LMNA Mutation Carriers Research Articles

Troponin T Assessment Allows for Identification of Mutation Carriers among Young Relatives of Patients with LMNA-Related Dilated Cardiomyopathy.

Background:LMNA-related dilated cardiomyopathy (LMNA-DCM) caused by mutations in the lamin A/C gene (LMNA) is one of the most common forms of hereditary DCM. Due to the high risk of mutation transmission to offspring and the high incidence of ventricular arrhythmia and sudden death even before the onset of heart failure symptoms, it is very important to identify LMNA-mutation carriers. However, many relatives of LMNA-DCM patients do not report to specialized centers for clinical or genetic screening. Therefore, an easily available tool to identify at-risk subjects is needed. Methods: We compared two cohorts of young, asymptomatic relatives of DCM patients who reported for screening: 29 LMNA mutation carriers and 43 individuals from the control group. Receiver operating characteristic (ROC) curves for potential indicators of mutation carriership status were analyzed. Results: PR interval, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and high-sensitivity cardiac troponin T (hscTnT) serum levels were higher in the LMNA mutation carrier cohort. Neither group differed significantly with regard to creatinine concentration or left ventricular ejection fraction. The best mutation carriership discriminator was hscTnT level with an optimal cut-off value at 5.5 ng/L, for which sensitivity and specificity were 86% and 93%, respectively. The median hscTnT level was 11.0 ng/L in LMNA mutation carriers vs. <3.0 ng/L in the control group, p < 0.001. Conclusions: Wherever access to genetic testing is limited, LMNA mutation carriership status can be assessed reliably using the hscTnT assay. Among young symptomless relatives of LMNA-DCM patients, a hscTnT level >5.5 ng/L strongly suggests mutation carriers.

Clinical Profile, Arrhythmias, and Adverse Cardiac Outcomes in Emery-Dreifuss Muscular Dystrophies: A Systematic Review of the Literature.

Simple SummaryCardiolaminopathies portend an augmented risk of atrial and ventricular arrhythmias, thromboembolic events, ventricular dysfunction, and mortality. A high level of evidence on the clinical management of cardiac involvement in this setting is still lacking, and strong recommendations cannot be formulated. Our systematic review reported the incidence rates for the main cardiovascular outcomes in 1070 LMNA mutation carriers and 40 EMD mutation carriers, with a minimum follow-up of one-year. Our results stressed the importance of a structured follow-up aiming at the early recognition of atrial arrhythmias and the prevention of thromboembolic events. In patients with a need for pacing, cardioverter–defibrillator implantation should be considered due to the high burden of malignant ventricular arrhythmias.Cardiolaminopathies are a heterogeneous group of disorders which are due to mutations in the genes encoding for nuclear lamins or their binding proteins. The whole spectrum of cardiac manifestations encompasses atrial arrhythmias, conduction disturbances, progressive systolic dysfunction, and malignant ventricular arrhythmias. Despite the prognostic significance of cardiac involvement in this setting, the current recommendations lack strong evidence. The aim of our work was to systematically review the current data on the main cardiovascular outcomes in cardiolaminopathies. We searched PubMed/Embase for studies focusing on cardiovascular outcomes in LMNA mutation carriers (atrial arrhythmias, ventricular arrhythmias, sudden cardiac death, conduction disturbances, thromboembolic events, systolic dysfunction, heart transplantation, and all-cause and cardiovascular mortality). In total, 11 studies were included (1070 patients, mean age between 26–45 years, with follow-up periods ranging from 2.5 years up to 45 ± 12). When available, data on the EMD-mutated population were separately reported (40 patients). The incidence rates (IR) were individually assessed for the outcomes of interest. The IR for atrial fibrillation/atrial flutter/atrial tachycardia ranged between 6.1 and 13.9 events/100 pts–year. The IR of atrial standstill ranged between 0 and 2 events/100 pts-year. The IR for malignant ventricular arrhythmias reached 10.2 events/100 pts–year and 15.6 events/100 pts–year for appropriate implantable cardioverter–defibrillator (ICD) interventions. The IR for advanced conduction disturbances ranged between 3.2 and 7.7 events/100 pts–year. The IR of thromboembolic events reached up to 8.9 events/100 pts–year. Our results strengthen the need for periodic cardiological evaluation focusing on the early recognition of atrial arrhythmias, and possibly for the choice of preventive strategies for thromboembolic events. The frequent need for cardiac pacing due to advanced conduction disturbances should be counterbalanced with the high risk of malignant ventricular arrhythmias that would justify ICD over pacemaker implantation.

Timing of pacemaker and ICD implantation in LMNA mutation carriers

AimsLMNA-cardiomyopathy is often associated with pathology in the cardiac conduction system necessitating device implantations. The aim was to study the timing and types of device implantations and need for re-implantations...

Can Circulating Cardiac Biomarkers Be Helpful in the Assessment of LMNA Mutation Carriers?

Mutations in the lamin A/C gene are variably phenotypically expressed; however, it is unclear whether circulating cardiac biomarkers are helpful in the detection and risk assessment of cardiolaminopathies. We sought to assess (1) clinical characteristics including serum biomarkers: high sensitivity troponin T (hsTnT) and N-terminal prohormone brain natriuretic peptide (NT-proBNP) in clinically stable cardiolaminopathy patients, and (2) outcome among pathogenic/likely pathogenic lamin A/C gene (LMNA) mutation carriers. Our single-centre cohort included 53 patients from 21 families. Clinical, laboratory, follow-up data were analysed. Median follow-up was 1522 days. The earliest abnormality, emerging in the second and third decades of life, was elevated hsTnT (in 12% and in 27% of patients, respectively), followed by the presence of atrioventricular block, heart failure, and malignant ventricular arrhythmia (MVA). In patients with missense vs. other mutations, we found no difference in MVA occurrence and, surprisingly, worse transplant-free survival. Increased levels of both hsTnT and NT-proBNP were strongly associated with MVA occurrence (HR > 13, p ≤ 0.02 in both) in univariable analysis. In multivariable analysis, NT-proBNP level > 150 pg/mL was the only independent indicator of MVA. We conclude that assessment of circulating cardiac biomarkers may help in the detection and risk assessment of cardiolaminopathies.

External validation of risk factors for malignant ventricular arrhythmias in lamin a/c mutation carriers

International recommendations state that implantable cardiovertor defibrillator should be considered early in patients with a confirmed disease-causing LMNA mutation with clinical risk factors, especially in the presence of non-sustained ventricular tachycardia, LVEF < 45%, male sex or non-missense mutations. The prognostic model derived from these recommendations hasn’t been validated on a separate external sample of patients. To evaluate the performance of the 4 prognosis factors on a separate external cohort of LMNA patients. We identified 101 consecutive LMNA mutation carriers who have been managed and genotyped in our center between 2004 and 2015. We recorded for all patients the values of the 4 previous identified predictive factors and whether they experienced a malignant ventricular aarhythmia (MVA) or not. The mean follow-up was 4.7 years. MVA was oberserved in 16 patients. