryanarayana

    2011-01-01

    Mucopolysaccharidosis I (MPS I) is a rare inherited disorder that belongs to a group of clinically progressive disorders and is caused by the deficiency of the lysosomal enzyme, α(1)-iduronidase. MPS I has been recently classified into a severe (Hurler syndrome) and an attenuated type (Hurler-Scheie and Scheie syndromes). The purpose of this article was to describe a rare case of MPS type I, attenuated type (Hurler-Scheie) affecting a 15-year-old Indian child. PMID:22114460

  17. Complex regional pain syndrome type 1 in a pediatric patient: Case report

    PubMed Central

    Demirdal, Ümit Seçil; Bükülmez, Ayşegül; Solak, Özlem

    2014-01-01

    Complex regional pain syndrome type 1 is one of the causes of morbidity of childhood which is also named reflex symphathetic dystrophia. The syndrome is characterized with regional pain and vasomotor, sudomotor and sensory changes in the distal parts of the extremities involved. Complex regional pain syndrome type 1 shows difference in children in terms of clinical picture and imaging methods compared to adults. The most important point is that the prognosis is generally better in children if early diagnosis and treatment is provided. On the other hand, causes including presence of psychological factors or less contribution of imaging methods in children lead to delayed diagnosis or erroneous diagnosis. In this article, a 10 year-old male patient who was diagnosed with complex regional pain syndrome type 1 was described. Thus, we aimed to remind clinicians that this syndrome should also be kept in mind in the differential diagnosis of pain in children. PMID:26078637

  18. Type 1 diabetes: Syndromes in resource-challenged settings.

    PubMed

    Nagesh, V Sri; Kalra, Sanjay

    2015-06-01

    Type 1 Diabetes is a complex disorder that is made more complex by the myriad of co-morbid conditions associated with it. Mauriac Syndrome is a well-known but nowadays uncommon condition that presents with growth retardation secondary to poor glycaemic control. Limited Joint Mobility is an often-missed association of diabetes. Its importance lies in the fact that it can cause significant impairment of fine movements in T1DM children. It also indicates poor glycaemic control over a long period of time and can be used as a surrogate marker for development of diabetic microvascular complications. Anaemia in T1DM is protean and can develop due to a combination of nutritional factors, chronic renal disease, coeliac disease and worm infestation. Management is etiological. Vitamin deficiencies are ubiquitous in T1DM and if left untreated, can lead to neurological, haematological and skeletal dysfunction. The best-known co-morbid conditions are the local site reactions clubbed together under the moniker lipodystrophies. These can be either atrophic or hypertrophic and are usually due to repeated injections at the same site, improper technique and needle re-use. Management is often difficult and they are best prevented by appropriate diabetes education and emphasis on proper injection techniques at the time of T1DM diagnosis, with periodic reinforcement. Amyloidosis is a little known condition that shares a lot of features in common with the lipodystrophies and often needs to be differentiated from lipohypertrophy. T1DM is a disease which is often associated with a poor quality of life and these co-morbid conditions also need to be treated for effective general and psychological well-being. PMID:26060173

  19. Management of patients with complex regional pain syndrome type I.

    PubMed

    Gatti, D; Rossini, M; Adami, S

    2016-08-01

    Complex regional pain syndrome type I (CRPS-I) includes different conditions characterized by regional pain and sensory, motor, sudomotor, vasomotor, and/or trophic findings, affecting a peripheral limb usually after a noxious event, such as a trauma or surgery. The pathophysiology is still poorly understood. Limited data are available on the incidence of CRPS-I, and the disease is underestimated and under-diagnosed. The disease shows a female preponderance approximately 3:1 with a peak age of incidence around the 5th and 6th decade. The available diagnostic criteria for CRPS-I rely on clinical criteria that are unfortunately focused on the signs and symptoms of the chronic and late disease, while little emphasis is given to the typical imaging (X-rays, bone scintigraphy, MRI) findings of the early phase. Over the last decades, several therapies have been proposed but the few studies available are often too small to be conclusive and rarely evolved to randomized controlled trials (RCTs). On the basis of the results of a few RCTs, only short courses of high bisphosphonate doses appear to provide substantial benefits. The best results are seen in patients in the early phase of the disease, often with the persistent remission or complete healing of the conditions. Since the only accredited mechanism of action of bisphosphonates is the suppression of osteoclastic bone resorption, it is likely the initial dramatic bone loss plays a role in the maintenance and evolution of CRPS-I. Short courses of high doses of bisphosphonates should be considered the treatment of choice for patients with CRPS-I. PMID:26928187

  20. Screening of three Usher syndrome type II candidate genes

    SciTech Connect

    Bloemker, B.K.; Swaroop, A.; Kimberling, W.J.

    1994-09-01

    Usher syndrome type II (US2) is an autosomal recessive disorder that results in blindness due to retinitis pigmentosa and congenital hearing loss. The disease affects approximately 1 in 20,000 individuals in the general population and is responsible for over 50% of all cases of deafness with blindness. The underlying US2 defect is unknown. The US2 gene has been localized to the 1q41 region of chromosome 1 by linkage studies. Three genes previously localized to 1q were analyzed to assess their candidacy as the US2 gene. These were evaluated by PCR assays using DNA from a YAC contig spanning the US2 region on chromosome 1. The first gene evaluated was the human choroideremia-like gene (hCHML), which had been mapped to chromosome 1q. The sequence on 1q is a homologue of the human choroideremia gene on chromosome X. Choroideremia is a degenerative disorder causing ocular pathology similar to that observed in US2 patients. Therefore, hCHML is a candidate for the US2 gene. Two cDNAs (A and B) from an enriched human retinal pigment epithelium library have been mapped to 1q41 by in situ hybridization. Both cDNAs are considered good candidates. The hCHML and cDNA A were ruled out as candidates for the US2 gene based on negative results from PCR assays performed on YACs spanning the US2 region. cDNA B could not be ruled out as a candidate for the US2 gene by these assays. Answers to many clinical questions regarding US2 will only be resolved after the gene is identified and characterized. Eventually, understanding the function and expression of the US2 gene will provide a basis for the development of therapy.

  1. Characterization of a recombination event excluding the Harvey-ras-1 (H-ras-1) locus in a Ramano-Ward Long QT syndrome family linked to Chromosome 11q15 and isolation of a polymorphic repeat telomeric to H-ras-1

    SciTech Connect

    Russell, M.W.; Brody, L.C.; Munroe, D.

    1994-09-01

    The Romano-Ward Long QT syndrome (RWLQTS) has been linked to 11p15.5 in several large families but demonstrates genetic heterogeneity, since in other families the RWLQTS phenotype is not linked to 11p15. To date, no recombinants between the H-Ras-1 locus and RWLQTS in families linked to 11p15 have been published. In a large family, we demonstrate linkage of RWLQTS to marker D11S932 on chromosome 11p15.4 with a LOD score of 3.14 ({theta}=0;90% penetrance). An unaffected individual and her two unaffected offspring inherited the affected haplotype for the H-ras-1 region telomeric to D11S932. All three have QTc measurements of {le} 0.40 seconds and no history of syncope, making the diagnosis of RWLQTS extremely unlikely. This suggests that, although the gene for the RWlQTS is linked to 11p15 in this family, a recombination event may have occurred that separated the RWLQTS gene from the affected H-ras-1 region haplotype. To investigate a possible telomeric recombination event, cosmids telomeric to H-ras-1 were isolated. A highly polymorphic, complex CA/CT repeat marker (78% heterozygosity) was characterized and its location telomeric to H-ras-1 verified by interphase FISH. The same three unaffected individuals had the affected allele for this marker, ruling our recombination telomeric to H-ras-1 but proximal to the new marker. As the most telemeric marker on 11p to date, this marker will aid the physical and genetic mapping of the 11p telomere. The potential recombination event in this family apparently excludes H-ras-1 as a candidate gene and may aid the localization of the RWLQTS gene linked to 11p15.5. However, it remains a possibility that another genetic locus on 11p15, in addition to the one near the H-ras-1 gene, can cause the RWLQTS phenotype. This is the first report of recombination between H-ras-1 and RWLQTS in a family linked to 11p15.

  2. Giant bladder diverticulum in Ehlers-Danlos syndrome type I causing outflow obstruction.

    PubMed

    Burrows, N P; Monk, B E; Harrison, J B; Pope, F M

    1998-05-01

    We describe a 16-year-old patient with Ehlers-Danlos syndrome (EDS) type I and recurrent urinary retention caused by giant bladder diverticulum and review the literature on this association. PMID:9861737

  3. [Potassium channelopathies and Morvan's syndromes].

    PubMed

    Serratrice, Georges; Pellissier, Jean-François; Serra-Trice, Jacques; Weiller, Pierre-Jean

    2010-02-01

    Interest in Morvan's disease or syndrome has grown, owing to its close links with various potassium channelopathies. Potassium is crucial for gating mechanisms (channel opening and closing), and especially for repolarization. Defective potassium regulation can lead to neuronal hyperexcitability. There are three families of potassium channels: voltage-gated potassium channels or VGKC (Kv1.1-Kv1.8), inward rectifier K+ channels (Kir), and two-pore channels (K2p). VGK channels are the commonest, and especially those belonging to the Shaker group (neuromyotonia and Morvan's syndrome, limbic encephalitis, and type 1 episodic ataxia). Brain and heart K+ channelopathies are a separate group due to KCNQ1 mutation (severe type 2 long QT syndrome). Kv7 channel mutations (in KNQ2 and KCNQ3) are responsible for benign familial neonatal seizures. Mutation of the Ca+ activated K+ channel gene causes epilepsy and paroxysmal dyskinesia. Inward rectifier K+ channels regulate intracellular potassium levels. The DEND syndrome, a treatable channelopathy of the brain and pancreas, is due to KCNJ1 mutation. Andersen's syndrome, due to KCNJ2 mutation, is characterized by periodic paralysis, cardiac arrythmia, and dysmorphia. Voltage-insensitive K2p channelopathies form a final group. PMID:21166127

  4. The pathogenesis of the clinical features of oral-facial-digital syndrome type I

    PubMed Central

    AlKattan, Wael M.; Al-Qattan, Mohammad M.; Bafaqeeh, Sameer A.

    2015-01-01

    Oral-facial-digital syndrome type I (OFDI) is an X-linked syndrome, which has several craniofacial and limb features; and hence, patients frequently present to craniofacial and plastic surgeons. Oral-facial-digital syndrome type I is caused by mutations in the CXORF5 gene. The gene product is one of the basal body proteins of a slim microtubule-based organelle called the “primary cilium”. Most of the clinical features of OFDI patients are related to dysfunctions of the primary cilium leading to abnormal Hedgehog signal transduction, depressed planar cell polarity pathway, and errors in cell cycle control. PMID:26593159

  5. Pharmacological approach to the treatment of long and short QT syndromes☆

    PubMed Central

    Patel, Chinmay; Antzelevitch, Charles

    2008-01-01

    Inherited channelopathies have received increasing attention in recent years. The past decade has witnessed impressive progress in our understanding of the molecular and cellular basis of arrhythmogenesis associated with inherited channelopathies. An imbalance in ionic forces induced by these channelopathies affects the duration of ventricular repolarization and amplifies the intrinsic electrical heterogeneity of the myocardium, creating an arrhythmogenic milieu. Today, many of the channelopathies have been linked to mutations in specific genes encoding either components of ion channels or membrane or regulatory proteins. Many of the channelopathies are genetically heterogeneous with a variable degree of expression of the disease. Defining the molecular basis of channelopathies can have a profound impact on patient management, particularly in cases in which genotype-specific pharmacotherapy is available. The long QT syndrome (LQTS) is one of the first identified and most studied channelopathies where abnormal prolongation of ventricular repolarization predisposes an individual to life threatening ventricular arrhythmia called Torsade de Pointes. On the other hand of the spectrum, molecular defects favoring premature repolarization lead to Short QT syndrome (SQTS), a recently described inherited channelopathy. Both of these channelopathies are associated with a high risk of sudden cardiac death due to malignant ventricular arrhythmia. Whereas pharmacological therapy is first line treatment for LQTS, defibrillators are considered as primary treatment for SQTS. This review provides a comprehensive review of the molecular genetics, clinical features, genotype–phenotype correlations and genotype-specific approach to pharmacotherapy of these two mirror-image channelopathies, SQTS and LQTS. PMID:18378319

  6. Semen analysis in the Usher syndrome type 2A.

    PubMed

    van Aarem, A; Wagenaar, M; Tonnaer, E; Pieke Dahl, S; Bisseling, J; Janssen, H; Bastiaans, B; Kimberling, W; Cremers, C

    1999-01-01

    Semen analysis in patients with Usher syndrome suggested that defective connecting cilia axonemes may be involved in the irreversible, progressive loss of photoreceptors in Usher's syndrome. In the framework of clinical genetic research into Usher syndrome, a pilot study was set up to test these findings. The semen of 6 Usher 2A patients was analysed. The fertility status of the study group of Usher 2A patients was evaluated, including semen analysis, supplemented by electron microscopic examination of the spermatozoa. Except for a significantly increased pH value, no abnormalities were found in the functional semen analysis, whereas electron microscopy revealed microtubular tail abnormalities. The latter finding was of little relevance, however, in view of the normal motility of the spermatozoa observed in these patients. There were no fertility problems in our group of Usher 2A patients, nor have any been mentioned in Usher patients in general. Earlier study findings were not supported by our data. PMID:10325550

  7. Type IV Ehlers-Danlos Syndrome: A Surgical Emergency? A Case of Massive Retroperitoneal Hemorrhage.

    PubMed

    Chun, Stephen G; Pedro, Patrick; Yu, Mihae; Takanishi, Danny M

    2011-01-01

    Retroperitoneal hemorrhagic bleeding is a known manifestation of Type-IV Ehlers-Danlos Syndrome that is caused by loss-of-function mutations of the pro-alpha-1 chains of type III pro-collagen (COL3A1) resulting in vascular fragility. A number of previous reports describe futile surgical intervention for retroperitoneal bleeding in Type-IV Ehlers-Danlos Syndrome with high post-operative mortality, although the rarity of retroperitoneal bleeding associated with Type-IV Ehlers-Danlos Syndrome precludes an evidence-based approach to clinical management. We report a 23-year-old male with history of Type-IV Ehlers-Danlos Syndrome who presented with severe abdominal pain and tachycardia following an episode of vomiting. Further work-up of his abdominal pain revealed massive retroperitoneal bleeding by CT-scan of the abdomen. Given numerous cases of catastrophic injury caused by surgical intervention in Type-IV Ehlers-Danlos Syndrome, the patient was treated non-operatively, and the patient made a full recovery. This case suggests that even in cases of large retroperitoneal hemorrhages associated with Ehlers-Danlos Syndrome, it may not truly represent a surgical emergency. PMID:21966332

  8. Impact of Human Immunodeficiency Virus Type 1 (HIV-1) Genetic Diversity on Performance of Four Commercial Viral Load Assays: LCx HIV RNA Quantitative, AMPLICOR HIV-1 MONITOR v1.5, VERSANT HIV-1 RNA 3.0, and NucliSens HIV-1 QT

    PubMed Central

    Swanson, Priscilla; de Mendoza, Carmen; Joshi, Yagnya; Golden, Alan; Hodinka, Richard L.; Soriano, Vincent; Devare, Sushil G.; Hackett, John

    2005-01-01

    Human immunodeficiency virus type 1 (HIV-1) evolution and changing strain distribution present a challenge to nucleic acid-based assays. Reliable patient monitoring of viral loads requires the detection and accurate quantification of genetically diverse HIV-1. A panel of 97 HIV-1-seropositive plasma samples collected from Cameroon, Brazil, and South Africa was used to compare the performance of four commercially available HIV RNA quantitative tests: Abbott LCx HIV RNA Quantitative assay (LCx), Bayer Versant HIV-1 RNA 3.0 (bDNA), Roche AMPLICOR HIV-1 MONITOR v1.5 (Monitor v1.5), and bioMérieux NucliSens HIV-1 QT (NucliSens). The panel included group M, group O, and recombinant viruses based on sequence analysis of gag p24, pol integrase, and env gp41. The LCx HIV assay quantified viral RNA in 97 (100%) of the samples. In comparison, bDNA, Monitor v1.5, and NucliSens quantified viral RNA in 96.9%, 94.8%, and 88.6% of the samples, respectively. The two group O specimens were quantified only by the LCx HIV assay. Analysis of nucleotide mismatches at the primer/probe binding sites for Monitor v1.5, NucliSens, and LCx assays revealed that performance characteristics reflected differences in the level of genetic conservation within the target regions. PMID:16081923

  9. A Critical Evaluation of the Down Syndrome Diagnosis for LB1, Type Specimen of Homo floresiensis.

    PubMed

    Baab, Karen L; Brown, Peter; Falk, Dean; Richtsmeier, Joan T; Hildebolt, Charles F; Smith, Kirk; Jungers, William

    2016-01-01

    The Liang Bua hominins from Flores, Indonesia, have been the subject of intense scrutiny and debate since their initial description and classification in 2004. These remains have been assigned to a new species, Homo floresiensis, with the partial skeleton LB1 as the type specimen. The Liang Bua hominins are notable for their short stature, small endocranial volume, and many features that appear phylogenetically primitive relative to modern humans, despite their late Pleistocene age. Recently, some workers suggested that the remains represent members of a small-bodied island population of modern Austro-Melanesian humans, with LB1 exhibiting clinical signs of Down syndrome. Many classic Down syndrome signs are soft tissue features that could not be assessed in skeletal remains. Moreover, a definitive diagnosis of Down syndrome can only be made by genetic analysis as the phenotypes associated with Down syndrome are variable. Most features that contribute to the Down syndrome phenotype are not restricted to Down syndrome but are seen in other chromosomal disorders and in the general population. Nevertheless, we re-evaluated the presence of those phenotypic features used to support this classification by comparing LB1 to samples of modern humans diagnosed with Down syndrome and euploid modern humans using comparative morphometric analyses. We present new data regarding neurocranial, brain, and symphyseal shape in Down syndrome, additional estimates of stature for LB1, and analyses of inter- and intralimb proportions. The presence of cranial sinuses is addressed using CT images of LB1. We found minimal congruence between the LB1 phenotype and clinical descriptions of Down syndrome. We present important differences between the phenotypes of LB1 and individuals with Down syndrome, and quantitative data that characterize LB1 as an outlier compared with Down syndrome and non-Down syndrome groups. Homo floresiensis remains a phenotypically unique, valid species with its roots

  10. 15 YEARS OF PARAGANGLIOMA: Clinical manifestations of paraganglioma syndromes types 1–5

    PubMed Central

    Benn, Diana E; Robinson, Bruce G; Clifton-Bligh, Roderick J

    2015-01-01

    The paraganglioma (PGL) syndromes types 1–5 are autosomal dominant disorders characterized by familial predisposition to PGLs, phaeochromocytomas (PCs), renal cell cancers, gastrointestinal stromal tumours and, rarely, pituitary adenomas. Each syndrome is associated with mutation in a gene encoding a particular subunit (or assembly factor) of succinate dehydrogenase (SDHx). The clinical manifestations of these syndromes are protean: patients may present with features of catecholamine excess (including the classic triad of headache, sweating and palpitations), or with symptoms from local tumour mass, or increasingly as an incidental finding on imaging performed for some other purpose. As genetic testing for these syndromes becomes more widespread, presymptomatic diagnosis is also possible, although penetrance of disease in these syndromes is highly variable and tumour development does not clearly follow a predetermined pattern. PGL1 syndrome (SDHD) and PGL2 syndrome (SDHAF2) are notable for high frequency of multifocal tumour development and for parent-of-origin inheritance: disease is almost only ever manifest in subjects inheriting the defective allele from their father. PGL4 syndrome (SDHB) is notable for an increased risk of malignant PGL or PC. PGL3 syndrome (SDHC) and PGL5 syndrome (SDHA) are less common and appear to be associated with lower penetrance of tumour development. Although these syndromes are all associated with SDH deficiency, few genotype–phenotype relationships have yet been established, and indeed it is remarkable that such divergent phenotypes can arise from disruption of a common molecular pathway. This article reviews the clinical presentations of these syndromes, including their component tumours and underlying genetic basis. PMID:26273102

  11. A Critical Evaluation of the Down Syndrome Diagnosis for LB1, Type Specimen of Homo floresiensis

    PubMed Central

    Baab, Karen L.; Brown, Peter; Falk, Dean; Richtsmeier, Joan T.; Hildebolt, Charles F.; Smith, Kirk; Jungers, William

    2016-01-01

    The Liang Bua hominins from Flores, Indonesia, have been the subject of intense scrutiny and debate since their initial description and classification in 2004. These remains have been assigned to a new species, Homo floresiensis, with the partial skeleton LB1 as the type specimen. The Liang Bua hominins are notable for their short stature, small endocranial volume, and many features that appear phylogenetically primitive relative to modern humans, despite their late Pleistocene age. Recently, some workers suggested that the remains represent members of a small-bodied island population of modern Austro-Melanesian humans, with LB1 exhibiting clinical signs of Down syndrome. Many classic Down syndrome signs are soft tissue features that could not be assessed in skeletal remains. Moreover, a definitive diagnosis of Down syndrome can only be made by genetic analysis as the phenotypes associated with Down syndrome are variable. Most features that contribute to the Down syndrome phenotype are not restricted to Down syndrome but are seen in other chromosomal disorders and in the general population. Nevertheless, we re-evaluated the presence of those phenotypic features used to support this classification by comparing LB1 to samples of modern humans diagnosed with Down syndrome and euploid modern humans using comparative morphometric analyses. We present new data regarding neurocranial, brain, and symphyseal shape in Down syndrome, additional estimates of stature for LB1, and analyses of inter- and intralimb proportions. The presence of cranial sinuses is addressed using CT images of LB1. We found minimal congruence between the LB1 phenotype and clinical descriptions of Down syndrome. We present important differences between the phenotypes of LB1 and individuals with Down syndrome, and quantitative data that characterize LB1 as an outlier compared with Down syndrome and non-Down syndrome groups. Homo floresiensis remains a phenotypically unique, valid species with its roots

  12. People with Usher Syndrome, Type II: Issues and Adaptations.

    ERIC Educational Resources Information Center

    Miner, I. D.

    1997-01-01

    Describes the experiences of individuals with Usher Syndrome, discusses the lack of appropriate services and the failure of professionals to provide sufficient information on the condition, and stresses the importance of access to information and the acquisition of new skills before the visual impairment becomes severe. (Author/CR)

  13. Abnormalities of the electrocardiogram during hypoglycaemia: the cause of the dead in bed syndrome?

    PubMed

    Heller, Simon R

    2002-07-01

    We have previously demonstrated that experimental hypoglycaemia in adults with type 1 diabetes causes an abnormal electrocardiogram (ECG), with increases in QT interval and dispersion. These abnormalities in cardiac repolarisation indicate a risk of ventricular tachycardia and sudden death in other conditions, including ischemic heart disease and congenital long QT syndrome. We have hypothesised that they could contribute to the dead in bed syndrome--the recently described sudden unexpected death in young people with type 1 diabetes--which occurs around three times more frequently than in those without diabetes. It is clearly impossible to explore the causes of a rare and fatal complication by direct observation. We have therefore explored the pathophysiology in a series of experimental studies involving non-diabetic subjects and surrogate endpoints. These have demonstrated that abnormal cardiac repolarisation occurs consistently during insulin-induced hypoglycaemia and that either potassium infusion or beta-blockade prevents increased QT dispersion but only partially prevents QT lengthening. The sympathoadrenal discharge induced by hypoglycaemia alters cardiac repolarisation by both direct and indirect (by reducing extracellular potassium) mechanisms. Other factors that might contribute to the clinical risk of cardiac arrhythmias during nocturnal hypoglycaemia include autonomic neuropathy. This is associated with prolonged QT interval in the non-hypoglycaemic state and has been proposed as a cause of sudden death in those affected. We have examined cardiac repolarisation during clamped hypoglycaemia in patients with type 1 diabetes, with and without autonomic neuropathy. Our data demonstrate lengthening of QTc (QT interval corrected for heart rate) during hypoglycaemia in all groups with no significant differences between the groups, suggesting that autonomic dysfunction does not contribute to hypoglycaemia-induced QTc lengthening in type 1 diabetes. Our

  14. Utility of Corrected QT Interval in Orthostatic Intolerance

    PubMed Central

    Kim, Jung Bin; Hong, Soonwoong; Park, Jin-Woo; Cho, Dong-Hyuk; Park, Ki-Jong; Kim, Byung-Jo

    2014-01-01

    We performed this study to determine whether electrocardiographic corrected QT (QTc) interval predicts alterations in sympathovagal balance during orthostatic intolerance (OI). We reviewed 1,368 patients presenting with symptoms suggestive of OI who underwent electrocardiography and composite autonomic function tests (AFTs). Patients with a positive response to the head-up tilt test were classified into orthostatic hypotension (OH), neurocardiogenic syncope (NCS), or postural orthostatic tachycardia syndrome (POTS) groups. A total of 275 patients (159 OH, 54 NCS, and 62 POTS) were included in the final analysis. Between-group comparisons of OI symptom grade, QTc interval, QTc dispersion, and each AFT measure were performed. QTc interval and dispersion were correlated with AFT measures. OH Patients had the most severe OI symptom grade and NCS patients the mildest. Patients with OH showed the longest QTc interval (448.8±33.6 msec), QTc dispersion (59.5±30.3 msec) and the lowest values in heart rate response to deep breathing (HRDB) (10.3±6.0 beats/min) and Valsalva ratio (1.3±0.2). Patients with POTS showed the shortest QTc interval (421.7±28.6 msec), the highest HRDB values (24.5±9.2 beats/min), Valsalva ratio (1.8±0.3), and proximal and distal leg sweat volumes in the quantitative sudomotor axon reflex test. QTc interval correlated negatively with HRDB (r = −0.443, p<0.001) and Valsalva ratio (r = −0.425, p<0.001). We found negative correlations between QTc interval and AFT values representing cardiovagal function in patients with OI. Our findings suggest that prolonged QTc interval may be considered to be a biomarker for detecting alterations in sympathovagal balance, especially cardiovagal dysfunction in OH. PMID:25180969

  15. Who Is at Risk for Long QT Syndrome?

    MedlinePlus

    ... excessive vomiting or diarrhea or other conditions that cause low blood levels of potassium or sodium. These conditions include the eating disorders anorexia nervosa and bulimia, as well as some ...

  16. X-linked albinism-deafness syndrome and Waardenburg syndrome type II: A hypothesis

    SciTech Connect

    Zlotogora, J.

    1995-11-20

    Margolis reported on a large pedigree with a {open_quotes}new{close_quotes} X-linked syndrome of profound deafness and albinism (MIM 300700, albinism-deafness syndrome). The affected males presented with profound deafness and severe pigmentary abnormalities of the skin. At birth the skin appeared as almost albinotic except for areas of light pigmentation over the gluteal and scrotal areas, and thereafter pigmentation gradually increased over the body. Skin changes ultimately included areas of hypopigmentation and spots of hyperpigmentation. Some of the affected males also had blue irides, heterochromia, or segmental color iris changes. In carrier females, variable hearing impairment was documented without any pigmentary changes. 9 refs., 1 fig.

  17. Pharmacometabolomic Approach to Predict QT Prolongation in Guinea Pigs

    PubMed Central

    Lee, Hae Won; Lim, Mi-sun; Seong, Sook Jin; Seo, Jeong Ju; Kim, Eun-Jung; Kang, Wonku; Yoon, Young-Ran

    2013-01-01

    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. PMID:23593245

  18. Surgical treatment for Scheie's syndrome (mucopolysaccharidosis type I-S): report of two cases.

    PubMed

    Minakata, K; Konishi, Y; Matsumoto, M; Miwa, S

    1998-09-01

    Scheie's syndrome (mucopolysaccharidosis type I-S) is a rare genetic lysosomal storage disease affecting mucopolysaccharide metabolism, and is known to include cardiovascular disease. Surgical treatment was carried out in 2 patients with Scheie's syndrome. Patient 1 was a 56-year-old man with triple-vessel coronary artery disease, who successfully underwent coronary artery bypass grafting. Patient 2 was a 52-year-old man with aortic and mitral valve stenosis, who successfully underwent combined aortic and mitral valve replacement. The literature on Scheie's syndrome associated with valvular and coronary artery disease is also reviewed. PMID:9766711

  19. Nonfunctional Metastatic Parathyroid Carcinoma in the Setting of Multiple Endocrine Neoplasia Type 2A Syndrome.

    PubMed

    Posada-González, María; Gómez-Ramírez, Joaquín; Luque-Ramírez, Manuel; Guijarro, Mercedes; Martín-Pérez, Elena; Rodríguez-Sánchez, Ana; García-Sanz, Iñigo; Larrañaga, Eduardo

    2014-01-01

    Parathyroid carcinoma is a very rare malignancy. It has been associated with hyperparathyroidism-jaw tumour syndrome, familial isolated primary hyperparathyroidism, and multiple endocrine neoplasia type 1 (MEN-1) and 2A (MEN-2A) syndromes. We report a 54-year-old man with a MEN-2A which presents with a nonfunctional metastatic parathyroid carcinoma and a pheochromocytoma in the absence of medullary thyroid carcinoma. Only a few cases of parathyroid carcinoma have been reported in the literature associated with this syndrome. PMID:25374962

  20. Waardenburg syndrome type I with heterochromia iridis and circumscribed hypopigmentation of the skin.

    PubMed

    Eigelshoven, Sibylle; Kameda, Gitta; Kortüm, Anne-Katrin; Hübsch, Simone; Angerstein, Wolfgang; Singh, Preeti; Vöhringer, Renate; Goecke, Timm; Mayatepek, Ertan; Ruzicka, Thomas; Wildhardt, Gabriele; Meissner, Thomas; Kruse, Roland

    2009-01-01

    We report a 3-year-old girl with autosomal dominant inherited Waardenburg syndrome type I showing circumscribed hypopigmentation of the skin, heterochromia iridis, sensorineural deafness, and dental aberrations. Clinical diagnosis was confirmed by the identification of an underlying missense mutation (C811T) in the PAX3 gene. Early diagnosis of Waardenburg syndrome among children with pigment anomalies enables a successful interdisciplinary medical care. PMID:20199465

  1. Mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome) in the pre-Columbian culture of Colombia

    PubMed Central

    Rodriguez, Carlos Armando

    2014-01-01

    Mucopolysaccharidosis type VI or Maroteaux Lamy syndrome is an autosomal recessive lysosomal storage disorder resulting from a deficiency of arylsulfatase B, the clinical features include short stature, hepatosplenomegaly, dysostosis multiplex, stiff joints, corneal clouding, cardiac abnormalities, and facial dysmorphism, with intelligence usually normal. We present evidence of the possible existence of Maroteaux Lamy syndrome in pre-Columbian pottery 2000 years ago, in the Colombo-Ecuadorian Pacific coast of the Tumaco-Tolita culture. PMID:25100895

  2. Mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome) in the pre-Columbian culture of Colombia.

    PubMed

    Pachajoa, Harry; Rodriguez, Carlos Armando

    2014-01-01

    Mucopolysaccharidosis type VI or Maroteaux Lamy syndrome is an autosomal recessive lysosomal storage disorder resulting from a deficiency of arylsulfatase B, the clinical features include short stature, hepatosplenomegaly, dysostosis multiplex, stiff joints, corneal clouding, cardiac abnormalities, and facial dysmorphism, with intelligence usually normal. We present evidence of the possible existence of Maroteaux Lamy syndrome in pre-Columbian pottery 2000 years ago, in the Colombo-Ecuadorian Pacific coast of the Tumaco-Tolita culture. PMID:25100895

  3. Perisigmoid Abscess Leading to a Diagnosis of Ehlers-Danlos Syndrome Type IV

    PubMed Central

    Kesavan, Anil; Srikumar, Pillai B.; McConnie, Randolph M.

    2016-01-01

    The Ehlers-Danlos syndromes (EDS) are a group of connective tissue disorders characterized by triad of joint hypermobility, skin extensibility, and tissue fragility. Ehlers-Danlos syndrome type IV places patients at risk for life-threatening, spontaneous, vascular or visceral rupture due to reduced or abnormal secretion of type III collagen. We present an adolescent male who was found to have a perisigmoid abscess with a fistula connecting to adjacent sigmoid colon secondary to undiagnosed EDS type IV. Conservative management with antibiotics and bowel rest was pursued to allow for elective resection for his acute complicated diverticulitis at a safer time. PMID:26958560

  4. Perisigmoid Abscess Leading to a Diagnosis of Ehlers-Danlos Syndrome Type IV.

    PubMed

    Normatov, Inessa; Kesavan, Anil; Srikumar, Pillai B; McConnie, Randolph M

    2016-01-01

    The Ehlers-Danlos syndromes (EDS) are a group of connective tissue disorders characterized by triad of joint hypermobility, skin extensibility, and tissue fragility. Ehlers-Danlos syndrome type IV places patients at risk for life-threatening, spontaneous, vascular or visceral rupture due to reduced or abnormal secretion of type III collagen. We present an adolescent male who was found to have a perisigmoid abscess with a fistula connecting to adjacent sigmoid colon secondary to undiagnosed EDS type IV. Conservative management with antibiotics and bowel rest was pursued to allow for elective resection for his acute complicated diverticulitis at a safer time. PMID:26958560

  5. A study of migraine characteristics in joint hypermobility syndrome a.k.a. Ehlers-Danlos syndrome, hypermobility type.

    PubMed

    Puledda, Francesca; Viganò, Alessandro; Celletti, Claudia; Petolicchio, Barbara; Toscano, Massimiliano; Vicenzini, Edoardo; Castori, Marco; Laudani, Guido; Valente, Donatella; Camerota, Filippo; Di Piero, Vittorio

    2015-08-01

    Joint hypermobility syndrome (JHS) and Ehlers-Danlos syndrome, hypermobility type (EDS-HT) are two clinically overlapping heritable connective tissue disorders strongly associated with musculoskeletal pain, fatigue and headache. Migraine with or without aura is considered the most common form of headache in JHS/EDS-HT. In this population of chronically ill patients, we investigated whether migraine characteristics were different from those of a control population of migraine patients. The study was carried out on 33 selected JHS/EDS-HT patients, diagnosed according to current criteria. Sixty-six migraine subjects matching age and gender were consecutively selected as controls (MO group) among patients attending our Headache Clinic. JHS/EDS-HT and MO were screened for a series of headache characteristics, such as frequency, intensity, age of onset, level of disability, use of rescue and prophylactic medications. Differences between the two groups were tested by using independent group comparisons. Results showed that in JHS/EDS-HT: (1) migraine has an earlier onset (12.6 vs 17 years of age; p = 0.005); (2) the rate of migraine days/month is higher (15 vs 9.3 days/month; p = 0.01); (3) accompanying symptoms are usually more frequent; (4) HIT-6 and MIDAS scores are higher (p = 0.04 and p = 0.03); (5) efficacy of rescue medication is almost identical, although, total drug consumption is significantly lower (p < 0.04). Joint hypermobility syndrome and Ehlers-Danlos syndrome, hypermobility type patients have a more severe headache syndrome with respect to the MO group, therefore demonstrating that migraine has a very high impact on quality of life in this disease. PMID:25791889

  6. Relationship between Fatigue and Gait Abnormality in Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome Hypermobility Type

    ERIC Educational Resources Information Center

    Celletti, Claudia; Galli, Manuela; Cimolin, Veronica; Castori, Marco; Albertini, Giorgio; Camerota, Filippo

    2012-01-01

    Ehlers-Danlos syndrome (EDS) is a clinically and genetically heterogeneous group of inherited connective tissue disorders characterised by joint hypermobility, skin hyperextensibility and tissue fragility. It has recently been shown that muscle weakness occurs frequently in EDS, and that fatigue is a common and clinically important symptom. The…

  7. The QT dispersion and QTc dispersion in patients presenting with acute neurological events and its impact on early prognosis

    PubMed Central

    Rahar, Kailash Kumar; Pahadiya, Hans Raj; Barupal, Kishan Gopal; Mathur, C. P.; Lakhotia, Manoj

    2016-01-01

    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

  8. Sugar-Sweetened Beverages and Risk of Metabolic Syndrome and Type 2 Diabetes

    PubMed Central

    Malik, Vasanti S.; Popkin, Barry M.; Bray, George A.; Després, Jean-Pierre; Willett, Walter C.; Hu, Frank B.

    2010-01-01

    OBJECTIVE Consumption of sugar-sweetened beverages (SSBs), which include soft drinks, fruit drinks, iced tea, and energy and vitamin water drinks has risen across the globe. Regular consumption of SSBs has been associated with weight gain and risk of overweight and obesity, but the role of SSBs in the development of related chronic metabolic diseases, such as metabolic syndrome and type 2 diabetes, has not been quantitatively reviewed. RESEARCH DESIGN AND METHODS We searched the MEDLINE database up to May 2010 for prospective cohort studies of SSB intake and risk of metabolic syndrome and type 2 diabetes. We identified 11 studies (three for metabolic syndrome and eight for type 2 diabetes) for inclusion in a random-effects meta-analysis comparing SSB intake in the highest to lowest quantiles in relation to risk of metabolic syndrome and type 2 diabetes. RESULTS Based on data from these studies, including 310,819 participants and 15,043 cases of type 2 diabetes, individuals in the highest quantile of SSB intake (most often 1–2 servings/day) had a 26% greater risk of developing type 2 diabetes than those in the lowest quantile (none or <1 serving/month) (relative risk [RR] 1.26 [95% CI 1.12–1.41]). Among studies evaluating metabolic syndrome, including 19,431 participants and 5,803 cases, the pooled RR was 1.20 [1.02–1.42]. CONCLUSIONS In addition to weight gain, higher consumption of SSBs is associated with development of metabolic syndrome and type 2 diabetes. These data provide empirical evidence that intake of SSBs should be limited to reduce obesity-related risk of chronic metabolic diseases. PMID:20693348

  9. Demographic and clinical correlates of metabolic syndrome in Native African type-2 diabetic patients.

    PubMed Central

    Isezuo, S. A.; Ezunu, E.

    2005-01-01

    OBJECTIVES: To describe the metabolic syndrome and its demographic and clinical correlates in native African type-2 diabetic patients. METHODS: Cross-sectional analysis of 254 type-2 diabetic indigenous Nigerians consecutively recruited in a teaching hospital. The main outcome measure was metabolic syndrome. Variables of interest included family history/duration of diabetes mellitus and hypertension, gender, socioeconomic class, occupation and place of domicile (urban or rural). Intergroup comparisons were made with Chi-squared tests or t-tests. RESULTS: Patients were aged 35-80 years (mean: 52.0 +/- 11.7 years) and made of 154 (60.6%) males and 100 (39.4%) females. Full-blown metabolic syndrome was noted in 52 patients (20.5%). Metabolic syndrome, as defined by the WHO, was noted in 150 patients (59.1%). About 72.4% of patients were dyslipidemic, 54.3% were hypertensive, 42.5% were obese, 44.9% were microalbuminuric and 32.3% were hyperuricemic. Ischemic heart disease (myocardial infarction) occurred in only 2.4% of patients. Concurrent hypertension and dyslipidemia; obesity and dyslipidemia; and hypertension and obesity occurred in 44.4%, 42.5% and 33.1% of type-2 diabetics, respectively. Compared to the diabetics without metabolic syndrome, those with the syndrome had a significantly higher proportion of patients with a family history of hypertension and diabetes (44% versus 25%; p = 0.003); among the upper/middle socioeconomic class: 52.0% versus 30.8% (p = 0.001); and among the urban dwelling: 68.0% versus 49.0% (p = 0.004). Metabolic syndrome was inversely proportional to the physical activity of an individual (chi2 = 21.69, df = 5, p = 0.001). Blood pressure was significantly higher among patients with metabolic syndrome than those without it (140.6 +/- 22.9/85.2 +/- 12.9 mmHg versus 126.9 +/- 15.4 mmHg; P < 0.01). CONCLUSIONS: The development of metabolic syndrome in African type-2 diabetic patients is influenced by demographic and clinical factors

  10. Mucopolysaccharidosis type-IS presenting with onset of carpal tunnel syndrome at adolescence.

    PubMed

    Bahadir, Cengiz; Kurtulus, Duygu; Cihandide, Ercan

    2009-12-01

    Mucopolysaccharidosis type I (MPS I) results from deficiency of the lysosomal enzyme alpha-L iduronidase. Three subtypes, based on severity of clinical findings, have been described, of which MPS type IS (also called Scheie syndrome) is the mildest form. A woman (age, 30 years) and her little brother (age, 21 years) presented to our clinic complaining of atrophy of the thenar muscles, numbness in both hands, and contractures in the finger joints. Electrophysiologic examination showed severe carpal tunnel syndrome for both patients. Findings of cardiac and ocular involvements and decreased level of alpha-L iduronidase confirmed the diagnosis of Scheie syndrome. Enzyme replacement therapy was initiated for the further prevention of musculoskeletal and other organ complications. Delayed diagnosis of MPS type-IS and the musculoskeletal findings are discussed in these 2 familial patients. PMID:19955999

  11. First Case Report of Turcot Syndrome Type 1 in Colombia

    PubMed Central

    Dora, Vallejo; Diego, Garnica; Rómulo, Bonilla; Natalia, Olaya

    2012-01-01

    Turcot syndrome is an autosomal recessive disorder clinically characterized by the occurrence of primary tumors of the central nervous system and adenomatous colonic polyps during the first or second decades of life, with a spectrum of clinical features such as “café-au-lait” spots, axillary freckling, and hyperpigmented spots. Currently its prevalence globally and in Colombia remains unknown. We present the case of a 20-year-old male with a clinical presentation of both glioblastoma multiforme and multiple adenomatous colonic polyps. The molecular genetics study revealed a mutation in KrasAsp12 gene and altered expression of HMSH2 and HMSH6 proteins encoded by the DNA mismatch repair genes in two of the colonic polyps. Even though this clinical presentation may suggest a shorter survival rate, this patient is still alive after seven months of treatment. A literature review complements this report. PMID:23320220

  12. Cardiovascular pathologies in mucopolysaccharidosis type VII (Sly Syndrome).

    PubMed

    Gniadek, Thomas J; Singer, Nicole; Barker, Norman J; Spevak, Philip J; Crain, Barbara J; Valle, David; Halushka, Marc K

    2015-01-01

    We present the cardiac findings from the autopsy of a 28-year-old male with mucopolysaccharidosis VII (MPS VII), also known as Sly Syndrome, whose diagnosis was confirmed by biochemical testing. The patient died a sudden cardiac death. Autopsy showed thickened and stenotic aortic valve leaflets as well as marked concentric intimal thickening of the aorta and muscular arteries. There was left ventricular hypertrophy as well as mild papillary muscle thickening and fusion. Increased colloid iron staining was seen in the small- and medium-sized arteries of the heart and at the intercalated discs. We discuss the patient's premortem echocardiographic and electrocardiographic studies. In addition, we discuss the pathogenesis of MPS VII and review previous literature on its anatomic and pathologic features. PMID:26141114

  13. Intestinal lymphangiectasia in a patient with autoimmune polyglandular syndrome type III.

    PubMed

    Choudhury, Bipul Kumar; Saiki, Uma Kaimal; Sarm, Dipti; Choudhury, Bikash Narayan; Choudhury, Sarojini Dutta; Saharia, Dhiren; Saikia, Mihir

    2011-11-01

    Autoimmune polyglandular syndromes (APS) comprise a wide clinical spectrum of autoimmune disorders. APS is divided into Type I, Type II, Type I and Type IV depending upon the pattern of disease combination. Ghronic diarrhoea is one of the many manifestations of APS and many aetiological factors have been suggested for it. Apart from the established aetiological factors, intestinal lymphangiectasia may be responsible for chronic diarrhea in some cases.Intestinal lymphangiectasia has been reported in Type I APS. We report a case of Type III APS with hypocalcaemia and hypothyroidism who had chronic diarrhea of long duration and was finally diagnosed to have intestinal lymphangiectasia. PMID:22616341

  14. [Severe type A insulin resistance syndrome due to a mutation in the insulin receptor gene].

