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Case Reports
. 2019 Dec 17;19(1):298.
doi: 10.1186/s12872-019-01282-6.

Case reports of a c.475G>T, p.E159* lamin A/C mutation with a family history of conduction disorder, dilated cardiomyopathy and sudden cardiac death

Tetsuro Yokokawa  1   2 , Shohei Ichimura  3 , Naoko Hijioka  3 , Takashi Kaneshiro  3   4 , Akiomi Yoshihisa  3   5 , Hiroyuki Kunii  3 , Kazuhiko Nakazato  3 , Takafumi Ishida  3 , Osamu Suzuki  6 , Seiko Ohno  7   8 , Takeshi Aiba  9 , Hiroshi Ohtani  10 , Yasuchika Takeishi  3
Affiliations
Case Reports

Case reports of a c.475G>T, p.E159* lamin A/C mutation with a family history of conduction disorder, dilated cardiomyopathy and sudden cardiac death

Tetsuro Yokokawa et al. BMC Cardiovasc Disord. .

Abstract

Background: Patients with some mutations in the lamin A/C (LMNA) gene are characterized by the presence of dilated cardiomyopathy (DCM), conduction abnormalities, ventricular tachyarrhythmias (VT), and sudden cardiac death (SCD). Various clinical features have been observed among patients who have the same LMNA mutation. Here, we show a family with cardiac laminopathy with a c.475G > T, p.E159* LMNA mutation, and a family history of conduction disorder, DCM, VT, and SCD.

Case presentation: A proband (female) with atrial fibrillation and bradycardia was implanted with a pacemaker in her fifties. Twenty years later, she experienced a loss of consciousness due to polymorphic VT. She had a serious family history; her mother and elder sister died suddenly in their fifties and sixties, respectively, and her nephew and son were diagnosed as having DCM. Genetic screening of the proband, her son, and nephew identified a nonsense mutation (c.475G > T, p.E159*) in the LMNA gene. Although the proband's left ventricular ejection fraction remained relatively preserved, her son and nephew's left ventricular ejection fraction were reduced, resulting in cardiac resynchronization therapy by implantation of a defibrillator.

Conclusions: In this family with cardiac laminopathy with a c.475G > T, p.E159* LMNA mutation, DCM, SCD, and malignant VT occurred. Clinical manifestation of various atrial and ventricular arrhythmias and heart failure with reduced ejection fraction occurred in an age-dependent manner in all family members who had the nonsense mutation. It appears highly likely that the E159* LMNA mutation is related to various cardiac problems in the family of the current report.

Keywords: Case report; Dilated cardiomyopathy; Lamin A/C; Sudden cardiac death; c.475G > T; p.E159*.

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Conflict of interest statement

Tetsuro Yokokawa belongs to a department supported by Actelion Pharmaceuticals Japan. Takashi Kaneshiro belongs to a department supported by Biotronic Japan and Abbot Japan. Akiomi Yoshihisa belongs to a department supported by Fukuda Denshi Co. Ltd. These companies were not associated with the contents of this study.

Figures

Fig. 1
Fig. 1
Images of Case 1 (II-4). a On admission, electrocardiogram showed pacing rhythm, a heart rate of 70 ppm, and a QTc interval of 441 msec. b Polymorphic ventricular tachycardia intermittently occurred. c Chest X-ray revealed slight congestion, with a cardiothoracic ratio of 71.0% with a pacemaker. d Echocardiogram showed a normal left ventricular ejection fraction of 62%, a slightly large left ventricular diastolic diameter of 53.8 mm, and a large left atrial diameter of 54 mm
Fig. 2
Fig. 2
a Pedigree and results of Sanger sequencing. Genetic testing was performed in Case 1 (II-4), 2 (III-1), 3 (III-4), and the second son of the patient of Case 1 (III-6). An LMNA nonsense mutation, E159*, was identified in Cases 1, 2, and 3. The second son did not have any LMNA mutations. The proband is indicated by an arrow. Cases with the E159* LMNA mutation are shown as (+), and those without the mutation are shown as (−). Squares represent males, and circles represent females. b Direct sequencing revealed a nonsense mutation of LMNA (E159*) in Case 1. c Structure of LMNA (top) and lamin A (bottom) and C (middle) protein. AF, atrial fibrillation; CAVB, complete atrioventricular block; CRTD, cardiac resynchronization therapy defibrillator; DCM, dilated cardiomyopathy; LMNA, lamin A/C; NLS, nuclear localization signal; PMI, pacemaker implantation; SCD, sudden cardiac death; SSS, sick sinus syndrome; VF, ventricular fibrillation; VT, ventricular tachyarrhythmia
Fig. 3
Fig. 3
Clinical courses. The patient in Case 1 (female, II-4, proband) presented with AF with bradycardia in her fifties, and polymorphic VT in her seventies. The elder sister (II-2) of the patient in Case 1, who did not undergo genetic testing, presented with SSS with PMI in her sixties, and died suddenly due to VF. The patient in Case 2 (male, III-1) presented with CAVB in his forties, and DCM and VT in his fifties. The patient in Case 3 (male, III-4) presented with AF, CAVB, DCM, and VT in his fifties. AF, atrial fibrillation; CAVB, complete atrioventricular block; CRTD, cardiac resynchronization therapy defibrillator; DCM, dilated cardiomyopathy; LVEF, left ventricular ejection fraction; PMI, pacemaker implantation; SCD, sudden cardiac death; SSS, sick sinus syndrome; VF, ventricular fibrillation; VT, ventricular tachyarrhythmia
Fig. 4
Fig. 4
Images of Case 2 (III-1). a Case 2 developed complete atrioventricular block in his forties. b Five years after implantation of a pacemaker, he was admitted to hospital due to ventricular tachycardia. c On admission, electrocardiogram showed pacing rhythm, a heart rate of 60 ppm, and a QTc interval of 480 msec. d Chest X-ray revealed no congestion or pleural effusion, and a cardiothoracic ratio of 48.5% with a pacemaker. e Echocardiogram showed a reduced left ventricular ejection fraction of 33.2%, a large left ventricular diastolic diameter of 54.1 mm, and a left atrial diameter of 35.6 mm
Fig. 5
Fig. 5
Images of Case 3 (III-4). a On admission, electrocardiogram showed atrial fibrillation with complete atrioventricular block and a heart rate of 40 bpm. b Monitor electrocardiogram revealed non-sustained ventricular tachycardia. c After the implantation of a cardiac resynchronization therapy defibrillator, electrocardiogram showed pacing rhythm, and a heart rate of 60 ppm. d Chest X-ray showed slight congestion with a cardiothoracic ratio of 60.4%. e Echocardiogram showed a reduced left ventricular ejection fraction of 33.1%, a large left ventricular diastolic diameter of 62.4 mm, and a large left atrial diameter of 45.9 mm. f Cardiovascular magnetic resonance showed late gadolinium enhancement in the left ventricle. g, h Left ventricular endomyocardial biopsy revealed interstitial fibrosis by Hematoxylin and eosin staining (g; magnification, × 50) and Elastica-Masson staining (h; magnification, × 50), but no significant findings of myocarditis, amyloidosis, or sarcoidosis
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