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Eur Heart J Case Rep
Eur Heart J Case Rep
ehjcr
European Heart Journal. Case Reports
2514-2119
Oxford University Press UK

10.1093/ehjcr/ytae423
ytae423
Case Report
AcademicSubjects/MED00200
Eurheartj/27
Eurheartj/29
Severe familial dilated cardiomyopathy in a young adult due to a rare LMNA mutation: a case report
https://orcid.org/0000-0001-5424-2732
Belcher Adam M CAMC Institute for Academic Medicine, Charleston Area Medical Center, 3044 Chesterfield Ave, Charleston, WV 25304, USA

https://orcid.org/0000-0001-8423-4119
Annie Frank H CAMC Institute for Academic Medicine, Charleston Area Medical Center, 3044 Chesterfield Ave, Charleston, WV 25304, USA

Rinehart Sarah CAMC Department of Cardiology, Charleston Area Medical Center, 3200 MacCorkle Ave SE, Charleston, WV 25304, USA

Elashery Ahmad CAMC Department of Cardiology, Charleston Area Medical Center, 3200 MacCorkle Ave SE, Charleston, WV 25304, USA

Amer Muhammad CAMC Department of Cardiology, Charleston Area Medical Center, 3200 MacCorkle Ave SE, Charleston, WV 25304, USA

Nuzzi Vincenzo Handling Editor
Sacco Alice Editor
Falconer Debbie Editor
Jakstaite Aiste Monika Editor
Monosilio Sara Editor
Corresponding author. Tel: +304 388 9920, Email: adam.belcher@vandaliahealth.org
Conflict of interest: None declared.

9 2024
14 8 2024
14 8 2024
8 9 ytae42316 2 2024
01 5 2024
07 8 2024
05 9 2024
© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.
2024
https://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background

Familial dilated cardiomyopathy prognosis and disease progression vary greatly depending upon the type of genetic mutation. Family history and genetic testing are paramount in developing the best treatment plan for a patient. However, with rare or novel mutations, the significance may be unknown. Regarding this, the following case report highlights the importance of vigilance and suspicion when treating a patient with a variant of unknown significance. Additionally, it shows the importance of thoroughly investigating the family history of cardiovascular disease.

Case summary

A 25-year-old Caucasian male was found to have a right bundle branch block and dilated cardiomyopathy upon presentation to the emergency department. Later testing showed that the dilated cardiomyopathy was due to an incredibly rare lamin A/C (LMNA) gene mutation, R349L. Despite treatment with a maximum-tolerable medication regimen and an automatic implantable cardioverter-defibrillator, the patient continued to decline and required a heart transplant.

Discussion

This case provides more information on the severity of this specific LMNA mutation that has only been documented once before. Of note, the time from the initial emergency department visit to the heart transplant was approximately 2 years. Given the patient’s young age and rapid disease progression, in addition to a strong family history of sudden cardiac death, the significance of this mutation should not be understated. The additional knowledge gained from this case report can be used to aid in timely interventions and prognosis evaluation.

Dilated cardiomyopathy
LMNA
Genetic disease
Heart failure
Case report
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pmcLearning points

Investigating family history and published literature plays an important role in determining variant pathogenicity and prognosis of familial dilated cardiomyopathy.

Several factors, including New York Heart Association class, conduction abnormalities, sudden cardiac death risk, disease progression, and current guidelines, should be considered when determining optimal treatment strategies.

This case presented a few key challenges: young onset of the disease, a genetic variant with only one previously published case report and scant in vitro work, and quick progression of the disease despite using optimal therapies. Close follow-up and timely interventions were paramount in this case.