    PubMed

    Ros, P; Colino-Alcol, E; Grasso, V; Barbetti, F; Argente, J

    2015-01-01

    Insulin resistance syndromes without lipodystrophy are an infrequent and heterogeneous group of disorders with variable clinical phenotypes, associated with hyperglycemia and hyperinsulinemia. The three conditions related to mutations in the insulin receptor gene are leprechaunism or Donohue syndrome, Rabson-Mendenhall syndrome, and Type A syndrome. A case is presented on a patient diagnosed with type A insulin resistance, defined by the triad of extreme insulin resistance, acanthosis nigricans, and hyperandrogenism, carrying a heterozygous mutation in exon 19 of the insulin receptor gene coding for its tyrosine kinase domain that is crucial for the catalytic activity of the receptor. The molecular basis of the syndrome is reviewed, focusing on the structure-function relationships of the insulin receptor, knowing that the criteria for survival are linked to residual insulin receptor function. It is also pointed out that, although type A insulin resistance appears to represent a somewhat less severe condition, these patients have a high morbidity and their treatment is still unsatisfactory. PMID:25027621

  15. Comparison of Two Commercial Type 1 Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) Modified Live Vaccines against Heterologous Type 1 and Type 2 PRRSV Challenge in Growing Pigs

    PubMed Central

    Kim, Taeyeon; Park, Changhoon; Choi, Kyuhyung; Jeong, Jiwoon; Kang, Ikjae; Park, Su-Jin

    2015-01-01

    The objective of the present study was to compare the efficacy of two commercial type 1 porcine reproductive and respiratory syndrome virus (PRRSV) modified live vaccines against heterologous type 1 and type 2 PRRSV challenge in growing pigs. Vaccination with a type 1 PRRSV vaccine reduced the level of viremia after type 1 PRRSV challenge but did not reduce the level of viremia after the type 2 PRRSV challenge in pigs. Increased levels of interleukin-10 (IL-10) stimulated by type 2 PRRSV coincided with the low numbers of type 2 PRRSV-specific interferon gamma-secreting cells (IFN-γ-SC) in vaccinated pigs after type 2 PRRSV challenge, whereas low levels of IL-10 stimulated by type 1 PRRSV coincided with high numbers of type 1 PRRSV-specific IFN-γ-SC in vaccinated pigs after type 1 PRRSV challenge. Additionally, vaccination with the type 1 PRRSV vaccine effectively reduced the lung lesions and type 1 PRRSV nucleic acids in type 1 PRRSV-challenged pigs but did not reduce lung lesions and type 2 PRRSV nucleic acids in type 2 PRRSV-challenged pigs. There were no significant differences between two commercial type 1 PRRSV vaccines against type 1 and type 2 PRRSV challenge based on virological results, immunological responses, and pathological outcomes. This study demonstrates that vaccinating pigs with the type 1 PRRSV vaccine provides partial protection against respiratory disease with heterologous type 1 PRRSV challenge but no protection with heterologous type 2 PRRSV challenge. PMID:25855554

  16. [Duane's retraction syndrome--overview and diagnosis of clinical types].

    PubMed

    Otradovec, J

    2001-05-01

    The author presents a postgraduate review of the problem. In the introduction he reviews typical features of Duane's retraction syndrome (DS) and its main symptoms and reminds of the main approaches to classification: (1) Malbrane s (Duane I, II and III), (2) Huber's which is based on EMG findings in ZOS and (3) Kaufman's which classifies DS according to the enforced position of the head. The author maintains that even according to the above many atypical rare pictures cannot be classified or explained pathogenetically. Some are mentioned: (1) "Inverse" DS, which was recorded and documented by Chytilová-Divisová (1949) in a girl with congenital paralysis of abduction on both eyes retraction of the bulbus developed and narrowing of the palpebral aperture when attempting abduction (1) of the eye, (2) Bilateral acquired DS in a female patient with a tumour of the brain stem confirmed by EMG records of both horizontal muscles. (3) Unilateral DS in a child from a family with familial incidence of congenital ZOS fibrosis with an obscure ratio of the neurogenic and myogenic and fibrous component of the two pictures. In another member of this family the Marcus Gunn phenomenon was present. The latter findings support the idea that in the development of the fairly uniform picture of DS a combination of neurogenic, myogenic and connective tissue changes participate. PMID:11433591

  17. Extended phenotypes in a boy and his mother with oto-palato-digital-syndrome type II.

    PubMed

    Kaissi, Ali Al; Kraschl, Raimund; Kaulfersch, Wilhelm; Grill, Franz; Ganger, Rudolf

    2015-09-01

    We describe additional phenotypic features in a boy and his mother. Both manifested the phenotypic/genotypic correlation of oto-palato-digital syndrome type II. The mother's radiographs showed wormian bones of the skull, and paranasal bossing, her feet showed bilateral fusion of the cuboid with the lateral cuneiform bone with subsequent development of metatarsus varus associated with dysplastic distal phalanges. PMID:26401283

  18. Psychosocial Implications of Usher Syndrome, Type I, throughout the Life Cycle.

    ERIC Educational Resources Information Center

    Miner, I. D.

    1995-01-01

    Usher syndrome, Type I, requires multiple adaptations throughout the life cycle because each stage of life has tasks and losses associated with deafness and progressive retinitis pigmentosa. This article examines the issues raised at each stage, using clinical vignettes from persons who have this condition and their families. (Author/DB)

  19. Metachronous Bilateral Posterior Tibial Artery Aneurysms in Ehlers-Danlos Syndrome Type IV

    SciTech Connect

    Hagspiel, Klaus D.; Bonatti, Hugo; Sabri, Saher; Arslan, Bulent; Harthun, Nancy L.

    2011-04-15

    Ehlers-Danlos syndrome type IV is a life-threatening genetic connective tissue disorder. We report a 24-year-old woman with EDS-IV who presented with metachronous bilateral aneurysms/pseudoaneurysms of the posterior tibial arteries 15 months apart. Both were treated successfully with transarterial coil embolization from a distal posterior tibial approach.

  20. Physical and Psychological Health in Persons with Deafblindness that Is due to Usher Syndrome Type II

    ERIC Educational Resources Information Center

    Wahlqvist, Moa; Moller, Claes; Moller, Kerstin; Danermark, Berth

    2013-01-01

    Introduction: The objectives of the study reported here were to describe the physical and psychological health of persons with Usher syndrome Type II (USH2) and to explore any differences in terms of gender. Methods: The participants were recruited from the Swedish Usher database. In the first step, 122 persons received the questionnaire by mail,…

  1. Glucose Transporter Type 1 Deficiency Syndrome with Carbohydrate-Responsive Symptoms but without Epilepsy

    ERIC Educational Resources Information Center

    Koy, Anne; Assmann, Birgit; Klepper, Joerg; Mayatepek, Ertan

    2011-01-01

    Glucose transporter type 1 deficiency syndrome (GLUT1-DS) is caused by a defect in glucose transport across the blood-brain barrier. The main symptoms are epilepsy, developmental delay, movement disorders, and deceleration of head circumference. A ketogenic diet has been shown to be effective in controlling epilepsy in GLUT1-DS. We report a female…

  2. Phenotype of the fibroblast growth factor receptor 2 Ser351Cys mutation: Pfeiffer syndrome type III.

    PubMed

    Gripp, K W; Stolle, C A; McDonald-McGinn, D M; Markowitz, R I; Bartlett, S P; Katowitz, J A; Muenke, M; Zackai, E H

    1998-07-24

    We present a patient with pansynostosis, hydrocephalus, seizures, extreme proptosis with luxation of the eyes out of the lids, apnea and airway obstruction, intestinal non-rotation, and severe developmental delay. His skeletal abnormalities include bilateral elbow ankylosis, radial head dislocation, and unilateral broad and deviated first toe. The phenotype of this patient is consistent with that previously reported in Pfeiffer syndrome type III, but is unusual for the lack of broad thumbs. Our patient most closely resembles the case described by Kerr et al. [1996: Am J Med Genet 66:138-143] as Pfeiffer syndrome type III with normal thumbs. Mutations in the genes for fibroblast growth factor receptors (FGFR) 1 and 2 have previously been seen in patients with Pfeiffer syndrome type I. The mutation identified in our patient, Ser351Cys in FGFR2, represents the first reported cause of Pfeiffer syndrome type III. An identical mutation was described once previously by Pulleyn et al., in a patient whose brief clinical description included cloverleaf skull, significant developmental delay, and normal hands and feet [Eur. J. Hum. Genet. 4: 283-291, 1996]. In our patient, previously performed single-strand conformation polymorphism analysis failed to detect a band shift; the mutation was identified only after independent sequence analysis. PMID:9714439

  3. Genomic sequence and virulence comparison of four type 2 porcine reproductive and respiratory syndrome virus strains

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Porcine reproductive and respiratory syndrome virus (PRRSV) is a ubiquitous and costly virus that exhibits substantial sequence and virulence disparity among diverse isolates. In this study, we compared the whole genomic sequence and virulence of 4 North American Type 2 PRRSV isolates. Among the 4 i...

  4. A rare type of congenital Sturge-Weber Syndrome: presenting with history of perinatal asphyxia.

    PubMed

    Ejike, Obuoha; Odume, Calistus; Ekwochi, Uchenna; Ndu, Ikenna; Imanyikwa, Ugochukwu

    2016-08-01

    The presentation of a newborn with perinatal asphyxia and poor developmental milestones in a resource-poor setting. Many a times, obscured, unsuspected, and uncommon etiologies compound well-known causes of failure to thrive; in this case a rare finding of Type III Sturge-Weber Syndrome was revealed by Brain CT scanning. PMID:27525070

  5. Exploration of Differences in Types of Sleep Disturbance and Severity of Sleep Problems between Individuals with Cri du Chat Syndrome, Down's Syndrome, and Jacobsen Syndrome: A Case Control Study

    ERIC Educational Resources Information Center

    Maas, Anneke P. H. M.; Didden, Robert; Korzilius, Hubert; Curfs, Leopold M. G.

    2012-01-01

    The prevalence of sleep problems in individuals with intellectual disability (ID) seems to vary between genetic syndromes associated with ID. Different types of sleep disturbances may indicate underlying causes of sleep problems and these types of sleep disturbances may vary between different genetic syndromes. We examined and compared five types…

  6. Herpes simplex virus type 1 encephalitis in acquired immunodeficiency syndrome.

    PubMed

    Chrétien, F; Bélec, L; Hilton, D A; Flament-Saillour, M; Guillon, F; Wingertsmann, L; Baudrimont, M; de Truchis, P; Keohane, C; Vital, C; Love, S; Gray, F

    1996-10-01

    Herpes simplex (HSV) infection of the central nervous system is uncommon in AIDS and usually has an atypical topography. This review is centred around the case of a 49-year-old homosexual patient with AIDS who died from diffuse encephalopathy. Neuropathological examination revealed necrotic and haemorrhagic changes involving both temporal lobes, insulae and cingulate gyri. Cowdry type A intranuclear inclusion bodies were abundant but inflammation was minimal. Electron microscopy confirmed characteristic herpes virus particles. Immunocyto-chemistry was positive for HSV type 1 and 2. In situ hybridization and PCR, however, were positive for HSV type 1 but excluded HSV type 2. There was associated cytomegalovirus ventriculitis but clearly separated from HSV encephalitis. There were no histological features of HIV encephalitis and HIV could not be demonstrated by immunocytochemistry or by PCR to demonstrate proviral DNA. Apoptotic neurons were numerous in areas with a severe macrophage reaction. Only two pathological cases with characteristic limbic distribution and necrotic haemorrhagic histologic have been reported previously. The rarity of these reports suggests that in advanced AIDS, the immune reaction causing a typical necrotizing encephalitis cannot be mounted. Distinction between HSV type 1 and 2 infection may be difficult by immunocytochemistry and usually requires in situ hybridization, tissue culture or PCR. In AIDS patients, HSV-1 has been identified as responsible for encephalitis whereas HSV-2 has been more responsible for myelitis. Associated productive HIV infection of the CNS was found in none of the cases. In contrast, cytomegalovirus encephalitis was found in nine of 11 cases of AIDS-associated HSV encephalitis. PMID:8930949

  7. Type 1 diabetes mellitus in a 3 1/2 year-old girl with Turner's syndrome.

    PubMed

    Gonc, E Nazli; Ozon, Alev; Alikasifoglu, Ayfer; Kandemir, Nurgun

    2002-01-01

    Turner's syndrome is associated with autoimmune disorders. Autoimmune endocrinopathy in Turner's syndrome seems to be limited to autoimmune thyroiditis. A small number of patients with Turner's syndrome has also been associated with celiac disease, inflammatory bowel disease and juvenile rheumatoid arthritis. Type 1 diabetes mellitus in Turner's syndrome has been rarely reported. We present here the youngest patient with Turner's syndrome who developed type 1 diabetes mellitus. At the age of 3.5 years she was hospitalized with diabetic ketoacidosis. Anti-islet cell and anti-insulin antibodies were positive and C-peptide level was low. When she was investigated for recurrent urinary tract infections, horseshoe kidney was detected by ultrasonography. Karyotype analysis revealed 45,XO. She has been followed for 2 years with an insulin dose of 0.9 U/kg per day. The prevalence of type 1 diabetes mellitus associated with Turner's syndrome is still unknown. PMID:12387520

  8. Pulmonary Alveolar Type II Epithelial Cells and Adult Respiratory Distress Syndrome

    PubMed Central

    Mason, Robert J.

    1985-01-01

    During the past ten years, functions of alveolar type II cells have been well characterized with isolated cells in vitro. Some of the functions were well known from studies in vivo, but others such as transepithelial sodium transport were unsuspected. A better understanding of this important pulmonary cell type improves our knowledge of the pathophysiology of adult respiratory distress syndrome and may in time lead to new therapeutic strategies. ImagesFigure 1.Figure 2.Figure 3.Figure 4. PMID:3909639

  9. Increased incidence of neonatal respiratory distress in infants with mucopolysaccharidosis type II (MPS II, Hunter syndrome).

    PubMed

    Dodsworth, Charlotte; Burton, Barbara K

    2014-02-01

    Records were reviewed on all patients with mucopolysaccharidosis type II (Hunter syndrome) seen at a single institution from 1999 to 2013 to identify those with a history of neonatal intensive care. Eleven of 34 patients were in a neonatal intensive care unit and all had respiratory distress with 8 diagnoses of respiratory distress syndrome and 3 of transient tachypnea of the newborn. None of the infants were premature; four were delivered by cesarean section. These findings suggest that respiratory distress is more commonly observed in neonates with MPS II than in the general population. This may reflect airway disease already present in this disorder at the time of birth. PMID:24238892

  10. Type B aortic dissection triggered by heart transplantation in a patient with Marfan syndrome.

    PubMed

    Audenaert, Tjorven; De Pauw, Michel; François, Katrien; De Backer, Julie

    2015-01-01

    Heart transplantation in patients with Marfan syndrome is challenging and raises concerns with regards to the haemodynamic and immunosuppressive-induced effects on the inherently fragile aorta. Most aortic events following transplantation reported so far in the literature occurred in patients with pre-existent distal aortic dissection. We report a case of successful orthotopic heart transplantation in a patient with Marfan syndrome that was complicated by late-onset type B dissection in pre-existing mild and stable distal aortic dilation. Serial aortic imaging revealed progressive growth at the level of the descending thoracic aorta. An open thoracoabdominal aortic repair procedure was successfully performed 6 months after the transplantation. PMID:26475875

  11. Familial partial lipodystrophy: two types of an X linked dominant syndrome, lethal in the hemizygous state.

    PubMed Central

    Köbberling, J; Dunnigan, M G

    1986-01-01

    Familial lipodystrophy (referred to in publications as the Köbberling-Dunnigan syndrome) comprises at least two clinical phenotypes which are consistent within each pedigree. In type 1 familial lipodystrophy, loss of subcutaneous fat is confined to the limbs, sparing the face and trunk. In type 2 familial lipodystrophy, the trunk is also affected with the exception of the vulva, giving an appearance of labial hypertrophy. Diabetes mellitus, hyperlipoproteinaemia, and acanthosis nigricans are present to a variable degree in some but not all patients with familial lipodystrophy, and the abnormal distribution of subcutaneous fat is the essential hallmark of the syndrome. In addition to a survey of published reports, new cases with the syndrome are described. Both types of partial lipodystrophy, occurring either as familial disease or as sporadic cases, have only been observed in female patients. Study of the pedigrees of five families with familial lipodystrophy (two Scottish and three German) suggests an X linked dominant mode of transmission, lethal in the hemizygous (XY) state. The two clinical phenotypes with their variably expressive metabolic abnormalities are consistent either with different mutants of the same allele or with two genes on adjacent loci. Other clinical phenotypes of familial lipodystrophy may exist due to further mutations of the same allele or of genes on adjacent loci. The nature of the disorder in patients with familial lipodystrophy usually escapes recognition for many years and the syndrome is almost certainly much commoner than the few families described to date suggest. Images PMID:3712389

  12. Precocious presentation of autoimmune polyglandular syndrome type 2 associated with an AIRE mutation.

    PubMed

    Resende, Eduarda; Gόmez, Gemma Novoa; Nascimento, Marta; Loidi, Lourdes; Saborido Fiaño, Rebeca; Cabanas Rodrίguez, Paloma; Castro-Feijoo, Lidia; Barreiro Conde, Jesús

    2015-01-01

    Autoimmune polyglandular syndrome type 2 (type 2 APS), or Schmidt's syndrome, is defined by the presence of Addison's disease in combination with type 1 diabetes and/or autoimmune thyroid disease. The estimated prevalence of this syndrome is 1.4-4.5 per 100,000 inhabitants and it is more frequent in middle-aged females, whilst it is quite rare in children. Type 2 APS, which shows a pattern of autosomal dominant inheritance with low penetrance, has been associated with HLA specific DR3/DQ2 and DR4/DQ8 haplotypes. However, it has been hypothesized that genetic variability in the AIRE gene, which causing type 1 APS, may play a role in more common organ-specific autoimmune conditions like type 1 diabetes, Hashimoto's disease and type 2 APS, among others. Here we present the case of an 8-year-old girl, with a past medical history of type 1 diabetes diagnosed at the age of 3. She was taken to the Emergency Department because she complained of abdominal pain, nausea and vomiting, and her blood analysis revealed a severe hyponatremia. She also had seizures as a consequence of the hyponatremia and frequent hypoglycemia. She was ultimately found to be suffering from autoimmune primary adrenal insufficiency. The combination of both mentioned conditions, type 1 diabetes and Addison's disease, in the absence of chronic mucocutaneous candidiasis, made a diagnosis of type 2 APS plausible in this girl. The genetic study showed two heterozygous variants: NM_000383.2:C.1411C>T (p. Arg471Cys) in exon 12 and IVS9+6G>A in intron 9 of the AIRE gene. The description of an uncommon case of type 2 APS with precocious presentation associated with an AIRE mutation in a very young girl could help to clarify the role of AIRE in the development of autoimmune diseases. PMID:25402387

  13. Scimitar Syndrome and H-type Tracheo-esophageal Fistula in a Newborn Infant.

    PubMed

    Lastinger, Allison; El Yaman, Malek; Gustafson, Robert; Yossuck, Panitan

    2016-06-01

    Scimitar syndrome is a rare congenital anomaly characterized by partial anomalous pulmonary venous drainage of the right lung to the inferior vena cava (IVC) creating a tubular opacity paralleling the right cardiac border on chest radiography which resembles a curved Turkish sword or scimitar. Associated pulmonary and vascular anomalies have been reported in cases of Scimitar syndrome, most commonly hypoplasia of right lung, dextroposition of the heart, hypoplasia of the right pulmonary artery, and aberrant arterial supply from the descending aorta to the affected lobe of the right lung. To the best of our knowledge, this is the first case of Scimitar syndrome with an H-type tracheoesophageal fistula that has ever been reported. PMID:24269859

  14. Tricho-rhino-phalangeal syndrome type 1 as an outcome of in vitro fertilization?

    PubMed

    Karaer, K; Yüksel, Z

    2014-01-01

    Trichorhinophalangeal syndrome type I [OMIM #190350] is an autosomal dominant disorder. Common features are: Slowly growing sparse hair, laterally thin eyebrows, bulbous tip of the nose, long philtrum, thin upper lip, protruding ears. Common skeletal anomalies include shortening of phalanges and metacarpals causing mild to severe brachydactyly, cone shaped epiphyses, hip dysplasia and short stature. Recently many reports have been published on the use of assisted reproductive technology (ART) and the increased risk of congenital major malformations or syndromes. We present a 6 years old Turkish Trichorhinophalangeal syndrome (TRPS) case of a twin pair after in vitro fertilization (IVF). TRPS with IVF pregnancy has not been reported previously. This new case reported herein will contribute to a better understanding whether ART pregnancy increases congenital malformations. PMID:24783650

  15. Unusual phenotype of glucose transport protein type 1 deficiency syndrome: A case report and literature review

    PubMed Central

    Posar, Annio; Santucci, Margherita

    2014-01-01

    The glucose transport protein type 1 (GLUT1) deficit causes a chronic brain energy failure. The classic phenotype of GLUT1 deficiency syndrome is characterized by: Mild to severe motor delay and mental retardation; infantile-onset epilepsy; head growth deceleration; movement disorders (ataxia, dystonia, spasticity); and non-epileptic paroxysmal events (intermittent ataxia, periodic confusion, recurrent headaches). During last years the classic phenotype of this syndrome, as originally reported, has expanded. We report the atypical phenotype of a boy with GLUT1 deficiency syndrome, characterized by mild mental retardation and drug-resistant absence seizures with onset at the age of 6 years, without movement disorders nor decrease of head circumference. A prompt diagnosis of this disorder is mandatory since the ketogenic diet might represent an effective treatment. PMID:24891901

  16. Unusual phenotype of glucose transport protein type 1 deficiency syndrome: A case report and literature review.

    PubMed

    Posar, Annio; Santucci, Margherita

    2014-01-01

    The glucose transport protein type 1 (GLUT1) deficit causes a chronic brain energy failure. The classic phenotype of GLUT1 deficiency syndrome is characterized by: Mild to severe motor delay and mental retardation; infantile-onset epilepsy; head growth deceleration; movement disorders (ataxia, dystonia, spasticity); and non-epileptic paroxysmal events (intermittent ataxia, periodic confusion, recurrent headaches). During last years the classic phenotype of this syndrome, as originally reported, has expanded. We report the atypical phenotype of a boy with GLUT1 deficiency syndrome, characterized by mild mental retardation and drug-resistant absence seizures with onset at the age of 6 years, without movement disorders nor decrease of head circumference. A prompt diagnosis of this disorder is mandatory since the ketogenic diet might represent an effective treatment. PMID:24891901

  17. Radiographic and Tomographic Analysis in Patients with Stickler Syndrome Type I

    PubMed Central

    Al Kaissi, Ali; Chehida, Farid Ben; Ganger, Rudolf; Kenis, Vladimir; Zandieh, Shahin; Hofstaetter, Jochen G; Klaushofer, Klaus; Grill, Franz

    2013-01-01

    Objective: To further investigate the underlying pathology of axial and appendicular skeletal abnormalities such as painful spine stiffness, gait abnormalities, early onset osteoarthritis and patellar instability in patients with Stickler syndrome type I. Radiographic and tomographic analyses were organized. Methods: From a series of Stickler syndrome patients followed from early life to late childhood. Ten patients (6 boys and four girls of different ethnic origins were consistent with the diagnosis of Stickler syndrome type I ). Phenotypic characterization was the baseline tool applied for all patients and genotypic correlation was performed on four families Results: A constellation of axial abnormalities namely; anterolateral ossification of the anterior longitudinal spinal ligament with subsequent fusion of two cervical vertebrae, early onset Forestier disease (progressive spinal hyperostosis with subsequent vertebral fusion on top of bridging osteophytes and “Bamboo-like spine” resembling ankylosing spondylitis) and severe premature spine degeneration were evident. Appendicular abnormalities in connection with generalized epiphyseal dysplasia were the underlying aetiology in patients with Intoeing gait and femoral anteversion, early onset severe osteoarthritis of the weight bearing joint. Remarkable trochleo-patellar dysplasia secondary to severe osteoarthritis causing effectively the development of patellar instability was additional pathology. Mutation of COL2A1 has been confirmed as the causative gene for Stickler syndrome type I Conclusion: We concluded that conventional radiographs and the molecular determination of a COL2A1 in patients with (Stickler syndrome type I) are insufficient tools to explain the reasons behind the tremendous magnitude of axial and appendicular skeletal abnormalities. We were able to modify the criteria of the clinical phenotype as designated by Rose et al in accordance with the novel axial and appendicular criteria as

  18. Spontaneous rupture of the spleen in type IV Ehlers-Danlos syndrome: report of a case.

    PubMed

    Privitera, Antonio; Milkhu, Chaz; Datta, Vivek; Sayegh, Mazim; Cohen, Richard; Windsor, Alastair

    2009-01-01

    The vascular type of Ehlers-Danlos syndrome, type IV, is associated with severe complications, including arterial rupture and visceral perforation. However, to our knowledge, there has been only one previous report of splenic rupture caused by a spontaneous hemorrhage in type IV Ehlers-Danlos syndrome. We report another case of this uncommon complication, occurring in a 35-year-old woman who presented after the sudden onset of acute abdominal pain. Patients should be stabilized quickly in the intensive care unit and the most timesaving surgical techniques used. Moreover, tissues must be handled with great care intraoperatively in view of their extreme fragility. Despite prompt and appropriate treatment, the prognosis is often dismal. PMID:19132469

  19. C5orf42 is the major gene responsible for OFD syndrome type VI.

    PubMed

    Lopez, Estelle; Thauvin-Robinet, Christel; Reversade, Bruno; Khartoufi, Nadia El; Devisme, Louise; Holder, Muriel; Ansart-Franquet, Hélène; Avila, Magali; Lacombe, Didier; Kleinfinger, Pascale; Kaori, Irahara; Takanashi, Jun-Ichi; Le Merrer, Martine; Martinovic, Jelena; Noël, Catherine; Shboul, Mohammad; Ho, Lena; Güven, Yeliz; Razavi, Ferechté; Burglen, Lydie; Gigot, Nadège; Darmency-Stamboul, Véronique; Thevenon, Julien; Aral, Bernard; Kayserili, Hülya; Huet, Frédéric; Lyonnet, Stanislas; Le Caignec, Cédric; Franco, Brunella; Rivière, Jean-Baptiste; Faivre, Laurence; Attié-Bitach, Tania

    2014-03-01

    Oral-facial-digital syndrome type VI (OFD VI) is a recessive ciliopathy defined by two diagnostic criteria: molar tooth sign (MTS) and one or more of the following: (1) tongue hamartoma (s) and/or additional frenula and/or upper lip notch; (2) mesoaxial polydactyly of one or more hands or feet; (3) hypothalamic hamartoma. Because of the MTS, OFD VI belongs to the "Joubert syndrome related disorders". Its genetic aetiology remains largely unknown although mutations in the TMEM216 gene, responsible for Joubert (JBS2) and Meckel-Gruber (MKS2) syndromes, have been reported in two OFD VI patients. To explore the molecular cause(s) of OFD VI syndrome, we used an exome sequencing strategy in six unrelated families followed by Sanger sequencing. We identified a total of 14 novel mutations in the C5orf42 gene in 9/11 families with positive OFD VI diagnostic criteria including a severe fetal case with microphthalmia, cerebellar hypoplasia, corpus callosum agenesis, polydactyly and skeletal dysplasia. C5orf42 mutations have already been reported in Joubert syndrome confirming that OFD VI and JBS are allelic disorders, thus enhancing our knowledge of the complex, highly heterogeneous nature of ciliopathies. PMID:24178751

  20. Myocardial infarction resulting from coronary artery dissection in an adolescent with Ehlers-Danlos syndrome type IV due to a type III collagen mutation.

    PubMed Central

    Adès, L. C.; Waltham, R. D.; Chiodo, A. A.; Bateman, J. F.

    1995-01-01

    Ehlers-Danlos syndrome encompasses a group of inherited disorders of connective tissue, some of which are characterised by abnormalities of collagen metabolism. The chromosomal location, identified genes and biochemical defects, inheritance pattern, and clinical features for the various known subtypes are outlined. Prenatal diagnosis is possible for types IV, VI, VIIA1, and VIIA2. An unusual presentation of type IV Ehlers-Danlos syndrome in a 16 year old boy with an anterior myocardial infarction resulting from dissection of the left anterior descending coronary artery is reported here. A clinical diagnosis of type IV Ehlers-Danlos syndrome was made subsequently and confirmed by the reduced production, impaired secretion, and abnormally slow electrophoretic migration of type III collagen, indicating an underlying mutation in the COL3A1 gene. This patient represents the first case of type IV Ehlers-Danlos syndrome with symptomatic coronary artery dissection. Images PMID:7546986

  1. Plasma Fibrinogen in Type 2 Diabetic Patients with Metabolic Syndrome and its Relation with Ischemic Heart Disease (IHD) and Retinopathy

    PubMed Central

    Mahendra, J.V.; Anuradha, T.S.; Talikoti, Prashanth; Nagaraj, R.S.; Vishali, V.

    2015-01-01

    Introduction: Metabolic syndrome or Syndrome X is characterized by hyperlipidemia, increased blood pressure, abdominal obesity and hyperglycemia, which increases the risk of cardiovascular complications. In addition to these, it is also associated with nontraditional risk factor like C- reactive protein, Plasminogen activator and fibrinogen. Various studies have documented association of these nontraditional risk factor, in Type 2 diabetes mellitus. Thus patients with diabetes mellitus are higher risk of developing micro and macro vascular complications like ischemic heart disease (IHD) and diabetic retinopathy. Diabetic retinopathy is the leading cause of decreased visual acuity, which is associated with maculopathy and profierative complications of it. Chronic hyperglycemia and its associated nonenzymatic glycation play an important role in the development of microangiopathy. Aims and Objectives: To study the prevalence of the metabolic syndrome in type 2 diabetes mellitus. To study the plasma fibrinogen and its relationship with IHD and retinopathy in type 2 Diabetes mellitus patients with metabolic syndrome. Materials and Methods: Patients of type 2 diabetes Mellitus were recruited based on the inclusion and exclusion criteria. History of IHD and ECG evidence of ischemia was obtained. Retinopathy was diagnosed by direct opthalmoscopy. Fasting glucose, lipid profile and plasma fibrinogen were analyzed. Stastical analysis was carried by Chi square test and student‘t’ test. Results: The prevalence of metabolic syndrome in study population of 100 type 2 diabetic patients is 58% and is significantly associated with duration of the disease (p<0.001). Fifty eight patients have hyperfibrinogenemia and mean fibrinogen level is significantly high in diabetic patients with metabolic syndrome when compared to diabetic patients without metabolic syndrome (p<0.001). Diabetic patient with metabolic syndrome and hyperfibrinogenemia have higher prevalence of IHD and

  2. Knowledge, assessment, and management of adults with joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type among Flemish physiotherapists.

    PubMed

    Rombaut, Lies; Deane, Janet; Simmonds, Jane; De Wandele, Inge; De Paepe, Anne; Malfait, Fransiska; Calders, Patrick

    2015-03-01

    Physiotherapy plays a fundamental role in managing adults with the joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type (JHS/EDS-HT). However, it is a challenge for both the patient and the physiotherapist as the condition is poorly understood and treatment for JHS/EDS-HT is currently undefined. Insight into current practice is, therefore, necessary in order to establish baseline knowledge in this area and in the long term to improve the standard of patient care. Therefore, the purpose of this study was to evaluate current physiotherapists' knowledge of JHS/EDS-HT and to gain insight into current physiotherapy practice with emphasis on assessment, management, and treatment efficacy. Three hundred twenty-five Flemish physiotherapists participated in the study by filling out electronically a modified version of the "Hypermobility and Hypermobility Syndrome Questionnaire" (HHQ), which covered theoretical constructs such as general knowledge, assessment, management, and learning in relation to generalized joint hypermobility and JHS/EDS-HT. The results show that physiotherapists report a low level of confidence with regard to assessment and management of JHS/EDS-HT. Knowledge of hypermobility and JHS/EDS-HT is weak, especially regarding the features associated with JHS/EDS-HT. Many treatment approaches are used by physiotherapists with the majority showing preference for education, reassurance, muscle strengthening, proprioceptive and core stability training. Almost all approaches were perceived as being clinically effective by the physiotherapists, highlighting a lack of consensus. In conclusion, this study in Flemish physiotherapists confirms that JHS/EDS-HT is under-recognized, not well known and deemed difficult to treat. Further education is required and sought by the physiotherapists surveyed, and future research is needed. PMID:25821093

  3. Inflammatory Cytokine Profile Associated with Metabolic Syndrome in Adult Patients with Type 1 Diabetes

    PubMed Central

    Ferreira-Hermosillo, Aldo; Molina-Ayala, Mario; Ramírez-Rentería, Claudia; Vargas, Guadalupe; Gonzalez, Baldomero; Isibasi, Armando; Archundia-Riveros, Irma; Mendoza, Victoria

    2015-01-01

    Objective. To compare the serum concentration of IL-6, IL-10, TNF, IL-8, resistin, and adiponectin in type 1 diabetic patients with and without metabolic syndrome and to determine the cut-off point of the estimated glucose disposal rate that accurately differentiated these groups. Design. We conducted a cross-sectional evaluation of all patients in our type 1 diabetes clinic from January 2012 to January 2013. Patients were considered to have metabolic syndrome when they fulfilled the joint statement criteria and were evaluated for clinical, biochemical, and immunological features. Methods. We determined serum IL-6, IL-8, IL-10, and TNF with flow cytometry and adiponectin and resistin concentrations with enzyme linked immunosorbent assay in patients with and without metabolic syndrome. We also compared estimated glucose disposal rate between groups. Results. We tested 140 patients. Forty-four percent fulfilled the metabolic syndrome criteria (n = 61), 54% had central obesity, 30% had hypertriglyceridemia, 29% had hypoalphalipoproteinemia, and 19% had hypertension. We observed that resistin concentrations were higher in patients with MS. Conclusion. We found a high prevalence of MS in Mexican patients with T1D. The increased level of resistin may be related to the increased fat mass and could be involved in the development of insulin resistance. PMID:26273680

  4. Clinical Presentation of Mucopolysaccharidosis Type II (Hunter's Syndrome)

    PubMed Central

    Chinawa, JM; Adimora, GN; Obu, HA; Tagbo, B; Ujunwa, F; Onubogu, I

    2012-01-01

    We present a rare case of mucopolysaccharidosis (MPS) with a typical presentation of mental retardation and absence of corneal clouding. The purpose of presenting this case report is to highlight the distinctive manifestation of MPS (Hunter's disease) and to provide a concise report of Hunter's disease for medical practitioners with the hope that such information will help identify boys earlier in the course of their disease. This report is of a 7-year-old boy who presented to the children outpatient through a referral with a history of inability to grasp objects, inability to express self, and coarse skin, which started 5 years ago. On examination, he was short statured, with a big head, protruding abdomen, coarse skin, swollen wrist joints, and clubbed fingers. There was mild mental retardation. Investigations revealed mucopolysaccharides in urine ad radiographic findings were in keeping with diagnosis. Based on the clinical features and radiological findings, one can diagnose a case of MPS. However, careful and critical approach is necessary to exactly diagnose the type of MPS as enzymatic studies are not available in most centers. PMID:23209998

  5. Polyglandular endocrinopathy type II (Schmidt's syndrome) in a Dobermann pinscher.

    PubMed

    Cartwright, J A; Stone, J; Rick, M; Dunning, M D

    2016-09-01

    A three-year-old, female neutered, Dobermann pinscher was presented for investigation of lethargy, episodic collapse, ataxia and myxoedema. Primary hypothyroidism and primary cortisol-deficient hypoadrenocorticism were diagnosed based on history, physical examination and compatible hormonal analysis. Increased serum concentrations of thyroglobulin autoantibodies and 21-hydroxylase autoantibodies indicated an immune-mediated aetiology. The case was complicated by lymphadenopathy with hand-mirror lymphocytes, classically identified in lymphoma. A polymerase chain reaction test for antigen receptor rearrangement indicated polyclonality and therefore reactive lymphadenopathy. The dog's clinical signs resolved following introduction of levothyroxine and prednisolone. Prioritising the problem-based approach in this case facilitated the diagnosis of hypoadrenocorticism in addition to hypothyroidism due to the persistence of clinical signs despite thyroxine replacement. Importantly, atypical adrenal gland dysfunction was not misinterpreted as inadequate therapeutic response to thyroxine supplementation. The observation that polyglandular endocrinopathy type II can occur in dogs suggests that in dogs with a suboptimal response to treatment for hypothyroidism or hypoadrenocorticism comorbid endocrinopathies should be investigated. PMID:27487017

  6. Heart rate, conduction and ultrasound abnormalities in adults with joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type.

