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The cardiac sodium channel mutation delQKP 1507-1509 is associated with the expanding phenotypic spectrum of LQT3, conduction disorder, dilated cardiomyopathy, and high incidence of youth sudden death.

Shi R, Zhang Y, Yang C, Huang C, Zhou X, Qiang H, Grace AA, Huang CL, Ma A - Europace (2008)

Bottom Line: Transthoracal echocardiography then revealed left ventricular dilatation and reduced systolic function.Two additional subjects died suddenly at 13 and 33 years.This data compliments and expands the spectrum of phenotypes resulting from this known gain-of-function mutation, including not only LQT3, cardiac conduction defects, and sudden death but also DCM, hitherto associated with loss-of-function mutations, for the first time.

View Article: PubMed Central - PubMed

Affiliation: 1Department of Paediatrics, First Affiliated Hospital, Cardiovascular Ion Channel Disease Laboratory, Medical College of Xi'an Jiaotong University, Xi'an, Peoples Republic of China.

ABSTRACT

Aim: We report diverse phenotypic consequences of the delQKP-1507-1509 cardiac sodium channel mutation in three generations of a Chinese family.

Methods and results: Clinical and electrocardiographic (ECG), echocardiographic examination was followed by direct sequencing of SCN5A, KCNQ1, HERG, and LAMIN A/C to screen genomic DNA from blood samples. Of two mutation carriers, the proband was born with conduction disorders including second-degree atrioventricular (AV) block with prolonged QTc interval, additionally showing left anterior fascicular block (LAFB), incomplete right bundle-branch block (IRBBB), and intermittent third-degree AV block at 2 years, and clinical presentations of multiple syncope despite normal electroencephalograms at 8 years. Continuous ECG monitoring following presentation at 13 years revealed prolonged QTc and biphasic T-waves, multiple episodes of ventricular tachycardia, ventricular fibrillation, and torsades de pointes. Transthoracal echocardiography then revealed left ventricular dilatation and reduced systolic function. Another mutation carrier showed features of long QT syndrome type 3 (LQT3), LAFB, and dilated cardiomyopathy (DCM). Two additional subjects died suddenly at 13 and 33 years.

Conclusion: This data compliments and expands the spectrum of phenotypes resulting from this known gain-of-function mutation, including not only LQT3, cardiac conduction defects, and sudden death but also DCM, hitherto associated with loss-of-function mutations, for the first time.

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Twelve-lead electrocardiography (ECG) and transthoracal echocardiography results of proband. (A) 12-lead ECG (25 mm/s). Leads I, II, III, aVR, aVL, aVF (10 mm/mV), and V1–V6 (5 mV/mm) showed prolonged QTc, with the former showing biphasic T waves, and the latter alternating upright and inverting T-waves (T-wave alternans). ECG records also show intraventricular conduction delay of left anterior fascicular block (LAFB) and incomplete right bundle-branch block (IRBBB). (B) An example of an episode of torsades de pointes. (C) Transthoracal echocardiographic image demonstrating dilated left ventricle by apex position. (D) Colour Doppler image showed dysfunction of the left ventricular wall (wall velocity approximately 4.35 cm/s).
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EUN202F2: Twelve-lead electrocardiography (ECG) and transthoracal echocardiography results of proband. (A) 12-lead ECG (25 mm/s). Leads I, II, III, aVR, aVL, aVF (10 mm/mV), and V1–V6 (5 mV/mm) showed prolonged QTc, with the former showing biphasic T waves, and the latter alternating upright and inverting T-waves (T-wave alternans). ECG records also show intraventricular conduction delay of left anterior fascicular block (LAFB) and incomplete right bundle-branch block (IRBBB). (B) An example of an episode of torsades de pointes. (C) Transthoracal echocardiographic image demonstrating dilated left ventricle by apex position. (D) Colour Doppler image showed dysfunction of the left ventricular wall (wall velocity approximately 4.35 cm/s).

Mentions: At the end of this period, she was a paediatric cardiological patient, presenting with multiple episodes of syncope and seizure. Within hours following admission, continuous ECG monitoring during such multiple episodes led to a diagnosis of ventricular fibrillation and torsade de pointe (TdP) that was reversed by electrode defibrillation. Subsequent 12-lead ECG recording revealed a sinus rate with a relative risk interval of 680 ms, which on some follow-up measurements increased to as much as 1132 ms. In addition, there was a borderline PR interval (200 ms) and normal QRS durations (100 ms), features of intraventricular conduction delay consisting of LAFB and incomplete right bundle-branch block (IRBBB). QTc interval was prolonged (750 ms) and T-waves were biphasic with a delayed onset (Figure 2A). Continuous ECG monitoring revealed self-terminating episodes of TdP (Fig. 2B). Transthoracic echocardiography revealed a LV dilatation with end-diastolic and end-systolic volumes (LVEDV and LVESV) of 156 mL and 98 mL, respectively, low ejection fraction (EF) of 37% (Table 1) and a thin ventricular wall (Figure 2C). There was a clear reduction of LV myocardial motion on Doppler tissue imaging to 4 mm/s (Figure 2D). Immediate treatment involved insertion of a temporary cardiac pacemaker; this was succeeded by β-adrenergic blocker maintenance therapy.


The cardiac sodium channel mutation delQKP 1507-1509 is associated with the expanding phenotypic spectrum of LQT3, conduction disorder, dilated cardiomyopathy, and high incidence of youth sudden death.

Shi R, Zhang Y, Yang C, Huang C, Zhou X, Qiang H, Grace AA, Huang CL, Ma A - Europace (2008)

Twelve-lead electrocardiography (ECG) and transthoracal echocardiography results of proband. (A) 12-lead ECG (25 mm/s). Leads I, II, III, aVR, aVL, aVF (10 mm/mV), and V1–V6 (5 mV/mm) showed prolonged QTc, with the former showing biphasic T waves, and the latter alternating upright and inverting T-waves (T-wave alternans). ECG records also show intraventricular conduction delay of left anterior fascicular block (LAFB) and incomplete right bundle-branch block (IRBBB). (B) An example of an episode of torsades de pointes. (C) Transthoracal echocardiographic image demonstrating dilated left ventricle by apex position. (D) Colour Doppler image showed dysfunction of the left ventricular wall (wall velocity approximately 4.35 cm/s).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2573028&req=5

EUN202F2: Twelve-lead electrocardiography (ECG) and transthoracal echocardiography results of proband. (A) 12-lead ECG (25 mm/s). Leads I, II, III, aVR, aVL, aVF (10 mm/mV), and V1–V6 (5 mV/mm) showed prolonged QTc, with the former showing biphasic T waves, and the latter alternating upright and inverting T-waves (T-wave alternans). ECG records also show intraventricular conduction delay of left anterior fascicular block (LAFB) and incomplete right bundle-branch block (IRBBB). (B) An example of an episode of torsades de pointes. (C) Transthoracal echocardiographic image demonstrating dilated left ventricle by apex position. (D) Colour Doppler image showed dysfunction of the left ventricular wall (wall velocity approximately 4.35 cm/s).
Mentions: At the end of this period, she was a paediatric cardiological patient, presenting with multiple episodes of syncope and seizure. Within hours following admission, continuous ECG monitoring during such multiple episodes led to a diagnosis of ventricular fibrillation and torsade de pointe (TdP) that was reversed by electrode defibrillation. Subsequent 12-lead ECG recording revealed a sinus rate with a relative risk interval of 680 ms, which on some follow-up measurements increased to as much as 1132 ms. In addition, there was a borderline PR interval (200 ms) and normal QRS durations (100 ms), features of intraventricular conduction delay consisting of LAFB and incomplete right bundle-branch block (IRBBB). QTc interval was prolonged (750 ms) and T-waves were biphasic with a delayed onset (Figure 2A). Continuous ECG monitoring revealed self-terminating episodes of TdP (Fig. 2B). Transthoracic echocardiography revealed a LV dilatation with end-diastolic and end-systolic volumes (LVEDV and LVESV) of 156 mL and 98 mL, respectively, low ejection fraction (EF) of 37% (Table 1) and a thin ventricular wall (Figure 2C). There was a clear reduction of LV myocardial motion on Doppler tissue imaging to 4 mm/s (Figure 2D). Immediate treatment involved insertion of a temporary cardiac pacemaker; this was succeeded by β-adrenergic blocker maintenance therapy.

Bottom Line: Transthoracal echocardiography then revealed left ventricular dilatation and reduced systolic function.Two additional subjects died suddenly at 13 and 33 years.This data compliments and expands the spectrum of phenotypes resulting from this known gain-of-function mutation, including not only LQT3, cardiac conduction defects, and sudden death but also DCM, hitherto associated with loss-of-function mutations, for the first time.

View Article: PubMed Central - PubMed

Affiliation: 1Department of Paediatrics, First Affiliated Hospital, Cardiovascular Ion Channel Disease Laboratory, Medical College of Xi'an Jiaotong University, Xi'an, Peoples Republic of China.

ABSTRACT

Aim: We report diverse phenotypic consequences of the delQKP-1507-1509 cardiac sodium channel mutation in three generations of a Chinese family.

Methods and results: Clinical and electrocardiographic (ECG), echocardiographic examination was followed by direct sequencing of SCN5A, KCNQ1, HERG, and LAMIN A/C to screen genomic DNA from blood samples. Of two mutation carriers, the proband was born with conduction disorders including second-degree atrioventricular (AV) block with prolonged QTc interval, additionally showing left anterior fascicular block (LAFB), incomplete right bundle-branch block (IRBBB), and intermittent third-degree AV block at 2 years, and clinical presentations of multiple syncope despite normal electroencephalograms at 8 years. Continuous ECG monitoring following presentation at 13 years revealed prolonged QTc and biphasic T-waves, multiple episodes of ventricular tachycardia, ventricular fibrillation, and torsades de pointes. Transthoracal echocardiography then revealed left ventricular dilatation and reduced systolic function. Another mutation carrier showed features of long QT syndrome type 3 (LQT3), LAFB, and dilated cardiomyopathy (DCM). Two additional subjects died suddenly at 13 and 33 years.

Conclusion: This data compliments and expands the spectrum of phenotypes resulting from this known gain-of-function mutation, including not only LQT3, cardiac conduction defects, and sudden death but also DCM, hitherto associated with loss-of-function mutations, for the first time.

Show MeSH
Related in: MedlinePlus