ABSTRACT
Objective@#To explore the clinical and molecular genetic features of a Chinese patient with catecholaminergic polymorphic ventricular tachycardia (CPVT).@*Methods@#Clinical data including resting electrocardiography, echocardiography and treadmill exercise testing of a patient with CPVT admitted to our department in March 2013 were analyzed, and the peripheral venous blood samples of the patient and his family members and 400 ethnicity-matched healthy controls were obtained. All exons and exon-intron boundaries of the six CPVT-related genes including RYR2, CASQ2, TRDN, CALM1, KCNJ2 and ANKB were sequenced to detect the variants related to CPVT. The relationship between the genotypes and phenotypes was analyzed to direct the target therapy.@*Results@#Recurrent syncope induced either by exercise or extreme frightened fear was observed in this patient. There was no positive family history of syncope or sudden death. The resting electrocardiography and echocardiography of the patient were normal, while the exercise testing revealed bidirectional and polymorphic ventricular tachycardia. A cardiac ryanodine receptor gene mutation (R2401H) was identified in this patient, while this mutation was absent in his parents and sister and 400 controls. No variant was detected in the remaining five candidate genes. Treatment with high dose of metoprolol succinate (118.75 mg/d) was effective and patient was free of syncopal attack during the 2 years follow-up.@*Conclusion@#This is the first report on RyR2-R2401H mutation in Chinese patient with CPVT, and high dose of metoptolol is the effective therapy option for CPVT related to RyR2 mutation.
ABSTRACT
<p><b>OBJECTIVES</b>We identified the long QT syndrome (LQTS) patients, and detected the potential risk of LQTS in family members by using genetic testing and electrophysiological analysis, which helped provide clinical evaluation and appropriate treatment.</p><p><b>METHODS</b>Detailed clinical characteristics and familiar history were obtained from the whole family members of an idiopathic pediatric LQTS patient. Two hundred healthy subjects with the same ethnic background were recruited as controls. The entire coding sequences of three candidate genes including KCNQ1, KCNH2 and SCN5A were screened for mutations in the proband. The function of the mutation was then explored by whole-cell patch clamp techniques, and the genetic testing and risk assessment of the family members were performed.</p><p><b>RESULTS</b>The proband was clinically preliminary diagnosed as LQTS by 12-lead electrocardiogram. On the third day of metoprolol intake (25 mg, bid), she died suddenly at lunch. One heterozygous missense mutation (SCN5A-V411M) was identified in this proband, but the mutation was absent in 200 healthy subjects. The electrophysiological analysis indicated that SCN5A-V411M significantly increased the peak current density ((230.8 ± 27.6)pA/pF vs. (101.2 ± 10.9)pA/pF, n=10, P<0.01) and the late sodium current ((156.6 ± 13.6)pA/pF vs. (95.9 ± 7.9)pA/pF, n=12, P<0.01) of sodium channel compared to wide type. The enhanced sodium channel activation with a negative shift in the peak I-V relationship was significantly higher by -50 mV than wide type (85.0%± 7.4% vs. 41.5% ± 2.6%, P<0.01), while the steady-state inactivation curves remained unchanged. Additionally, mother and grandmother of the proband were the silent mutation carriers with no symptoms, who needed the appropriate clinical assessment and follow-up. The proband's twin sister and aunt died of sudden infant death syndrome.</p><p><b>CONCLUSIONS</b>We firstly reported a heterozygote missense mutation (SCN5A-V411M) in this Chinese family. V411M induced "gain of function" of sodium channel and formed the basis of type-3 LQTS. Genetic testing could help to increase the diagnostic accuracy, and facilitate clinical assessment and appropriate therapy to prevent sudden cardiac death of individuals with SCN5A-V411M mutation.</p>
Subject(s)
Humans , Cardiac Conduction System Disease , Death, Sudden, Cardiac , Genetic Testing , Incidence , Long QT Syndrome , Mutation , Patch-Clamp TechniquesABSTRACT
Objective To evaluate expression of HDAC2 in peripheral blood mononuclear cells(PBMCs)from glucocorticoid-resistant versus glucocorticoid-sensitive patients with sudden sensorineural hearing loss and identi-ty the relationship between the level of HDAC2 and glucocorticoid insensitivity.Methods PBMCs were collected from10 patients with deviation of nasal septum (control group)and 20 sudden sensorineural hearing loss patients be-fore and after intratympanic methylprednisolone for 10 days.We divided the SSNHL patients into 2 groups (GC sensitive group and GC insensitive group)according to their hearing recovery.Real time PCR and HDAC2 Assay Kit were used to detect the expression level of HDAC2 mRNA and HDAC2 activity in PBMCs.The data were analyzed with SPSS 17.0 software.ResuIts Before intratympanic methylprednisolone,the level of HDAC2 activity were sig-nificantly depressed in SSNHL patients,while the HDAC2 mRNA expressing much higher than the control group. The expression level of HDAC2 mRNA increased significantly after intratympanic methylprednisolone.The HDAC2 activity in GC sensitive group increased significantly.ConcIusion Knockdown of HDAC2 expression induces corti-costeroid in-sensitivity.Glucocorticoids can increase the expression of HDAC2 mRNA.HDAC2 activity can be down-regulated by post-translational modifications.