    PubMed

    Camerota, Filippo; Castori, Marco; Celletti, Claudia; Colotto, Marco; Amato, Silvia; Colella, Alessandra; Curione, Mario; Danese, Chiara

    2014-07-01

    Joint hypermobility syndrome (JHS) and Ehlers-Danlos syndrome, hypermobility type (EDS-HT) are two clinically overlapping heritable connective tissue disorders strongly associating with pain, fatigue and other secondary aspects. Though not considered a diagnostic criterion for most EDS subtypes, cardiovascular involvement is a well-known complication in EDS. A case-control study was carried out on 28 adults with JHS/EDS-HT diagnosed according to current criteria, compared to 29 healthy subjects evaluating resting electrocardiographic (ECG), 24-h ECG and resting heart ultrasound data. Results obtained in the ECG studies showed a moderate excess in duration of the PR interval and P wave, an excess of heart conduction and rate abnormalities and an increased rate of mitral and tricuspid valve insufficiency often complicating with "true" mitral valve prolapse in the ecocardiographic study. These variable ECG subclinical anomalies reported in our sample may represent the resting surrogate of such a subnormal cardiovascular response to postural changes that are known to be present in patients with JHS/EDS-HT. Our findings indicate the usefulness of a full cardiologic evaluation of adults with JHS/EDS-HT for the correct management. PMID:24752348

  7. The role of narrative medicine in the management of joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type.

    PubMed

    Knight, Isobel

    2015-03-01

    Joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type (JHS/EDS-HT) is a hereditary connective tissue disorder affecting every bodily system. It is largely underdiagnosed by many practitioners, with the result of a considerable delay in diagnosis and, consequently, in the onset of adequate management schedule and treatment. Patients may also experience to be misbelieved, erroneously considered affected by a psychiatric or psychosomatic disorders, and rejected by the medical profession, which can lead to feelings of anger and resentment. Patient journeys are often long and complicated, but if doctors allowed the patient time to tell the full story, and were more prepared to think holistically, there may be a far more positive outcome. Here, the patients' perspective is presented with a narrative medicine approach, illustrating the tri-dimensional experience of a JHS/EDS-HT patient, who is also a Bowen Practitioner and a medical writer/educator. Narrative medicine would be invaluable in working with JHS/EDS-HT so that the patient can tell the story, and offer the practitioner a whole picture of her/his suffering and, often, the key for understanding the cause(s). Once this has been achieved, it might be possible to build upon a more positive and therapeutic dialogue which would result in better treatment and more effective management. It is also important for doctors to communicate with JHS/EDS-HT experts who will ultimately improve the patient journey and treatment outcomes of such a complex connective tissue disorder. PMID:25821096

  8. Rous-associated virus type 7 induces a syndrome in chickens characterized by stunting and obesity.

    PubMed Central

    Carter, J K; Ow, C L; Smith, R E

    1983-01-01

    Infection of 10-day-old chicken embryos with an avian retrovirus. Rous-associated virus type 7, resulted in a disease characterized by stunting and hyperlipidemia. By 20 days after hatch, infected chickens were smaller than hatchmates and developed ataxia and obesity over the next 30 days. Histological examinations of livers from infected chickens revealed a diffuse panlobular fatty infiltrate involving an accumulation of fat in microdroplets. Electron microscopic examinations of livers from infected chickens revealed hepatocytes with swollen mitochondria that lacked cristae. The thyroid and pancreas were infiltrated with lymphoblastoid cells by 1 week after hatch. An examination of the blood revealed a mild anemia, a frank lipemia, and high levels of uric acid. This syndrome induced by Rous-associated virus type 7 in chickens may be useful for elucidating the nature of several diseases, including that found in the fatty liver and kidney syndrome of chickens and that observed in a strain of obese chickens. Images PMID:6295959

  9. Acute respiratory distress syndrome in adenovirus type 4 pneumonia: A case report.

    PubMed

    Narra, R; Bono, P; Zoccoli, A; Orlandi, A; Piconi, S; Grasselli, G; Crotti, S; Girello, A; Piralla, A; Baldanti, F; Lunghi, G

    2016-08-01

    Human adenoviruses (HAdVs) cause a wide spectrum of clinical syndromes, depending on species and types, from mild respiratory infections to deadly pneumonia: in particular, severe infections occur in immunocompromised patients. In this report, we describe the case of a 36 years-old woman admitted to our intensive care unit (ICU) with severe respiratory distress syndrome caused by adenovirus pneumonia, that required invasive respiratory support (mechanical ventilation and extracorporeal membrane oxygenation). Molecular assays detected the virus in respiratory and plasma specimen and sequencing procedure identified HAdV type 4. Patient improved after cidofovir administration. Leukopenia and subsequent bacterial infection occurred, but the patient recovered completely and was discharged from the hospital after 54days. PMID:27354307

  10. Daughter and mother with orofaciodigital syndrome type 1 and glomerulocystic kidney disease.

    PubMed

    Iijima, Takashi; Hoshino, Junichi; Mise, Koki; Sumida, Keiichi; Suwabe, Tatsuya; Hayami, Noriko; Ueno, Toshiharu; Takaichi, Kenmei; Fujii, Takeshi; Ohashi, Kenichi; Morisada, Naoya; Iijima, Kazumoto; Ubara, Yoshifumi

    2016-09-01

    A 35-year-old woman was admitted to our hospital for evaluation of end-stage renal failure. Diagnostic imaging, including ultrasonography and magnetic resonance imaging, showed polycystic kidneys and peribiliary hepatic cysts, but the renal cysts were isointense and her kidneys were smaller than the end-stage kidneys of patients with autosomal dominant polycystic kidney disease. Glomerulocystic kidney disease was diagnosed by renal biopsy. Clinical examination revealed findings such as a missing maxillary canine, lingual anomalies, and brachydactyly. Genetic testing gave a diagnosis of orofaciodigital syndrome type 1 with a 5 nucleotide deletion indicating a frameshift mutation in exon 9. The patient's mother had the same mutation and similar clinical findings. This case is useful for understanding kidney and liver involvement in orofaciodigital syndrome type 1. PMID:27131853

  11. Cardiac arrest refractory to standard intervention in atypical Timothy syndrome (LQT8 type 2).

    PubMed

    Philipp, Lucas R; Rodriguez, Fred H

    2016-04-01

    Timothy syndrome (TS) is a rare, multisystem disorder most commonly associated with profound QTc prolongation and cutaneous dysmorphia arising from mutations of the L-type calcium channel. We present a case of a 12-day-old newborn who presented with respiratory distress and cyanosis. Diagnostic workup was notable for multiple cardiac abnormalities, and genetic analysis was consistent with an exon 8 mutation of the CACNA1C gene, which is diagnostic for TS type 2 (atypical TS). This patient presented with a novel constellation of symptoms, without dysmorphic features, and with a more moderate QTc interval. The heterogeneity of phenotypes suggests that this disorder may be characterized by variable expressivity or a spectrum of disease rather than a clearly defined syndrome. PMID:27034553

  12. Cardiac arrest refractory to standard intervention in atypical Timothy syndrome (LQT8 type 2)

    PubMed Central

    Rodriguez, Fred H.

    2016-01-01

    Timothy syndrome (TS) is a rare, multisystem disorder most commonly associated with profound QTc prolongation and cutaneous dysmorphia arising from mutations of the L-type calcium channel. We present a case of a 12-day-old newborn who presented with respiratory distress and cyanosis. Diagnostic workup was notable for multiple cardiac abnormalities, and genetic analysis was consistent with an exon 8 mutation of the CACNA1C gene, which is diagnostic for TS type 2 (atypical TS). This patient presented with a novel constellation of symptoms, without dysmorphic features, and with a more moderate QTc interval. The heterogeneity of phenotypes suggests that this disorder may be characterized by variable expressivity or a spectrum of disease rather than a clearly defined syndrome. PMID:27034553

  13. A novel PAX3 mutation in a Japanese boy with Waardenburg syndrome type 1

    PubMed Central

    Yoshida, Yu; Doi, Rieko; Adachi, Kaori; Nanba, Eiji; Kodani, Isamu; Ryoke, Kazuo

    2016-01-01

    Waardenburg syndrome type 1 (WS1) is a rare autosomal dominant disorder characterized by hair hypopigmentation, abnormal iris pigmentation, and congenital hearing loss. WS1 is caused by mutations in paired box gene 3 (PAX3). We identified a novel PAX3 mutation (c.1107 C>G, p.Ser369Arg) in a Japanese WS1 patient showing abnormal right iris pigmentation, right-sided congenital hearing loss, synophrys, incomplete left cleft lip, and cryptorchidism. PMID:27081571

  14. A novel PAX3 mutation in a Japanese boy with Waardenburg syndrome type 1.

    PubMed

    Yoshida, Yu; Doi, Rieko; Adachi, Kaori; Nanba, Eiji; Kodani, Isamu; Ryoke, Kazuo

    2016-01-01

    Waardenburg syndrome type 1 (WS1) is a rare autosomal dominant disorder characterized by hair hypopigmentation, abnormal iris pigmentation, and congenital hearing loss. WS1 is caused by mutations in paired box gene 3 (PAX3). We identified a novel PAX3 mutation (c.1107 C>G, p.Ser369Arg) in a Japanese WS1 patient showing abnormal right iris pigmentation, right-sided congenital hearing loss, synophrys, incomplete left cleft lip, and cryptorchidism. PMID:27081571

  15. Extended phenotypes in a boy and his mother with oto-palato-digital-syndrome type II

    PubMed Central

    Kaissi, Ali Al; Kraschl, Raimund; Kaulfersch, Wilhelm; Grill, Franz; Ganger, Rudolf

    2015-01-01

    Key Clinical Message We describe additional phenotypic features in a boy and his mother. Both manifested the phenotypic/genotypic correlation of oto-palato-digital syndrome type II. The mother′s radiographs showed wormian bones of the skull, and paranasal bossing, her feet showed bilateral fusion of the cuboid with the lateral cuneiform bone with subsequent development of metatarsus varus associated with dysplastic distal phalanges. PMID:26401283

  16. Aromatase excess syndrome presenting with prepubertal gynecomastia in an Egyptian child with type 1 neurofibromatosis

    PubMed Central

    Metwalley, Kotb Abbass; Farghaly, Hekma Saad

    2013-01-01

    A romatase excess syndrome (AEXS) is a rare autosomal dominant disorder characterized by prepubertal gynecomastia, it responds well to medical treatment. In the absence of prompt suspicion, it can expose the patient to the risk of unnecessary surgical intervention. Up to our best knowledge, the association between AEXS and neurofibromatosis type 1 (NF1) was not reported before. Here, we describe a AEXS presenting with prepubertal gynecomastia in an Egyptian child with NF1 that improved with aromatase inhibitors. PMID:24497716

  17. Prolonged QT interval in a man with anorexia nervosa

    PubMed Central

    Macías-Robles, María Dolores; Perez-Clemente, Ana María; Maciá-Bobes, Carmen; Alvarez-Rueda, María Asunción; Pozo-Nuevo, Sergio

    2009-01-01

    Anorexia nervosa is an eating disorder characterized by the avoidance of food intake, which usually leads to a weight loss. Cardiac co-morbility is common and we can find sometimes a mass loss from the left ventricle, which can be seen by echocardiography. But the commonest complications are rhythm variations, typically bradycardia with a prolonged QT interval in up to a 40% of the cases, which altogether elevates ventricular tachycardia and sudden death risk. We present the case of a male who was diagnosed with anorexia nervosa and developed asthenia, a long QT interval and also a severe both hypokalaemia and hypomagnesaemia. We intend to discuss the pathogenic paths as well as prophylactic and therapeutic measures to this potentially-lethal pathology. PMID:19646241

  18. Prolonged QT interval in a man with anorexia nervosa.

    PubMed

    Macías-Robles, María Dolores; Perez-Clemente, Ana María; Maciá-Bobes, Carmen; Alvarez-Rueda, María Asunción; Pozo-Nuevo, Sergio

    2009-01-01

    Anorexia nervosa is an eating disorder characterized by the avoidance of food intake, which usually leads to a weight loss. Cardiac co-morbility is common and we can find sometimes a mass loss from the left ventricle, which can be seen by echocardiography. But the commonest complications are rhythm variations, typically bradycardia with a prolonged QT interval in up to a 40% of the cases, which altogether elevates ventricular tachycardia and sudden death risk. We present the case of a male who was diagnosed with anorexia nervosa and developed asthenia, a long QT interval and also a severe both hypokalaemia and hypomagnesaemia. We intend to discuss the pathogenic paths as well as prophylactic and therapeutic measures to this potentially-lethal pathology. PMID:19646241

  19. Math Learning Disability and Math LD Subtypes: Evidence from Studies of Turner Syndrome, Fragile X Syndrome, and Neurofibromatosis Type 1.

    ERIC Educational Resources Information Center

    Mazzocco, Michele M. M.

    2001-01-01

    This study examined whether indicators of math learning disability were observed in 35 5- and 6-year-olds with either neurofibromatosis, Turner Syndrome, or fragile X syndrome and compared to controls. Findings indicate that girls with fragile X or Turner syndrome but not neurofibromatosis are significantly more likely to have specific math…

  20. Different impacts of metabolic syndrome components on insulin resistance in type 2 diabetes.

    PubMed

    Hsu, Chung-Hua

    2013-01-01

    Objective. To examine the different impacts of MS components on insulin resistance in type 2 diabetes. Methods. A number of subjects (144) who met the criteria of (1) age between 30 and 75 years, (2) had type 2 diabetes for more than one year, and (3) taking gliclazide and metformin for more than 6 months were enrolled. All subjects were assigned to one of the four HOMA index categories. The HOMA index quartile 4 denotes the highest insulin resistance. The main outcome evaluated is the odds ratios (ORs) of different MS components on HOMA index quartile 4. The characteristics in HOMA index quartiles and groups of nonmetabolic syndrome (NMS; number of components < 2), metabolic syndrome A (MSA; number of components = 2), and metabolic syndrome B (MSB; number of components > 2) were also evaluated. Results. The results showed that both MSA and MSB groups had higher ORs (5.9 and 13.8 times, resp.) than the NMS group; and that subjects with large waist circumference (LWC) and high triglyceride (HTG) level have higher ORs (6.1 and 2.6 times, resp.) in developing higher insulin resistance than normal control subjects. Conclusion. Type 2 diabetic patients with greater number of MS components have higher ORs in developing increased insulin resistance. PMID:23431295

  1. Clinical and molecular characterization of two patients with palmoplantar keratoderma-congenital alopecia syndrome type 2.

    PubMed

    Castori, M; Morlino, S; Sana, M E; Paradisi, M; Tadini, G; Angioni, A; Malacarne, M; Grammatico, P; Iascone, M; Forzano, F

    2016-08-01

    Palmoplantar keratoderma-congenital alopecia (PPKCA) syndrome is a rare genodermatosis, with two clinically recognizable forms: dominant (Type 1) and recessive (Type 2). Reports of only 18 patients have been published to date, and the molecular basis of the condition is unknown. We describe two cases with PPKCA Type 2 (PPKCA2), comprising a novel patient, originally reported as an example of autosomal ichthyosis follicularis-atrichia-photophobia syndrome, and the 6-year follow-up of a previously published case. Extensive molecular studies of both patients excluded mutations in all the known genes associated with PPK and partially overlapping syndromes. The striking similarities between these two patients confirm PPKCA2 as a discrete genodermatosis, of which the main features are congenital and universal alopecia, diffuse keratosis pilaris, facial erythema, and a specific PPK with predominant involvement of the fingertips and borders of the hands and feet, with evolution of sclerodactyly, contractures and constrictions. Clinical follow-up of these patients has demonstrated progressive worsening of the hand involvement and attenuation of facial erythema. PMID:27339777

  2. QT interval dispersion in the patients with central serous chorioretinopathy

    PubMed Central

    Dagli, Necati; Turgut, Burak; Tanyildizi, Rumeysa; Kobat, Sabiha; Kobat, Mehmet Ali; Dogdu, Orhan

    2015-01-01

    AIM To evaluate QT dispersion (QTD) in patients with central serous chorioretinopathy (CSC). METHODS This clinical, comperative, case-control study included 30 patients with CSC at acute phase (Group 1) and 30 age- and sex-matched healthy subjects (Group 2, the control group). From all subjects, a 12-lead surface electrocardiography was obtained. The heart rate (HR), QT maximum (QTmax), QT minimum (QTmin), QT corrected (QTc), QTD and Tmean were manually measured and analyzed. Student's t-test and Pearson's method of correlation were used for statistical analysis. RESULTS The patient and control groups were matched for age, smoking status (rate and duration) and gender. There were no significant differences with regard to these among the groups (P>0.05). The participants included 19 men (63.3%) and 11 women (36.7%) in Group 1, 20 men (66.7%) and 10 women (33.3%) in Group 2. QTmax, QTD and QTc were significantly higher than those of healthy controls (P<0.001 for QTmax, P=0.01 for QTD and P=0.001 for QTc). QTmin, Tmean and HR did not differ significantly between the study groups (P=0.28 for QTmin, P=0.56 for Tmean and P>0.05 for HR). No significant correlation was found between duration of the disorder and QTD values (r=0.13, P>0.05). CONCLUSION These findings suggest that CSC may be associated with an increase in QTD and that the patients might be at risk for ventricular arrhythmia. PMID:25709909

  3. Modelling PK/QT relationships from Phase I dose-escalation trials for drug combinations and developing quantitative risk assessments of clinically relevant QT prolongations.

    PubMed

    Sinclair, Karen; Kinable, Els; Grosch, Kai; Wang, Jixian

    2016-05-01

    In current industry practice, it is difficult to assess QT effects at potential therapeutic doses based on Phase I dose-escalation trials in oncology due to data scarcity, particularly in combinations trials. In this paper, we propose to use dose-concentration and concentration-QT models jointly to model the exposures and effects of multiple drugs in combination. The fitted models then can be used to make early predictions for QT prolongation to aid choosing recommended dose combinations for further investigation. The models consider potential correlation between concentrations of test drugs and potential drug-drug interactions at PK and QT levels. In addition, this approach allows for the assessment of the probability of QT prolongation exceeding given thresholds of clinical significance. The performance of this approach was examined via simulation under practical scenarios for dose-escalation trials for a combination of two drugs. The simulation results show that invaluable information of QT effects at therapeutic dose combinations can be gained by the proposed approaches. Early detection of dose combinations with substantial QT prolongation is evaluated effectively through the CIs of the predicted peak QT prolongation at each dose combination. Furthermore, the probability of QT prolongation exceeding a certain threshold is also computed to support early detection of safety signals while accounting for uncertainty associated with data from Phase I studies. While the prediction of QT effects is sensitive to the dose escalation process, the sensitivity and limited sample size should be considered when providing support to the decision-making process for further developing certain dose combinations. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26991506

  4. A Bayesian Approach for Investigating the Risk of QT Prolongation

    PubMed Central

    Anand, Suraj P.; Ghosh, Sujit K.

    2009-01-01

    The standard approach to investigating a drug for its potential for QT prolongation is to construct a 90% two-sided (or a 95% one-sided) confidence interval (CI), for the difference in baseline corrected mean QTc (heart-rate corrected version of QT) between drug and placebo at each time-point, and to conclude non-inferiority if the upper limit for each CI is less than a pre-specified constant. An alternative approach is to base the non-inferiority inference on the largest difference in population mean QTc (baseline corrected) between drug and placebo. In this paper, we propose a Bayesian approach to resolving this problem using a Monte Carlo simulation method. We use simulated data to assess the performance of the proposed approach, discuss its advantages over the standard approach, and illustrate the method by applying it to a real data set obtained from a thorough QT study conducted at GlaxoSmithKline (GSK). PMID:21857840

  5. Antibodies with beta-adrenergic activity from chronic chagasic patients modulate the QT interval and M cell action potential duration

    PubMed Central

    Medei, Emiliano Horacio; Nascimento, José H.M.; Pedrosa, Roberto C.; Barcellos, Luciane; Masuda, Masako O.; Sicouri, Serge; Elizari, Marcelo V.; Campos de Carvalho, Antonio C.

    2009-01-01

    Aims The aim of this study was to investigate whether the sera from chronic chagasic patients (CChPs) with beta-1 adrenergic activity (Ab-β) can modulate ventricular repolarization. Beta-adrenergic activity has been described in CChP. It increases the L-type calcium current and heart rate in isolated hearts, but its effects on ventricular repolarization has not been described. Methods and results In isolated rabbit hearts, under pacing condition, QT interval was measured under Ab-β perfusion. Beta-adrenergic activity was also tested in guinea pig ventricular M cells. Furthermore, the immunoglobulin fraction (IgG-β) of the Ab-β was tested on Ito, ICa, and Iks currents in rat, rabbit, and guinea pig myocytes, respectively. Beta-adrenergic activity shortened the QT interval. This effect was abolished in the presence of propranolol. In addition, sera from CChP without beta-adrenergic activity (Ab-β) did not modulate QT interval. The M cell action potential duration (APD) was reversibly shortened by Ab-β. Atenolol inhibited this effect of Ab-β, and Ab- did not modulate the AP of M cells. Ito was not modulated by isoproterenol nor by IgG-β. However, IgG-β increased ICa and IKs. Conclusion The shortening of the QT interval and APD in M cells and the increase of IKs and ICa induced by IgG-β contribute to repolarization changes that may trigger malignant ventricular arrhythmias observed in patients with chronic chagasic or idiopathic cardiomyopathy. PMID:18515284

  6. Latent polyglandular autoimmune syndrome type 2 case diagnosed during a shock manifestation.

    PubMed

    Gürkan, Eren; Çetinarslan, Berrin; Güzelmansur, İsmail; Kocabaş, Beyza

    2016-07-01

    There are many types of polyglandular autoimmune syndrome (PAS). PAS type 2 is the most common type among adults. For PAS type 2 (PAS-2) diagnosis, detection of Addison's disease with autoimmune thyroid disease and/or type 1 diabetes mellitus are required. Premature ovarian insufficiency, pernicious anemia, vitiligo, alopecia, myasthenia gravis, celiac disease and autoimmune diabetes insipidus may be comorbidities of this condition. Contrary to the common belief, latent PAS is more common than the manifest forms. Here, we present a PAS-2 case diagnosed via adrenal crisis. At the time of diagnosis, the case was observed to have thyroid, adrenal and ovarian involvement. Therefore, PAS-2 and possible immunologic disorders were discussed. PMID:26806667

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

    PubMed

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

    2014-09-01

    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 approved (1st January 2006 to 1st June 2012) in the European Union (EU) and the United States (US), of which 66 mentioned the term 'QT' (two EU only, 28 US only, 36 both). The agreement between authorities about the message on QT prolongation (does not prolong, unclear, possibly prolongs, prolongs) was moderate (kappa 0.434). However, the agreement in expected clinical decisions based on the product labels was much higher (kappa 0.673). The US drug label tends to be more explicit, especially when it considers absence of QT effects. PMID:24973646

  8. Successful management of complex regional pain syndrome type 1 using single injection interscalene brachial plexus block

    PubMed Central

    Fallatah, Summayah M.A.

    2014-01-01

    Complex regional pain syndrome (CRPS) type 1 of the upper limb is a painful and debilitating condition. Interscalene brachial plexus block (ISB) in conjugation with other modalities was shown to be a feasible therapy with variable success. We reported a case of CRPS type 1 as diagnosed by International Association for the Study of Pain criteria in which pharmacological approaches failed to achieve adequate pain relief and even were associated with progressive dysfunction of the upper extremity. Single injection ISB, in combination with physical therapy and botulinum toxin injection, was successful to alleviate pain with functional restoration. PMID:25422619

  9. Addison's disease in a patient with hypothyroidism: autoimmune polyglandular syndrome type 2.

    PubMed

    Bain, Anna; Stewart, Munro; Mwamure, Peter; Nirmalaraj, Kingsley

    2015-01-01

    A 57-year-old Caucasian woman with known autoimmune hypothyroidism diagnosed in 2006 presented to hospital with flu-like symptoms and circulatory collapse. She reported weight loss and gradual increase in her skin pigmentation over a 1-year period. Aggressive fluid resuscitation was instituted. Hormonal tests showed primary adrenal insufficiency. Appropriate steroid replacement was started with rapid clinical response. Subsequent antibody tests confirmed the diagnosis of autoimmune polyglandular type 2 (Schmidt's) syndrome. The adrenal crisis had been precipitated by influenza virus type B infection. PMID:26240101

  10. QCD Prediction of ATT for Small QT Dimuon Production in pp and pp-bar Collisions

    SciTech Connect

    Kawamura, Hiroyuki; Kodaira, Jiro; Tanaka, Kazuhiro

    2007-06-13

    We present QCD prediction of double-spin asymmetries (ATT) in transversely polarized Drell-Yan process at small transverse momentum QT of dimuon. Resummation of large logarithmic corrections, relevant in small QT region, is performed up to next-to-leading logarithmic (NLL) accuracy. ATT at RHIC, J-PARC and GSI are studied numerically in the corresponding kinematic regions. We show that the large ATT is obtained for small QT and moderate energies.

  11. Waardenburg syndrome type 4: report of two new cases caused by SOX10 mutations in Spain.

    PubMed

    Fernández, Raquel M; Núñez-Ramos, Raquel; Enguix-Riego, M Valle; Román-Rodríguez, Francisco José; Galán-Gómez, Enrique; Blesa-Sánchez, Emilio; Antiñolo, Guillermo; Núñez-Núñez, Ramón; Borrego, Salud

    2014-02-01

    Shah-Waardenburg syndrome or Waardenburg syndrome type 4 (WS4) is a neurocristopathy characterized by the association of deafness, depigmentation and Hirschsprung disease. Three disease-causing genes have been identified so far for WS4: EDNRB, EDN3, and SOX10. SOX10 mutations, found in 45-55% of WS4 patients, are inherited in autosomal dominant way. In addition, mutations in SOX10 are also responsible for an extended syndrome involving peripheral and central neurological phenotypes, referred to as PCWH (peripheral demyelinating neuropathy, central dysmyelinating leucodystrophy, Waardenburg syndrome, Hirschsprung disease). Such mutations are mostly private, and a high intra- and inter-familial variability exists. In this report, we present a patient with WS4 and a second with PCWH due to SOX10 mutations supporting again the genetic and phenotypic heterogeneity of these syndromes. Interestingly, the WS4 family carries an insertion of 19 nucleotides in exon 5 of SOX10, which results in distinct phenotypes along three different generations: hypopigmentation in the maternal grandmother, hearing loss in the mother, and WS4 in the proband. Since mosaicism cannot explain the three different related-WS features observed in this family, we propose as the most plausible explanation the existence of additional molecular events, acting in an additive or multiplicative fashion, in genes or regulatory regions unidentified so far. On the other hand, the PCWH case was due to a de novo deletion in exon 5 of the gene. Efforts should be devoted to unravel the mechanisms underlying the intrafamilial phenotypic variability observed in the families affected, and to identify new genes responsible for the still unsolved WS4 cases. PMID:24311220

  12. Discovery of a Genetic Metabolic Cause for Mauriac Syndrome in Type 1 Diabetes.

    PubMed

    MacDonald, Michael J; Hasan, Noaman M; Ansari, Israr-Ul H; Longacre, Melissa J; Kendrick, Mindy A; Stoker, Scott W

    2016-07-01

    A mechanistic cause for Mauriac syndrome, a syndrome of growth failure and delayed puberty associated with massive liver enlargement from glycogen deposition in children with poorly controlled type 1 diabetes, is unknown. We discovered a mutation in the catalytic subunit of liver glycogen phosphorylase kinase in a patient with Mauriac syndrome whose liver extended into his pelvis. Glycogen phosphorylase kinase activates glycogen phosphorylase, the enzyme that catalyzes the first step in glycogen breakdown. We show that the mutant subunit acts in a dominant manner to completely inhibit glycogen phosphorylase kinase enzyme activity and that this interferes with glycogenolysis causing increased levels of glycogen in human liver cells. It is known that even normal blood glucose levels physiologically inhibit glycogen phosphorylase to diminish glucose release from the liver when glycogenolysis is not needed. The patient's mother possessed the same mutant glycogen phosphorylase kinase subunit, but did not have diabetes or hepatomegaly. His father had childhood type 1 diabetes in poor glycemic control, but lacked the mutation and had neither hepatomegaly nor growth failure. This case proves that the effect of a mutant enzyme of glycogen metabolism can combine with hyperglycemia to directly hyperinhibit glycogen phosphorylase, in turn blocking glycogenolysis causing the massive liver in Mauriac disease. PMID:27207549

  13. Alu-mediated deletion of SOX10 regulatory elements in Waardenburg syndrome type 4.

    PubMed

    Bondurand, Nadége; Fouquet, Virginie; Baral, Viviane; Lecerf, Laure; Loundon, Natalie; Goossens, Michel; Duriez, Benedicte; Labrune, Philippe; Pingault, Veronique

    2012-09-01

    Waardenburg syndrome type 4 (WS4) is a rare neural crest disorder defined by the combination of Waardenburg syndrome (sensorineural hearing loss and pigmentation defects) and Hirschsprung disease (intestinal aganglionosis). Three genes are known to be involved in this syndrome, that is, EDN3 (endothelin-3), EDNRB (endothelin receptor type B), and SOX10. However, 15-35% of WS4 remains unexplained at the molecular level, suggesting that other genes could be involved and/or that mutations within known genes may have escaped previous screenings. Here, we searched for deletions within recently identified SOX10 regulatory sequences and describe the first characterization of a WS4 patient presenting with a large deletion encompassing three of these enhancers. Analysis of the breakpoint region suggests a complex rearrangement involving three Alu sequences that could be mediated by a FosTes/MMBIR replication mechanism. Taken together with recent reports, our results demonstrate that the disruption of highly conserved non-coding elements located within or at a long distance from the coding sequences of key genes can result in several neurocristopathies. This opens up new routes to the molecular dissection of neural crest disorders. PMID:22378281

  14. Impact of angiotensin II type 1 receptor gene polymorphism on insulin resistance in polycystic ovary syndrome.

    PubMed

    El-Mesallamy, H; El-Refaie, T; El-Razek, R A

    2013-04-01

    Insulin resistance is allegedly a target pathophysiological mechanism in the pathogenesis of polycystic ovary syndrome. Moreover, this metabolic alteration is possibly genetically determined. In view of the recent evidence implicating genetic variants of the renin-angiotensin system as candidates in several metabolic disorders, we investigated the allele and genotype frequencies of the A1166 C polymorphism of the angiotensin II type 1 receptor in relation with various metabolic and biochemical parameters in affected females trying to asses its role in the pathogenesis of this syndrome. The study was conducted on 83 females of which 39 females served as the control group. The participants were matched for age, body mass index and degree of obesity. For all subjects biochemical parameters were assayed including soluble CD40 ligand together with fasting glucose and insulin which were used for calculation of insulin resistance indices, Genotyping performed using real time polymerase chain reaction revealed that the C allele frequency and the AC genotype were less frequently observed in patients compared to controls, however this difference was not statistically significant (p=0.146). Lack of the C allele was associated with adverse metabolic parameters including higher rate of insulin resistance as well as solubes CD40 ligand in the patients group. Results of the current study support a causative role for the A1166 C polymorphism of the angiotensin II type 1 gene polymorphism in the pathogenesis or phenotypic expression of polycystic ovary syndrome. PMID:23564192

  15. Transcriptome-Wide Expression Profiling in Skin Fibroblasts of Patients with Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome Hypermobility Type

    PubMed Central

    Chiarelli, Nicola; Carini, Giulia; Zoppi, Nicoletta; Dordoni, Chiara; Ritelli, Marco; Venturini, Marina; Castori, Marco; Colombi, Marina

    2016-01-01

    Joint hypermobility syndrome/Ehlers–Danlos syndrome hypermobility type (JHS/EDS-HT), is likely the most common systemic heritable connective tissue disorder, and is mostly recognized by generalized joint hypermobility, joint instability complications, minor skin changes and a wide range of satellite features. JHS/EDS-HT is considered an autosomal dominant trait but is still without a defined molecular basis. The absence of (a) causative gene(s) for JHS/EDS-HT is likely attributable to marked genetic heterogeneity and/or interaction of multiple loci. In order to help in deciphering such a complex molecular background, we carried out a comprehensive immunofluorescence analysis and gene expression profiling in cultured skin fibroblasts from five women affected with JHS/EDS-HT. Protein study revealed disarray of several matrix structural components such as fibrillins, tenascins, elastin, collagens, fibronectin, and their integrin receptors. Transcriptome analysis indicated perturbation of different signaling cascades that are required for homeostatic regulation either during development or in adult tissues as well as altered expression of several genes involved in maintenance of extracellular matrix architecture and homeostasis (e.g., SPON2, TGM2, MMP16, GPC4, SULF1), cell-cell adhesion (e.g., CDH2, CHD10, PCDH9, CLDN11, FLG, DSP), immune/inflammatory/pain responses (e.g., CFD, AQP9, COLEC12, KCNQ5, PRLR), and essential for redox balance (e.g., ADH1C, AKR1C2, AKR1C3, MAOB, GSTM5). Our findings provide a picture of the gene expression profile and dysregulated pathways in JHS/EDS-HT skin fibroblasts that correlate well with the systemic phenotype of the patients. PMID:27518164

  16. Unexpected association between joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type and obsessive-compulsive personality disorder.

    PubMed

    Pasquini, Massimo; Celletti, Claudia; Berardelli, Isabella; Roselli, Valentina; Mastroeni, Simona; Castori, Marco; Biondi, Massimo; Camerota, Filippo

    2014-05-01

    Joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type (JHS/EDS-HT) is a largely unrecognized, heritable connective tissue disorder, mainly characterized by joint instability complications, widespread musculoskeletal pain, and minor skin features. In a case-control study, 47 consecutive JHS/EDS-HT patients were investigated for the prevalence of psychiatric disorders and compared to 45 healthy controls in a single center. The psychiatric evaluation consisted of structured clinical interview for DSM-IV criteria by using the SCID-I and the SCID-II. Symptom severity was assessed using the Hamilton Anxiety Rating Scale (HAM-A), the Hamilton Depression Rating Scale (HAM-D), and the Brief Psychiatric Rating Scale (BPRS). The Global Assessment of Functioning Scale (GAF) was used to assess the overall severity of psychological, social, and occupational functions. JHS/EDS-HT patients had significantly higher mean scores for all questionnaires: HAM-A (6.7 vs. 3.8), HAM-D (6.4 vs. 2.7), GAF (75.0 vs. 86.1), and BPRS (27.5 vs. 25.6). The JHS/EDS-HT group had a 4.3 higher risk of being affected by any psychiatric disorder, and in particular, a 5.8 higher risk of having a personality disorder. In particular, 5 JHS/EDS-HT suffered from obsessive-compulsive personality disorder with an observed prevalence rate of 10.6 % (3.6-23.1). Psychiatric assessment of JHS/EDS-HT patients showed an extremely high prevalence of personality disorders (21 %), and of Axis-I disorders (38 %), mostly depressive. This study did not confirm the previously reported increased rate of panic disorders in JHS/EDS-HT. PMID:24272065

  17. Transcriptome-Wide Expression Profiling in Skin Fibroblasts of Patients with Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome Hypermobility Type.

    PubMed

    Chiarelli, Nicola; Carini, Giulia; Zoppi, Nicoletta; Dordoni, Chiara; Ritelli, Marco; Venturini, Marina; Castori, Marco; Colombi, Marina

    2016-01-01

    Joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type (JHS/EDS-HT), is likely the most common systemic heritable connective tissue disorder, and is mostly recognized by generalized joint hypermobility, joint instability complications, minor skin changes and a wide range of satellite features. JHS/EDS-HT is considered an autosomal dominant trait but is still without a defined molecular basis. The absence of (a) causative gene(s) for JHS/EDS-HT is likely attributable to marked genetic heterogeneity and/or interaction of multiple loci. In order to help in deciphering such a complex molecular background, we carried out a comprehensive immunofluorescence analysis and gene expression profiling in cultured skin fibroblasts from five women affected with JHS/EDS-HT. Protein study revealed disarray of several matrix structural components such as fibrillins, tenascins, elastin, collagens, fibronectin, and their integrin receptors. Transcriptome analysis indicated perturbation of different signaling cascades that are required for homeostatic regulation either during development or in adult tissues as well as altered expression of several genes involved in maintenance of extracellular matrix architecture and homeostasis (e.g., SPON2, TGM2, MMP16, GPC4, SULF1), cell-cell adhesion (e.g., CDH2, CHD10, PCDH9, CLDN11, FLG, DSP), immune/inflammatory/pain responses (e.g., CFD, AQP9, COLEC12, KCNQ5, PRLR), and essential for redox balance (e.g., ADH1C, AKR1C2, AKR1C3, MAOB, GSTM5). Our findings provide a picture of the gene expression profile and dysregulated pathways in JHS/EDS-HT skin fibroblasts that correlate well with the systemic phenotype of the patients. PMID:27518164

  18. Spectrum of mucocutaneous manifestations in 277 patients with joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type.

    PubMed

    Castori, Marco; Dordoni, Chiara; Morlino, Silvia; Sperduti, Isabella; Ritelli, Marco; Valiante, Michele; Chiarelli, Nicola; Zanca, Arianna; Celletti, Claudia; Venturini, Marina; Camerota, Filippo; Calzavara-Pinton, Piergiacomo; Grammatico, Paola; Colombi, Marina

    2015-03-01

    Cutaneous manifestations are a diagnostic criterion of Ehlers-Danlos syndrome, hypermobility type (EDS-HT) and joint hypermobility syndrome (JHS). These two conditions, originally considered different disorders, are now accepted as clinically indistinguishable and often segregate as a single-familial trait. EDS-HT and JHS are still exclusion diagnoses not supported by any specific laboratory test. Accuracy of clinical diagnosis is, therefore, crucial for appropriate patients' classification and management, but it is actually hampered by the low consistency of many applied criteria including the cutaneous one. We report on mucocutaneous findings in 277 patients with JHS/EDS-HT with both sexes and various ages. Sixteen objective and five anamnestic items were selected and ascertained in two specialized outpatient clinics. Feature rates were compared by sex and age by a series of statistical tools. Data were also used for a multivariate correspondence analysis with the attempt to identify non-causal associations of features depicting recognizable phenotypic clusters. Our findings identified a few differences between sexes and thus indicated an attenuated sexual dimorphism for mucocutaneous features in JHS/EDS-HT. Ten features showed significantly distinct rates at different ages and this evidence corroborated the concept of an evolving phenotype in JHS/EDS-HT also affecting the skin. Multivariate correspondence analysis identified three relatively discrete phenotypic profiles, which may represent the cutaneous counterparts of the three disease phases previously proposed for JHS/EDS-HT. These findings could be used for revising the cutaneous criterion in a future consensus for the clinical diagnosis of JHS/EDS-HT. PMID:25655071

  19. Changing epidemiology of metabolic syndrome and type 2 diabetes in Chinese youth.

    PubMed

    Fu, JunFen; Prasad, Heranmaye C

    2014-01-01

    China is gradually taking its place as one of the world's economic giants and concurrently learning to understand how to bear the burdens of diseases that are more common in the fully developed world, such as pediatric obesity, metabolic syndrome, and type 2 diabetes mellitus. The purpose of this review is to consolidate the available information regarding these and draw the focus toward their sequential progression and increasing prevalence in Chinese children. Studies were collected in both English and Chinese, and the data were reviewed on the basis of disease prevalence and risk factors that are known from scientific literature that has been published to date. The majority of studies with appropriate content for inclusion here have been conducted within the last 15 years and up to date information from recent local and international research has also been included. Several factors have been implicated for the rise in obesity, most notably, the progressing economic expansion and exposure of local Chinese populations to Western influences. With this, metabolic syndrome has become a growing concern, as it is a precursor to cardiovascular disease and type 2 diabetes, leading to the alarmingly rapid development of deleterious consequences in children. The International Diabetes Federation proposed a definition for metabolic syndrome in 2007 (MS-IDF2007) worldwide, but whether it is also suitable for the Chinese population remains uncertain, so we have created the Chinese definition of metabolic syndrome upon the IDF framework. This MS-CHN2012 definition is based on multicenter studies to simplify and standardize primary care screening methods and is the first of its kind in China. Juvenile type 2 diabetes is the most worrisome result of obesity and metabolic syndrome, and studies have shown that the prevalence has doubled within 5 years-surpassing the prevalence of juvenile type 1 diabetes. Because of the extremely low number of studies currently published on these

  20. Changes in QT intervals in patients with end-stage renal disease before and after hemodialysis.

    PubMed

    Malhis, Mahmoud; Al-Bitar, Sami; Farhood, Saleh; Zaiat, Khair Al-Deen

    2010-05-01

    Increased dispersion of QT intervals is known to predispose to ventricular arrhythmias and sudden cardiac death. To assess the effect of hemodialysis (HD) on QT and corrected QT (QTc) intervals and their dispersions in chronic hemodialyzed patients we studied 85 patients (male/female = 48/37; mean age 44 +/- 17 year) on chronic hemodialysis. Simultaneous 12-lead ECG was recorded before and after HD in a standard setting. The QT intervals for each lead were measured manually by one observer using calipers. Each QT interval was corrected for heart rate: QTc= QT/ mean square root of R-R (in milliseconds [ms]). ECG parameters, body weight, blood pressure, heart rate, electrolytes (Na+, K+, Ca++, phosphate), urea, and creatinine were measured before and after HD. The mean of pre and post dialysis cycle intervals was 828 +/- 132 ms and 798 +/- 122 ms respectively; the difference was not significant. The mean of QTmax intervals changed significantly from 446 +/- 47 to 465 +/- 72 ms (P < 0.05). The mean of corrected QTcmax intervals increased significantly from 472 +/- 38 to 492 +/- 58 ms (P < 0.05). The mean of QT dispersions and the corrected QT interval dispersions changed from 60 +/- 29 to 76 +/- 32 ms (P < 0.05) from 72 +/- 46 to 98 +/- 56 ms (P < 0.05), respectively. During HD, the serum potassium and phosphate levels decreased whereas the calcium levels increased. We conclude that QT and QTc interval and dispersion increase in HD patients. PMID:20427869

  1. A Rare Clinical Variant of Oromandibular Limb Hypogenesis Syndrome Type I B.

    PubMed

    Kalaskar, Ritesh Rambharos; Godhane, Alkesh; Kalaskar, Ashita; Demble, Swati

    2016-01-01

    Aglossia is a rare congenital malformation that often occurs as an isolated disorder or is observed in association with other congenital deformities, particularly limb defects. We present a unique case of a 7-year-old girl with aglossia, hypodactyli, rudimentary ears, retrognathic and V-shaped mandible. Her parental history revealed intrauterine exposure of medicines. The patient had problems in difficulty in eating, speech, taste sensation and hearing. The present case does not fit into Hall's classification of oromandibular limb hypogenesis syndrome (OLHS) which best describes hypoglossia and limb deformities. Therefore, the purpose of this article is to document the rare variant of OLHS which can be included in Hall's classification. How to cite this article: Kalaskar RR, Godhane A, Kalaskar A, Demble S. A Rare Clinical Variant of Oromandibular Limb Hypogenesis Syndrome Type I B. Int J Clin Pediatr Dent 2016;9(1):78-81. PMID:27274161

  2. Detection of human papillomavirus type 10 DNA in eccrine syringofibroadenomatosis occurring in Clouston's syndrome.

    PubMed

    Carlson, J A; Rohwedder, A; Daulat, S; Schwartz, J; Schaller, J

    1999-02-01

    Syringofibroadenomatosis is often associated with an underlying condition such as diabetes mellitus or hidrotic ectodermal dysplasia. By reason of these associations, a reactive or hamartomatous cause is suspected. We report a case of a 71-year-old woman with Clouston's syndrome in whom progressive multiple palmoplantar syringofibroadenomas developed over a 10-year period. The syringofibroadenomas formed flat-topped papules simulating verruca plana; the widespread distribution and chronic progressive course resembled epidermodysplasia verruciformis. Contiguous with the syringofibroadenoma's characteristic epithelial-stromal proliferation were epidermal changes of verruca plana. Evidence of human papillomavirus (HPV) infection was verified by immunolabeling with antibodies to bovine papillomavirus type 1 and detection of HPV 10 viral DNA by means of polymerase chain reaction. Rather than a hamartomatous process, these findings suggest that syringofibroadenomas occurring in the setting of Clouston's syndrome could represent an HPV-induced epithelial proliferation. PMID:10025758

  3. Hypocretin Deficiency Associated with Narcolepsy Type 1 and Central Hypoventilation Syndrome in Neurosarcoidosis of the Hypothalamus

    PubMed Central

    Mayo, Mary Catherine; Deng, Jane C.; Albores, Jeffrey; Zeidler, Michelle; Harper, Ronald M.; Avidan, Alon Y.