Background

Non-ischaemic dilated cardiomyopathy (DCM) is estimated to occur in approximately 1:250, and of those, approximately 30–50% are assumed to be familial.1 Lamin A/C (LMNA) gene mutations are a known cause of familial DCM, conveying a high risk of sudden cardiac death (SCD) at an estimated rate as high as 46%.2 In a retrospective study of 49 families of patients with DCM in Colorado, USA, and Italy, carriers of an LMNA mutation were more likely to be younger (22–32 years old) than non-carriers at the time of diagnosis. They were also much more likely to have conduction abnormalities, a heart transplant, and SCD.3 The European Society of Cardiology recommends consideration for a cardioverter-defibrillator in patients with DCM and a confirmed disease-causing LMNA mutation coupled with other clinical risk factors.4,5

Summary figure

Case report

A 25-year-old Caucasian landscaper presented to the emergency department (ED) with the chief complaints of lifelong recurrent, sudden onset palpitations, and an episode of vision loss that occurred 3 days prior and lasted for 30 min before resolving on its own. He reports developing a headache after his vision returned. Physical examination was unremarkable, with a temperature of 36.4°C, blood pressure of 112/72 mmHg, and peripheral pulse rate of 70 b.p.m.

The patient had no significant past medical history or known cardiovascular risk factors aside from previously stated episodes of palpitations. Initial family history revealed that the patient’s mother died in her 30s from DCM. Further investigation elucidated a family history very significant for heart failure and SCD.

At presentation, ophthalmic migraine, reduced blood flow, and stroke were considerations for the sudden vision loss of the left eye. Panic disorder is not a likely cause of his palpitations, given his long history of these palpitations without any known history of psychological issues or triggers. Given the patient’s extensive family history of early-onset heart failure and SCD, young age, and palpitations, genetic cardiomyopathy was the primary consideration.

Initial testing at presentation included a 12-lead electrocardiogram (ECG) and a high-sensitivity troponin test. The ECG showed sinus rhythm with a normal PR interval and a right bundle branch block (RBBB) (Figure 1). High-sensitivity troponin was 25 pg/mL (normal ≤ 20 pg/mL) with minimal delta. Head computed tomography (CT) and magnetic resonance imaging (MRI) were unremarkable. Transthoracic echocardiogram findings were significant for mildly dilated, severely diffuse hypokinetic left ventricle with an ejection fraction (EF) of 20–25%, a grade III diastolic dysfunction with elevated atrial pressure, and mild–moderate mitral and tricuspid valve regurgitation (Supplementary material online, Video S1). Right ventricle cavity size was mildly increased, and systolic function was mildly reduced. A cardiac MRI showed a left ventricular EF (LVEF) of 38% and a right ventricular EF of 30%, no evidence of prior infarction or late gadolinium enhancement, and an increased T1 mapping signal of 1350 ms (Figure 2) (Supplementary material online, Video S2). Coronary CT angiography revealed no coronary artery disease or anomaly (Figure 3). A genetic testing panel for cardiomyopathy was performed per the guidelines concerning newly diagnosed cardiomyopathy. At this time, he was classified as a class II heart failure following the New York Heart Association (NYHA) guidelines.

Figure 1 Intake electrocardiogram. Baseline 12-lead electrocardiogram with normal sinus rhythm and PR interval with a right bundle branch block and repolarization changes.

Figure 2 Cardiac magnetic resonance imaging. Cardiac magnetic resonance imaging showing cross-sectional short-axis images with no late gadolinium enhancement. Ao, aorta; PA, pulmonary artery; LA, left atrium; RA, right atrium; IVC, inferior vena cava; AV, aortic valve; RVOT: right ventricle outflow tract; LVOT, left ventricle outflow tract; IVS, interventricular septum; LV, left ventricle; RV, right ventricle; Ant., anterior left ventricle wall; Lat., lateral left ventricle wall; Inf., inferior left ventricle wall; APM, anterolateral papillary muscle; PPM, posteromedial papillary muscle.

Figure 3 Coronary computed tomography angiography. The coronary computed tomography angiography showed no obvious signs of arterial disease or other abnormalities. LAD, left anterior descending; LCx, left circumflex; OM, obtuse marginal; RCA, right coronary artery.

He was then discharged from the hospital with a maximum-tolerable guideline-directed medical therapy for heart failure (aspirin 81 mg, atorvastatin 40 mg, losartan 25 mg, and metoprolol 25 mg) and a wearable cardioverter-defibrillator (WCD). He was instructed to promptly return to the ED if anything changed. He was also scheduled for an exercise stress test and a follow-up appointment with his cardiologist.

The exercise stress test was non-diagnostic due to his heart rate only reaching 77% of the maximum predicted heart rate, and the test was stopped after 12 min due to fatigue. Blood pressure increased from 96/67 to 130/62 mmHg, and heart rate increased from 70 to 150 b.p.m. during the stress test. Isolated premature ventricular contractions and rare ventricular couplets were seen during the test.

Genetic testing confirmed that the patient was heterozygous for a likely pathogenic missense single nucleotide mutation (rs58789393) in exon 6 codon 349 (R349L) of the LMNA gene, which confirms our suspicion of familial DCM. Further in-depth screening of the patient’s family history revealed a potential association between the mutation and heart failure (Figure 4).

Figure 4 Genetic cascade screening. LMNA mutation pedigree chart of biological family detailing R349L carrier, or presumed carrier, status, and applicable cardiovascular health.

A few weeks after the initial ED visit, the patient presented to the ED due to episodes of ventricular tachycardia detected by the WCD, followed by WCD discharge. The patient stated that the WCD detected ventricular tachycardia during physical activity (Figure 5). This led him to reduce his workload and physical activity. Upon follow-up, it was determined that an automatic implantable cardioverter-defibrillator (AICD) was the best course of action over cardiac resynchronization therapy given his continual decline despite 3 months of optimal therapy, non-ischaemic cardiomyopathy with non-sustained ventricular tachycardia, NYHA class II, RBBB with sinus rhythm, and a strong family history of SCD. Additionally, he was instructed to stop taking his losartan for 2 days and then begin taking sacubitril/valsartan (24/26 mg) twice a day.

Figure 5 Wearable cardioverter-defibrillator notification. Wide complex, non-sustained ventricular tachycardia with the wearable cardioverter-defibrillator.

In the following year, the patient’s health declined. He reported increased shortness of breath, especially when climbing stairs, and he had to leave his occupation as a landscaper. Given this continued decline, he was referred to an out-of-state facility for further evaluation. At that time, he was found to have a massive amount of tricuspid regurgitation, mild–moderate mitral valve regurgitation, an LVEF of 17%, worsened function in both ventricles, and a significantly elevated N-terminal B-type natriuretic peptide level at 4918 pg/mL (normal 0–449 pg/mL) (Supplementary material online, Video S1). He was placed on a transplant list and underwent a successful transplant a few months later. The new heart showed a 55–60% LVEF with normal valve and ventricle function. He has since remained stable and is closely followed by cardiology.

Discussion

The R349L mutation has, to the best of our knowledge, only been documented once. In 2004, Hermida-Prieto et al.6 described a case of severe familial cardiomyopathy in a mother (index patient), and her identical twin daughters referred to their cardiomyopathy clinic in Spain that were heterozygous for the R349L mutation. The index patient was reportedly symptomatic at age 31 and received a transplant at age 36, and the twin daughters were symptomatic at age 17 and received transplants at age 18 and 20. The R349L mutation is upstream of the nuclear localization signal which is associated with a more severe phenotype.6 No family history of musculoskeletal disorders or progeroid syndromes was reported. Interestingly, musculoskeletal disorders and progeroid syndromes have been seen in a different mutation of the same codon (R349W).7

This mutation has been classified as ‘likely pathogenic’ based on the previously reported case8 and in silico pathogenicity models.9 The R349L variant has not yet been detected in large-scale sequencing projects or aggregate databases. Therefore, allele frequency within a population or ethnicity is unknown.