    2015-01-01

    We report a case of a 53-year-old man presenting with depressed alertness and severe excessive sleepiness in the setting of neurosarcoidosis. Neuroimaging demonstrated hypothalamic destruction due to sarcoidosis with a CSF hypocretin level of 0 pg/mL. The patient also experienced respiratory depression that presumably resulted from hypocretin-mediated hypothalamic dysfunction as a result of extensive diencephalic injury. This is a novel case, demonstrating both hypocretin deficiency syndrome, as well as respiratory dysfunction from destruction of hypocretin neurons and extensive destruction of key diencephalic structures secondary to the underlying neurosarcoidosis. Citation: May MC, Deng JC, Albores J, Zeidler M, Harper RM, Avidan AY. Hypocretin deficiency associated with narcolepsy type 1 and central hypoventilation syndrome in neurosarcoidosis of the hypothalamus. J Clin Sleep Med 2015;11(9):1063–1065. PMID:25979096

  4. Dietary carbohydrate restriction in type 2 diabetes mellitus and metabolic syndrome: time for a critical appraisal

    PubMed Central

    Accurso, Anthony; Bernstein, Richard K; Dahlqvist, Annika; Draznin, Boris; Feinman, Richard D; Fine, Eugene J; Gleed, Amy; Jacobs, David B; Larson, Gabriel; Lustig, Robert H; Manninen, Anssi H; McFarlane, Samy I; Morrison, Katharine; Nielsen, Jørgen Vesti; Ravnskov, Uffe; Roth, Karl S; Silvestre, Ricardo; Sowers, James R; Sundberg, Ralf; Volek, Jeff S; Westman, Eric C; Wood, Richard J; Wortman, Jay; Vernon, Mary C

    2008-01-01

    Current nutritional approaches to metabolic syndrome and type 2 diabetes generally rely on reductions in dietary fat. The success of such approaches has been limited and therapy more generally relies on pharmacology. The argument is made that a re-evaluation of the role of carbohydrate restriction, the historical and intuitive approach to the problem, may provide an alternative and possibly superior dietary strategy. The rationale is that carbohydrate restriction improves glycemic control and reduces insulin fluctuations which are primary targets. Experiments are summarized showing that carbohydrate-restricted diets are at least as effective for weight loss as low-fat diets and that substitution of fat for carbohydrate is generally beneficial for risk of cardiovascular disease. These beneficial effects of carbohydrate restriction do not require weight loss. Finally, the point is reiterated that carbohydrate restriction improves all of the features of metabolic syndrome. PMID:18397522

  5. A Rare Clinical Variant of Oromandibular Limb Hypogenesis Syndrome Type I B

    PubMed Central

    Godhane, Alkesh; Kalaskar, Ashita; Demble, Swati

    2016-01-01

    ABSTRACT Aglossia is a rare congenital malformation that often occurs as an isolated disorder or is observed in association with other congenital deformities, particularly limb defects. We present a unique case of a 7-year-old girl with aglossia, hypodactyli, rudimentary ears, retrognathic and V-shaped mandible. Her parental history revealed intrauterine exposure of medicines. The patient had problems in difficulty in eating, speech, taste sensation and hearing. The present case does not fit into Hall’s classification of oromandibular limb hypogenesis syndrome (OLHS) which best describes hypoglossia and limb deformities. Therefore, the purpose of this article is to document the rare variant of OLHS which can be included in Hall’s classification. How to cite this article: Kalaskar RR, Godhane A, Kalaskar A, Demble S. A Rare Clinical Variant of Oromandibular Limb Hypogenesis Syndrome Type I B. Int J Clin Pediatr Dent 2016;9(1):78-81. PMID:27274161

  6. Oral-facial-digital syndrome type VI: is C5orf42 really the major gene?

    PubMed

    Romani, Marta; Mancini, Francesca; Micalizzi, Alessia; Poretti, Andrea; Miccinilli, Elide; Accorsi, Patrizia; Avola, Emanuela; Bertini, Enrico; Borgatti, Renato; Romaniello, Romina; Ceylaner, Serdar; Coppola, Giangennaro; D'Arrigo, Stefano; Giordano, Lucio; Janecke, Andreas R; Lituania, Mario; Ludwig, Kathrin; Martorell, Loreto; Mazza, Tommaso; Odent, Sylvie; Pinelli, Lorenzo; Poo, Pilar; Santucci, Margherita; Signorini, Sabrina; Simonati, Alessandro; Spiegel, Ronen; Stanzial, Franco; Steinlin, Maja; Tabarki, Brahim; Wolf, Nicole I; Zibordi, Federica; Boltshauser, Eugen; Valente, Enza Maria

    2015-01-01

    Oral-facial-digital type VI syndrome (OFDVI) is a rare phenotype of Joubert syndrome (JS). Recently, C5orf42 was suggested as the major OFDVI gene, being mutated in 9 of 11 families (82 %). We sequenced C5orf42 in 313 JS probands and identified mutations in 28 (8.9 %), most with a phenotype of pure JS. Only 2 out of 17 OFDVI patients (11.7 %) were mutated. A comparison of mutated vs. non-mutated OFDVI patients showed that preaxial and mesoaxial polydactyly, hypothalamic hamartoma and other congenital defects may predict C5orf42 mutations, while tongue hamartomas are more common in negative patients. PMID:25407461

  7. Atherogenic dyslipidemia in metabolic syndrome and type 2 diabetes: therapeutic options beyond statins

    PubMed Central

    Tenenbaum, Alexander; Fisman, Enrique Z; Motro, Michael; Adler, Yehuda

    2006-01-01

    Lowering of low-density lipoprotein cholesterol with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) is clearly efficacious in the treatment and prevention of coronary artery disease. However, despite increasing use of statins, a significant number of coronary events still occur and many of such events take place in patients presenting with type 2 diabetes and metabolic syndrome. More and more attention is being paid now to combined atherogenic dyslipidemia which typically presents in patients with type 2 diabetes and metabolic syndrome. This mixed dyslipidemia (or "lipid quartet"): hypertriglyceridemia, low high-density lipoprotein cholesterol levels, a preponderance of small, dense low-density lipoprotein particles and an accumulation of cholesterol-rich remnant particles (e.g. high levels of apolipoprotein B) – emerged as the greatest "competitor" of low-density lipoprotein-cholesterol among lipid risk factors for cardiovascular disease. Most recent extensions of the fibrates trials (BIP – Bezafibrate Infarction Prevention study, HHS – Helsinki Heart Study, VAHIT – Veterans Affairs High-density lipoprotein cholesterol Intervention Trial and FIELD – Fenofibrate Intervention and Event Lowering in Diabetes) give further support to the hypothesis that patients with insulin-resistant syndromes such as diabetes and/or metabolic syndrome might be the ones to derive the most benefit from therapy with fibrates. However, different fibrates may have a somewhat different spectrum of effects. Other lipid-modifying strategies included using of niacin, ezetimibe, bile acid sequestrants and cholesteryl ester transfer protein inhibition. In addition, bezafibrate as pan-peroxisome proliferator activated receptor activator has clearly demonstrated beneficial pleiotropic effects related to glucose metabolism and insulin sensitivity. Because fibrates, niacin, ezetimibe and statins each regulate serum lipids by different mechanisms, combination therapy

  8. Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome.

    PubMed

    Meuwissen, Marije E C; Schot, Rachel; Buta, Sofija; Oudesluijs, Grétel; Tinschert, Sigrid; Speer, Scott D; Li, Zhi; van Unen, Leontine; Heijsman, Daphne; Goldmann, Tobias; Lequin, Maarten H; Kros, Johan M; Stam, Wendy; Hermann, Mark; Willemsen, Rob; Brouwer, Rutger W W; Van IJcken, Wilfred F J; Martin-Fernandez, Marta; de Coo, Irenaeus; Dudink, Jeroen; de Vries, Femke A T; Bertoli Avella, Aida; Prinz, Marco; Crow, Yanick J; Verheijen, Frans W; Pellegrini, Sandra; Bogunovic, Dusan; Mancini, Grazia M S

    2016-06-27

    Pseudo-TORCH syndrome (PTS) is characterized by microcephaly, enlarged ventricles, cerebral calcification, and, occasionally, by systemic features at birth resembling the sequelae of congenital infection but in the absence of an infectious agent. Genetic defects resulting in activation of type 1 interferon (IFN) responses have been documented to cause Aicardi-Goutières syndrome, which is a cause of PTS. Ubiquitin-specific peptidase 18 (USP18) is a key negative regulator of type I IFN signaling. In this study, we identified loss-of-function recessive mutations of USP18 in five PTS patients from two unrelated families. Ex vivo brain autopsy material demonstrated innate immune inflammation with calcification and polymicrogyria. In vitro, patient fibroblasts displayed severely enhanced IFN-induced inflammation, which was completely rescued by lentiviral transduction of USP18. These findings add USP18 deficiency to the list of genetic disorders collectively termed type I interferonopathies. Moreover, USP18 deficiency represents the first genetic disorder of PTS caused by dysregulation of the response to type I IFNs. Therapeutically, this places USP18 as a promising target not only for genetic but also acquired IFN-mediated CNS disorders. PMID:27325888

  9. An unfortunate challenge: Ketogenic diet for the treatment of Lennox-Gastaut syndrome in tyrosinemia type 1.

    PubMed

    De Lucia, Silvana; Pichard, Samia; Ilea, Adina; Greneche, Marie-Odile; François, Laurent; Delanoë, Catherine; Schiff, Manuel; Auvin, Stéphane

    2016-07-01

    The ketogenic diet is an evidence-based treatment for resistant epilepsy including Lennox-Gastaut syndrome. This diet is based on low carbohydrate-high fat intakes. Dietary treatment is also therapeutic for inborn errors of metabolism such as aminoacdiopathies. We report a child with both Lennox-Gastaut syndrome and tyrosinemia type 1. This epilepsy syndrome resulted form a porencephalic cyst secondary to brain abscesses that occurred during the management of malnutrition due to untreated tyrosinemia type 1. We used a ketogenic diet as treatment for Lennox-Gastaut syndrome taking into account dietary requirements for tyrosinemia type 1. The patient was transiently responder during a 6-month period. This report illustrates that ketogenic diet remains a therapeutic option even when additional dietary requirements are needed. PMID:27052529

  10. Impact of clinical decision support preventing the use of QT-prolonging medications for patients at risk for torsade de pointes.

    PubMed

    Sorita, Atsushi; Bos, J Martijn; Morlan, Bruce W; Tarrell, Robert F; Ackerman, Michael J; Caraballo, Pedro J

    2015-04-01

    We developed and implemented a 'CPOE-QT Alert' system, that is, clinical decision support integrated in the computerized physician order entry system (CPOE), in 2011. The system identifies any attempts to order medications with risk of torsade de pointes (TdP) for patients with a history of significant QT prolongation (QTc ≥500 ms) and alerts the provider entering the order. We assessed its impact by comparing orders and subsequent medication administration before and after activation of the system. We found a significant decrease in the proportion of completed order per ordering attempt after system activation (94% (1293/1379) vs 77% (1888/2453), difference 16.8%; p<0.001). This resulted in a 13.9% reduction in the administration of those medications to patients. A significant decrease was observed across all provider types, educational levels, and specialties. The CPOE-QT Alert system successfully reduced exposure to QT-prolonging medications in high risk patients. PMID:25324555

  11. Correlation Between the Type of Acute Coronary Syndrome With the Needs of Hospitalized Patients

    PubMed Central

    Polikandrioti, Maria; Goudevenos, John; Michalis, Lampros K.; Koutelekos, Ioannis; Georgiadi, Elpida; Karakostas, Kostas; Elisaf, Moses

    2016-01-01

    Introduction: Acute Coronary Syndromes (ACS) comprise life-threatening health problems that demand emergency care and immediate intervention. As patients are abruptly transitioning from healthy state into suffering, they consequently experience several needs, mainly attributed to the type of the syndrome including the therapeutic regimen. Objectives: To access the correlation between the type of acute coronary syndrome (ACS) with the needs of hospitalized patients. Methods: A sample of 454 hospitalized patients with ACS, recruited from 4 hospitals in Greece, was enrolled in the study. Data were collected by the completion of questionnaire which apart from socio-demographic and clinical characteristics, it also included the questionnaire “Needs of hospitalized patients with coronary artery disease” which is consisted 6 subscales: a) need for support and guidance, b) need for information from the medical-nursing staff, c) need for being in contact with other patient groups and ensuring communication with relatives, d) need for individualized treatment and for the patient’s personal participation to his/her treatment e) need to meet the emotional and physical needs f) need to trust the medical-nursing staff. Statistical methods used were Kolmogorov-Smirnov test, chi2 test of independence, Kruskal wallis-test and multiple regression. Results: The type of ACS was statistically significant correlated with the place of residence (p=0.002), management of disease (p<0.001) and prior experience of hospitalization (p=0.003). All six needs were statistically significantly correlated with the type of ACS, (p<0.001 for the need for support and guidance, p<0.001 for the need to be informed from the medical and nursing staff, p<0.001 for the need for being in contact with other patient groups, and ensuring communication with relatives, p<0.001 for the need for individualized treatment and for the patient’s personal participation to his/her treatment, p<0.001 for the need

  12. Candidate regions for Waardenburg syndrome type II: Search for a second WS locus

    SciTech Connect

    Nance, W.E.; Pandya, A.; Blanton, S.H.

    1994-09-01

    Waardenburg syndrome is an autosomal dominant disorder characterized by deafness and pigmentary abnormalities such as heterochromia of irides, hypopigmented skin patches, white forlock and premature graying. Clinically the syndrome has been classified into three types. Type II differs from type I in that dystopia canthorum is generally absent, and type III has associated limb anomalies. Recently linkage analysis localized the gene for WSI to chromosome 2q. PAX-3, which is a human analogue of the murine pax-3 locus, maps to this region and mutations in this gene have been found to segregate with WSI. However genetic heterogeneity clearly exists: most if not all WSII families are unlinked to PAX-3 while most if not all WSI cases are linked. We ascertained a four-year-old female child with an interstitial deletion of chromosome 13 who had features of WS including bilateral congenital sensorineural hearing loss, pale blue irides and pinched nostrils as well as hypertelorism microcephaly, bilateral eyelid ptosis, digitalization of thumbs and fifth finger clinodactyly. High resolution chromosomal analysis revealed a de novo interstitial deletion of 13q22-33.2. There was no family history of WS or retardation. A similar deletion in the region of 13q21-32 has been described in a 13-year-old boy with features of WSII. These two cases strongly suggested that this chromosomal region may include a second locus for WS. We have identified eight families with clinical features of WS type I which have been excluded from linkage to the PAX-3 locus. We have typed these families for microsatellite markers spanning chromosome 13. Linkage between WSII and the chromosome 13 markers was excluded in these families. Hirschsprung disease has been associated with WS and it has recently been mapped to chromosome 10q11.2-q21.1. We are currently typing the 8 families for microsatellites in this region.

  13. Cardiorenal Syndrome Type 5: In Vitro Cytotoxicity Effects on Renal Tubular Cells and Inflammatory Profile

    PubMed Central

    Brocca, Alessandra; Virzì, Grazia Maria; Pasqualin, Chiara; Pastori, Silvia; Marcante, Stefano; de Cal, Massimo; Ronco, Claudio

    2015-01-01

    Background. Cardiorenal Syndrome Type 5 (CRS Type 5) reflects concomitant cardiac and renal dysfunctions in the setting of a wide spectrum of systemic disorders. Our aim was to study in vitro effects of CRS Type 5 plasma on renal tubular cells (RTCs), in terms of cellular death and the characterization of inflammatory plasma profile in these patients. Material and Methods. We enrolled 11 CRS Type 5 patients from ICU and 16 healthy controls. Plasma from patients and controls was incubated with renal tubular cells (RTCs) and cell death was evaluated. Plasma cytokines were detected. Results. RTCs incubated with CRS Type 5 plasma showed significantly higher apoptosis and necrosis with respect to controls. Plasma cytokine profile of CRS Type 5 patients was significantly different from controls: we observed the production of pro- and anti-inflammatory mediators in these patients. Caspase-3, caspase-8, and caspase-9 were activated in cells treated with CRS Type 5 plasma compared to controls. Conclusions. Our results underline the cytotoxic effect of CRS Type 5 mediators on RTC viability, probably due to the activation of both intrinsic and extrinsic pathways of apoptosis and to the deregulation of cytokine release. The consequence may be the damage of distant organs which lead to the worsening of condition of patients. PMID:26266085

  14. Scintigraphic portrayal of the syndrome of multiple endocrine neoplasia type-2B

    SciTech Connect

    Yobbagy, J.J.; Levatter, R.; Sisson, J.C.; Shulkin, B.L.; Polley, T.

    1988-06-01

    The scintigraphic appearance of the neoplasms in multiple endocrine neoplasia type 2B (MEN-2B) and the interpretations of the image patterns are described. An 18-year-old male patient with the MEN-2B syndrome underwent TI-201 imaging that showed concentrations of TI-201 in the primary medullary thyroid carcinoma (MTC) tumor and in cervical lymph node metastases. After total thyroidectomy and lymph node dissection, the TI-201 image was normal. Catecholamine levels in the blood and urine were only borderline elevated. Yet, greater than normal concentrations of I-131 metaiodobenzylguanidine (I-131 MIBG) were present in both adrenal glands. Computed tomography of the abdomen showed normal adrenal glands. These results were consistent with the diagnosis of adrenal medullary hyperplasia, a precursor of pheochromocytoma. No operation was indicated to remove the adrenal glands. Imaging with TI-201 appears to be useful in identifying sites of MTC in patients with the MEN-2B syndrome. I-131 MIBG imaging, in conjunction with computed tomography of the adrenal glands and appropriate catecholamine measurements, should be performed in patients with the MEN-2B syndrome to determine the status of the adrenal medullae, which then may be classified as normal, hyperplastic, or tumorous with pheochromocytoma.

  15. Herpes simplex virus type 1 colitis in a patient with common variable immunodeficiency syndrome.

    PubMed

    Dray, Xavier; Treton, Xavier; Mazeron, Marie-Christine; Lavergne-Slove, Anne; Joly, Francisca; Mimram, Dora; Attar, Alain; Tobelem, Gérard; Bouhnik, Yoram

    2006-05-01

    We report on a case of herpes simplex virus (HSV) type 1 colitis in a 69-year-old patient with common variable immunodeficiency syndrome. A treatment with polyvalent immunoglobulins was discontinued in April 2001. In March 2004 she developed chronic diarrhoea related to rectosigmoidal and caecal ulcerations. In November 2004, HSV was recovered in tissue culture from colonic biopsies. Valaciclovir was then started, leading the patient to clinical remission at day 4, and continued for a 6-week course (without any secondary antiviral prophylaxis). Colonic biopsies were negative for HSV by tissue culture and PCR within 3 weeks of antiviral treatment. Intravenous polyvalent immunoglobulin infusions were readministered within the third week of antiviral treatment. She has declared no clinical event since this period. Three months after the antiviral treatment was achieved, a rectosigmoidoscopy showed an ad-integrum macroscopic and histological mucosal healing whereas PCR was negative for HSV in the colonic tissue. As a large proportion of patients with common variable immunodeficiency syndrome present not only as a humoral immunodeficiency but also as a defect in the cellular immunity compartment (with T-cell deficits), HSV, as well as cytomegalovirus, should be investigated in patients with common variable immunodeficiency syndrome presenting colitis. PMID:16607152

  16. Frequency of Usher syndrome type 1 in deaf children by massively parallel DNA sequencing.

    PubMed

    Yoshimura, Hidekane; Miyagawa, Maiko; Kumakawa, Kozo; Nishio, Shin-Ya; Usami, Shin-Ichi

    2016-05-01

    Usher syndrome type 1 (USH1) is the most severe of the three USH subtypes due to its profound hearing loss, absent vestibular response and retinitis pigmentosa appearing at a prepubescent age. Six causative genes have been identified for USH1, making early diagnosis and therapy possible through DNA testing. Targeted exon sequencing of selected genes using massively parallel DNA sequencing (MPS) technology enables clinicians to systematically tackle previously intractable monogenic disorders and improve molecular diagnosis. Using MPS along with direct sequence analysis, we screened 227 unrelated non-syndromic deaf children and detected recessive mutations in USH1 causative genes in five patients (2.2%): three patients harbored MYO7A mutations and one each carried CDH23 or PCDH15 mutations. As indicated by an earlier genotype-phenotype correlation study of the CDH23 and PCDH15 genes, we considered the latter two patients to have USH1. Based on clinical findings, it was also highly likely that one patient with MYO7A mutations possessed USH1 due to a late onset age of walking. This first report describing the frequency (1.3-2.2%) of USH1 among non-syndromic deaf children highlights the importance of comprehensive genetic testing for early disease diagnosis. PMID:26791358

  17. Frequency of Usher syndrome type 1 in deaf children by massively parallel DNA sequencing

    PubMed Central

    Yoshimura, Hidekane; Miyagawa, Maiko; Kumakawa, Kozo; Nishio, Shin-ya; Usami, Shin-ichi

    2016-01-01

    Usher syndrome type 1 (USH1) is the most severe of the three USH subtypes due to its profound hearing loss, absent vestibular response and retinitis pigmentosa appearing at a prepubescent age. Six causative genes have been identified for USH1, making early diagnosis and therapy possible through DNA testing. Targeted exon sequencing of selected genes using massively parallel DNA sequencing (MPS) technology enables clinicians to systematically tackle previously intractable monogenic disorders and improve molecular diagnosis. Using MPS along with direct sequence analysis, we screened 227 unrelated non-syndromic deaf children and detected recessive mutations in USH1 causative genes in five patients (2.2%): three patients harbored MYO7A mutations and one each carried CDH23 or PCDH15 mutations. As indicated by an earlier genotype–phenotype correlation study of the CDH23 and PCDH15 genes, we considered the latter two patients to have USH1. Based on clinical findings, it was also highly likely that one patient with MYO7A mutations possessed USH1 due to a late onset age of walking. This first report describing the frequency (1.3–2.2%) of USH1 among non-syndromic deaf children highlights the importance of comprehensive genetic testing for early disease diagnosis. PMID:26791358

  18. A Multiparametric Computational Algorithm for Comprehensive Assessment of Genetic Mutations in Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome)

    PubMed Central

    Thomas, Clayton L.; Lee, Shaun W.

    2015-01-01

    Mucopolysaccharidosis type IIIA (MPS-IIIA, Sanfilippo syndrome) is a Lysosomal Storage Disease caused by cellular deficiency of N-sulfoglucosamine sulfohydrolase (SGSH). Given the large heterogeneity of genetic mutations responsible for the disease, a comprehensive understanding of the mechanisms by which these mutations affect enzyme function is needed to guide effective therapies. We developed a multiparametric computational algorithm to assess how patient genetic mutations in SGSH affect overall enzyme biogenesis, stability, and function. 107 patient mutations for the SGSH gene were obtained from the Human Gene Mutation Database representing all of the clinical mutations documented for Sanfilippo syndrome. We assessed each mutation individually using ten distinct parameters to give a comprehensive predictive score of the stability and misfolding capacity of the SGSH enzyme resulting from each of these mutations. The predictive score generated by our multiparametric algorithm yielded a standardized quantitative assessment of the severity of a given SGSH genetic mutation toward overall enzyme activity. Application of our algorithm has identified SGSH mutations in which enzymatic malfunction of the gene product is specifically due to impairments in protein folding. These scores provide an assessment of the degree to which a particular mutation could be treated using approaches such as chaperone therapies. Our multiparametric protein biogenesis algorithm advances a key understanding in the overall biochemical mechanism underlying Sanfilippo syndrome. Importantly, the design of our multiparametric algorithm can be tailored to many other diseases of genetic heterogeneity for which protein misfolding phenotypes may constitute a major component of disease manifestation. PMID:25807448

  19. Pregnancy and delivery in ehlers-danlos syndrome (hypermobility type): review of the literature.

    PubMed

    Dutta, Indranil; Wilson, Helen; Oteri, Odiri

    2011-01-01

    Ehlers-Danlos syndrome (EDS) is a group of connective tissue disorders which are divided into various distinguishable phenotypes. The type of EDS determines the potential obstetric complications. Due to the spectrum of clinical manifestation and overlap between phenotypes, there are no standardised obstetric management guidelines. Existing literature illustrates different obstetric management in hypermobility type of EDS, including uneventful term vaginal deliveries as well as preterm cesarean section deliveries. This paper discusses obstetric management of a woman with EDS hypermobility type. Cesarean section was deemed the most appropriate delivery method in this patient due to the possible complications including risk of joint dislocation and pain morbidity. No obstetric complications were experienced, and good maternal and neonatal outcomes were achieved. PMID:21765833

  20. Laparoscopic Treatment of Type III Mirizzi Syndrome by T-Tube Drainage

    PubMed Central

    Yetışır, Fahri; Şarer, Akgün Ebru; Acar, H. Zafer; Polat, Yılmaz; Osmanoglu, Gokhan; Aygar, Muhittin; Ciftciler, A. Erdinc; Parlak, Omer

    2016-01-01

    Mirizzi syndrome (MS) is an impacted stone in the cystic duct or Hartmann's pouch that mechanically obstructs the common bile duct. We would like to report laparoscopic treatment of type III MS. A 75-year-old man was admitted with the complaint of abdominal pain and jaundice. The patient was accepted as MS type III according to radiological imaging and intraoperative view. Laparoscopic subtotal cholecystectomy, extraction of impacted stone by opening anterior surface of dilated cystic duct and choledochus, and repair of this opening by using the remaining part of gallbladder over the T-tube drainage were performed in a patient with type III MS. Application of reinforcement suture over stump was done in light of the checking with oliclinomel N4 injection trough the T-tube. At the 18-month follow-up, he was symptom-free with normal liver function tests. PMID:27293947

  1. Griscelli syndrome types 1 and 3: analysis of four new cases and long-term evaluation of previously diagnosed patients.

    PubMed

    Cağdaş, Deniz; Ozgür, Tuba Turul; Asal, Gülten Türkkanı; Tezcan, Ilhan; Metin, Ayşe; Lambert, Nathalie; de Saint Basile, Geneiveve; Sanal, Ozden

    2012-10-01

    Griscelli syndrome (GS) is a rare autosomal recessive disorder characterized by partial albinism. Three different types are caused by defects in three different genes. Patients with GS type 1 have primary central nervous system dysfunction, type 2 patients commonly develop hemophagocytic lymphohistiocytosis, and type 3 patients have only partial albinism. While hematopoietic stem cell transplantation is life saving in type 2, no specific therapy is required for types 1 and 3. Patients with GS types 1 and 3 are very rare. To date, only 2 patients with type 3 and about 20 GS type 1 patients, including the patients described as Elejalde syndrome, have been reported. The neurological deficits in Elejalde syndrome were reported as severe neurodevelopmental delay, seizures, hypotonia, and ophthalmological problems including nystagmus, diplopia, and retinal problems. However, none of these patients' clinical progresses were reported. We described here our two new type 1 and two type 3 patients along with the progresses of our previously diagnosed patients with GS types 1 and 3. Our previous patient with GS type I is alive at age 21 without any other problems except severe mental and motor retardation, patients with type 3 are healthy at ages 21 and 24 years having only pigmentary dilution; silvery gray hair, eye brows, and eyelashes. Since prognosis, treatment options, and genetic counseling markedly differ among different types, molecular characterization has utmost importance in GS. PMID:22711375

  2. Three novel ZBTB24 mutations identified in Japanese and Cape Verdean type 2 ICF syndrome patients.

    PubMed

    Nitta, Hirohisa; Unoki, Motoko; Ichiyanagi, Kenji; Kosho, Tomoki; Shigemura, Tomonari; Takahashi, Hiroshi; Velasco, Guillaume; Francastel, Claire; Picard, Capucine; Kubota, Takeo; Sasaki, Hiroyuki

    2013-07-01

    Immunodeficiency, centromeric instability and facial anomalies (ICF) syndrome is a rare autosomal recessive disorder that shows DNA hypomethylation at pericentromeric satellite-2 and -3 repeats in chromosomes 1, 9 and 16. ICF syndrome is classified into two groups: type 1 (ICF1) patients have mutations in the DNMT3B gene and about half of type 2 (ICF2) patients have mutations in the ZBTB24 gene. Besides satellite-2 and -3 repeats, α-satellite repeats are also hypomethylated in ICF2. In this study, we report three novel ZBTB24 mutations in ICF2. A Japanese patient was homozygous for a missense mutation (C383Y), and a Cape Verdean patient was compound heterozygous for a nonsense mutation (K263X) and a frame-shift mutation (C327W fsX54). In addition, the second Japanese patient was homozygous for a previously reported nonsense mutation (R320X). The C383Y mutation abolished a C2H2 motif in one of the eight zinc-finger domains, and the other three mutations caused a complete or large loss of the zinc-finger domains. Our immunofluorescence analysis revealed that mouse Zbtb24 proteins possessing a mutation corresponding to either C383Y or R320X are mislocalized from pericentrometic heterochromatin, suggesting the importance of the zinc-finger domains in proper intranuclear localization of this protein. We further revealed that the proper localization of wild-type Zbtb24 protein does not require DNA methylation. PMID:23739126

  3. Blunt aortic trauma in a patient with the Ehlers–Danlos syndrome type VI

    PubMed Central

    Yung, Marco Yat Hang; Murray, Jennifer; Thompson, Errington C.

    2016-01-01

    A 24-year-old male with the Ehlers–Danlos syndrome (EDS) type VI (ocular scoliotic) who was kicked in the abdomen presented to the emergency room (ER) with abdominal pain. He was found to have a blunt traumatic aortic injury. The patient was treated nonoperatively. He was stable and discharged home on the eighth day. The patient returned to the ER several days later hypotensive and tachycardic. The patient was taken immediately to the operating room, but vascular repair was not possible. The patient expired. We discuss the challenges of taking care of a patient with EDS and offer suggestions that might improve future patient's outcome. PMID:26956239

  4. A gene for Usher syndrome type I (USH1A) maps to chromosome 14q

    SciTech Connect

    Kaplan, J.; Gerber, S.; Rozet, J.M.; Delrieu, O.; Briard, M.L.; Dollfus, H.; Frezal, J.; Munnich, A. ); Bonneau, D. ); Ghazi, I. )

    1992-12-01

    Usher syndrome (US) is an autosomal recessive disease characterized by congenital hearing impairment and retinitis pigmentosa. It is the most frequent cause of deaf-blindness in adults and accounts for 3 to 6% of deaf children. Here, the authors report the genetic mapping of a gene for US type I (USH1A), the most severe form of the disease, to the long arm of chromosome 14, by linkage to probe MLJ14 at the D14S13 locus in 10 families of Western France ancestry ([cflx Z] = 4.13 at [cflx [theta

  5. Renal-type Clear Cell Carcinoma Occurring in the Prostate With Zinner Syndrome

    PubMed Central

    Sato, Yuichi; Kataoka, Masao; Hata, Junya; Akaihata, Hidenori; Ogawa, Soichiro; Kojima, Yoshiyuki

    2016-01-01

    We report a case of clear cell carcinoma occurring in the prostate with Zinner syndrome in a 64-year-old man. Based on the immunohistochemical findings, it was concluded that this tumor represented primary renal-type clear cell carcinoma arising in the prostate. After receiving radical cystoprostatectomy, he was treated with tyrosine kinase inhibitor (TKI) therapy for local recurrence in accordance with the protocol of renal cell carcinoma (RCC) treatment, because microarray cluster analysis using a resected sample demonstrated that the present case belonged to the cluster group of RCC. PMID:26793589

  6. Renal-type Clear Cell Carcinoma Occurring in the Prostate With Zinner Syndrome.

    PubMed

    Sato, Yuichi; Kataoka, Masao; Hata, Junya; Akaihata, Hidenori; Ogawa, Soichiro; Kojima, Yoshiyuki

    2016-03-01

    We report a case of clear cell carcinoma occurring in the prostate with Zinner syndrome in a 64-year-old man. Based on the immunohistochemical findings, it was concluded that this tumor represented primary renal-type clear cell carcinoma arising in the prostate. After receiving radical cystoprostatectomy, he was treated with tyrosine kinase inhibitor (TKI) therapy for local recurrence in accordance with the protocol of renal cell carcinoma (RCC) treatment, because microarray cluster analysis using a resected sample demonstrated that the present case belonged to the cluster group of RCC. PMID:26793589

  7. 'Moya' than meets the eye: neurofibromatosis type 1 associated with Moyamoya syndrome.

    PubMed

    Tan, R M; Chng, S M; Seow, W T; Wong, J; Lim, C C

    2008-04-01

    Moyamoya syndrome (MMS) is an uncommon association of neurofibromatosis type 1 (NF1). We describe a seven-year-old chinese girl with NF1 and unilateral MMS with multiple hyperintensities on T2-weighted magnetic resonance (MR) images. The ischaemic lesions in the ipsilateral white matter were hypointense on fluid attenuated inversion recovery (FLAIR) MR images, in contrast to the hyperintense "unidentified bright objects" (UBOs) of NF1. Neuroradiologists should be aware of associated MMS in NF1 patients, and distinguish the effects of ischaemia from UBOs, especially on FLAIR MR imaging. PMID:18418511

  8. Glucose transporter type 1 deficiency syndrome effectively treated with modified Atkins diet.

    PubMed

    Haberlandt, Edda; Karall, Daniela; Jud, Veronika; Baumgartner, Sara Sigl; Zotter, Sibylle; Rostasy, Kevin; Baumann, Matthias; Scholl-Buergi, Sabine

    2014-04-01

    This is a report on the successful treatment of a 6-year-old girl with genetically proven glucose transporter type 1 deficiency syndrome (GLUT1-DS) with modified Atkins diet (MAD). GLUT1-DS is an inborn disorder of glucose transport across the blood-brain barrier, which leads to energy deficiency of the brain with a broad spectrum of neurological symptoms including therapy-resistant epilepsy. Usually classical ketogenic diet (KD) is the standard treatment for patients with GLUT1-DS. Treatment with MAD, a variant of KD, for an observation period of 17 months resulted in improvement of seizures, alertness, cognitive abilities, and electroencephalography in this patient. PMID:23888468

  9. Mirror visual feedback for the treatment of complex regional pain syndrome (type 1).

    PubMed

    McCabe, Candida S; Haigh, Richard C; Blake, David R

    2008-04-01

    Mirror visual feedback was originally devised as a therapeutic tool to relieve perceived involuntarily movements and paralysis in the phantom limb. Since this pioneering work was conducted in the mid-1990s, the technique has been applied to relieve pain and enhance movement in other chronic conditions such as stroke and complex regional pain syndrome (CRPS) type 1. This review describes how mirror visual feedback was first developed with amputees, its original application in CRPS, and how further research has demonstrated its potential benefit within graded motor imagery programs. We discuss the potential mechanisms behind this technique and consider the implications for clinical practice. PMID:18474189

  10. Multiple developmental dental anomalies and hypermobility type Ehlers-Danlos syndrome.

    PubMed

    Yassin, Othman M; Rihani, Farouk B

    2006-01-01

    Concurrent existence of multiple developmental dental anomalies: hypodontia of permanent mandibular incisors, dentin dysplasia, transmigration, root dilaceration, ectopic eruption and delayed eruption combined with systemic abnormalities including joint hyperlaxity and skin hyperextensibility aided in diagnosis of a sporadic case of hypermobility type of Ehlers-Danlos syndrome in a Jordanian Arab male. In dental practice the presence of multiple developmental dental anomalies expressing simultaneous defects in different stages of tooth development should raise suspicion of possible of manifestation of an underlying systemic abnormality. PMID:16937863

  11. Interstitial type granuloma annulare associated with Sjögren's syndrome.

    PubMed

    Sumikawa, Yasuyuki; Ansai, Shinichi; Kimura, Tetsunori; Nakamura, Junnosuke; Inui, Shigeki; Katayama, Ichiro

    2010-05-01

    We describe a case of granuloma annulare (GA) associated with Sjögren's syndrome (SS) in a 69-year-old woman. She complained of erythematous plaques on the left forearm and neck in addition to dry eyes and mouth. The laboratory and clinical findings also fulfilled the criteria for diagnosis of SS. Histopathological examination revealed the features of interstitial type GA. It is not rare that granulomatous diseases are associated with autoimmune diseases. This case indicated that granulomatous diseases and SS are closely related and that GA should be recognized as a cutaneous manifestation associated with autoimmune diseases, including SS. PMID:20536658

  12. Blunt aortic trauma in a patient with the Ehlers-Danlos syndrome type VI.

    PubMed

    Yung, Marco Yat Hang; Murray, Jennifer; Thompson, Errington C

    2016-01-01

    A 24-year-old male with the Ehlers-Danlos syndrome (EDS) type VI (ocular scoliotic) who was kicked in the abdomen presented to the emergency room (ER) with abdominal pain. He was found to have a blunt traumatic aortic injury. The patient was treated nonoperatively. He was stable and discharged home on the eighth day. The patient returned to the ER several days later hypotensive and tachycardic. The patient was taken immediately to the operating room, but vascular repair was not possible. The patient expired. We discuss the challenges of taking care of a patient with EDS and offer suggestions that might improve future patient's outcome. PMID:26956239

  13. The Jervell and Lange-Nielsen syndrome.

    PubMed

    Komsuoğlu, B; Göldeli, O; Kulan, K; Budak, F; Gedik, Y; Tuncer, C; Komsuoğlu, S S

    1994-12-01

    The association of prolongation of the QT interval with recurrent attacks of syncope, sudden death, and malignant ventricular arrhythmias is known as the long QT syndrome. The syndrome may be familial with or without congenital deafness, or idiopatic. The syndrome with deafness (Jervell and Lange-Nielsen syndrome) is inherited through an autosomal recessive mechanism. In this study, we attempted to identify patients with the Jervell Lange-Nielsen syndrome amongst 154 deaf mute school children. Two patients had a corrected QT interval of 0.52 and congenital sensorineural hearing loss with the other electrocardiographic changes characteristic of the syndrome, such as inverted or bifid T wave. There was no evidence of electrocardiographic (ECG) abnormality in family members, except only one case of parental deafness. This is the first and preliminary report that analyzed the incidence of the Jervell and Lange-Nielsen syndrome amongst 154 deaf mute school children in Turkey. Our study was conducted to identify patients with this syndrome amongst children of another deaf mute school in Turkey. PMID:7721491

  14. Oxidative Stress: Dual Pathway Induction in Cardiorenal Syndrome Type 1 Pathogenesis

    PubMed Central

    Virzì, Grazia Maria; Clementi, Anna; de Cal, Massimo; Brocca, Alessandra; Day, Sonya; Pastori, Silvia; Bolin, Chiara; Vescovo, Giorgio; Ronco, Claudio

    2015-01-01

    Cardiorenal Syndrome Type 1 (Type 1) is a specific condition which is characterized by a rapid worsening of cardiac function leading to acute kidney injury (AKI). Even though its pathophysiology is complex and not still completely understood, oxidative stress seems to play a pivotal role. In this study, we examined the putative role of oxidative stress in the pathogenesis of CRS Type 1. Twenty-three patients with acute heart failure (AHF) were included in the study. Subsequently, 11 patients who developed AKI due to AHF were classified as CRS Type 1. Quantitative determinations for IL-6, myeloperoxidase (MPO), nitric oxide (NO), copper/zinc superoxide dismutase (Cu/ZnSOD), and endogenous peroxidase activity (EPA) were performed. CRS Type 1 patients displayed significant augmentation in circulating ROS and RNS, as well as expression of IL-6. Quantitative analysis of all oxidative stress markers showed significantly lower oxidative stress levels in controls and AHF compared to CRS Type 1 patients (P < 0.05). This pilot study demonstrates the significantly heightened presence of dual oxidative stress pathway induction in CRS Type 1 compared to AHF patients. Our findings indicate that oxidative stress is a potential therapeutic target, as it promotes inflammation by ROS/RNS-linked pathogenesis. PMID:25821554

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

    PubMed Central

    Schächtele, Simone; Tümena, Thomas; Gaßmann, Karl-Günter; Fromm, Martin F.; Maas, Renke

    2016-01-01

    Background 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. Objective 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. Methods 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). Results 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. Conclusion In a geriatric study population co-prescriptions of two and more QT-drugs were common. A considerable proportion of QT

  16. [Complex regional pain syndrome type I (CRPS I). Pathophysiology, diagnostics, and therapy].

    PubMed

    Köck, F X; Borisch, N; Koester, B; Grifka, J

    2003-05-01

    Complex regional pain syndrome type I (CRPS type I)--formerly termed Sudeck's atrophy or reflex sympathetic dystrophy (RSD)--causes chronic, poorly controllable pain, autonomic, sensorimotor disorders,and serious trophic alterations in the later stages. It develops in the distal extremities mostly after minimal trauma or surgical intervention and rarely spontaneously. The severity of symptoms is disproportionate to the causative event. The latest scientific findings show that the previously called reflex sympathetic dystrophy (RSD), which was supposed to be a result of a hyperreactive autonomic nervous system,is a very complex syndrome that occurs on different integration levels of the nervous system. Sympathetically maintained pain (SMP) may be facultatively characteristic, but is not to be misunderstood as an underlying mechanism. A neurogenic inflammation reaction has recently been discussed, just as had been postulated by Paul Sudeck long before. That was the reason why the International Association for the Study of Pain (ISAP) introduced the more descriptive term "complex regional pain syndrome" (CRPS) type I in 1994. Due to the complexity of the process necessitating qualified knowledge, it is important to immediately refer patients to a specialized pain OPD or clinic. The diagnosis of CRPS type I is based upon a carefully taken case history and a clinical examination by an experienced practitioner. Imaging diagnostic tools and laboratory findings are of no or only low predicative value. The question of whether SMP exists after diagnosing CRPS type I is eminent for therapy planning. Therefore, diagnostic regional anesthetics are still important in spite of their uncertain prognostic relevance. Physical therapy, occupational therapy, medical treatment, and psychotherapy play an important role in the primary treatment of CRPS type I as noninvasive procedures. Despite heavy criticism, invasive sympathetic block, subsequent to adequate diagnostics, is an

  17. Food and Insulin Effect on QT/QTC Interval of ECG

    ClinicalTrials.gov

    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

  18. Impact of Psychotropic Drugs on QT Interval Dispersion in Adult Patients

    PubMed Central

    Claudio, Bruno de Queiroz; Costa, Marcelle Azevedo Nossar; Penna, Filipe; Konder, Mariana Teixeira; Celoria, Bruno Miguel Jorge; de Souza, Luciana Lopes; Pozzan, Roberto; Schneider, Roberta Siuffo; Albuquerque, Felipe Neves; Albuquerque, Denilson Campos

    2014-01-01

    Background Drug-induced increase in QT dispersion has been associated with potentially fatal ventricular arrhythmias. Little is known about the use of psychotropic substances, alone or in combination with other drugs on QT dispersion. Objectives To evaluate the impact of psychotropic drugs on QT interval dispersion in adults. Methods An observational cohort study was designed involving 161 patients hospitalized from an emergency department at a tertiary hospital, divided into psychotropic users or non-users. Demographic, clinical, laboratory data and drugs used on a regular basis were collected on admission, in addition to 12-lead electrocardiogram with QT dispersion measurement. Results QT dispersion was significantly higher in the psychotropic user group compared to non-users (69.25 ± 25.5 ms vs. 57.08 ± 23.4 ms; p = 0.002). The QT interval corrected by Bazzett formula was also higher in the psychotropic drugs user group, with statistical significance. (439.79 ± 31.14 ms vs. 427.71 ± 28.42 ms; p = 0.011). A regression analysis model showed a positive association between the number of psychotropic drugs used and QT interval dispersion, with r = 0.341 and p < 0.001. Conclusions The use of psychotropic drugs was associated with increased QT dispersion and this increase was accentuated, as the number of psychotropic drugs used was higher. PMID:24830389

  19. Importance of Laparoscopic Assessment of the Uterine Adnexa in a Mayer-Rokitansky-Kuster-Hauser Syndrome Type II Case

    PubMed Central

    DRAGUSIN, ROXANA; TUDORACHE, ȘTEFANIA; SURLIN, V.; LICHIARDOPOL, CORINA; ILIESCU, D.G.

    2014-01-01

    In the case reported, diagnosed with Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome, the presence of normal ovaries proved to be challenging to confirm due to unusual high positioned (ectopic) ovaries. MRKH syndrome is a rare pathological condition characterized by a spectrum of the Mullerian duct abnormalities resulting in congenital aplasia of the uterus and of the upper part (2/3) of the vagina, developed during embryogenesis. At the same time, the mullerian development is interdependent with the Wolffian (mesonephric) duct and this explains the associated renal abnormalities (MRKH type II). Laparoscopic assessment was of great importance in defining the exact anatomic characteristics of MRKH syndrome. PMID:25729598

  20. Usher Syndrome

    MedlinePlus

    Usher syndrome is an inherited disease that causes serious hearing loss and retinitis pigmentosa, an eye disorder ... hearing and vision. There are three types of Usher syndrome: People with type I are deaf from ...

  1. Bloom's Syndrome

    MedlinePlus

    ... Glycogen Storage Disease, Type 1A Joubert Syndrome Maple Syrup Urine Disease and DLD Mucolipidosis IV (MLIV) Nemaline ... Glycogen Storage Disease, Type 1A Joubert Syndrome Maple Syrup Urine Disease and DLD Mucolipidosis IV (MLIV) Nemaline ...

  2. Association of Parental Age and the Type of Down Syndrome on the Territory of Bosnia and Herzegovina

    PubMed Central

    Sotonica, Mia; Mackic-Djurovic, Mirela; Hasic, Sabaheta; Kiseljakovic, Emina; Jadric, Radivoj; Ibrulj, Slavka

    2016-01-01

    Background: Advanced paternal and/or maternal age is a classic risk factor for Down syndrome. The aim of the study was to investigate the frequency of Down syndrome types in children and its association with maternal and paternal age in Bosnia and Herzegovina. Subjects and Methods: The cross sectional, observational study included 127 children, 49 girls and 78 boys, aged 1-180 months suspected to have Down syndrome, admitted to the Centre for Genetics, Faculty of Medicine University of Sarajevo, for cytogenetic analysis and differential diagnosis of Down syndrome during the period from January 2010 to May 2015. Standard method of 72 hours cultivation of peripheral blood lymphocytes has been applied. The accepted level of statistical significance was p<0.05. Study Results: The most common type of Down syndrome was standard trisomy (86.6%), comparing to translocation and mosaicism (7.1%; 6.3%, respectively). The highest frequency of Down syndrome cases was in mother and father’s group from 30-39 years old (57; 57 children, respectively) compared to mother and father’s groups with younger than 30 (44; 29, respectively) and 40 and older (26; 41, respectively). The significant difference was found in maternal age between translocation and mosaicism groups (p=0.036). Difference between parental years and type of Down syndrome was significant when Standard trisomy 21 and translocation (p=0.045), as well as mosaicism and translocation (p=0.036), were compared. Conclusion: The most common type of Down syndrome was standard trisomy 21, with highest occurrence in parents from 30 to 39 years old. Parents were the youngest in translocation group. Obtained results suggest that multidisciplinary approach to identifying the trigger for trisomy appearance and the influence of maternal age is required. PMID:27147778

  3. Randomized, Controlled, Thorough QT/QTc Study Shows Absence of QT Prolongation with Luseogliflozin in Healthy Japanese Subjects

    PubMed Central

    Kumagai, Yuji; Hasunuma, Tomoko; Sakai, Soichi; Ochiai, Hidekazu; Samukawa, Yoshishige

    2015-01-01

    Luseogliflozin is a selective sodium glucose co-transporter 2 (SGLT2) inhibitor. To evaluate the cardiac safety of luseogliflozin, a thorough QT/QTc study was conducted in healthy Japanese subjects. The effects of moxifloxacin on QT prolongation in Japanese subjects were also evaluated. In this double-blind, placebo- and open-label positive-controlled, 4-way crossover study, 28 male and 28 female subjects received a single dose of luseogliflozin 5 mg (therapeutic dose), luseogliflozin 20 mg (supratherapeutic dose), placebo, and moxifloxacin 400 mg. Serial triplicate digital 12-lead electrocardiograms (ECGs) were recorded before and after dosing, and results were analyzed using the Fridericia correction (QTcF) method. Serial blood sampling was performed for pharmacokinetic analyses of luseogliflozin and moxifloxacin to analyze the relationship between QTcF interval and plasma concentration. The upper limits of the two-sided 90% confidence intervals (CIs) for baseline and placebo-adjusted QTcF intervals (ΔΔQTcF) in the 5 mg and 20 mg luseogliflozin groups were less than 10 ms at all time points. No correlation between plasma luseogliflozin concentrations and ΔΔQTcF was observed. In the moxifloxacin group, the lower limits of the two-sided 90% CIs for ΔΔQTcF were greater than 5 ms at all time points. A positive relationship was observed between plasma moxifloxacin concentration and change in ΔΔQTcF. Luseogliflozin was well tolerated at both dose levels. The majority of adverse events were mild in severity, and no serious or life-threatening adverse events occurred. Neither therapeutic (5 mg) nor supratherapeutic (20 mg) doses of luseogliflozin affected QT prolongation in healthy Japanese subjects. PMID:26444986

  4. Abducens Nerve in Patients with Type 3 Duane’s Retraction Syndrome

    PubMed Central

    Hwang, Jeong-Min

    2016-01-01

    Background We have previously reported that the presence of the abducens nerve was variable in patients with type 3 Duane’s retraction syndrome (DRS), being present in 2 of 5 eyes (40%) and absent in 3 (60%) on magnetic resonance imaging (MRI). The previous study included only 5 eyes with unilateral DRS type 3. Objectives To supplement existing scarce pathologic information by evaluating the presence of the abducens nerve using high resolution thin-section MRI system in a larger number of patients with DRS type 3, thus to provide further insight into the pathogenesis of DRS. Data Extraction A retrospective review of medical records on ophthalmologic examination and high resolution thin-section MRI at the brainstem level and orbit was performed. A total of 31 patients who showed the typical signs of DRS type 3, including abduction and adduction deficit, globe retraction, narrowing of fissure on adduction and upshoot and/or downshoot, were included. The abducens nerve and any other extraocular muscle abnormalities discovered by MRI were noted. Results DRS was unilateral in 26 patients (84%) and bilateral in 5 patients (16%). Two out of 5 bilateral patients had DRS type 3 in the right eye and DRS type 1 in the left eye. Of the 34 affected orbits with DRS type 3 in 31 patients, the abducens nerve was absent or hypoplastic in 31 eyes (91%) and present in 3 eyes (9%). Patients with a present abducens nerve showed more limitation in adduction compared to patients with an absent abducens nerve (P = 0.030). Conclusions The abducens nerve is absent or hypoplastic in 91% of DRS type 3. Patients with a present abducens nerve showed more prominent limitation of adduction. As DRS type 3 partly share the same pathophysiology with type 1 and 2 DRS, the classification of DRS may have to be revised according to MRI findings. PMID:27352171

  5. Recovery from alopecia areata in a patient with autoimmune polyglandular syndrome type 3

    PubMed Central

    Uchihashi, Takeshi; Kataoka, Yasuo; Fujiwara, Masayoshi

    2015-01-01

    Summary Recovery from alopecia is rare in autoimmune polyglandular syndrome (APS). A 41-year-old male was admitted to our hospital with hyperglycemia. He developed alopecia areata (AA) 5 months before admission and developed thirst, polyuria, and anorexia in 2 weeks. His plasma glucose level upon admission was 912 mg/dl (50.63 mmol/l) and HbA1c was 13.7%. Although urinary and plasma C-peptide levels showed that insulin secretion was not depleted, anti-insulinoma-associated antigen 2 antibody was present. In addition, measurement of thyroid autoantibodies revealed the presence of Hashimoto's thyroiditis. These findings suggested a diagnosis of APS type 3. The patient has showed signs of improvement with the continuation of insulin therapy. During the successful control of diabetes, he had total hair regrowth within 2–3 months. Human leukocyte antigen typing showed that DRB1*1501-DQB1*0602 and DQB1*0301 were present. Similar cases should be accumulated to clarify the association of APS type 3 with recovery from AA. Learning points Alopecia in diabetic patients is a suspicious manifestation of autoimmune type 1 diabetes.Patients with autoimmune type 1 diabetes specifically manifesting alopecia should be further examined for diagnosis of APS.Insulin-mediated metabolic improvement may be a factor, but not the sole factor, determining a favorable outcome of alopecia in patients with autoimmune type 1 diabetes. PMID:25759758

  6. Clinical and genetic investigation of families with type II Waardenburg syndrome.

    PubMed

    Chen, Yong; Yang, Fuwei; Zheng, Hexin; Zhou, Jianda; Zhu, Ganghua; Hu, Peng; Wu, Weijing

    2016-03-01

    The present study aimed to investigate the molecular pathology of Waardenburg syndrome type II in three families, in order to provide genetic diagnosis and hereditary counseling for family members. Relevant clinical examinations were conducted on the probands of the three pedigrees. Peripheral blood samples of the probands and related family members were collected and genomic DNA was extracted. The coding sequences of paired box 3 (PAX3), microphthalmia‑associated transcription factor (MITF), sex‑determining region Y‑box 10 (SOX10) and snail family zinc finger 2 (SNAI2) were analyzed by polymerase chain reaction and DNA sequencing. The heterozygous mutation, c.649_651delAGA in exon 7 of the MITF gene was detected in the proband and all patients of pedigree 1; however, no pathological mutation of the relevant genes (MITF, SNAI2, SOX10 or PAX3) was detected in pedigrees 2 and 3. The heterozygous mutation c.649_651delAGA in exon 7 of the MITF gene is therefore considered the disease‑causing mutation in pedigree 1. However, there are novel disease‑causing genes in Waardenburg syndrome type II, which require further research. PMID:26781036

  7. Clinical and genetic investigation of families with type II Waardenburg syndrome

    PubMed Central

    CHEN, YONG; YANG, FUWEI; ZHENG, HEXIN; ZHOU, JIANDA; ZHU, GANGHUA; HU, PENG; WU, WEIJING

    2016-01-01

    The present study aimed to investigate the molecular pathology of Waardenburg syndrome type II in three families, in order to provide genetic diagnosis and hereditary counseling for family members. Relevant clinical examinations were conducted on the probands of the three pedigrees. Peripheral blood samples of the probands and related family members were collected and genomic DNA was extracted. The coding sequences of paired box 3 (PAX3), microphthalmia-associated transcription factor (MITF), sex-determining region Y-box 10 (SOX10) and snail family zinc finger 2 (SNAI2) were analyzed by polymerase chain reaction and DNA sequencing. The heterozygous mutation, c.649_651delAGA in exon 7 of the MITF gene was detected in the proband and all patients of pedigree 1; however, no pathological mutation of the relevant genes (MITF, SNAI2, SOX10 or PAX3) was detected in pedigrees 2 and 3. The heterozygous mutation c.649_651delAGA in exon 7 of the MITF gene is therefore considered the disease-causing mutation in pedigree 1. However, there are novel disease-causing genes in Waardenburg syndrome type II, which require further research. PMID:26781036

  8. Type III Guyon Syndrome in 'B Boy' Break-Dancer: A Case Report.

    PubMed

    Hu, Soo-Young; Choi, Jin-Gyu; Son, Byung-Chul

    2015-10-01

    Although the musculoskeletal injuries associated with break-dancing which is gaining more popularity among adolescent and young people has been reported, the report regarding a peripheral nerve injury associated with breakdance is scarce. We report a rare case of a young amateur break-dancer, 'b-boy' who suffered from a painful paresthesia in his left hand, later diagnosed as type III Guyon's canal syndrome. A 23-year-old, right handed college man presented with a tenderness over the left hypothenar eminence and painful paresthesia over the ring and little fingers of 3 months duration. He trained himself as an amateur 'b boy' break-dancer for the last 10 months. Conservative management under the diagnosis of wrist sprain before presentation did not improve his hand pain. An magnetic resonance imaging and electrodiagnostic study revealed that painful paresthesia was caused by type III Guyon's canal syndrome, and 4 weeks of corticosteroid treatment was given with resolution of pain and paresthesia. PMID:27169091

  9. Macrophage involvement in mitral valve pathology in mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome).

    PubMed

    Brands, Marion; Roelants, Jorine; de Krijger, Ronald; Bogers, Ad; Reuser, Arnold; van der Ploeg, Ans; Helbing, Wim

    2013-10-01

    Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI) is a rare lysosomal storage disorder in which the pathologic storage of glycosaminoglycans in various tissues can lead to severe symptoms, including cardiomyopathy. We report on a child with Maroteaux-Lamy syndrome whose cardiac condition deteriorated and eventually led to cardiac failure at the age of 7 years due to severe mitral regurgitation. She received a mitral valve replacement and tricuspid repair with successful outcome. Histologic examination of the mitral valve showed abundant "clear" cells in both the leaflets and chordae tendineae. In Hurler disease (MPS I), similar cells have been identified as activated valvular interstitial cells (VICs, a myofibroblast like cell type). Here we report that the "clear" cells are CD68 positive, a frequently used marker of macrophage lineage. The "clear" cells remained unstained with the more specific macrophage marker CD14 while persistent staining of other cells demonstrated macrophage infiltration. From these observations, we infer that macrophages are involved in mitral valve pathology in MPS VI. PMID:23949968

  10. Type III Guyon Syndrome in 'B Boy' Break-Dancer: A Case Report

    PubMed Central

    Hu, Soo-young; Choi, Jin-gyu

    2015-01-01

    Although the musculoskeletal injuries associated with break-dancing which is gaining more popularity among adolescent and young people has been reported, the report regarding a peripheral nerve injury associated with breakdance is scarce. We report a rare case of a young amateur break-dancer, 'b-boy' who suffered from a painful paresthesia in his left hand, later diagnosed as type III Guyon's canal syndrome. A 23-year-old, right handed college man presented with a tenderness over the left hypothenar eminence and painful paresthesia over the ring and little fingers of 3 months duration. He trained himself as an amateur 'b boy' break-dancer for the last 10 months. Conservative management under the diagnosis of wrist sprain before presentation did not improve his hand pain. An magnetic resonance imaging and electrodiagnostic study revealed that painful paresthesia was caused by type III Guyon's canal syndrome, and 4 weeks of corticosteroid treatment was given with resolution of pain and paresthesia. PMID:27169091

  11. The multifaceted and complex hypermobility syndrome (a.k.a. Ehlers-Danlos Syndrome Hypermobility Type): evaluation and management through a rehabilitative approach.

    PubMed

    Celletti, C; Camerota, F

    2013-01-01

    Joint hypermobility syndrome (JHS) is a hereditary disorder of connective tissue recently considered the one and the same as the Ehlers-Danlos Syndrome Hypermobility Type (EDS-HT). The JHS/EDS-HT is mainly characterized by joint hypermobility, chronic pain and a variable skin involvement. Clinical manifestations expressed by patients are multiple and varied. The rehabilitative approach may play a fundamental role in the understanding and management of symptoms and clinical manifestation. Aim of this study is to make a literature revision of all the aspects of this not so rare disease. PMID:24045532

  12. Expanding the spectrum of genetic mutations in antenatal Bartter syndrome type II.

    PubMed

    Fretzayas, Andreas; Gole, Evangelia; Attilakos, Achilleas; Daskalaki, Anna; Nicolaidou, Polyxeni; Papadopoulou, Anna

    2013-06-01

    Bartter syndrome (BS) is a group of genetic disorders characterized by hypokalemic metabolic alkalosis, hyponatremia and elevated renin and aldosterone plasma concentrations. BS type II is caused by mutations in the KCNJ1 gene and usually presents with transient hyperkalemia. We report here a novel KCNJ1 mutation in a male neonate, prematurely born after a pregnancy complicated by polyhydramnios. The infant presented with typical clinical and laboratory findings of BS type II, such as hyponatremia, hypochloremic metabolic alkalosis, severe weight loss, elevated renin and aldosterone levels and transient hyperkalemia in the early postnatal period, which were later normalized. Molecular analysis revealed a compound heterozygous mutation in the KCNJ1 gene, consisting of a novel K76E and an already described V315G mutation, both affecting functional domains of the channel protein. Typical manifestations of antenatal BS in combination with hyperkalemia should prompt the clinician to search for mutations in the KCNJ1 gene first. PMID:23782368

  13. [WPW syndrome combined with AV block 2 in an adult with glycogenosis (Type II)].

    PubMed

    Francesconi, M; Auff, E; Ursin, C; Sluga, E

    1982-08-01

    A 31 year-old female with a five year history of muscle weakness, cardiac palpitations and elevation of activity of some serum enzymes of muscular origin, showed signs of the WPW syndrome on ECG, often in combination with grade 2 A-V block. Type II glycogenosis (Pompe's disease) was diagnosed on the basis of the results of physical examination, laboratory findings--especially subtotal deficiency of acid maltase (a-1,4 glucosidase) activity-and morphological aspects of light and electron microscopy of a quadriceps muscle biopsy specimen. To our knowledge the coincidence of such a rarely encountered arrhythmia with glycogenosis type II in an adult has never been reported so far. PMID:6959422

  14. Change of QT variability index during general anesthesia

    PubMed Central

    Kim, Dae-Young; Sung, Minha; Lee, Minhyun; Park, Soon Eun

    2016-01-01

    Background The QT variability index (QTVI)–a non-invasive measure of beat-to-beat QT interval (QTI) fluctuations–is related to myocardial repolarization lability. The QTVI represents the relationship between QTI and the RR interval. Elevated QTVI is associated with an increased risk of malignant ventricular arrhythmias and sudden death. We investigated the influence of general anesthesia and tourniquets on the QTVI. Methods We studied fifty patients who received total knee replacement arthroplasty under sevoflurane anesthesia. We measured QTI, corrected QTI (QTc), T-wave peak-to-end interval (TPE), QTVI, and heart rate variability. All variables were calculated at baseline (B), 30 min after general anesthesia (A), 30 min (TQ1) and 60 min (TQ2) after tourniquet inflation, and at tourniquet deflation (TQR). Results Prolongation of QTI was detected at all times, and QTc was significantly prolonged TQR. TPE was unchanged during general anesthesia. The QTVI was significantly decreased and more negative during anesthesia and tourniquet inflation. After deflation of the tourniquet, the QTVI was restored to preanesthetic values. Low frequency (LF) was significantly decreased during general anesthesia, but high frequency (HF) was somewhat maintained, except at TQ2. The LF/HF ratio was significantly decreased at A and TQ2. Conclusions Sevoflurane based general anesthesia induced repolarization stability and, more negativity of the QTVI, in patients undergoing total knee replacement arthroplasty. PMID:27274370

  15. Pharmacokinetic–pharmacodynamic modelling of QT interval prolongation following citalopram overdoses

    PubMed Central

    Friberg, Lena E; Isbister, Geoffrey K; Duffull, Stephen B

    2006-01-01

    Aims To develop a pharmacokinetic–pharmacodynamic model describing the time-course of QT interval prolongation after citalopram overdose and to evaluate the effect of charcoal on the relative risk of developing abnormal QT and heart-rate combinations. Methods Plasma concentrations and electrocardiograph (ECG) data from 52 patients after 62 citalopram overdose events were analysed in WinBUGS using a Bayesian approach. The reported doses ranged from 20 to 1700 mg and on 17 of the events a single dose of activated charcoal was administered. The developed pharmacokinetic–pharmacodynamic model was used for predicting the probability of having abnormal combinations of QT-RR, which was assumed to be related to an increased risk for torsade de pointes (TdP). Results The absolute QT interval was related to the observed heart rate with an estimated individual heart-rate correction factor [α = 0.36, between-subject coefficient of variation (CV) =29%]. The heart-rate corrected QT interval was linearly dependent on the predicted citalopram concentration (slope = 40 ms l mg−1, between-subject CV =70%) in a hypothetical effect-compartment (half-life of effect-delay = 1.4 h). The heart-rate corrected QT was predicted to be higher in women than in men and to increase with age. Administration of activated charcoal resulted in a pronounced reduction of the QT prolongation and was shown to reduce the risk of having abnormal combinations of QT-RR by approximately 60% for citalopram doses above 600 mg. Conclusion Citalopram caused a delayed lengthening of the QT interval. Administration of activated charcoal was shown to reduce the risk that the QT interval exceeds a previously defined threshold and therefore is expected to reduce the risk of TdP. PMID:16433872

  16. Rubinstein-Taybi syndrome associated with Chiari type I malformation caused by a large 16p13.3 microdeletion: a contiguous gene syndrome?

    PubMed

    Wójcik, Cezary; Volz, Kim; Ranola, Maria; Kitch, Karla; Karim, Tariza; O'Neil, Joseph; Smith, Jodi; Torres-Martinez, Wilfredo

    2010-02-01

    Rubinstein-Taybi Syndrome (RSTS, OMIM 180849) is a rare condition, which in 65% of cases is caused by haploinsufficiency of CREBBP (cAMP response element binding protein binding protein) localized to 16p13.3. A small subset of RSTS cases caused by 16p13.3 microdeletions involving neighboring genes have been recently suggested to be a true contiguous gene syndrome called severe RSTS or 16p13.3 deletion syndrome (OMIM 610543). In the present report, we describe a case of a 2-year-old female with RSTS who, besides most of the typical features of RSTS has corpus callosum dysgenesis and a Chiari type I malformation which required neurosurgical decompression. CGH microarray showed a approximately 520.7 kb microdeletion on 16p13.3 involving CREBBP, ADCY9, and SRL genes. We hypothesize that the manifestations in this patient might be influenced by the haploinsufficiency for ADCY9 and SRL. PMID:20101707

  17. Conservative management of small bowel perforation in Ehlers-Danlos syndrome type IV.

    PubMed

    Allaparthi, Satya; Verma, Himanshu; Burns, David L; Joyce, Ann M

    2013-08-16

    Ehlers-Danlos syndrome (EDS) is a group of inherited connective tissue disorders caused by collagen synthesis defects. EDS type IV, or vascular EDS, is caused by loss-of-function mutations in the type III pro-collagen gene (COL3A1). Common complications of EDS type IV include gastrointestinal bleeding and bowel perforations, posing diagnostic and therapeutic dilemmas for both surgeons and gastroenterologists. Here, we describe a complicated case of EDS type IV in a 35-year-old caucasian female who presented with overt gastrointestinal bleeding. The patient had a prior history of spontaneous colonic perforation, and an uncomplicated upper endoscopy was performed. A careful ileoscopy was terminated early due to tachycardia and severe abdominal pain, and a subsequent computed tomography scan confirmed the diagnosis of ileal perforation. The patient was managed conservatively, and demonstrated daily improvement. At the time of hospital discharge, no further episodes of gastrointestinal blood loss had occurred. This case highlights the benefit of conservative management for EDS patients with gastrointestinal hemorrhage. It is recommended that surgical treatment should be reserved for patients who fail conservative treatment or in cases of hemodynamic instability. Finally, this case demonstrates the necessity for a higher threshold of operative or endoscopic interventions in EDS type IV patients. PMID:23951395

  18. Evolutionary diversification of type 2 porcine reproductive and respiratory syndrome virus.

    PubMed

    Brar, Manreetpal Singh; Shi, Mang; Murtaugh, Michael P; Leung, Frederick Chi-Ching

    2015-07-01

    Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the leading swine pathogens causing tremendous economic loss to the global swine industry due to its virulence, pathogenesis, infectivity and transmissibility. Although formally recognized only two and half decades ago, molecular dating estimation indicates a more ancient evolutionary history, which involved divergence into two genotypes (type 1 and type 2) prior to the 'initial' outbreaks of the late 1980s. Type 2 PRRSV circulates primarily in North America and Asia. The relatively greater availability of sequence data for this genotype from widespread geographical territories has enabled a better understanding of the evolving genotype. However, there are a number of challenges in terms of the vastness of data available and what this indicates in the context of viral diversity. Accordingly, here we revisit the mechanisms by which PRRSV generates variability, describe a means of organizing type 2 diversity captured in voluminous ORF5 sequences in a phylogenetic framework and provide a holistic view of known global type 2 diversity in the same setting. The consequences of the expanding diversity for control measures such as vaccination are discussed, as well as the contribution of modified live vaccines to the circulation of field isolates. We end by highlighting some limitations of current molecular epidemiology studies in relation to inferring PRRSV diversity, and what steps can be taken to overcome these and additionally enable PRRSV sequence data to be informative about viral phenotypic traits such as virulence. PMID:25711962

  19. Cardiac valve disease: an unreported feature in Ehlers Danlos syndrome arthrocalasia type?

    PubMed

    Melis, Daniela; Cappuccio, Gerarda; Ginocchio, Virginia Maria; Minopoli, Giorgia; Valli, Maurizia; Corradi, Massimiliano; Andria, Generoso

    2012-01-01

    Ehlers Danlos syndrome (EDS) athrocalasia type (type VII), is characterized by joint hypermobility, skin hyperextensibility and tissue fragility. No heart involvement has been reported. Two forms have been described: type VII A and VII B. The abnormally processed collagen α2(I) and the skipping of the exon 6 in COL1A2 gene are typically detected in EDS type VII B. We describe a seven-year old female, with a phenotype consistent with EDS type VII B and a diagnosis further confirmed by biochemical and molecular analyses. Cardiac ultrasound showed normal data in the first year of life. When she was 5 years old, the patient developed mitral valve regurgitation, and aortic and tricuspidal insufficiency at 7 years of age. To our knowledge, this is the first report of cardiac valvular involvement in EDS VII B. This feature probably has been underreported for the limited follow-up of the patients. Echocardiography might be warranted in the clinical assessment of EDS VII patients. PMID:23158907

  20. Differential diagnosis and diagnostic flow chart of joint hypermobility syndrome/ehlers-danlos syndrome hypermobility type compared to other heritable connective tissue disorders.

    PubMed

    Colombi, Marina; Dordoni, Chiara; Chiarelli, Nicola; Ritelli, Marco

    2015-03-01

    Joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type (JHS/EDS-HT) is an evolving and protean disorder mostly recognized by generalized joint hypermobility and without a defined molecular basis. JHS/EDS-HT also presents with other connective tissue features affecting a variety of structures and organs, such as skin, eye, bone, and internal organs. However, most of these signs are present in variable combinations and severity in many other heritable connective tissue disorders. Accordingly, JHS/EDS-HT is an "exclusion" diagnosis which needs the absence of any consistent feature indicative of other partially overlapping connective tissue disorders. While both Villefranche and Brighton criteria include such an exclusion as a mandatory item, a systematic approach for reaching a stringent clinical diagnosis of JHS/EDS-HT is still lacking. The absence of a consensus on the diagnostic approach to JHS/EDS-HT concerning its clinical boundaries with similar conditions contribute to limit our actual understanding of the pathologic and molecular bases of this disorder. In this review, we revise the differential diagnosis of JHS/EDS-HT with those heritable connective tissue disorders which show a significant overlap with the former and mostly include EDS classic, vascular and kyphoscoliotic types, osteogenesis imperfecta, Marfan syndrome, Loeys-Dietz syndrome, arterial tortuosity syndrome, and lateral meningocele syndrome. A diagnostic flow chart is also offered with the attempt to support the less experienced clinician in stringently recognizing JHS/EDS-HT and stimulate the debate in the scientific community for both management and research purposes. PMID:25821090

  1. Energy Types of Snoring Sounds in Patients with Obstructive Sleep Apnea Syndrome: A Preliminary Observation

    PubMed Central

    Lee, Li-Ang; Yu, Jen-Fang; Lo, Yu-Lun; Chen, Yen-Sheng; Wang, Ding-Li; Cho, Chih-Ming; Ni, Yung-Lun; Chen, Ning-Hung; Fang, Tuan-Jen; Huang, Chung-Guei; Li, Hsueh-Yu

    2012-01-01

    Background Annoying snore is the principle symptom and problem in obstructive sleep apnea syndrome (OSAS). However, investigation has been hampered by the complex snoring sound analyses. Objective This study was aimed to investigate the energy types of the full-night snoring sounds in patients with OSAS. Patients and Method Twenty male OSAS patients underwent snoring sound recording throughout 6 hours of in-lab overnight polysomnogragphy. Snoring sounds were processed and analyzed by a new sound analytic program, named as Snore Map®. We transformed the 6-hour snoring sound power spectra into the energy spectrum and classified it as snore map type 1 (monosyllabic low-frequency snore), type 2 (duplex low-&mid-frequency snore), type 3 (duplex low- & high-frequency snore), and type 4 (triplex low-, mid-, & high-frequency snore). The interrator and test-retest reliabilities of snore map typing were assessed. The snore map types and their associations among demographic data, subjective snoring questionnaires, and polysomnographic parameters were explored. Results The interrator reliability of snore map typing were almost perfect (κ = 0.87) and the test-retest reliability was high (r = 0.71). The snore map type was proportional to the body mass index (r = 0.63, P = 0.003) and neck circumference (r = 0.52, P = 0.018). Snore map types were unrelated to subjective snoring questionnaire scores (All P>0.05). After adjustment for body mass index and neck circumference, snore map type 3–4 was significantly associated with severity of OSAS (r = 0.52, P = 0.026). Conclusions Snore map typing of a full-night energy spectrum is feasible and reliable. The presence of a higher snore map type is a warning sign of severe OSAS and indicated priority OSAS management. Future studies are warranted to evaluate whether snore map type can be used to discriminate OSAS from primary snoring and whether it is affected by OSAS management. PMID:23300931

  2. Genetic analysis of Tunisian families with Usher syndrome type 1: toward improving early molecular diagnosis

    PubMed Central

    Ben-Rebeh, Imen; Bonnet, Crystel; Bouassida, Walid; Hadjamor, Imen; Ayadi, Hammadi; Ghorbel, Abdelmonem; Petit, Christine; Masmoudi, Saber

    2016-01-01

    Purpose Usher syndrome accounts for about 50% of all hereditary deaf-blindness cases. The most severe form of this syndrome, Usher syndrome type I (USH1), is characterized by profound congenital sensorineural deafness, vestibular dysfunction, and retinitis pigmentosa. Six USH1 genes have been identified, MYO7A, CDH23, PCDH15, USH1C, SANS, and CIB2, encoding myosin VIIA, cadherin-23, protocadherin-15, harmonin, scaffold protein containing ankyrin repeats and a sterile alpha motif (SAM) domain, and calcium- and integrin-binding member 2, respectively. Methods In the present study, we recruited four Tunisian families with a diagnosis of USH1, together with healthy unrelated controls. Affected members underwent detailed audiologic and ocular examinations. We used the North African Deafness (NADf) chip to search for known North African mutations associated with USH. Then, we selected microsatellite markers covering USH1 known loci to genotype the DNA samples. Finally, we performed DNA sequencing of three known USH1 genes: MYO7A, PCDH15, and USH1C. Results Four biallelic mutations, all single base changes, were found in the MYO7A, USH1C, and PCDH15 genes. These mutations consist of a previously reported splicing defect c.470+1G>A in MYO7A, three novel variants, including two nonsense (p.Arg3X and p.Arg134X) in USH1C and PCDH15, respectively, and one frameshift (p.Lys615Asnfs*6) in MYO7A. Conclusions We found a remarkable genetic heterogeneity in the studied families with USH1 with a variety of mutations, among which three were novel. These novel mutations will be included in the NADf mutation screening chip that will allow a higher diagnosis efficiency of this extremely genetically heterogeneous disease. Ultimately, efficient molecular diagnosis of USH in a patient’s early childhood is of utmost importance, allowing better educational and therapeutic management. PMID:27440999

  3. QT Interval Variability Index and QT Interval Duration in Different Sleep Stages: Analysis of Polysomnographic Recordings in Nonapneic Male Patients

    PubMed Central

    Viigimae, Moonika; Karai, Deniss; Pirn, Peeter; Pilt, Kristjan; Meigas, Kalju; Kaik, Jyri

    2015-01-01

    The aim of the study was to determine whether different sleep stages, especially REM sleep, affect QT interval duration and variability in male patients without obstructive sleep apnea (OSA). Polysomnographic recordings of 30 patients were analyzed. Beat-to-beat QT interval variability was calculated using QTV index (QTVI) formula. For QTc interval calculation, in addition to Bazett's formula, linear and parabolic heart rate correction formulas with two separate α values were used. QTVI and QTc values were calculated as means of 2 awake, 3 NREM, and 3 REM sleep episodes; the duration of each episode was 300 sec. Mean QTVI values were not statistically different between sleep stages. Therefore, elevated QTVI values found in patients with OSA cannot be interpreted as physiological sympathetic impact during REM sleep and should be considered as a risk factor for potentially life-threatening ventricular arrhythmias. The absence of difference of the mean QTc interval values between NREM and REM stages seems to confirm our conclusion that sympathetic surges during REM stage do not induce repolarization variability. In patients without notable structural and electrical remodeling of myocardium, physiological elevation in sympathetic activity during REM sleep remains subthreshold concerning clinically significant increase of myocardial electrical instability. PMID:26693490

  4. Pathological and biochemical studies of mucopolysaccharidosis type IIIB (Sanfilippo syndrome type B) in juvenile emus (Dromaius novaehollandiae).

    PubMed

    Palmieri, C; Giger, U; Wang, P; Pizarro, M; Shivaprasad, H L

    2015-01-01

    Mucopolysaccharidosis (MPS) type IIIB was diagnosed in 14 juvenile emus (Dromaius novaehollandiae), ages 3 weeks to 6 months, based on pathological and biochemical analyses. The animals had a history of neurological signs or sudden death; one of the birds with neurological signs and 3 others experienced acute hemoabdomen. Histopathologically, neuronal swelling and vacuolation in the cerebrum, cerebellum, brainstem, and spinal cord (80%-92%); retina (100%); autonomic ganglia of the intestine (71%); gizzard (50%); adrenal gland (27%); and ear (50%) were noted in affected but not healthy emus. Cytoplasmic vacuoles were also observed in the pancreas, liver, intestine, adrenal glands, and kidneys. The intracytoplasmic inclusions were periodic acid-Schiff and Luxol Fast Blue positive, consistent with a storage disease. Foamy macrophages infiltrated the liver, intestine, tunica media of the aorta, and spleen. By transmission electron microscopy, typical lamellated cytoplasmic bodies were detected in neurons of the brain and retina, while electron-dense bodies consistent with glycosaminoglycan inclusions were observed in hepatocytes and/or hepatic macrophages. The livers of the 2 affected emus studied contained large amounts of heparan sulfate, which is suggestive of MPS type III. Compared with normal controls, hepatic and serum α-N-acetylglucosaminidase activity was very low (<8% of control), while other enzyme activities were normal to increased in the 2 affected emus studied. Moreover, affected emus were homozygous for a 2-bp deletion in the NAGLU gene. This study characterizes the pathology of MPS type IIIB in emus, which is one of the rare inborn errors in birds, showing the homology of this condition to Sanfilippo syndrome in humans. PMID:24723233

  5. Recurring and generalized visceroptosis in Ehlers-Danlos syndrome hypermobility type.

    PubMed

    Dordoni, Chiara; Ritelli, Marco; Venturini, Marina; Chiarelli, Nicola; Pezzani, Lidia; Vascellaro, Annalisa; Calzavara-Pinton, Piergiacomo; Colombi, Marina

    2013-05-01

    Visceroptosis is described in several heritable connective tissue disorders, including the hypermobility type of Ehlers-Danlos syndrome (hEDS), a.k.a. joint hypermobility syndrome (JHS). Clinical features of hEDS comprise joint hypermobility, mild skin hyperextensibility, joint instability complications, chronic joint/limb pain, and positive family history. Uterine and rectal prolapse has been reported in nulliparous women. We report on a family with two patients with hEDS. The proposita, a 38-year-old woman, present bilateral kidney prolapse requiring three nephropexies, gastric ptosis treated with gastropexy and Billroth I gastrectomy, and liver prolapse treated with a non-codified hepatopexy procedure. Radiological evaluation also showed ovarian and heart prolapse. To our knowledge this is the first case of multiple visceral ptoses in hEDS. Visceral prolapse may lead to severe morbidity, affecting quality of life and a high rate of relapses after surgical procedures. Further investigations are needed to understand the molecular basis of the disease and retrospective studies on surgical outcomes, presentation of case series can be effective in order to offer a better treatment and prevention for hEDS patients. PMID:23533212

  6. Waardenburg syndrome type I: Dental phenotypes and genetic analysis of an extended family

    PubMed Central

    de Aquino, Sibele-Nascimento; Paranaíba, Lívia-Maris-R.; Gomes, Andreia; dos-Santos-Neto, Pedro; Coletta, Ricardo-D.; Cardoso, Aline-Francoise; Frota, Ana-Cláudia; Martelli-Júnior, Hercílio

    2016-01-01

    Background The aim of this study was to describe the pattern of inheritance and the clinical features in a large family with Waardenburg syndrome type I (WS1), detailing the dental abnormalities and screening for PAX3 mutations. Material and Methods To characterize the pattern of inheritance and clinical features, 29 family members were evaluated by dermatologic, ophthalmologic, otorhinolaryngologic and orofacial examination. Molecular analysis of the PAX3 gene was performed. Results The pedigree of the family,including the last four generations, was constructed and revealed non-consanguineous marriages. Out of 29 descendants, 16 family members showed features of WS1, with 9 members showing two major criteria indicative of WS1. Five patients showed white forelock and iris hypopigmentation, and four showed dystopia canthorum and iris hypopigmentation. Two patients had hearing loss. Dental abnormalities were identified in three family members, including dental agenesis, conical teeth and taurodontism. Sequencing analysis failed to identify mutations in the PAX3 gene. Conclusions These results confirm that WS1 was transmitted in this family in an autosomal dominant pattern with variable expressivity and high penetrance. The presence of dental manifestations, especially tooth agenesis and conical teeth which resulted in considerable aesthetic impact on affected individuals was a major clinical feature. Clinical relevance: This article reveals the presence of well-defined dental changes associated with WS1 and tries to establish a possible association between these two entities showing a new spectrum of WS1. Key words:Waardenburg syndrome, hearing loss, oral manifestations, mutation. PMID:27031059

  7. A novel mutation in PAX3 associated with Waardenburg syndrome type I in a Chinese family.

    PubMed

    Xiao, Yun; Luo, Jianfen; Zhang, Fengguo; Li, Jianfeng; Han, Yuechen; Zhang, Daogong; Wang, Mingming; Ma, Yalin; Xu, Lei; Bai, Xiaohui; Wang, Haibo

    2016-05-01

    Conclusion The novel compound heterozygous mutation in PAX3 was the key genetic reason for WS1 in this family, which was useful to the molecular diagnosis of WS1. Purpose Screening the pathogenic mutations in a four generation Chinese family with Waardenburg syndrome type I (WS1). Methods WS1 was diagnosed in a 4-year-old boy according to the Waardenburg syndrome Consortium criteria. The detailed family history revealed four affected members in the family. Routine clinical, audiological examination, and ophthalmologic evaluation were performed on four affected and 10 healthy members in this family. The genetic analysis was conducted, including the targeted next-generation sequencing of 127 known deafness genes combined with Sanger sequencing, TA clone and bioinformatic analysis. Results A novel compound heterozygous mutation c.[169_170insC;172_174delAAG] (p.His57ProfsX55) was identified in PAX3, which was co-segregated with WS1 in the Chinese family. This mutation was absent in the unaffected family members and 200 ethnicity-matched controls. The phylogenetic analysis and three-dimensional (3D) modeling of Pax3 protein further confirmed that the novel compound heterozygous mutation was pathogenic. PMID:26824486

  8. Wild type microglia do not arrest pathology in mouse models of Rett syndrome

    PubMed Central

    Wang, Jieqi; Wegener, Jan Eike; Huang, Teng-Wei; Sripathy, Smitha; De Jesus-Cortes, Hector; Xu, Pin; Tran, Stephanie; Knobbe, Whitney; Leko, Vid; Britt, Jeremiah; Starwalt, Ruth; McDaniel, Latisha; Ward, Chris; Parra, Diana; Newcomb, Benjamin; Lao, Uyen; Flowers, David A.; Cullen, Sean; Jorstad, Nikolas L; Yang, Yue; Glaskova, Lena; Vigneau, Sebastian; Kozlitina, Julia; Reichardt, Sybille D.; Reichardt, Holger M.; Gärtner, Jutta; Bartolomei, Marisa S.; Fang, Min; Loeb, Keith; Keene, C. Dirk; Bernstein, Irwin; Goodell, Margaret; Brat, Daniel J.

    2015-01-01

    Rett syndrome (RTT) is a severe neurodevelopmental disorder caused by mutations in the X chromosomal gene Methyl-CpG-binding Protein 2 (MECP2) (1). RTT treatment so far is symptomatic. Mecp2 disruption in mice phenocopies major features of the syndrome (2) that can be reversed upon re-expression of Mecp2 (3. It has recently been reported that transplantation of wild type (WT) bone marrow (BMT) into lethally irradiated Mecp2tm1.1Jae/y mice prevented neurologic decline and early death by restoring microglial phagocytic activity against apoptotic targets (4). Based on this report, clinical trials of BMT for patients with RTT have been initiated (5). We aimed to replicate and extend the BMT experiments in three different RTT mouse models but found that despite robust microglial engraftment, BMT from WT donors did not rescue early death or ameliorate neurologic deficits. Furthermore, early and specific genetic expression of Mecp2 in microglia did not rescue Mecp2-deficient mice. In conclusion our experiments do not support BMT as therapy for RTT. PMID:25993969

  9. [Dietary fibers: current trends and health benefits in the metabolic syndrome and type 2 diabetes].

    PubMed

    Mello, Vanessa D de; Laaksonen, David E

    2009-07-01

    Dietary fiber may contribute to both the prevention and treatment of type 2 diabetes mellitus (T2DM). In epidemiological studies the intake of insoluble fiber, but not the intake of soluble fiber, has been inversely associated with the incidence of T2DM. In contrast, in postprandial studies, meals containing sufficiently quantities of beta-glucan, psyllium, or guar gum have decreased insulin and glucose responses in both healthy individuals and patients with T2DM. Diets enriched sufficiently in soluble fiber may also improve overall glycemic control in T2DM. Insoluble fiber has little effect on postprandial insulin and glucose responses. Fiber increases satiety. In some studies, insoluble fiber has been associated with less weight gain over time. Limited cross-sectional evidence suggests an inverse relationship between intake of cereal fiber and whole-grains and the prevalence of the metabolic syndrome. Although long-term data from trials focusing on specifically dietary fiber are lacking, meeting current recommendations for a minimum fiber intake of 25 g/d based on a diet rich in whole grains, fruits and legumes will probably decrease the risk of obesity, the metabolic syndrome and T2DM. PMID:19768242

  10. Vascular Ehlers-Danlos syndrome mutations in type III collagen differently stall the triple helical folding.

    PubMed

    Mizuno, Kazunori; Boudko, Sergei; Engel, Jürgen; Bächinger, Hans Peter

    2013-06-28

    Vascular Ehlers-Danlos syndrome (EDS) type IV is the most severe form of EDS. In many cases the disease is caused by a point mutation of Gly in type III collagen. A slower folding of the collagen helix is a potential cause for over-modifications. However, little is known about the rate of folding of type III collagen in patients with EDS. To understand the molecular mechanism of the effect of mutations, a system was developed for bacterial production of homotrimeric model polypeptides. The C-terminal quarter, 252 residues, of the natural human type III collagen was attached to (GPP)7 with the type XIX collagen trimerization domain (NC2). The natural collagen domain forms a triple helical structure without 4-hydroxylation of proline at a low temperature. At 33 °C, the natural collagenous part is denatured, but the C-terminal (GPP)7-NC2 remains intact. Switching to a low temperature triggers the folding of the type III collagen domain in a zipper-like fashion that resembles the natural process. We used this system for the two known EDS mutations (Gly-to-Val) in the middle at Gly-910 and at the C terminus at Gly-1018. In addition, wild-type and Gly-to-Ala mutants were made. The mutations significantly slow down the overall rate of triple helix formation. The effect of the Gly-to-Val mutation is much more severe compared with Gly-to-Ala. This is the first report on the folding of collagen with EDS mutations, which demonstrates local delays in the triple helix propagation around the mutated residue. PMID:23645670

  11. Vascular Ehlers-Danlos Syndrome Mutations in Type III Collagen Differently Stall the Triple Helical Folding*

    PubMed Central

    Mizuno, Kazunori; Boudko, Sergei; Engel, Jürgen; Bächinger, Hans Peter

    2013-01-01

    Vascular Ehlers-Danlos syndrome (EDS) type IV is the most severe form of EDS. In many cases the disease is caused by a point mutation of Gly in type III collagen. A slower folding of the collagen helix is a potential cause for over-modifications. However, little is known about the rate of folding of type III collagen in patients with EDS. To understand the molecular mechanism of the effect of mutations, a system was developed for bacterial production of homotrimeric model polypeptides. The C-terminal quarter, 252 residues, of the natural human type III collagen was attached to (GPP)7 with the type XIX collagen trimerization domain (NC2). The natural collagen domain forms a triple helical structure without 4-hydroxylation of proline at a low temperature. At 33 °C, the natural collagenous part is denatured, but the C-terminal (GPP)7-NC2 remains intact. Switching to a low temperature triggers the folding of the type III collagen domain in a zipper-like fashion that resembles the natural process. We used this system for the two known EDS mutations (Gly-to-Val) in the middle at Gly-910 and at the C terminus at Gly-1018. In addition, wild-type and Gly-to-Ala mutants were made. The mutations significantly slow down the overall rate of triple helix formation. The effect of the Gly-to-Val mutation is much more severe compared with Gly-to-Ala. This is the first report on the folding of collagen with EDS mutations, which demonstrates local delays in the triple helix propagation around the mutated residue. PMID:23645670

  12. Aberrant splicing of U12-type introns is the hallmark of ZRSR2 mutant myelodysplastic syndrome

    PubMed Central

    Madan, Vikas; Kanojia, Deepika; Li, Jia; Okamoto, Ryoko; Sato-Otsubo, Aiko; Kohlmann, Alexander; Sanada, Masashi; Grossmann, Vera; Sundaresan, Janani; Shiraishi, Yuichi; Miyano, Satoru; Thol, Felicitas; Ganser, Arnold; Yang, Henry; Haferlach, Torsten; Ogawa, Seishi; Koeffler, H. Phillip

    2014-01-01

    Somatic mutations in the spliceosome gene ZRSR2 — located on the X chromosome — are associated with myelodysplastic syndrome (MDS). ZRSR2 is involved in the recognition of 3΄ splice site during the early stages of spliceosome assembly; however, its precise role in RNA splicing has remained unclear. Here, we characterize ZRSR2 as an essential component of the minor spliceosome (U12-dependent) assembly. shRNA mediated knockdown of ZRSR2 leads to impaired splicing of the U12-type introns, and RNA-Sequencing of MDS bone marrow reveals that loss of ZRSR2 activity causes increased mis-splicing. These splicing defects involve retention of the U12-type introns while splicing of the U2-type introns remain mostly unaffected. ZRSR2 deficient cells also exhibit reduced proliferation potential and distinct alterations in myeloid and erythroid differentiation in vitro. These data identify a specific role for ZRSR2 in RNA splicing and highlight dysregulated splicing of U12-type introns as a characteristic feature of ZRSR2 mutations in MDS. PMID:25586593

  13. Impaired Empathic Abilities among Patients with Complex Regional Pain Syndrome (Type I)

    PubMed Central

    Sohn, Hong-Suk; Lee, Do-Hyeong; Lee, Kyung-Jun; Noh, Eun Chung; Choi, Soo-Hee; Jang, Joon Hwan; Kim, Yong Chul

    2016-01-01

    Objective The aims of this study were to evaluate differences in empathic abilities between patients with complex regional pain syndrome (CRPS) Type I and healthy control subjects (HCs) and to assess correlations between empathic abilities and multidimensional aspects of pain. Methods Empathic ability was measured in 32 patients with CRPS Type I and in 36 HCs using the Interpersonal Reactivity Index (IRI). A comprehensive assessment of pain was conducted in the patient group using the West Haven-Yale Multidimensional Pain Inventory (WHYMPI). Psychiatric symptoms were assessed using the Beck Depression and Anxiety Inventories (BDI and BAI), and quality of life was evaluated using the WHO Quality of Life (WHOQOL-BREF) questionnaire. Results Patients with CRPS showed impaired cognitive and emotional empathic abilities compared with HCs. Significantly lower levels of perspective taking and empathic concern and higher levels of personal distress on the IRI were exhibited by the patient group. Perspective taking and personal distress were associated with affective distress and poor quality of life in social contexts (BDI, BAI, and WHOQOL). However, empathic concern was positively correlated with pain severity and social support from others (WHYMPI). Conclusion A tendency toward self-oriented distress in social cognition was exhibited among patients with CRPS Type I. Impaired empathic ability was shown to have potentially negative effects on subjective emotional outcomes and social performance in the lives of patients. Interventions to improve emotional awareness and theory of mind would be beneficial for enhancing social functioning in patients with CRPS Type I. PMID:26766944

  14. Aberrant splicing of U12-type introns is the hallmark of ZRSR2 mutant myelodysplastic syndrome.

    PubMed

    Madan, Vikas; Kanojia, Deepika; Li, Jia; Okamoto, Ryoko; Sato-Otsubo, Aiko; Kohlmann, Alexander; Sanada, Masashi; Grossmann, Vera; Sundaresan, Janani; Shiraishi, Yuichi; Miyano, Satoru; Thol, Felicitas; Ganser, Arnold; Yang, Henry; Haferlach, Torsten; Ogawa, Seishi; Koeffler, H Phillip

    2015-01-01

    Somatic mutations in the spliceosome gene ZRSR2-located on the X chromosome-are associated with myelodysplastic syndrome (MDS). ZRSR2 is involved in the recognition of 3'-splice site during the early stages of spliceosome assembly; however, its precise role in RNA splicing has remained unclear. Here we characterize ZRSR2 as an essential component of the minor spliceosome (U12 dependent) assembly. shRNA-mediated knockdown of ZRSR2 leads to impaired splicing of the U12-type introns and RNA-sequencing of MDS bone marrow reveals that loss of ZRSR2 activity causes increased mis-splicing. These splicing defects involve retention of the U12-type introns, while splicing of the U2-type introns remain mostly unaffected. ZRSR2-deficient cells also exhibit reduced proliferation potential and distinct alterations in myeloid and erythroid differentiation in vitro. These data identify a specific role for ZRSR2 in RNA splicing and highlight dysregulated splicing of U12-type introns as a characteristic feature of ZRSR2 mutations in MDS. PMID:25586593

  15. Postweaning multisystemic wasting syndrome produced in gnotobiotic pigs following exposure to various amounts of porcine circovirus type 2a or type 2b

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In late 2005, a postweaning, high mortality syndrome spread rapidly through fattening barns in swine dense areas of the United States. Diagnostic investigations consistently isolated porcine circovirus type 2 (PCV2) from diseased tissues. Subsequent genetic analysis revealed the infectious agent was...

  16. Sturge-Weber syndrome type II treated with PDL 595 nm laser.

    PubMed

    Kowalska-Brocka, Joanna; Brocki, Maciej; Uczniak, Sebastian; Uczniak, Kamila; Kaszuba, Andrzej; Jurowski, Piotr

    2015-02-01

    Sturge-Weber syndrome (SWS) is rare congenital disorder presenting facial port-wine stains (PWS) eye abnormalities and cerebrovascular malformations. The frequency of SWS is estimated at 1 in 50 000. Cerebrovascular abnormalities can be responsible for seizures, hemiparesis, mental retardation and ophthalmologic abnormalities cause intraocular pressure, glaucoma. Etiopathogenesis of SWS remains elusive. We present a case of a 7-year-old girl with SWS type II. A port-wine stain involves the upper right part of half face and has been associated with glaucoma of both eyes. In the Department of Dermatology in 2009-2012 we performed 23 procedures within 2 months. We have been using PDL laser at wavelength 595 nm and very good cosmetic results were achieved. Given positive treatment effects, the laser therapy of port-wine stains is a method of selection. Port-wine stains in the course of SWS requires a large number of laser treatment. PMID:25821431

  17. Functional analysis of MITF gene mutations associated with Waardenburg syndrome type 2.

    PubMed

    Zhang, Hua; Luo, Hunjin; Chen, Hongsheng; Mei, Lingyun; He, Chufeng; Jiang, Lu; Li, Jia-Da; Feng, Yong

    2012-11-30

    MITF mutations results in an abnormal melanocyte development and lead to Waardenburg syndrome type 2 (WS2). Here, we analyzed the in vitro activities of two recently identified WS2-associated MITF mutations (p.R217I and p.T192fsX18). The R217I MITF retained partial activity, normal DNA-binding ability and nuclear distribution, whereas the T192fsX18 MITF failed to activate TYR promoter and showed aberrant subcellular localization which may be caused by deletion of nuclear localization signal (NLS) at aa 213-218 (ERRRRF). These results suggest that haploinsufficiency may be the underlying mechanism for the mild phenotypes of WS2 caused by these two mutations. PMID:23098757

  18. An Adult Case of Bartter Syndrome Type III Presenting with Proteinuria

    PubMed Central

    Cha, Eun Jung; Hwang, Won Min; Yun, Sung-Ro; Park, Moon Hyang

    2016-01-01

    Bartter syndrome (BS) I–IV is a rare autosomal recessive disorder affecting salt reabsorption in the thick ascending limb of the loop of Henle. This report highlights clinicopathological findings and genetic studies of classic BS in a 22-year-old female patient who presented with persistent mild proteinuria for 2 years. A renal biopsy demonstrated a mild to moderate increase in the mesangial cells and matrix of most glomeruli, along with marked juxtaglomerular cell hyperplasia. These findings suggested BS associated with mild IgA nephropathy. Focal tubular atrophy, interstitial fibrosis, and lymphocytic infiltration were also observed. A genetic study of the patient and her parents revealed a mutation of the CLCNKB genes. The patient was diagnosed with BS, type III. This case represents an atypical presentation of classic BS in an adult patient. Pathologic findings of renal biopsy combined with genetic analysis and clinicolaboratory findings are important in making an accurate diagnosis. PMID:26755355

  19. Stellate ganglion pulsed radiofrequency ablation for stretch induced complex regional pain syndrome type II

    PubMed Central

    Singh Rana, Shiv Pratap; Abraham, Mary; Gupta, Varun; Biswas, Shubhashish; Marda, Manish

    2015-01-01

    Complex regional pain syndrome (CRPS) following injury or nerve damage, as its name signifies, is a challenging entity, and its successful management requires a multidisciplinary approach. It not only manifests as severe pain, but also gives rise to functional disability, lack of sleep, lack of enjoyment of life and poor quality of life. Various pain interventional techniques have been described in the literature for the management of CRPS ranging from sympathetic blocks to spinal cord stimulator. A 34-year-old liver transplant donor, who developed position-induced right upper limb neuropathic pain suggestive of CRPS type II was managed initially with medications and later with stellate ganglion block under fluoroscopic guidance at cervical C7 position. Following an initial significant improvement in pain and allodynia, which was transient, a pulsed radiofrequency ablation of stellate ganglion was performed successfully to provide prolonged and sustained pain relief, which persisted up to 14 months of follow-up. PMID:26543471

  20. Concise Review: Methods and Cell Types Used to Generate Down Syndrome Induced Pluripotent Stem Cells

    PubMed Central

    Hibaoui, Youssef; Feki, Anis

    2015-01-01

    Down syndrome (DS, trisomy 21), is the most common viable chromosomal disorder, with an incidence of 1 in 800 live births. Its phenotypic characteristics include intellectual impairment and several other developmental abnormalities, for the majority of which the pathogenetic mechanisms remain unknown. Several models have been used to investigate the mechanisms by which the extra copy of chromosome 21 leads to the DS phenotype. In the last five years, several laboratories have been successful in reprogramming patient cells carrying the trisomy 21 anomaly into induced pluripotent stem cells, i.e., T21-iPSCs. In this review, we summarize the different T21-iPSCs that have been generated with a particular interest in the technical procedures and the somatic cell types used for the reprogramming. PMID:26239351

  1. Multiple congenital skull fractures as a presentation of Ehlers-Danlos syndrome type VIIC.

    PubMed

    Bar-Yosef, Omer; Polak-Charcon, Sylvie; Hoffman, Chen; Feldman, Zeev P; Frydman, Moshe; Kuint, Jacob

    2008-12-01

    We describe a newborn infant with multiple congenital skull fractures and intracranial hemorrhage. He also had multiple skin folds suggesting a connective tissue abnormality. Electron microscopy of the skin biopsy showed collagen abnormalities with a "hieroglyphic appearance." The analysis of the synthesis of collagen in the cultured dermal fibroblasts demonstrated an accumulation of procollagen I. Molecular analysis found a nonsense mutation Q225X in ADAMTS2 gene, which encodes procollagen I N-terminal proteinase. All these findings confirmed the diagnosis of Ehlers-Danlos syndrome type VIIC (MIM 225410). Family studies suggested a founder effect in Ashkenazi Jews originating from Belarus. Prenatal diagnosis in the subsequent pregnancy reassured the parents that the fetus was an unaffected carrier. PMID:18973246

  2. Generation of Hermansky Pudlak syndrome type 2 (HPS2) induced pluripotent stem cells (iPSCs).

    PubMed

    Maguire, Jean Ann; Lu, Lin; Mills, Jason A; Sullivan, Lisa M; Gadue, Paul; French, Deborah L

    2016-03-01

    Hermansky-Pudlak syndrome type 2 (HPS2) is a rare autosomal recessive disorder resulting from functional mutations in the adaptor-related protein complex 3, beta 1 subunit (AP3B1) gene. This gene plays a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. Here we describe the generation of an HPS2 iPS cell line (CHOPHPS2) using a Cre-excisable polycistronic STEMCCA lentivirus. This line was derived from human fibroblasts isolated from a patient carrying two mutations in the AP3B1 gene. The patient presented with severe neutropenia, ocular albinism, interstitial pulmonary fibrosis, hemorrhagic diathesis, and an absence of platelet-dense granules. PMID:27345985

  3. [Acute Kidney Injury, Type - 3 cardiorenal syndrome, Biomarkers, Renal Replacement Therapy].

    PubMed

    Di Lullo, Luca; Bellasi, Antonio; Barbera, Vincenzo; Cozzolino, Mario; Russo, Domenico; De Pascalis, Antonio; Santoboni, Francesca; Villani, Annalisa; De Rosa, Silvia; Colafelice, Marco; Russo, Luigi; Ronco, Claudio

    2016-01-01

    Cardiovascular disease and major cardiovascular events represent main cause of death in both acute and chronic kidney disease patients. Kidney and heart failure are common and frequently co-exist This organ-organ interaction, also called organ cross-talk, leads to well-known definition of cardiorenal syndrome (CRS). Here we will describe cardiovascular involvement in patients with acute kidney injury (AKI). Also known as Type-3 CRS or acute reno-cardiac CRS, it occurs when AKI contributes and/or precipitates development of acute cardiac injury. AKI may directly or indirectly produces an acute cardiac event and it can be associated with volume overload, metabolic acidosis and electrolytes disorders such as hyperkalemia and hypocalcemia, coronary artery disease, left ventricular dysfunction and fibrosis which has been also described in patients with AKI with the consequence of direct negative effects on cardiac performance. PMID:27374388

  4. Cardiorenal Syndrome Type 1: Renal Dysfunction in Acute Decompensated Heart Failure

    PubMed Central

    Prins, Kurt W.; Thenappan, Thenappan; Markowitz, Jeremy S.; Pritzker, Marc R.

    2016-01-01

    Objective To present a review of cardiorenal syndrome type 1 (CRS1). Methods Review of the literature. Results Acute kidney injury occurs in approximately one-third of patients with acute decompensated heart failure (ADHF) and the resultant condition was named CRS1. A growing body of literature shows CRS1 patients are at high risk for poor outcomes, and thus there is an urgent need to understand the pathophysiology and subsequently develop effective treatments. In this review we discuss prevalence, proposed pathophysiology including hemodynamic and nonhemodynamic factors, prognosticating variables, data for different treatment strategies, and ongoing clinical trials and highlight questions and problems physicians will face moving forward with this common and challenging condition. Conclusion Further research is needed to understand the pathophysiology of this complex clinical entity and to develop effective treatments. PMID:27158218

  5. Otopalatodigital syndrome type 2 in a male infant: A case report with a novel sequence variation

    PubMed Central

    Sankararaman, Senthilkumar; Kurepa, Dalibor; Shen, Yiping; Kakkilaya, Venkatakrishna; Ursin, Sussone; Chen, Harold

    2013-01-01

    We report a male infant with typical clinical, pathological and radiological features of otopalatodigital syndrome type 2 (OPD 2) with a novel sequence variation in the FLNA gene. His clinical manifestations include typical craniofacial features, cleft palate, hearing impairment, omphalocele, bowing of the long bones, absent fibulae and digital abnormalities consistent with OPD 2. Two hemizygous sequence variations in the FLNA gene were identified. The variation c.5290G>A/p.Ala1764Thr has been previously reported in a patient with periventricular nodular heterotopia, but subsequently it has been reported as a polymorphism. The other variation c.613T>C/p.Cys205Arg detected in the proband has not been previously reported and our analysis indicates that this is a novel disease-causing mutation for OPD2.

  6. Ehlers-Danlos syndrome (classic type): report of a case presenting with an unusual dental anomaly.

    PubMed

    Cho, Shiu-Yin

    2011-10-01

    Ehlers-Danlos syndrome (EDS) comprises a group of generalised connective tissue disorders. Deficiency or alteration of the collagen present in the tissues results in some classic signs such as skin hyper extensibility, joint hypermobility, and vascular fragility. Multiple supernumerary teeth, congenitally missing teeth, and odontogenic keratocysts have been reported in some patients with EDS. To the author's knowledge, transposition of permanent canines has not previously been reported in any case of EDS. This case report presents the dental findings of a sporadic case of classic-type EDS in a 14-year-old Chinese male who had transposition of a permanent maxillary canine as well as the presence of two supernumerary premolars in the mandible. PMID:21968044

  7. Serological evidence of type 2 (North American genotype) porcine reproductive and respiratory syndrome virus in Nepal.

    PubMed

    Sharma, Barun Kumar; Manandhar, Salina; Devleesschauwer, Brecht

    2016-03-01

    Porcine reproductive and respiratory syndrome virus (PRRSV) has spread throughout Asia, causing significant losses to commercial farmers and smallholders. However, little is known about PRRS in Nepal, a South Asian country with a gradually increasing pig industry. In 2011, a pilot project was initiated to identify the status of PRRSV in pigs of the Kathmandu Valley of Nepal. Out of 98 serum samples, 31 (32 %; 95 % CI 23-42 %) were found positive by ELISA. All positive samples belonged to the type 2 (North American) genotype. Molecular evaluation by real-time PCR however did not yield positive results. At the herd level, seropositivity was associated with a history of abortion and premature birth. Veterinarians, farmers and government should be aware of this threat to the Nepalese pig industry and initiate an appropriate response. PMID:26712360

  8. Molecular analysis of patients of Sardinian descent with Crigler-Najjar syndrome type I.

    PubMed Central

    Rosatelli, M C; Meloni, A; Faa, V; Saba, L; Crisponi, G; Clemente, M G; Meloni, G; Piga, M T; Cao, A

    1997-01-01

    This study reports the molecular characterisation of the bilirubin UDP-glucuronosyl-transferase gene (UGT1) in a group of patients of Sardinian descent with Crigler-Najjar syndrome type I and their relatives. Sequence analysis of both UGT1A exon 1 and common exons 2-5 was performed in all patients, leading to the detection of AF170 and a novel mutation (470insT), both residing in UGT1A exon 1. All but two heterozygotes for the AF170 mutation showed normal serum bilirubin levels. These two subjects were also heterozygous for the sequence variation A(TA)7TAA in the promoter region of the UGT1A gene. Images PMID:9039987

  9. Type 1 Diabetes in Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy Syndrome (APECED): A "Rare" Manifestation in a "Rare" Disease.

    PubMed

    Fierabracci, Alessandra

    2016-01-01

    Type 1 autoimmune polyglandular syndrome (APS1) is a rare autosomal recessive disease, caused by mutations in the autoimmune regulator gene (AIRE); the encoded Aire protein plays an important role in the establishment of the immunological tolerance acting as a transcriptional regulator of the expression of organ-specific antigens within the thymus in perinatal age. While a high prevalence for this rare syndrome is reported in Finland and Scandinavia (Norway), autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) cohorts of patients are also detected in continental Italy and Sardinia, among Iranian Jews, as well as in other countries. The syndrome is diagnosed when patients present at least two out of the three fundamental disorders including chronic mucocutaneous candidiasis, hypoparathyroidism, and Addison's disease. Among the associated conditions insulin-dependent diabetes mellitus (Type 1 diabetes) has been rarely reported in different series of patients and occurring more frequently in Finnish APECED patients. In this review, we analyze the incidence of Type 1 diabetes as a clinical manifestation of APECED in different populations highlighting the peculiar genetic and immunological features of the disease when occurring in the context of this syndrome. PMID:27420045

  10. Tics and Tourette Syndrome

    MedlinePlus

    MENU Return to Web version Tics and Tourette Syndrome Overview What is Tourette syndrome? Tourette syndrome is a type of tic disorder. Children who have Tourette syndrome will repeat both movements and ...

  11. Double-valve replacement for Scheie's syndrome subtype mucopolysaccaridosis type 1-S.

    PubMed

    Murashita, Takashi; Kobayashi, Junjiro; Shimahara, Yusuke; Toda, Koichi; Fujita, Tomoyuki; Nakajima, Hiroyuki

    2011-09-01

    Scheie's syndrome is a rare hereditary disorder of proteoglycan-degrading enzymes. Deposition of mucopolysaccharide can cause valvular and other tissue abnormalities. Few studies have reported surgical results for Scheie's syndrome, and the perioperative course is complicated. This is a report of a 35-year-old woman with Scheie's syndrome who underwent double-valve replacement with intensive perioperative management. PMID:21871308

  12. Metabolic syndrome, dyslipidemia, hypertension and type 2 diabetes in youth: from diagnosis to treatment

    PubMed Central

    2010-01-01

    Overweight and obesity in youth is a worldwide public health problem. Overweight and obesity in childhood and adolescents have a substantial effect upon many systems, resulting in clinical conditions such as metabolic syndrome, early atherosclerosis, dyslipidemia, hypertension and type 2 diabetes (T2D). Obesity and the type of body fat distribution are still the core aspects of insulin resistance and seem to be the physiopathologic links common to metabolic syndrome, cardiovascular disease and T2D. The earlier the appearance of the clustering of risk factors and the higher the time of exposure, the greater will be the chance of developing coronary disease with a more severe endpoint. The age when the event may occur seems to be related to the presence and aggregation of risk factors throughout life. The treatment in this age-group is non pharmacological and aims at promoting changes in lifestyle. However, pharmacological treatments are indicated in special situations. The major goals in dietary treatments are not only limited to weight loss, but also to an improvement in the quality of life. Modification of risk factors associated to comorbidities, personal satisfaction of the child or adolescent and trying to establish healthy life habits from an early age are also important. There is a continuous debate on the best possible exercise to do, for children or adolescents, in order to lose weight. The prescription of physical activity to children and adolescents requires extensive integrated work among multidisciplinary teams, patients and their families, in order to reach therapeutic success. The most important conclusion drawn from this symposium was that if the growing prevalence of overweight and obesity continues at this pace, the result will be a population of children and adolescents with metabolic syndrome. This would lead to high mortality rates in young adults, changing the current increasing trend of worldwide longevity. Government actions and a better

  13. Novel types of mutation responsible for the dermatosparactic type of Ehlers-Danlos syndrome (Type VIIC) and common polymorphisms in the ADAMTS2 gene.

    PubMed

    Colige, Alain; Nuytinck, Lieve; Hausser, Ingrid; van Essen, Anthonie J; Thiry, Marc; Herens, Christian; Adès, Lesley C; Malfait, Fransiska; Paepe, Anne De; Franck, Peter; Wolff, Gerhard; Oosterwijk, Jan C; Smitt, J H Sillevis; Lapière, Charles M; Nusgens, Betty V

    2004-10-01

    Ehlers-Danlos syndrome (EDS) type VIIC, or dermatosparactic type, is a recessively inherited connective tissue disorder characterized, among other symptoms, by an extreme skin fragility resulting from mutations inactivating ADAMTS-2, an enzyme excising the aminopropeptide of procollagens type I, II, and III. All previously described mutations create premature stop codons leading to a marked reduction in the level of mRNA. In this study, we analyzed the ADAMTS2 cDNA sequences from five patients displaying clinical and/or biochemical features consistent with a diagnosis of either typical or potentially mild form of EDS type VIIC. Three different alterations were detected in the two patients with typical EDS type VIIC. The first patient was homozygous for a genomic deletion causing an in-frame skipping of exons 3-5 in the transcript. In the second patient, the allele inherited from the mother lacks exon 3, generating a premature stop codon, whereas the paternal allele has a genomic deletion resulting in an in-frame skipping of exons 14-16 at the mRNA level. Although the exons 3-5 or 14-16 encode protein domains that have not been previously recognized as crucial for ADAMTS-2 activity, the aminoprocollagen processing was strongly impaired in vitro and in vivo, providing evidence for the requirement of these domains for proper enzyme function. The three other patients with a phenotype with some resemblance to EDS type VIIC only had silent and functionally neutral variations also frequently found in a normal population. PMID:15373769

  14. Isolation of avian bornaviruses from psittacine birds using QT6 quail cells in Japan

    PubMed Central

    HORIE, Masayuki; SASSA, Yukiko; IKI, Haruko; EBISAWA, Kazumasa; FUKUSHI, Hideto; YANAI, Tokuma; TOMONAGA, Keizo

    2015-01-01

    Avian bornaviruses (ABVs) were recently discovered as the causative agents of proventricular dilatation disease (PDD). Although molecular epidemiological studies revealed that ABVs exist in Japan, no Japanese isolate has been reported thus far. In this study, we isolated four strains of Psittaciform 1 bornavirus from psittacine birds affected by PDD using QT6 quail cells. To our knowledge, this is the first report to isolate ABVs in Japan and to show that QT6 cells are available for ABV isolation. These isolates and QT6 cells would be powerful tools for elucidating the fundamental biology and pathogenicity of ABVs. PMID:26346745

  15. Nomenclature, categorization and usage of formulae to adjust QT interval for heart rate

    PubMed Central

    Rabkin, Simon W; Cheng, Xin Bo

    2015-01-01

    Assessment of the QT interval on a standard 12 lead electrocardiogram is of value in the recognition of a number of conditions. A critical part of its use is the adjustment for the effect of heart rate on QT interval. A systematic search was conducted to identify studies that proposed formulae to standardize the QT interval by heart rate. A nomenclature was developed for current and subsequent equations based on whether they are corrective (QTc) or predictive (QTp). QTc formulae attempt to separate the dependence of the length of the QT interval from the length of the RR interval. QTp formulae utilize heart rate and the output QTp is compared to the uncorrected QT interval. The nomenclature consists of the first letter of the first author’s name followed by the next two consonance (whenever possible) in capital letters; with subscripts in lower case alphabetical letter if the first author develops more than one equation. The single exception was the Framingham equation, because this cohort has developed its own “name” amongst cardiovascular studies. Equations were further categorized according to whether they were linear, rational, exponential, logarithmic, or power based. Data show that a person’s QT interval adjusted for heart rate can vary dramatically with the different QTc and QTp formulae depending on the person’s heart rate and QT interval. The differences in the QT interval adjustment equations encompasses values that are considered normal or significant prolonged. To further compare the equations, we considered that the slope of QTc versus heart rate should be zero if there was no correlation between QT and heart rate. Reviewing a sample of 107 patient ECGs from a hospital setting, the rank order of the slope - from best (closest to zero) to worst was QTcDMT, QTcRTHa, QTcHDG, QTcGOT, QTcFRM, QTcFRD, QTcBZT and QTcMYD. For two recent formulae based on large data sets specifically QTcDMT and QTcRTHa, there was no significant deviation of the slope

  16. Nomenclature, categorization and usage of formulae to adjust QT interval for heart rate.

    PubMed

    Rabkin, Simon W; Cheng, Xin Bo

    2015-06-26

    Assessment of the QT interval on a standard 12 lead electrocardiogram is of value in the recognition of a number of conditions. A critical part of its use is the adjustment for the effect of heart rate on QT interval. A systematic search was conducted to identify studies that proposed formulae to standardize the QT interval by heart rate. A nomenclature was developed for current and subsequent equations based on whether they are corrective (QTc) or predictive (QTp). QTc formulae attempt to separate the dependence of the length of the QT interval from the length of the RR interval. QTp formulae utilize heart rate and the output QTp is compared to the uncorrected QT interval. The nomenclature consists of the first letter of the first author's name followed by the next two consonance (whenever possible) in capital letters; with subscripts in lower case alphabetical letter if the first author develops more than one equation. The single exception was the Framingham equation, because this cohort has developed its own "name" amongst cardiovascular studies. Equations were further categorized according to whether they were linear, rational, exponential, logarithmic, or power based. Data show that a person's QT interval adjusted for heart rate can vary dramatically with the different QTc and QTp formulae depending on the person's heart rate and QT interval. The differences in the QT interval adjustment equations encompasses values that are considered normal or significant prolonged. To further compare the equations, we considered that the slope of QTc versus heart rate should be zero if there was no correlation between QT and heart rate. Reviewing a sample of 107 patient ECGs from a hospital setting, the rank order of the slope - from best (closest to zero) to worst was QTcDMT, QTcRTHa, QTcHDG, QTcGOT, QTcFRM, QTcFRD, QTcBZT and QTcMYD. For two recent formulae based on large data sets specifically QTcDMT and QTcRTHa, there was no significant deviation of the slope from zero

  17. A single base mutation in COL5A2 causes Ehlers-Danlos syndrome type II.

    PubMed

    Richards, A J; Martin, S; Nicholls, A C; Harrison, J B; Pope, F M; Burrows, N P

    1998-10-01

    Ehlers-Danlos syndrome (EDS) is a heterogeneous group of connective tissue disorders. Recently mutations have been found in the genes for type V collagen in a small number of people with the most common forms of EDS, types I and II. Here we characterise a COL5A2 mutation in an EDS II family. Cultured dermal fibroblasts obtained from an affected subject synthesised abnormal type V collagen. Haplotype analysis excluded COL5A1 but was concordant with COL5A2 as the disease locus. The entire open reading frame of the COL5A2 cDNA was directly sequenced and a single base mutation detected. It substituted a glycine residue within the triple helical domain (G934R) of alpha2(V) collagen, typical of the dominant negative changes in other collagens, which cause various other inherited connective tissue disorders. All three affected family members possessed the single base change, which was absent in 50 normal chromosomes. PMID:9783710

  18. Cognitive dysfunction in type 2 diabetes patients accompanied with obstructive sleep apnea syndrome

    PubMed Central

    Li, Huanyin; Gong, Qi; Shao, Jinshan; Liu, Xueyuan; Zhao, Yanxin

    2014-01-01

    Objective: To investigate cognitive dysfunction of type 2 diabetes patients accompanied with obstructive sleep apnea syndrome (OSAS), and to analyze its relevant characteristics. Methods: Total 115 type 2 diabetes patients were divided into OSAS group (O group, n=83) and non-OSAS group (N group, n=32); Physical examination patients (C1 group, n=64) and OSAS patients without diabetes (C2 group, n=47) served as the control group. Apnea-hypopnea index (AHI), nocturnal lowest saturation of pulse oxygen (LSPO2) and simple mental state examination scale (MMSE) were evaluated. Results: Among diabetes patients, patients with OSAS have lower glycated hemoglobin, platelet count, thrombocytocrit, MMSE score and lowest mean arterial oxygen than non-OSAS patients; cognitive dysfunction state and glycemic control of patients are related to their diabetic duration, and then along with increase of diabetic duration, glycemic control becomes poor, so that cognitive dysfunction becomes more and more obvious. Conclusion: Along with increased diabetic duration in type 2 diabetes accompanied with OSAS, glycemic control becomes poor, so that cognitive dysfunction more easily occurs. Meanwhile, coagulation function of blood system in OSAS patients with diabetes is impacted to some extent. PMID:25674144

  19. Linkage of Usher syndrome type I gene (USH1B) to the long arm of chromosome 11

    SciTech Connect

    Kimberling, W.; Kenyon, J.B.; Grunkemeyers, J.A. ); Moeller, C.G. ); Davenport, S. ); Priluck, I.A. ); Beighton, H.; Greenberg, J. ); Reardon, W. ); Weston, M.D.