In younger patients with a strong family history of heart failure and SCD, genetic testing aids in the accurate diagnosis of familial DCM. The more severe phenotypes, such as the one seen in the R349L mutation, indicate a need for prompt treatment. This is evident in this case, where the patient continued to decline despite an aggressive treatment strategy utilizing an AICD and maximum-tolerable medications. Considering the patient’s continual decline, a heart transplant was ultimately needed. The rapid progression of disease in this patient’s family, as well as the one other documented family, shows the poor prognosis and severity associated with this mutation.

The presented case highlights the importance of genetic screening in patients with a strong family history of SCD and newly diagnosed cardiomyopathy. This case also highlighted some challenges faced in managing cardiomyopathy, such as identifying cardiomyopathy type, the progression of symptoms despite medical interventions, and the radical changes required in the patient’s physical activity and lifestyle. Ultimately, the patient underwent a successful heart transplant, and he has continued to improve and regain his previous quality of life.

Supplementary Material

ytae423_Supplementary_Data

Acknowledgements

We would like to thank and acknowledge the contributions that Fatima Ahmed, M.D., provided for this manuscript. Their expertise and assistance with this patient case helped with writing and presenting this case report.

Lead author biography

Adam Belcher is a research scientist at the Charleston Area Medical Center Institute for Academic Medicine. His primary interests are cardiovascular disease and molecular biology research.

Supplementary material

Supplementary material is available at European Heart Journal – Case Reports online.

 

Consent: In accordance with the standards established by the Committee on Publication Ethics (COPE) and the ICMJE recommendations, we have obtained patient consent to publish this manuscript and its associated contents, and we have taken steps to protect the patient’s identity.

Ethics approval: None declared.

Data availability

All data is presented within the article and in the associated online Supplementary material.
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References

1 McNally  EM, Mestroni  L. Dilated cardiomyopathy: genetic determinants and mechanisms. Circ Res  2017;121 :731–748.28912180
2 Kumar  S, Baldinger  SH, Gandjbakhch  E, Maury  P, Sellal  JM, Androulakis  AF, et al  Long-term arrhythmic and nonarrhythmic outcomes of lamin A/C mutation carriers. J Am Coll Cardiol  2016;68 :2299–2307.27884249
3 Taylor  MR, Fain  PR, Sinagra  G, Robinson  ML, Robertson  AD, Carniel  E, et al  Natural history of dilated cardiomyopathy due to lamin A/C gene mutations. J Am Coll Cardiol  2003;41 :771–780.12628721
4 Zeppenfeld  K, Tfelt-Hansen  J, de Riva  M, Winkel  BG, Behr  ER, Blom  NA, et al  2022 ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J  2022;43 :3997–4126.36017572
5 Arbelo  E, Protonotarios  A, Gimeno  JR, Arbustini  E, Barriales-Villa  R, Basso  C, et al  2023 ESC guidelines for the management of cardiomyopathies. Eur Heart J  2023;44 :3503–3626.37622657
6 Hermida-Prieto  M, Monserrat  L, Castro-Beiras  A, Laredo  R, Soler  R, Peteiro  J, et al  Familial dilated cardiomyopathy and isolated left ventricular noncompaction associated with lamin A/C gene mutations. Am J Cardiol  2004;94 :50–54.15219508
7 Captur  G, Arbustini  E, Syrris  P, Radenkovic  D, O'Brien  B, Mckenna  WJ, et al  Lamin mutation location predicts cardiac phenotype severity: combined analysis of the published literature. Open Heart  2018;5 :e000915.30402260
8 Mory  PB, Crispim  F, Freire  MB, Salles  JE, Valério  CM, Godoy-Matos  AF, et al  Phenotypic diversity in patients with lipodystrophy associated with LMNA mutations. Eur J Endocrinol  2012;167 :423–431.22700598
9 Cheng  J, Novati  G, Pan  J, Bycroft  C, Žemgulytė  A, Applebaum  T, et al  Accurate proteome-wide missense variant effect prediction with AlphaMissense. Science  2023;381 :eadg7492.37733863