    1992-12-01

    Usher syndrome is the most commonly recognized cause of combined visual and hearing loss in technologically developed countries. There are several different types and all are inherited in an autosomal recessive manner. There may be as many as five different genes responsible for at least two closely related phenotypes. The nature of the gene defects is unknown, and positional cloning strategies are being employed to identify the genes. This is a report of the localization of one gene for Usher syndrome type I to chromosome 11q, probably distal to marker D11S527. Another USH1 gene had been previously localized to chromosome 14q, and this second localization established the existence of a new and independent locus for Usher syndrome. 31 refs., 2 figs., 3 tabs.

  20. Results from the IQ-CSRC prospective study support replacement of the thorough QT study by QT assessment in the early clinical phase.

    PubMed

    Darpo, B; Benson, C; Dota, C; Ferber, G; Garnett, C; Green, C L; Jarugula, V; Johannesen, L; Keirns, J; Krudys, K; Liu, J; Ortemann-Renon, C; Riley, S; Sarapa, N; Smith, B; Stoltz, R R; Zhou, M; Stockbridge, N

    2015-04-01

    The QT effects of five "QT-positive" and one negative drug were tested to evaluate whether exposure-response analysis can detect QT effects in a small study with healthy subjects. Each drug was given to nine subjects (six for placebo) in two dose levels; positive drugs were chosen to cause 10 to 12 ms and 15 to 20 ms QTcF prolongation. The slope of the concentration/ΔQTc effect was significantly positive for ondansetron, quinine, dolasetron, moxifloxacin, and dofetilide. For the lower dose, an effect above 10 ms could not be excluded, i.e., the upper bound of the confidence interval for the predicted mean ΔΔQTcF effect was above 10 ms. For the negative drug, levocetirizine, a ΔΔQTcF effect above 10 ms was excluded at 6-fold the therapeutic dose. The study provides evidence that robust QT assessment in early-phase clinical studies can replace the thorough QT study. PMID:25670536

  1. Acquired von Willebrand syndrome with a type 2B phenotype: diagnostic and therapeutic dilemmas.

    PubMed

    Scepansky, Ellen; Othman, Maha; Smith, Hedy

    2014-01-01

    In this report, we provide evidence of an acquired von Willebrand syndrome (AVWS) with a type 2B phenotype rather than the expected type 1 or 2A. The patient was referred prior to surgical removal of a fibrous mass within the maxillary sinus. His first bleeding 7 years earlier following a retinal tear had been complicated by monocular blindness. Several mucocutanous bleedings followed. Hematological investigations revealed von Willebrand factor (VWF):Ag 91 IU/ml, factor VIII 86 IU/ml, VWF:RCo 34 IU/ml and profound thrombocytopenia with platelet clumping. VWF multimer analysis showed a loss of high-molecular-weight multimers and his plasma aggregated normal platelets under low ristocetin concentration, consistent with type 2B von Willebrand disease (VWD). Sequencing of VWF exon 28 and of the platelet GP1BA gene to investigate the possibility of platelet-type VWD failed to reveal mutations. Serum protein electrophoresis showed a monoclonal IgG protein and led to the diagnosis of monoclonal gammopathy of unknown significance (MGUS), raising suspicion of an AVWS. Over 2 years, he experienced severe gingival bleedings and traumatic intracerebral hemorrhage. Following debridement of the sinus mass, the patient required 20 units of packed red blood cells, despite high-dose Humate-P, continuous Amicar and twice-daily platelet transfusions. Bleeding finally ceased following infusion of activated factor VIIa. A history of prior uncomplicated vasectomy and tendon laceration, no family history of bleeding, the inability to identify a causative mutation in either exon 28 VWF or platelet GP1BA and the MGUS led to diagnosis of AVWS with a type 2B phenotype. This case highlights the difficulties in assigning a diagnosis and the management of bleeding in a patient with an atypical presentation of AVWS. PMID:24296552

  2. Re-writing the natural history of pain and related symptoms in the joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type.

    PubMed

    Castori, Marco; Morlino, Silvia; Celletti, Claudia; Ghibellini, Giulia; Bruschini, Michela; Grammatico, Paola; Blundo, Carlo; Camerota, Filippo

    2013-12-01

    Joint hypermobility syndrome (JHS) and Ehlers-Danlos syndrome, hypermobility type (EDS-HT) are two clinically overlapping connective tissue disorders characterized by chronic/recurrent pain, joint instability complications, and minor skin changes. Fatigue and headache are also common, although are not yet considered diagnostic criteria. JHS/EDS-HT is a unexpectedly common condition that remains underdiagnosed by most clinicians and pain specialists. This results in interventions limited to symptomatic and non-satisfactory treatments, lacking reasonable pathophysiologic rationale. In this manuscript the fragmented knowledge on pain, fatigue, and headache in JHS/EDS is presented with review of the available published information and a description of the clinical course by symptoms, on the basis of authors' experience. Pathogenic mechanisms are suggested through comparisons with other functional somatic syndromes (e.g., chronic fatigue syndrome, fibromyalgia, and functional gastrointestinal disorders). The re-writing of the natural history of JHS/EDS-HT is aimed to raise awareness among clinical geneticists and specialists treating chronic pain conditions about pain and other complications of JHS/EDS-HT. Symptoms' clustering by disease stage is proposed to investigate both the molecular causes and the symptoms management of JHS/EDS-HT in future studies. PMID:24254847

  3. Strategies and Considerations for Teaching an Adolescent with Down Syndrome and Type I Diabetes to Self-Administer Insulin.

    ERIC Educational Resources Information Center

    Bosner, Sylvia M.; Belfiore, Phillip J.

    2001-01-01

    In this study, a system of least prompts, partial participation, and parental involvement was used to successfully teach an adolescent with Down syndrome, moderate mental retardation, and Type I diabetes to self-administer an injection of insulin as part of an overall plan to increase self-determination and independence. (Contains seven…

  4. Ehlers-Danlos syndrome type IV is associated with a novel G984R COL3A1 mutation.

    PubMed

    Deng, Yao; Wei, Shijie; Hu, Shijun; Chen, Jinlan; Tan, Zhiping; Yang, Yifeng

    2015-07-01

    Ehlers-Danlos syndrome type IV is an autosomal dominant connective tissue disease. Mutations in COL3A1 have been identified to underlie this disease; however, to the best of our knowledge, no COL3A1 mutations have been reported in Ehlers-Danlos syndrome type IV patients with an ascending aortic aneurysm. In order to develop further understanding of COL3A1 mutations, an Ehlers-Danlos syndrome type IV patient diagnosed with an ascending aortic aneurysm and a familial history of sudden mortality was analyzed. Genomic DNA was isolated from the peripheral blood of the patient and his family members. All coding exons of eight aneurysm-related genes (FBN1, TGFBR1, TGFBR 2, MYH11, ACTA2, SLC2A10, NOTCH1 and COL3A1) were amplified using polymerase chain reaction (PCR). The PCR products were sequenced with the ABI 3100 Genetic Analyzer, and a mutation was predicted and identified using Polyphen-2, SIFT and Mutation Taster. The novel mutation was identified as c.2950G>A in COL3A1, which results in p.G984R. All three programs predicted this mutation to be deleterous to the protein function. The novel mutation identified in this study is potentially responsible for Ehlers-Danlos syndrome type IV in this patient, and expands the spectrum of COL3A1 mutations. PMID:25776230

  5. A Review of College-Level Health Textbooks for Coverage of Type 2 Diabetes, Prediabetes, and Metabolic Syndrome

    ERIC Educational Resources Information Center

    Ethan, Danna; Rennis, Lesley; Samuel, Lalitha; Seidel, Erica J.; Basch, Corey H.

    2014-01-01

    Objective: Type 2 diabetes, prediabetes, and metabolic syndrome are increasingly relevant health problems for United States (US) college-aged students and their family members. This study's aim was to determine the extent to which these chronic conditions were covered in leading college-level personal health textbooks and to what degree the…

  6. Pathogenicity of three type 2 Porcine Reproductive and Respiratory Syndrome virus strains in experimentally inoculated pregnant gilts

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Mechanisms of reproductive failure resulting from infection with porcine reproductive and respiratory syndrome virus (PRRSv) are still poorly understood. The present study, a side-by-side evaluation of the pathogenicity of three type 2 PRRSv strains in a reproductive model, was used as a pilot study...

  7. Jervell and Lange-Nielson Syndrome masquerading as intractable epilepsy.

    PubMed

    Goyal, Jagdish P; Sethi, Alka; Shah, V B

    2012-04-01

    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. PMID:22566733

  8. Jervell and Lange-Nielson Syndrome masquerading as intractable epilepsy

    PubMed Central

    Goyal, Jagdish P.; Sethi, Alka; Shah, V. B.

    2012-01-01

    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. PMID:22566733

  9. Impact of liver transplantation on the survival of patients treated for hepatorenal syndrome type 1.

    PubMed

    Boyer, Thomas D; Sanyal, Arun J; Garcia-Tsao, Guadalupe; Regenstein, Frederick; Rossaro, Lorenzo; Appenrodt, Beate; Gülberg, Veit; Sigal, Samuel; Bexon, Alice S; Teuber, Peter

    2011-11-01

    The development of hepatorenal syndrome type 1 (HRS1) is associated with a poor prognosis. Liver transplantation improves this prognosis, but the degree of the improvement is unclear. Most patients receive vasoconstrictors such as terlipressin before transplantation, and this may affect the posttransplant outcomes. We examined a cohort of patients with access to liver transplantation from our previously published study of terlipressin plus albumin versus albumin alone in the treatment of HRS1. The purpose of this analysis was the quantification of the survival benefits of liver transplantation for patients with HRS1. Ninety-nine patients were randomized to terlipressin or placebo. Thirty-five patients (35%) received a liver transplant. Among those receiving terlipressin plus albumin, the 180-day survival rates were 100% for transplant patients and 34% for nontransplant patients; among those receiving only albumin, the rates were 94% for transplant patients and 17% for nontransplant patients. The survival rate was significantly better for those achieving a reversal of hepatorenal syndrome (HRS) versus those not achieving a reversal (47% versus 4%, P < 0.001), but it was significantly lower for the responders versus those undergoing liver transplantation (97%). We conclude that the use of terlipressin plus albumin has no significant impact on posttransplant survival. Liver transplantation offers a clear survival benefit to HRS1 patients regardless of the therapy that they receive or the success or failure of HRS reversal. The most likely benefit of terlipressin in patients undergoing liver transplantation for HRS1 is improved pretransplant renal function, and this should make the posttransplant management of this difficult group of patients easier. For patients not undergoing transplantation, HRS reversal with terlipressin and/or albumin improves survival. PMID:21837734

  10. Impact of Liver Transplantation on the Survival of Patients Treated for Hepatorenal Syndrome Type 1

    PubMed Central

    Boyer, Thomas D.; Sanyal, Arun J.; Garcia-Tsao, Guadalupe; Regenstein, Frederick; Rossaro, Lorenzo; Appenrodt, Beate; Gülberg, Veit; Sigal, Samuel; Bexon, Alice S.; Teuber, Peter

    2013-01-01

    The development of hepatorenal syndrome type 1 (HRS1) is associated with a poor prognosis. Liver transplantation improves this prognosis, but the degree of the improvement is unclear. Most patients receive vasoconstrictors such as terlipressin before transplantation, and this may affect the posttransplant outcomes. We examined a cohort of patients with access to liver transplantation from our previously published study of terlipressin plus albumin versus albumin alone in the treatment of HRS1. The purpose of this analysis was the quantification of the survival benefits of liver transplantation for patients with HRS1. Ninety-nine patients were randomized to terlipressin or placebo. Thirty-five patients (35%) received a liver transplant. Among those receiving terlipressin plus albumin, the 180-day survival rates were 100% for transplant patients and 34% for nontransplant patients; among those receiving only albumin, the rates were 94% for transplant patients and 17% for nontransplant patients. The survival rate was significantly better for those achieving a reversal of hepatorenal syndrome (HRS) versus those not achieving a reversal (47% versus 4%, P < 0.001), but it was significantly lower for the responders versus those undergoing liver transplantation (97%). We conclude that the use of terlipressin plus albumin has no significant impact on posttransplant survival. Liver transplantation offers a clear survival benefit to HRS1 patients regardless of the therapy that they receive or the success or failure of HRS reversal. The most likely benefit of terlipressin in patients undergoing liver transplantation for HRS1 is improved pretransplant renal function, and this should make the posttransplant management of this difficult group of patients easier. For patients not undergoing transplantation, HRS reversal with terlipressin and/or albumin improves survival. PMID:21837734

  11. Is it worthwhile to screen patients with type 2 diabetes mellitus for subclinical Cushing's syndrome?

    PubMed

    Budyal, Sweta; Jadhav, Swati Sachin; Kasaliwal, Rajeev; Patt, Hiren; Khare, Shruti; Shivane, Vyankatesh; Lila, Anurag R; Bandgar, Tushar; Shah, Nalini S

    2015-12-01

    Variable prevalence of subclinical Cushing's syndrome (SCS) has been reported in patients with type 2 diabetes mellitus (T2DM), making the need for screening in this population uncertain. It is unknown if this variability is solely due to study-related methodological differences or a reflection of true differences in ethnic predisposition. The objective of this study is to explore the prevalence of SCS in Asian Indian patients with T2DM. In this prospective single center study conducted in a tertiary care referral center, 993 T2DM outpatients without any discriminatory clinical features (easy bruising, facial plethora, proximal muscle weakness, and/or striae) of hypercortisolism underwent an overnight 1 mg dexamethasone suppression test (ODST). ODST serum cortisol ≥1.8 μg/dl was considered positive, and those with positive results were subjected to 48 h, 2 mg/day low dose DST (LDDST). A stepwise evaluation for endogenous hypercortisolism was planned for patients with LDDST serum cortisol ≥1.8 μg/dl. Patients with positive ODST and negative LDDST were followed up clinically and re-evaluated a year later for the development of clinically evident Cushing's syndrome (CS). In this largest single center study reported to date, we found 37 out of 993 (3.72%) patients had ODST serum cortisol ≥1.8 μg/dl. None of them had LDDST cortisol ≥1.8 μg/dl, nor did they develop clinically evident CS over a follow-up period of 1 year. Specificity of ODST for screening of CS was 96.3% in our cohort. None of the T2DM outpatients in our cohort had SCS, hence cautioning against routine biochemical screening for SCS in this cohort. We suggest screening be based on clinical suspicion only. PMID:26420669

  12. Restless Leg Syndrome in Different Types of Demyelinating Neuropathies: A Single-Center Pilot Study

    PubMed Central

    Luigetti, Marco; Del Grande, Alessandra; Testani, Elisa; Bisogni, Giulia; Losurdo, Anna; Giannantoni, Nadia Mariagrazia; Mazza, Salvatore; Sabatelli, Mario; Della Marca, Giacomo

    2013-01-01

    Objective: to determine the prevalence of restless legs syndrome (RLS) in a cohort of patients with demyelinating neuropathies. Methods: Patients were retrospectively recruited from our cohort of different forms of demyelinating neuropathies, including chronic inflammatory demyelinating neuropathy (CIDP), Charcot-Marie-Tooth 1A (CMT1A), and hereditary neuropathy with liability to pressure palsies (HNPP) referred to our Department of Neurology in a 10-year period. The validated 4-item RLS questionnaire was used for diagnosis of RLS. All patients with RLS who fulfilled criteria underwent a suggested immobilization test to confirm the diagnosis. A group of outpatients referred to the sleep disorders unit and data from published literature were used as controls. Results: Prevalence of RLS in demyelinating neuropathy group was higher than prevalence observed in control population (p = 0.0142) or in the literature data (p = 0.0007). In particular, in comparison with both control population and literature data, prevalence of RLS was higher in CIDP group (p = 0.0266 and p = 0.0063, respectively) and in CMT1A group (p = 0.0312 and p = 0.0105, respectively), but not in HNPP (p = 1.000 and p = 0.9320, respectively). Conclusions: our study confirms a high prevalence of RLS in inflammatory neuropathies as CIDP and, among inherited neuropathies, in CMT1A but not in HNPP. Considering that this is only a small cohort from a single-center retrospective experience, the link between RLS and neuropathy remains uncertain, and larger multicenter studies are probably needed to clarify the real meaning of the association between RLS and neuropathy. Citation: Luigetti M; Del Grande A; Testani E; Bisogni G; Losurdo A; Giannantoni NM; Mazza S; Sabatelli M; Della Marca G. Restless leg syndrome in different types of demyelinating neuropathies: a single-center pilot study. J Clin Sleep Med 2013;9(9):945-949. PMID:23997707

  13. Cushing syndrome

    MedlinePlus

    ... Cushing syndrome is called exogenous Cushing syndrome . Prednisone, dexamethasone, and prednisolone are examples of this type of ... Blood cortisol levels Blood sugar Saliva cortisol levels Dexamethasone suppression test 24-hour urine for cortisol and ...

  14. Optimal weighted combinatorial forecasting model of QT dispersion of ECGs in Chinese adults

    NASA Astrophysics Data System (ADS)

    Wen, Zhang; Miao, Ge; Xinlei, Liu; Minyi, Cen

    2015-11-01

    This study aims to provide a scientific basis for unifying the reference value standard of QT dispersion of ECGs in Chinese adults. Three predictive models including regression model, principal component model, and artificial neural network model are combined to establish the optimal weighted combination model. The optimal weighted combination model and single model are verified and compared. Optimal weighted combinatorial model can reduce predicting risk of single model and improve the predicting precision. The reference value of geographical distribution of Chinese adults' QT dispersion was precisely made by using kriging methods. When geographical factors of a particular area are obtained, the reference value of QT dispersion of Chinese adults in this area can be estimated by using optimal weighted combinatorial model and reference value of the QT dispersion of Chinese adults anywhere in China can be obtained by using geographical distribution figure as well.

  15. Optimal weighted combinatorial forecasting model of QT dispersion of ECGs in Chinese adults

    NASA Astrophysics Data System (ADS)

    Wen, Zhang; Miao, Ge; Xinlei, Liu; Minyi, Cen

    2016-07-01

    This study aims to provide a scientific basis for unifying the reference value standard of QT dispersion of ECGs in Chinese adults. Three predictive models including regression model, principal component model, and artificial neural network model are combined to establish the optimal weighted combination model. The optimal weighted combination model and single model are verified and compared. Optimal weighted combinatorial model can reduce predicting risk of single model and improve the predicting precision. The reference value of geographical distribution of Chinese adults' QT dispersion was precisely made by using kriging methods. When geographical factors of a particular area are obtained, the reference value of QT dispersion of Chinese adults in this area can be estimated by using optimal weighted combinatorial model and reference value of the QT dispersion of Chinese adults anywhere in China can be obtained by using geographical distribution figure as well.

  16. Impacts of Usher Syndrome Type IB Mutations on Human Myosin VIIa Motor Function†

    PubMed Central

    Watanabe, Shinya; Umeki, Nobuhisa; Ikebe, Reiko; Ikebe, Mitsuo

    2010-01-01

    Usher syndrome (USH) is a human hereditary disorder characterized by profound congenital deafness, retinitis pigmentosa and vestibular dysfunction. Myosin VIIa has been identified as the responsible gene for USH type 1B, and a number of missense mutations have been identified in the affected families. However, the molecular basis of the dysfunction of USH gene, myosin VIIa, in the affected families is unknown to date. Here we clarified the effects of USH1B mutations on human myosin VIIa motor function for the first time. The missense mutations of USH1B significantly inhibited the actin activation of ATPase activity of myosin VIIa. G25R, R212C, A397D and E450Q mutations abolished the actin-activated ATPase activity completely. P503L mutation increased the basal ATPase activity for 2-3 fold, but reduced the actin-activated ATPase activity to 50% of the wild type. While all the mutations examined, except for R302H, reduced the affinity for actin and the ATP hydrolysis cycling rate, they did not largely decrease the rate of ADP release from acto-myosin, suggesting that the mutations reduce the duty ratio of myosin VIIa. Taken together, the results suggest that the mutations responsible for USH1B cause the complete loss of the actin-activated ATPase activity or the reduction of duty ratio of myosin VIIa. PMID:18700726

  17. Open angle glaucoma in a case of Type IV Ehler Danlos syndrome: a rarely reported association.

    PubMed

    Mitra, Arijit; Ramakrishnan, R; Kader, Mohideen Abdul

    2014-08-01

    A 26-year-old male presented to us with defective vision in the left eye. He had best corrected visual acuity (BCVA) of hand movement (HM) in right eye and 6/9 in left eye. He had ptosis with ectropion in both eyes and relative afferent pupillary defect (RAPD) in right eye. Intraocular pressure (IOP) was 46 and 44 mmHg in right and left eye, respectively. Fundus showed glaucomatous optic atrophy (GOA) in right eye and cup disc ratio (CDR) of 0.75 with bipolar rim thinning in left eye. Systemic examination showed hyperextensible skin and joints, acrogeria, hypodontia, high arched palate, and varicose veins. He gave history of easy bruising and tendency to fall and history of intestinal rupture 5 years ago for which he had undergone surgery. He was diagnosed as a case of Type IV Ehler-Danlos syndrome (EDS) with open angle glaucoma. He underwent trabeculectomy in both eyes. This is a rare case that shows glaucoma in a patient of EDS Type IV. Very few such cases have been reported in literature. PMID:25230966

  18. Spontaneous colon perforations associated with a vascular type of ehlers-danlos syndrome.

    PubMed

    Yoneda, Akira; Okada, Kazuya; Okubo, Hitoshi; Matsuo, Mitsutoshi; Kishikawa, Hiroki; Naing, Banyar Than; Watanabe, Atsushi; Shimada, Takashi

    2014-05-01

    Ehlers-Danlos syndrome, vascular type (vEDS) (MIM #130050) is an autosomal dominant disorder caused by mutation in the type III collagen gene, COL3A1, leading to fragility of blood vessels, bowel and uterus that leads to spontaneous rupture. We report a previously undiagnosed vEDS patient with bowel complications. A 20-year-old female patient was referred to our hospital with abdominal pain. Computed tomography showed notable dilatation of the sigmoid colon with intraperitoneal fluid. Laparotomy revealed dilatation of the sigmoid colon, breakdown of serosa and muscularis propria of the sigmoid colon with impending perforation, and intra-abdominal hemorrhage caused by breakdown of the mesenterium. Resection of the sigmoid colon with Hartmann's pouch and an end colostomy were performed. Physical examination showed joint hypermobility, translucent skin with venous prominence and facial structure abnormalities. Genetic analysis using cDNA extracted from the patient's fibroblasts by reverse transcriptase polymerase chain reaction direct sequencing showed a missense mutation within the triple helix region of COL3A1 (c.2150 G>A; Gly717Asp). PMID:24932165

  19. Lumbar Sympathetic Block with Botulinum Toxin Type B for Complex Regional Pain Syndrome: A Case Study.

    PubMed

    Choi, Eunjoo; Cho, Chan Woo; Kim, Hye Young; Lee, Pyung Bok; Nahm, Francis Sahngun

    2015-01-01

    Lumbar sympathetic block (LSB) is an effective method for relief of sympathetically mediated pain in the lower extremities. To prolong the sympathetic blockade, sympathetic destruction with alcohol or radiofrequency has been used. The pre-ganglionic sympathetic nerves are cholinergic, and botulinum toxin (BTX) has been found to inhibit the release of acetylcholine at the cholinergic nerve terminals. Moreover, BTX type B (BTX-B) is more convenient to use than BTX type A. Based on these findings, we performed LSB on the 2 patients with complex regional pain syndrome (CRPS) in the lower extremity. Levobupivacaine 0.25% 5 mL mixed with BTX-B 5,000 IU was given under fluoroscopic guidance. Two months after LSB with BTX-B, pain intensity and the Leeds assessment of neuropathic symptoms and signs (LANSS) score were significantly reduced. Allodynia and coldness disappeared and skin color came back to normal. In conclusion, BTX-B can produce an efficacious and durable sympathetic blocking effect on patients with CRPS. PMID:26431145

  20. Open angle glaucoma in a case of Type IV Ehler Danlos syndrome: A rarely reported association

    PubMed Central

    Mitra, Arijit; Ramakrishnan, R.; Kader, Mohideen Abdul

    2014-01-01

    A 26-year-old male presented to us with defective vision in the left eye. He had best corrected visual acuity (BCVA) of hand movement (HM) in right eye and 6/9 in left eye. He had ptosis with ectropion in both eyes and relative afferent pupillary defect (RAPD) in right eye. Intraocular pressure (IOP) was 46 and 44 mmHg in right and left eye, respectively. Fundus showed glaucomatous optic atrophy (GOA) in right eye and cup disc ratio (CDR) of 0.75 with bipolar rim thinning in left eye. Systemic examination showed hyperextensible skin and joints, acrogeria, hypodontia, high arched palate, and varicose veins. He gave history of easy bruising and tendency to fall and history of intestinal rupture 5 years ago for which he had undergone surgery. He was diagnosed as a case of Type IV Ehler-Danlos syndrome (EDS) with open angle glaucoma. He underwent trabeculectomy in both eyes. This is a rare case that shows glaucoma in a patient of EDS Type IV. Very few such cases have been reported in literature. PMID:25230966

  1. A Bayesian phylogeographical analysis of type 1 porcine reproductive and respiratory syndrome virus (PRRSV).

    PubMed

    Nguyen, V G; Kim, H K; Moon, H J; Park, S J; Chung, H C; Choi, M K; Park, B K

    2014-12-01

    Understanding viral transmission is an important factor for the effective prevention one of the most devastating swine diseases, porcine reproductive and respiratory syndrome. Focusing on molecular epidemiology of type 1 PRRSV, this study analysed a large ORF5 dataset collected worldwide from 1991 to 2012 using a coalescent-based Bayesian Markov chain Monte Carlo approach. The results suggested that the virus diversified into unique subpopulations in Russia & Belarus and Italy approximately 100 years ago. Previously unreported consecutive diffusions of the virus were identified, which showed that some countries, such as Spain and Germany, acted as distribution sources to some extent. This study also provided statistical evidence for the existence of an ORF5-based phylogeographical structure of type 1 PRRSV, in which the virus tended to cluster by geographical locations more tightly than expected by chance. In contrast to this tight geographical structure, the evolution of the ORF5 gene, based on mapping of non-synonymous/synonymous substitutions, was best described by a non-homogeneous process that could be implicated as a mechanism for viral immune evasion. PMID:23336975

  2. Urinary pyridinoline cross-links in Ehlers-Danlos syndrome type VI

    SciTech Connect

    Steinmann, B.; Eyre, D.R.; Shao, P. |

    1995-12-01

    The Ehlers-Danlos syndrome (EDS) is a heterogeneous group of heritable disorders of connective tissue, affecting skin, ligaments, joints, blood vessels, and internal organs. The main general findings are hyperextensibility and bruisability of the skin, with abnormal scarring, and joint laxity. On the basis of clinical, genetic, and biochemical findings, EDS can be classified today into at least 10 different types. Among them, EDS type VI (MIM 225400) is characterized by marked muscular hypotonia from birth; kyphoscoliosis, often present at birth and progressing to a severe form; marfanoid habitus; eye involvement, often with microcornea and a tendency of the eyeballs to rupture after minor trauma; osteoporosis; and sometimes spontaneous rupture of arteries. The disorder is due to a deficiency of lysyl hydroxylase (E.C.1.14.11.4), inherited in an autosomal recessive mode. Traditionally, the clinical diagnosis is confirmed by an insufficiency of hydroxylysine, on analysis of hydrolyzed dermis and/or reduced enzyme activity in cultured skin fibroblasts. 12 refs., 1 tab.

  3. Relationship between QT/QS2 ratio and angiographic severity of coronary heart disease.

    PubMed

    Cuomo, S; Acanfora, D; Papa, M; Covelluzzi, F; Tedeschi, C; Furgi, G; Rengo, F; De Caprio, L

    1988-08-01

    The relationship between QT/QS2 ratio and angiographic severity of coronary heart disease (CHD) was determined in 99 patients who underwent coronary arteriography because of chest pain. Sixteen control patients with normal coronary arteriograms and normal left ventricular function and 83 patients with angiographic evidence of CHD were studied. QT/QS2 ratio and systolic time intervals were calculated from poligraphic recordings taken at rest. In control subjects QT/QS2 ratio was significantly shorter (0.91 +/- 0.04) than in patients with double (0.95 +/- 0.07; p less than 0.05 versus control subjects) and triple vessel coronary artery disease (0.95 +/- 0.05; p less than 0.05 versus control subjects). QT/QS2 ratio was significantly higher (p less than 0.01) in patients with 3 areas or more of left ventricular abnormal wall motion (LV AWM) (0.98 +/- 0.05) than in patients with none (0.92 +/- 0.06) or just 1-2 areas (0.93 +/- 0.06) of LV AWM. Multiple regression analysis revealed no relation between the number of coronary stenoses and QT/QS2 (t = 0.86; p = NS), while a relation was identified between the number of asynergic segments and QT/QS2 (t = 1.99; p less than 0.05). A significant correlation was found between QT/QS2 and PEP/LVET (r = 0.39; p less than 0.001). Setting the upper normal limit at 2 standard deviations from the mean of control subjects (QT/QS2 = 0.99), QT/QS2 criterion yielded a 30% sensitivity, a 94% specificity and a 96% predictive accuracy in diagnosing CHD. We conclude that in CHD patients QT/QS2 ratio is influenced by the extension of LV AWM. Although a low sensitivity may limit its use, a QT/QS2 value higher than 0.99 in a patient with chest pain strongly suggests CHD and thus this criterion may be diagnostically useful. PMID:3243415

  4. Characterization of the human QT interval: novel distribution-based assessment of the repolarization effects of moxifloxacin.

    PubMed

    Holzgrefe, Henry H; Ferber, Georg; Morrison, Royce; Meyer, Olivier; Greiter-Wilke, Andrea; Singer, Thomas

    2012-08-01

    The authors have previously demonstrated rate-independent QT variability in the dog and cynomolgus monkey, where the QT associated with any RR was a normally distributed value that was accurately evaluated as the distribution mean. The present study investigated the rate-independent characteristics of the human QT. Digital electrocardiographs (1000 Hz) were collected for 24 hours in 51 patients (thorough QT study) and analyzed by computer. Distribution-based analysis was applied to the placebo and moxifloxacin (400 mg) arms to characterize the nature of the QT interval and to assess the efficacy of distribution-based analysis for QTc determination. Novel statistics using continuous means and bootstrapped 95% confidence intervals were developed to facilitate QT analysis. Machine-read QT values were compared with core laboratory semiautomated values for verification. RR intervals demonstrated repetitive protocol-dependent variations (50-250 milliseconds); QT intervals were normally distributed, spanning 60 to 100 milliseconds for each RR interval. Distribution-based analysis detected a moxifloxacin response identical to semiautomated analysis, but with reduced variability and improved statistical power, where n = 12 satisfied the ICH E14 criteria for a positive control. Distribution-based analysis has the potential to provide a universal method for clinical QT heart rate correction, enabling accurate detection of QT changes when limited numbers of volunteers are exposed to drug. PMID:21659628

  5. Fluency Disorders in Genetic Syndromes

    ERIC Educational Resources Information Center

    Van Borsel, John; Tetnowski, John A.

    2007-01-01

    The characteristics of various genetic syndromes have included "stuttering" as a primary symptom associated with that syndrome. Specifically, Down syndrome, fragile X syndrome, Prader-Willi syndrome, Tourette syndrome, Neurofibromatosis type I, and Turner syndrome all list "stuttering" as a characteristic of that syndrome. An extensive review of…

  6. In vivo synaptic transmission and morphology in mouse models of Tuberous sclerosis, Fragile X syndrome, Neurofibromatosis type 1, and Costello syndrome.

    PubMed

    Wang, Tiantian; de Kok, Laura; Willemsen, Rob; Elgersma, Ype; Borst, J Gerard G

    2015-01-01

    Defects in the rat sarcoma viral oncogene homolog (Ras)/extracellular-signal-regulated kinase and the phosphatidylinositol 3-kinase-mammalian target of rapamycin (mTOR) signaling pathways are responsible for several neurodevelopmental disorders. These disorders are an important cause for intellectual disability; additional manifestations include autism spectrum disorder, seizures, and brain malformations. Changes in synaptic function are thought to underlie the neurological conditions associated with these syndromes. We therefore studied morphology and in vivo synaptic transmission of the calyx of Held synapse, a relay synapse in the medial nucleus of the trapezoid body (MNTB) of the auditory brainstem, in mouse models of tuberous sclerosis complex (TSC), Fragile X syndrome (FXS), Neurofibromatosis type 1 (NF1), and Costello syndrome. Calyces from both Tsc1(+/-) and from Fmr1 knock-out (KO) mice showed increased volume and surface area compared to wild-type (WT) controls. In addition, in Fmr1 KO animals a larger fraction of calyces showed complex morphology. In MNTB principal neurons of Nf1 (+/) (-) mice the average delay between EPSPs and APs was slightly smaller compared to WT controls, which could indicate an increased excitability. Otherwise, no obvious changes in synaptic transmission, or short-term plasticity were observed during juxtacellular recordings in any of the four lines. Our results in these four mutants thus indicate that abnormalities of mTOR or Ras signaling do not necessarily result in changes in in vivo synaptic transmission. PMID:26190969

  7. In vivo synaptic transmission and morphology in mouse models of Tuberous sclerosis, Fragile X syndrome, Neurofibromatosis type 1, and Costello syndrome

    PubMed Central

    Wang, Tiantian; de Kok, Laura; Willemsen, Rob; Elgersma, Ype; Borst, J. Gerard G.

    2015-01-01

    Defects in the rat sarcoma viral oncogene homolog (Ras)/extracellular-signal-regulated kinase and the phosphatidylinositol 3-kinase-mammalian target of rapamycin (mTOR) signaling pathways are responsible for several neurodevelopmental disorders. These disorders are an important cause for intellectual disability; additional manifestations include autism spectrum disorder, seizures, and brain malformations. Changes in synaptic function are thought to underlie the neurological conditions associated with these syndromes. We therefore studied morphology and in vivo synaptic transmission of the calyx of Held synapse, a relay synapse in the medial nucleus of the trapezoid body (MNTB) of the auditory brainstem, in mouse models of tuberous sclerosis complex (TSC), Fragile X syndrome (FXS), Neurofibromatosis type 1 (NF1), and Costello syndrome. Calyces from both Tsc1+/- and from Fmr1 knock-out (KO) mice showed increased volume and surface area compared to wild-type (WT) controls. In addition, in Fmr1 KO animals a larger fraction of calyces showed complex morphology. In MNTB principal neurons of Nf1+/- mice the average delay between EPSPs and APs was slightly smaller compared to WT controls, which could indicate an increased excitability. Otherwise, no obvious changes in synaptic transmission, or short-term plasticity were observed during juxtacellular recordings in any of the four lines. Our results in these four mutants thus indicate that abnormalities of mTOR or Ras signaling do not necessarily result in changes in in vivo synaptic transmission. PMID:26190969

  8. Evaluation of drug-induced QT interval prolongation in animal and human studies: a literature review of concordance

    PubMed Central

    Vargas, Hugo M; Bass, Alan S; Koerner, John; Matis-Mitchell, Sherri; Pugsley, Michael K; Skinner, Matthew; Burnham, Matthew; Bridgland-Taylor, Matthew; Pettit, Syril; Valentin, Jean-Pierre

    2015-01-01

    Evaluating whether a new medication prolongs QT intervals is a critical safety activity that is conducted in a sensitive animal model during non-clinical drug development. The importance of QT liability detection has been reinforced by non-clinical [International Conference on Harmonization (ICH) S7B] and clinical (ICH E14) regulatory guidance from the International Conference on Harmonization. A key challenge for the cardiovascular safety community is to understand how the finding from a non-clinical in vivo QT assay in animals predicts the outcomes of a clinical QT evaluation in humans. The Health and Environmental Sciences Institute Pro-Arrhythmia Working Group performed a literature search (1960–2011) to identify both human and non-rodent animal studies that assessed QT signal concordance between species and identified drugs that prolonged or did not prolong the QT interval. The main finding was the excellent agreement between QT results in humans and non-rodent animals. Ninety-one percent (21 of 23) of drugs that prolonged the QT interval in humans also did so in animals, and 88% (15 of 17) of drugs that did not prolong the QT interval in humans had no effect on animals. This suggests that QT interval data derived from relevant non-rodent models has a 90% chance of predicting QT findings in humans. Disagreement can occur, but in the limited cases of QT discordance we identified, there appeared to be plausible explanations for the underlying disconnect between the human and non-rodent animal QT outcomes. PMID:26031452

  9. Evaluation of drug-induced QT interval prolongation in animal and human studies: a literature review of concordance.

    PubMed

    Vargas, Hugo M; Bass, Alan S; Koerner, John; Matis-Mitchell, Sherri; Pugsley, Michael K; Skinner, Matthew; Burnham, Matthew; Bridgland-Taylor, Matthew; Pettit, Syril; Valentin, Jean-Pierre

    2015-08-01

    Evaluating whether a new medication prolongs QT intervals is a critical safety activity that is conducted in a sensitive animal model during non-clinical drug development. The importance of QT liability detection has been reinforced by non-clinical [International Conference on Harmonization (ICH) S7B] and clinical (ICH E14) regulatory guidance from the International Conference on Harmonization. A key challenge for the cardiovascular safety community is to understand how the finding from a non-clinical in vivo QT assay in animals predicts the outcomes of a clinical QT evaluation in humans. The Health and Environmental Sciences Institute Pro-Arrhythmia Working Group performed a literature search (1960-2011) to identify both human and non-rodent animal studies that assessed QT signal concordance between species and identified drugs that prolonged or did not prolong the QT interval. The main finding was the excellent agreement between QT results in humans and non-rodent animals. Ninety-one percent (21 of 23) of drugs that prolonged the QT interval in humans also did so in animals, and 88% (15 of 17) of drugs that did not prolong the QT interval in humans had no effect on animals. This suggests that QT interval data derived from relevant non-rodent models has a 90% chance of predicting QT findings in humans. Disagreement can occur, but in the limited cases of QT discordance we identified, there appeared to be plausible explanations for the underlying disconnect between the human and non-rodent animal QT outcomes. PMID:26031452

  10. Influence of high ovarian hormones on QT interval duration in young African women

    PubMed Central

    Balayssac‐Siransy, Edwige; Ouattara, Soualiho; Adoubi, Anicet; Kouamé, Chantal; Hauhouot‐Attoungbré, Marie‐Laure; Dah, Cyrille; Bogui, Pascal

    2014-01-01

    Abstract The longer QT interval duration observed in women compared to men is usually attributed to sexual hormones. The aim of our study was to investigate, among black African women, the influence of hormonal variations during the menstrual cycle on the duration of the QT interval. Fourteen young black African women, healthy, sedentary, aged 24 ± 1.7 years, with a regular menstrual cycle (28 ± 1 days) were selected from 59 volunteers. At each phase of their menstrual cycle, menstrual 2.9 ± 0.6 days, follicular 13 ± 1.5 days, and luteal 23.1 ± 1.4 days, an electrocardiogram was performed in supine position after a resting period of 30 min, to measure QT interval duration. QT interval was corrected by Bazett's (QTcb) and Fridericia's (QTcf) formulae. Then, blood samples were obtained to measure estradiol, progesterone, and serum electrolytes (K+, Ca2+, Mg2+). There was no significant difference in uncorrected QT intervals between the three phases of the menstrual cycle. It was the same for QTcb and QTcf. Moreover, during the menstrual cycle, we did not observe any correlation between each QT, QTcb, QTcf, and estradiol levels which raised during the follicular phase (356.61 ± 160.77 pg/mL) and progesterone levels which raised during the luteal phase (16.38 ± 5.88 ng/mL). Finally, the method of Bland and Altman demonstrated that the corrections of QT by Bazett and Fridericia formulae were not interchangeable. The results of this study showed that high levels of estradiol and progesterone in young black African women did not influence the QT, QTcb and QTcf intervals duration during the menstrual cycle. PMID:24760517

  11. Association between Particulate Air Pollution and QT Interval Duration in an Elderly Cohort

    PubMed Central

    Mordukhovich, Irina; Kloog, Itai; Coull, Brent; Koutrakis, Petros; Vokonas, Pantel; Schwartz, Joel

    2016-01-01

    BACKGROUND Short-term fine particulate matter (PM2.5) exposure has been linked with increased QT interval duration, a marker of ventricular repolarization and a risk factor for cardiac arrhythmia and sudden death, in several studies. Only one previous study evaluated whether long-term PM exposure is related to the QT interval. We aim to evaluate whether sub-chronic and long-term exposure to PM2.5 at home is linked with QT duration in an elderly cohort. METHODS We measured heart-rate corrected QT interval duration among 404 participants from the Greater Boston area between 2003 and 2011. We modeled residential PM2.5 exposures using a hybrid satellite- and land use-based model. We evaluated associations between moving averages of short-term (1–2 day), sub-chronic (3–28 day) and long-term (1 year) pollutant exposures and corrected QT duration using linear mixed models. We also evaluated effect modification by oxidative stress genetic score using separated regression models and interaction terms. RESULTS We observed positive associations between sub-chronic and long-term PM2.5 exposure and corrected QT duration, with the strongest results for longer-term exposures. For example, a 1 standard deviation increase in 1-year PM2.5 was associated with a 6.3 ms increase in corrected QT (95% confidence interval: 1.8, 11). We observed somewhat greater effects among subjects with higher (8.5 ms) rather than lower (3.1 ms) oxidative stress allelic profiles (p-interaction=0.25). CONCLUSIONS PM2.5 was associated with increased corrected QT duration in an elderly cohort. While most previous studies focused on short-term air pollution exposures, our results suggest that longer-term exposures are associated with cardiac repolarization. PMID:26605812

  12. QT prolongation and sudden cardiac death in patients with alcoholic liver disease

    SciTech Connect

    Day, C.P.; James, O.F.W. . Dept. of Medicine); Butler, T.J. . Dept. of Medical Statistics); Campbell, R.W.F. . Dept. of Academic Cardiology)

    1993-06-05

    Cardiovascular death is the most important cause of mortality in alcoholics, yet alcohol may protect against ischemic heart disease. This could be explained if deaths were a consequence of alcohol-related arrhythmias rather than of coronary atheroma. In many conditions, abnormalities of the QT interval are markers of arrhythmia and for risk of sudden death. The authors examined the relation between QT intervals and mortality in patients with alcoholic liver disease.

  13. Rare coding TTN variants are associated with electrocardiographic QT interval in the general population

    PubMed Central

    Kapoor, Ashish; Bakshy, Kiranmayee; Xu, Linda; Nandakumar, Priyanka; Lee, Dongwon; Boerwinkle, Eric; Grove, Megan L.; Arking, Dan E.; Chakravarti, Aravinda

    2016-01-01

    We have shown previously that noncoding variants mapping around a specific set of 170 genes encoding cardiomyocyte intercalated disc (ID) proteins are more enriched for associations with QT interval than observed for genome-wide comparisons. At a false discovery rate (FDR) of 5%, we had identified 28 such ID protein-encoding genes. Here, we assessed whether coding variants at these 28 genes affect QT interval in the general population as well. We used exome sequencing in 4,469 European American (EA) and 1,880 African American (AA) ancestry individuals from the population-based ARIC (Atherosclerosis Risk In Communities) Study cohort to focus on rare (allele frequency <1%) potentially deleterious (nonsynonymous, stop-gain, splice) variants (n = 2,398 for EA; n = 1,693 for AA) and tested their effects on standardized QT interval residuals. We identified 27 nonsynonymous variants associated with QT interval (FDR 5%), 22 of which were in TTN. Taken together with the mapping of a QT interval GWAS locus near TTN, our observation of rare deleterious coding variants in TTN associated with QT interval show that TTN plays a role in regulation of cardiac electrical conductance and coupling, and is a risk factor for cardiac arrhythmias and sudden cardiac death. PMID:27321809

  14. Reevaluation of moxifloxacin pharmacokinetics and their direct effect on the QT interval.

    PubMed

    Grosjean, Philippe; Urien, Saïk

    2012-03-01

    The objectives of this study were to investigate the population pharmacokinetics of moxifloxacin and their relationship with the observed QT interval as well as the effect of covariates in healthy subjects using nonlinear mixed-effects modeling. A pool of 4 thorough QT studies were used, representing 99 healthy subjects who received moxifloxacin. The data were modeled using Monolix. Moxifloxacin pharmacokinetics were ascribed a 2- compartment open model. The TRANSIT model provided a better description of the delay in absorption than did the LAG model. The most significant covariate was lean body mass (LBM). The population estimates for clearance and central volume of distribution were 10.0 L/h per 60 kg of LBM and 131 L per 60 kg of LBM, respectively. The effect of moxifloxacin on QT was investigated using a direct effect model. The SLOPE model, relating the QT increase as a linear function of concentration, provided a better description of the pharmacodynamic effect than did the Emax model. The unique covariate was gender for both baseline QT and individual heart rate correction factor. The pharmacokinetics of moxifloxacin were satisfactorily described by an open 2-compartmental model with linear elimination. The trigonometric equation with a direct and proportional concentration effect satisfactorily described the effect on QT. PMID:21415283

  15. Rare coding TTN variants are associated with electrocardiographic QT interval in the general population.

    PubMed

    Kapoor, Ashish; Bakshy, Kiranmayee; Xu, Linda; Nandakumar, Priyanka; Lee, Dongwon; Boerwinkle, Eric; Grove, Megan L; Arking, Dan E; Chakravarti, Aravinda

    2016-01-01

    We have shown previously that noncoding variants mapping around a specific set of 170 genes encoding cardiomyocyte intercalated disc (ID) proteins are more enriched for associations with QT interval than observed for genome-wide comparisons. At a false discovery rate (FDR) of 5%, we had identified 28 such ID protein-encoding genes. Here, we assessed whether coding variants at these 28 genes affect QT interval in the general population as well. We used exome sequencing in 4,469 European American (EA) and 1,880 African American (AA) ancestry individuals from the population-based ARIC (Atherosclerosis Risk In Communities) Study cohort to focus on rare (allele frequency <1%) potentially deleterious (nonsynonymous, stop-gain, splice) variants (n = 2,398 for EA; n = 1,693 for AA) and tested their effects on standardized QT interval residuals. We identified 27 nonsynonymous variants associated with QT interval (FDR 5%), 22 of which were in TTN. Taken together with the mapping of a QT interval GWAS locus near TTN, our observation of rare deleterious coding variants in TTN associated with QT interval show that TTN plays a role in regulation of cardiac electrical conductance and coupling, and is a risk factor for cardiac arrhythmias and sudden cardiac death. PMID:27321809

  16. Acute Kidney Injury in Cardiorenal Syndrome Type 1 Patients: A Systematic Review and Meta-Analysis

    PubMed Central

    Vandenberghe, Wim; Gevaert, Sofie; Kellum, John A.; Bagshaw, Sean M.; Peperstraete, Harlinde; Herck, Ingrid; Decruyenaere, Johan; Hoste, Eric A.J.

    2016-01-01

    Background We evaluated the epidemiology and outcome of acute kidney injury (AKI) in patients with cardiorenal syndrome type 1 (CRS-1) and its subgroups: acute heart failure (AHF), acute coronary syndrome (ACS) and after cardiac surgery (CS). Summary We performed a systematic review and meta-analysis. CRS-1 was defined by AKI (based on RIFLE, AKIN and KDIGO), worsening renal failure (WRF) and renal replacement therapy (RRT). We investigated the three most common clinical causes of CRS-1: AHF, ACS and CS. Out of 332 potential papers, 64 were eligible - with AKI used in 41 studies, WRF in 25 and RRT in 20. The occurrence rate of CRS-1, defined by AKI, WRF and RRT, was 25.4, 22.4 and 2.6%, respectively. AHF patients had a higher occurrence rate of CRS-1 compared to ACS and CS patients (AKI: 47.4 vs. 14.9 vs. 22.1%), but RRT was evenly distributed among the types of acute cardiac disease. AKI was associated with an increased mortality rate (risk ratio = 5.14, 95% CI 3.81-6.94; 24 studies and 35,227 patients), a longer length of stay in the intensive care unit [LOSICU] (median duration = 1.37 days, 95% CI 0.41-2.33; 9 studies and 10,758 patients) and a longer LOS in hospital [LOShosp] (median duration = 3.94 days, 95% CI 1.74-6.15; 8 studies and 35,227 patients). Increasing AKI severity was associated with worse outcomes. The impact of CRS-1 defined by AKI on mortality was greatest in CS patients. RRT had an even greater impact compared to AKI (mortality risk ratio = 9.2, median duration of LOSICU = 10.6 days and that of LOShosp = 20.2 days). Key Messages Of all included patients, almost one quarter developed AKI and approximately 3% needed RRT. AHF patients experienced the highest occurrence rate of AKI, but the impact on mortality was greatest in CS patients. PMID:26989397

  17. Presymptomatic genetic analysis during pregnancy for vascular type Ehlers-Danlos syndrome.

    PubMed

    Naing, Banyar Than; Watanabe, Atsushi; Tanigaki, Shinji; Ono, Masae; Iwashita, Mitsutoshi; Shimada, Takashi

    2014-01-01

    The vascular type of Ehlers-Danlos syndrome (EDS), EDS type IV (Online Mendelian Inheritance in Man [MIM] #130050) is characterized by thin, translucent skin, easy bruising, and arterial, intestinal, and/or uterine fragility during pregnancy, which may lead to sudden death. It is an autosomal dominant inherited disorder caused by type III procollagen gene (COL3A1: MIM #120180) mutations. Approximately 50% of the COL3A1 mutations are inherited from an affected parent, and 50% are de novo mutations. Each child of an affected individual has a 50% chance of inheriting the mutation and developing the disorder. Pregnant women with vascular EDS are at an increased risk of uterine and arterial rupture during the peripartum period, with high maternal morbidity and mortality rates. We report the first case of an asymptomatic 35-year-old woman at a risk of complications of vascular EDS who underwent presymptomatic evaluation during pregnancy. The sequencing results of both her brother and mother had a one-base-pair deletion, resulting in Glutamate at position 730 changing to Lysine and causing a frame shift and premature termination codon at 61 amino acids from the mutation position (p. Glu730Lysfs*61) on exon 32 of COL3A1. This deletion caused frameshift, leading to a premature termination codon (TAG) at 181 nucleotides downstream in exon 35, which could not be detected by previous total RNA (ribonucleic acid) method. Thus, she was at risk of complications of vascular EDS, and diagnostic testing was employed at 8 weeks of pregnancy to minimize the risk of developing vascular EDS-related complications. The negative presymptomatic diagnostic result allowed the patient to choose normal delivery at term. Vascular EDS is a serious disorder, with high mortality, especially in high-risk women with vascular EDS during pregnancy. The presymptomatic genetic testing of vascular EDS during pregnancy for a high-risk family can help with the early establishment of preventive measures

  18. The phenotype of the musculocontractural type of Ehlers-Danlos syndrome due to CHST14 mutations.

    PubMed

    Janecke, Andreas R; Li, Ben; Boehm, Manfred; Krabichler, Birgit; Rohrbach, Marianne; Müller, Thomas; Fuchs, Irene; Golas, Gretchen; Katagiri, Yasuhiro; Ziegler, Shira G; Gahl, William A; Wilnai, Yael; Zoppi, Nicoletta; Geller, Herbert M; Giunta, Cecilia; Slavotinek, Anne; Steinmann, Beat

    2016-01-01

    The musculocontractural type of Ehlers-Danlos syndrome (MC-EDS) has been recently recognized as a clinical entity. MC-EDS represents a differential diagnosis within the congenital neuromuscular and connective tissue disorders spectrum. Thirty-one and three patients have been reported with MC-EDS so far with bi-allelic mutations identified in CHST14 and DSE, respectively, encoding two enzymes necessary for dermatan sulfate (DS) biosynthesis. We report seven additional patients with MC-EDS from four unrelated families, including the follow-up of a sib-pair originally reported with the kyphoscoliotic type of EDS in 1975. Brachycephaly, a characteristic facial appearance, an asthenic build, hyperextensible and bruisable skin, tapering fingers, instability of large joints, and recurrent formation of large subcutaneous hematomas are always present. Three of seven patients had mildly elevated serum creatine kinase. The oldest patient was blind due to retinal detachment at 45 years and died at 59 years from intracranial bleeding; her affected brother died at 28 years from fulminant endocarditis. All patients in this series harbored homozygous, predicted loss-of-function CHST14 mutations. Indeed, DS was not detectable in fibroblasts from two unrelated patients with homozygous mutations. Patient fibroblasts produced higher amounts of chondroitin sulfate, showed intracellular retention of collagen types I and III, and lacked decorin and thrombospondin fibrils compared with control. A great proportion of collagen fibrils were not integrated into fibers, and fiber bundles were dispersed into the ground substance in one patient, all of which is likely to contribute to the clinical phenotype. This report should increase awareness for MC-EDS. PMID:26373698

  19. A Type A and Type D Combined Personality Typology in Essential Hypertension and Acute Coronary Syndrome Patients: Associations with Demographic, Psychological, Clinical, and Lifestyle Indicators.

    PubMed

    Steca, Patrizia; D'Addario, Marco; Magrin, Maria Elena; Miglioretti, Massimo; Monzani, Dario; Pancani, Luca; Sarini, Marcello; Scrignaro, Marta; Vecchio, Luca; Fattirolli, Francesco; Giannattasio, Cristina; Cesana, Francesca; Riccobono, Salvatore Pio; Greco, Andrea

    2016-01-01

    Many studies have focused on Type A and Type D personality types in the context of cardiovascular diseases (CVDs), but nothing is known about how these personality types combine to create new profiles. The present study aimed to develop a typology of Type A and Type D personality in two groups of patients affected by and at risk for coronary disease. The study involved 711 patients: 51.6% with acute coronary syndrome, 48.4% with essential hypertension (mean age = 56.4 years; SD = 9.7 years; 70.7% men). Cluster analysis was applied. External variables, such as socio-demographic, psychological, lifestyle, and clinical parameters, were assessed. Six groups, each with its own unique combined personality profile scores, were identified: Type D, Type A-Negatively Affected, Not Type A-Negatively Affected, Socially Inhibited-Positively Affected, Not Socially Inhibited, and Not Type A-Not Type D. The Type A-Negatively Affected cluster and, to a lesser extent, the Type D cluster, displayed the worst profile: namely higher total cardiovascular risk index, physical inactivity, higher anxiety and depression, and lower self-esteem, optimism, and health status. Identifying combined personality profiles is important in clinical research and practice in cardiovascular diseases. Practical implications are discussed. PMID:27589065

  20. A new technique to determine the correlation between the QT interval and heart-rate for control and SIDS babies

    NASA Technical Reports Server (NTRS)

    Sadeh, D.; Shannon, D. C.; Abboud, S.; Akselrod, S.; Cohen, R. J.

    1987-01-01

    The ability of the autonomic nervous system to alter the QT interval in response to heart rate changes is essential to cardiovascular control. An accurate way to determine the relation between QT intervals and their corresponding RR intervals is described. A computer algorithm measures the RR intervals using digital filtering and cross-correlating the QRS sections of consecutive waveforms. The QT intervals is calculated by choosing a section of, the ECG that includes the T wave and cross-correlating it with all the consecutive T waves. At least 4000 pairs of QT-RR intervals are computed for each subject and a best fit correlation function determines the relations between the QT and RR intervals. This technique enables to establish a precise correlation between RR and QT in order to distinguish between control and SIDS babies.

  1. Surgical treatment for mitral stenosis in Scheie's syndrome: mucopolysaccharidosis type I-S.

    PubMed

    Kitabayashi, Katsukiyo; Matsumiya, Goro; Ichikawa, Hajime; Matsue, Hajime; Shimamura, Kazuo; Sawa, Yoshiki

    2007-08-01

    Scheie's syndrome is a subtype of mucopolysaccharidosis, which is a rare hereditary disorder of proteoglycan degrading enzymes. Deposition of mucopolysaccharide often causes cardiac disease, especially valvular lesion, but reports of its surgical treatment have been rare. We report a case of 41-year-old woman with Scheie's syndrome who successfully underwent mitral valve replacement for mitral stenosis. PMID:17643657

  2. Cinnamon: potential role in the prevention of insulin resistance, metabolic syndrome, and type 2 diabetes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The metabolic syndrome is associated with insulin resistance, elevated glucose and lipids, inflammation, decreased antioxidant activity, increased weight gain, and increased glycation of proteins. Cinnamon has been shown to improve aspects of metabolic syndrome in cells cultured in vitro, and in an...

  3. Proteome-wide survey of the autoimmune target repertoire in autoimmune polyendocrine syndrome type 1.

    PubMed

    Landegren, Nils; Sharon, Donald; Freyhult, Eva; Hallgren, Åsa; Eriksson, Daniel; Edqvist, Per-Henrik; Bensing, Sophie; Wahlberg, Jeanette; Nelson, Lawrence M; Gustafsson, Jan; Husebye, Eystein S; Anderson, Mark S; Snyder, Michael; Kämpe, Olle

    2016-01-01

    Autoimmune polyendocrine syndrome type 1 (APS1) is a monogenic disorder that features multiple autoimmune disease manifestations. It is caused by mutations in the Autoimmune regulator (AIRE) gene, which promote thymic display of thousands of peripheral tissue antigens in a process critical for establishing central immune tolerance. We here used proteome arrays to perform a comprehensive study of autoimmune targets in APS1. Interrogation of established autoantigens revealed highly reliable detection of autoantibodies, and by exploring the full panel of more than 9000 proteins we further identified MAGEB2 and PDILT as novel major autoantigens in APS1. Our proteome-wide assessment revealed a marked enrichment for tissue-specific immune targets, mirroring AIRE's selectiveness for this category of genes. Our findings also suggest that only a very limited portion of the proteome becomes targeted by the immune system in APS1, which contrasts the broad defect of thymic presentation associated with AIRE-deficiency and raises novel questions what other factors are needed for break of tolerance. PMID:26830021

  4. A case of variant biochemical phenotype of Niemann-Pick disease type C accompanying savant syndrome.

    PubMed

    Hamatani, Mio; Jingami, Naoto; Uemura, Kengo; Nakasone, Naoe; Kinoshita, Hisanori; Yamakado, Hodaka; Ninomiya, Haruaki; Takahashi, Ryosuke

    2016-06-22

    A 40-year-old man was referred to our hospital because of vertical supranuclear gaze palsy, frequent sudden loss of muscle tonus and ataxia for several years. He had a history of prolonged neonatal jaundice. He was given a diagnosis of autism in his childhood, followed by a diagnosis of schizophrenia in his teenage. He also developed a savant skill of calendar calculating. (123)I-IMP-SPECT showed decreased cerebral blood flow in the left frontotemporal lobe as often seen in savant syndrome. Although genetic analysis of NPC1 and NPC2 revealed no pathogenic mutation, filipin staining of cultured fibroblasts from his biopsied skin revealed a certain amount of intracellular cholesterol storage pattern, indicating a variant biochemical phenotype of Niemann-Pick disease type C (NPC). The diagnosis of adulthood onset NPC is difficult and challenging, especially for neurologists, because the symptoms and signs are not as clear as those in the classical childhood onset NPC and this subtype is not yet widely known. However, the diagnosis can be made by a combination of filipin staining of fibroblast and/or gene analysis. As a disease-specific therapy for NPC has been approved in Japan, the diagnosis of NPC is of significance. PMID:27181747

  5. Ehlers-Danlos syndrome, hypermobility type: A characterization of the patients' lived experience.

    PubMed

    Murray, Brittney; Yashar, Beverly M; Uhlmann, Wendy R; Clauw, Daniel J; Petty, Elizabeth M

    2013-12-01

    Hypermobility type Ehlers-Danlos syndrome (EDS-HT) is an inherited connective tissue disorder clinically diagnosed by the presence of significant joint hypermobility and associated skin manifestations. This article presents a large-scale study that reports the lived experience of EDS-HT patients, the broad range of symptoms that individuals with EDS-HT experience, and the impact these symptoms have on daily functioning. A 237-item online survey, including validated questions regarding pain and depression, was developed. Four hundred sixty-six (466) adults (90% female, 52% college or higher degree) with a self-reported diagnosis of EDS-HT made in a clinic or hospital were included. The most frequently reported symptoms were joint pain (99%), hypermobility (99%), and limb pain (91%). They also reported a high frequency of other conditions including chronic fatigue (82%), anxiety (73%), depression (69%), and fibromyalgia (42%). Forty-six percent of respondents reported constant pain often described as aching and tiring/exhausting. Despite multiple interventions and therapies, many individuals (53%) indicated that their diagnosis negatively affected their ability to work or attend school. Our results show that individuals with EDS-HT can experience a wide array of symptoms and co-morbid conditions. The degree of constant pain and disability experienced by the majority of EDS-HT respondents is striking and illustrates the impact this disorder has on quality of life as well as the clinical challenges inherent in managing this complex connective tissue disorder. PMID:24254846

  6. Management of spontaneous colonic perforation in Ehlers-Danlos syndrome type IV.

    PubMed

    Fuchs, Julie R; Fishman, Steven J

    2004-02-01

    A 14-year-old girl with a family history of fatal colonic rupture, presented with a 2-day history of abdominal pain and signs of peritonitis. At laparotomy, a full-thickness perforation of the sigmoid colon was found, which was exteriorized as a loop colostomy. Subsequently, molecular studies of the patient's cultured fibroblasts found a point mutation in the COL3A1 gene, confirming a diagnosis of Ehlers-Danlos syndrome type IV (EDS-IV). Four and a half years later, a total abdominal colectomy and ileoproctostomy were performed, restoring intestinal continuity. At 5 years follow-up, the patient has had no further complications. Although spontaneous colonic perforation is a well-reported manifestation of EDS-IV, a consensus on the surgical management of this complication in EDS-IV has yet to be determined. Given the high rate of reperforation in EDS-IV when the colon is left in place and the low incidence of reported small bowel and rectal perforations, subtotal colectomy is a reasonable treatment. Primary anastomosis and avoidance of an end-ileostomy was possible in this young patient, with no evidence of anastomotic leakage nor reperforation to date. Lifelong close follow-up should be continued in these patients, because the natural history of this anatomy in EDS-IV is not known. PMID:14966763

  7. Genetic and phenotypic heterogeneity in Chinese patients with Waardenburg syndrome type II.

    PubMed

    Yang, Shuzhi; Dai, Pu; Liu, Xin; Kang, Dongyang; Zhang, Xin; Yang, Weiyan; Zhou, Chengyong; Yang, Shiming; Yuan, Huijun

    2013-01-01

    Waardenburg Syndrome (WS) is an autosomal-dominant disorder characterized by sensorineural hearing loss and pigmentary abnormalities of the eyes, hair, and skin. Microphthalmia-associated transcription factor (MITF) gene mutations account for about 15% of WS type II (WS2) cases. To date, fewer than 40 different MITF gene mutations have been identified in human WS2 patients, and few of these were of Chinese descent. In this study, we report clinical findings and mutation identification in the MITF gene of 20 Chinese WS2 patients from 14 families. A high level of clinical variability was identified. Sensorineural hearing loss (17/20, 85.0%) and heterochromia iridum (20/20, 100.0%) were the most commonly observed clinical features in Chinese WS2 patients. Five affected individuals (5/20, 25.0%) had numerous brown freckles on the face, trunk, and limb extremities. Mutation screening of the MITF gene identified five mutations: c.20A>G, c.332C>T, c.647_649delGAA, c.649A>G, and c.763C>T. The total mutational frequency of the MITF gene was 21.4% (3/14), which is significantly higher than the 15.0% observed in the fair-skinned WS2 population. Our results indicate that MITF mutations are relatively common among Chinese WS2 patients. PMID:24194866

  8. Screening of MITF and SOX10 regulatory regions in Waardenburg syndrome type 2.

    PubMed

    Baral, Viviane; Chaoui, Asma; Watanabe, Yuli; Goossens, Michel; Attie-Bitach, Tania; Marlin, Sandrine; Pingault, Veronique; Bondurand, Nadege

    2012-01-01

    Waardenburg syndrome (WS) is a rare auditory-pigmentary disorder that exhibits varying combinations of sensorineural hearing loss and pigmentation defects. Four subtypes are clinically defined based on the presence or absence of additional symptoms. WS type 2 (WS2) can result from mutations within the MITF or SOX10 genes; however, 70% of WS2 cases remain unexplained at the molecular level, suggesting that other genes might be involved and/or that mutations within the known genes escaped previous screenings. The recent identification of a deletion encompassing three of the SOX10 regulatory elements in a patient presenting with another WS subtype, WS4, defined by its association with Hirschsprung disease, led us to search for deletions and point mutations within the MITF and SOX10 regulatory elements in 28 yet unexplained WS2 cases. Two nucleotide variations were identified: one in close proximity to the MITF distal enhancer (MDE) and one within the U1 SOX10 enhancer. Functional analyses argued against a pathogenic effect of these variations, suggesting that mutations within regulatory elements of WS genes are not a major cause of this neurocristopathy. PMID:22848661

  9. Alveolar Type II Epithelial Cell Dysfunction in Rat Experimental Hepatopulmonary Syndrome (HPS)

    PubMed Central

    Yang, Wenli; Hu, Bingqian; Wu, Wei; Batra, Sachin; Blackburn, Michael R.; Alcorn, Joseph L.; Fallon, Michael B.; Zhang, Junlan

    2014-01-01

    The hepatopulmonary syndrome (HPS) develops when pulmonary vasodilatation leads to abnormal gas exchange. However, in human HPS, restrictive ventilatory defects are also observed supporting that the alveolar epithelial compartment may also be affected. Alveolar type II epithelial cells (AT2) play a critical role in maintaining the alveolar compartment by producing four surfactant proteins (SPs, SP-A, SP-B, SP-C and SP-D) which also facilitate alveolar repair following injury. However, no studies have evaluated the alveolar epithelial compartment in experimental HPS. In this study, we evaluated the alveolar epithelial compartment and particularly AT2 cells in experimental HPS induced by common bile duct ligation (CBDL). We found a significant reduction in pulmonary SP production associated with increased apoptosis in AT2 cells after CBDL relative to controls. Lung morphology showed decreased mean alveolar chord length and lung volumes in CBDL animals that were not seen in control models supporting a selective reduction of alveolar airspace. Furthermore, we found that administration of TNF-α, the bile acid, chenodeoxycholic acid, and FXR nuclear receptor activation (GW4064) induced apoptosis and impaired SP-B and SP-C production in alveolar epithelial cells in vitro. These results imply that AT2 cell dysfunction occurs in experimental HPS and is associated with alterations in the alveolar epithelial compartment. Our findings support a novel contributing mechanism in experimental HPS that may be relevant to humans and a potential therapeutic target. PMID:25419825

  10. Successful vaginal birth after caesarean section in patient with Ehler-Danlos syndrome type 2

    PubMed Central

    Maraj, Hemant; Mohajer, Michelle; Bhattacharjee, Deepannita

    2011-01-01

    We present the case of a 31-year-old woman with Ehler-Danlos syndrome (EDS) type 2. She had a previous caesarean section and went on to have an uncomplicated vaginal birth in her last pregnancy. To our knowledge, this is the first case of a successful vaginal birth after caesarean section in a patient with EDS. EDS is a multisystem disorder involving a genetic defect in collagen and connective-tissue synthesis and structure. It is a heterogeneous group of 11 different inherited disorders. Obstetric complications in these patients include miscarriages, stillbirths, premature rupture of the membranes, preterm labour, uterine prolapse, uterine rupture and severe postpartum haemorrhage. There has been much controversy over the appropriate mode of delivery. Abdominal deliveries are complicated by delayed wound healing and increased perioperative blood loss. Vaginal deliveries may be complicated by tissue friability causing extensive perineal tears, pelvic floor and bladder lesions. Our case highlights that in specific, controlled situations it is possible to have a vaginal delivery even after previous caesarean section in patients with EDS.

  11. Augmented noncanonical BMP type II receptor signaling mediates the synaptic abnormality of fragile X syndrome.

    PubMed

    Kashima, Risa; Roy, Sougata; Ascano, Manuel; Martinez-Cerdeno, Veronica; Ariza-Torres, Jeanelle; Kim, Sunghwan; Louie, Justin; Lu, Yao; Leyton, Patricio; Bloch, Kenneth D; Kornberg, Thomas B; Hagerman, Paul J; Hagerman, Randi; Lagna, Giorgio; Hata, Akiko

    2016-01-01

    Epigenetic silencing of fragile X mental retardation 1 (FMR1) causes fragile X syndrome (FXS), a common inherited form of intellectual disability and autism. FXS correlates with abnormal synapse and dendritic spine development, but the molecular link between the absence of the FMR1 product FMRP, an RNA binding protein, and the neuropathology is unclear. We found that the messenger RNA encoding bone morphogenetic protein type II receptor (BMPR2) is a target of FMRP. Depletion of FMRP increased BMPR2 abundance, especially that of the full-length isoform that bound and activated LIM domain kinase 1 (LIMK1), a component of the noncanonical BMP signal transduction pathway that stimulates actin reorganization to promote neurite outgrowth and synapse formation. Heterozygosity for BMPR2 rescued the morphological abnormalities in neurons both in Drosophila and in mouse models of FXS, as did the postnatal pharmacological inhibition of LIMK1 activity. Compared with postmortem prefrontal cortex tissue from healthy subjects, the amount of full-length BMPR2 and of a marker of LIMK1 activity was increased in this brain region from FXS patients. These findings suggest that increased BMPR2 signal transduction is linked to FXS and that the BMPR2-LIMK1 pathway is a putative therapeutic target in patients with FXS and possibly other forms of autism. PMID:27273096

  12. Proteome-wide survey of the autoimmune target repertoire in autoimmune polyendocrine syndrome type 1

    PubMed Central

    Landegren, Nils; Sharon, Donald; Freyhult, Eva; Hallgren, Åsa; Eriksson, Daniel; Edqvist, Per-Henrik; Bensing, Sophie; Wahlberg, Jeanette; Nelson, Lawrence M.; Gustafsson, Jan; Husebye, Eystein S.; Anderson, Mark S.; Snyder, Michael; Kämpe, Olle

    2016-01-01

    Autoimmune polyendocrine syndrome type 1 (APS1) is a monogenic disorder that features multiple autoimmune disease manifestations. It is caused by mutations in the Autoimmune regulator (AIRE) gene, which promote thymic display of thousands of peripheral tissue antigens in a process critical for establishing central immune tolerance. We here used proteome arrays to perform a comprehensive study of autoimmune targets in APS1. Interrogation of established autoantigens revealed highly reliable detection of autoantibodies, and by exploring the full panel of more than 9000 proteins we further identified MAGEB2 and PDILT as novel major autoantigens in APS1. Our proteome-wide assessment revealed a marked enrichment for tissue-specific immune targets, mirroring AIRE’s selectiveness for this category of genes. Our findings also suggest that only a very limited portion of the proteome becomes targeted by the immune system in APS1, which contrasts the broad defect of thymic presentation associated with AIRE-deficiency and raises novel questions what other factors are needed for break of tolerance. PMID:26830021

  13. Cognitive skills and reading in adults with Usher syndrome type 2

    PubMed Central

    Henricson, Cecilia; Lidestam, Björn; Lyxell, Björn; Möller, Claes

    2015-01-01

    Objective: To investigate working memory (WM), phonological skills, lexical skills, and reading comprehension in adults with Usher syndrome type 2 (USH2). Design: The participants performed tests of phonological processing, lexical access, WM, and reading comprehension. The design of the test situation and tests was specifically considered for use with persons with low vision in combination with hearing impairment. The performance of the group with USH2 on the different cognitive measures was compared to that of a matched control group with normal hearing and vision (NVH). Study Sample: Thirteen participants with USH2 aged 21–60 years and a control group of 10 individuals with NVH, matched on age and level of education. Results: The group with USH2 displayed significantly lower performance on tests of phonological processing, and on measures requiring both fast visual judgment and phonological processing. There was a larger variation in performance among the individuals with USH2 than in the matched control group. Conclusion: The performance of the group with USH2 indicated similar problems with phonological processing skills and phonological WM as in individuals with long-term hearing loss. The group with USH2 also had significantly longer reaction times, indicating that processing of visual stimuli is difficult due to the visual impairment. These findings point toward the difficulties in accessing information that persons with USH2 experience, and could be part of the explanation of why individuals with USH2 report high levels of fatigue and feelings of stress (Wahlqvist et al., 2013). PMID:25859232

  14. Molecular findings of Colombian patients with type VI mucopolysaccharidosis (Maroteaux–Lamy syndrome)

    PubMed Central

    Giraldo, Gustavo Adolfo; Ayala-Ramírez, Paola; Prieto, Juan Carlos; García-Robles, Reggie; Acosta, Johanna Carolina

    2015-01-01

    Introduction Maroteaux–Lamy syndrome, or mucopolysaccharidosis (MPS) type VI, is an autosomal recessive lysosomal storage disease caused by a deficient activity of the enzyme arylsulfatase B (ARSB), required to degrade dermatan sulfate. The onset and progression of the disease vary, producing a spectrum of clinical presentation. So far, 133 mutations have been reported. The aim of this study is to determine the mutations in the ARSB gene that are responsible for this disease in Colombian patients. Results Fourteen patients with clinical manifestations and biochemical diagnosis of MPS VI were studied, including two siblings. The 8 exons of the gene were directly sequenced from patients' DNA, and 14 mutations were found. 57% of these mutations had not been previously reported (p.H111P, p.C121R, p.G446S, p.*534W, p.S334I, p.H147P, c.900T > G, and c.1531_1553del) and 43% had been previously reported (p.G144R, p.W322*, p.G302R, p.C447F, p.L128del, and c.1143-1G > C). Of the previously reported mutations, 80% have been associated with severe phenotypes and 20% with intermediate-severe phenotypes. Bioinformatic predictions indicate that the new mutations reported in this paper are also highly deleterious. Conclusions Most of the Colombian patients in this study had private mutations. PMID:26909334

  15. Is This Symptom Even a Food Allergy?: Clinical Types of Food Protein-induced Enterocolitis Syndrome

    PubMed Central

    2014-01-01

    Food protein-induced enterocolitis syndrome (FPIES) is an under-recognized non-IgE-mediated gastrointestinal food allergy. The diagnosis of FPIES is based on clinical history, sequential symptoms and the timing, after excluding other possible causes. It is definitively diagnosed by an oral food challenge test. Unfortunately, the diagnosis of FPIES is frequently delayed because of non-specific symptoms and insufficient definitive diagnostic biomarkers. FPIES is not well recognized by clinicians; the affected infants are often mismanaged as having viral gastroenteritis, food poisoning, sepsis, or a surgical disease. Familiarity with the clinical features of FPIES and awareness of the indexes of suspicion for FPIES are important to diagnose FPIES. Understanding the recently defined clinical terms and types of FPIES is mandatory to suspect and correctly diagnose FPIES. The aim of this review is to provide a case-driven presentation as a guide of how to recognize the clinical features of FPIES to improve diagnosis and management of patients with FPIES. PMID:25061581

  16. Linkage analysis in Usher syndrome type I (USH1) families from Spain.

    PubMed Central

    Espinós, C; Nájera, C; Millán, J M; Ayuso, C; Baiget, M; Pérez-Garrigues, H; Rodrigo, O; Vilela, C; Beneyto, M

    1998-01-01

    Usher syndrome (USH) is an autosomal recessive hereditary disorder characterised by congenital sensorineural hearing loss and gradual visual impairment secondary to retinitis pigmentosa (RP). The disorder is clinically and genetically heterogeneous. With regard to Usher type I (USH1), several subtypes have been described, the most frequent being USH1B located on chromosome 11q13.5. Of 18 USH1 families studied by linkage analysis, 12 (67%) showed significant lod score values for locus D11S527 (Zmax=14.032, theta=0.000) situated on chromosome 11q. Our findings suggest considerable genetic heterogeneity in the Spanish USH1 population. It is important to note that one of our families linked to the USH1B locus shows interesting intrafamilial clinical variability. As regards the remaining six USH1 families, the linkage analysis did not provide conclusive data, although two of them show slight linkage to markers located on chromosome 3q (Zmax=1.880, theta=0.000 for D3S1279), the same location that had previously been assigned to some USH3 families. Images PMID:9610802

  17. Sleep apnea-hypopnea syndrome and type 2 diabetes. A reciprocal relationship?

    PubMed

    Martínez Cerón, Elisabet; Casitas Mateos, Raquel; García-Río, Francisco

    2015-03-01

    Epidemiological data suggest that sleep apnea-hypopnea syndrome (SAHS) is independently associated with the development of insulin resistance and glucose intolerance. Moreover, despite significant methodological limitations, some studies report a high prevalence of SAHS in patients with type 2 diabetes mellitus (DM2). A recent meta-analysis shows that moderate-severe SAHS is associated with an increased risk of DM2 (relative risk=1.63 [1.09 to 2.45]), compared to the absence of apneas and hypopneas. Common alterations in various pathogenic pathways add biological plausibility to this relationship. Intermittent hypoxia and sleep fragmentation, caused by successive apnea-hypopnea episodes, induce several intermediate disorders, such as activation of the sympathetic nervous system, oxidative stress, systemic inflammation, alterations in appetite-regulating hormones and activation of the hypothalamic-pituitary-adrenal axis which, in turn, favor the development of insulin resistance, its progression to glucose intolerance and, ultimately, to DM2. Concomitant SAHS seems to increase DM2 severity, since it worsens glycemic control and enhances the effects of atherosclerosis on the development of macrovascular complications. Furthermore, SAHS may be associated with the development of microvascular complications: retinopathy, nephropathy or diabetic neuropathy in particular. Data are still scant, but it seems that DM2 may also worsen SAHS progression, by increasing the collapsibility of the upper airway and the development of central apneas and hypopneas. PMID:25145320

  18. No relevant excess prevalence of myotonic dystrophy type 2 in patients with suspected fibromyalgia syndrome.

    PubMed

    van Vliet, J; Verrips, A; Tieleman, A A; Scheffer, H; Cats, H A; den Broeder, A A; van Engelen, B G M

    2016-06-01

    Myotonic dystrophy type 2 (DM2) is a rare, autosomal dominant, multisystem disorder with proximal weakness, myotonia, pain and cataract as important symptoms. Given the assumed underreporting of DM2 in the Netherlands combined with the predominant role of pain in DM2 as well as in fibromyalgia syndrome (FMS), we hypothesized there will be an excess prevalence of DM2 in patients with (suspected) FMS. Our objective was to determine the prevalence of DM2 in patients with suspected FMS. A prevalence of 2% was considered a relevant excess frequency. Between November 2011 and April 2014, 398 patients with suspected FMS who had been assessed by a rheumatologist participated in this cross-sectional study. 95% of the study population was female, with a mean age of 42 years. The final ICD-9 diagnoses were collected, in 96% the diagnosis was FMS. 92% met the 2010 American College of Rheumatology (ACR) diagnostic criteria for FMS. A questionnaire including neuromuscular symptoms was completed. Creatine kinase was determined, and genetic testing for DM2 was conducted in all patients. DM2 was established in only one patient (0.25%, 95% CI 0.04-1.4%), thus disapproving our hypothesis of a relevant prevalence of 2%. Our results suggest that patients with suspected FMS should not routinely be tested for DM2. PMID:27132119

  19. Spinal cord detethering in children with tethered cord syndrome and Chiari type 1 malformations.

    PubMed

    Glenn, Chad; Cheema, Ahmed A; Safavi-Abbasi, Sam; Gross, Naina L; Martin, Michael D; Mapstone, Timothy B

    2015-11-01

    We discuss the association between tethered cord syndrome (TCS) and Chiari type 1 malformation (CM1), and report on the surgical outcomes of children with CM1 and TCS who underwent sectioning of the filum terminale (SFT). The relationship between TCS and CM1 is unclear. A retrospective review of 170 consecutive spinal cord detetherings between 2008 and 2012 was performed. We identified 17 children with CM1 who underwent SFT. Information regarding clinical presentation, radiographic findings, surgical procedures, and clinical outcomes was analyzed. A mean tonsillar herniation of 10.0mm (range: 5-21) was noted. Children with a fatty or thickened filum terminale demonstrated a greater amount of tonsillar displacement (p<0.005). A low conus medullaris was found in 12 children and a syrinx was present in three. The preoperative symptoms improved in all children. The postoperative MRI (mean 21.8 months) revealed an unchanged tonsillar position in all but one child. No worsening of neurologic function was noted. Pediatric patients who have both CM1 and TCS, but do not demonstrate classic Chiari-related symptoms, may experience symptomatic improvement after filum terminale sectioning. PMID:26165471

  20. Fluctuating mixed-type hearing loss associated with synovitis-acne-pustulosis-hyperostosis-osteomyelitis (SAPHO) syndrome.

    PubMed

    Shimizu, Shigetaka; Yukawa, Kumiko; Kawaguchi, Sachie; Okubo, Yukari; Suzuki, Mamoru

    2010-08-01

    Synovitis, acne, palmoplantar pustulosis (PPP), hyperostosis, and osteitis (SAPHO) are the characteristic features of SAPHO syndrome. A 53-year-old woman had been treated for PPP for 2 years. She complained of hearing loss in the right ear, and otitis externa was diagnosed. The pure-tone audiogram (PTA) indicated mild hearing loss in the right ear, and her hearing continued to deteriorate despite recovery from inflammation. Her tympanogram was of the As-type, and acoustic reflex was absent in the right ear. A computed tomography (CT) scan revealed bilateral normal ossicles and cochleas. Bone scintigraphy revealed tracer uptake in the bilateral sternoclavicular joints, glenohumeral joints, and the capital humerus. She was hospitalized for arthralgia, and the pain was controlled with steroid therapy. Her right hearing deteriorated soon after the tapering of the steroid; her hearing recovered after cyclosporine therapy was initiated. The first tonsil provocation test showed increased blood cells in the urine, and the second test showed exacerbation of pustulosis. Despite immunosuppressant therapy, the arthritis attacks and hearing loss persisted; therefore, tonsillectomy was performed, which improved PPP. However, her hearing remained unchanged after the operation. We considered that irreversible changes might have already developed in the ossicular joints, and ossicular reconstruction was performed. Thereafter, her hearing and earache improved. PMID:19864094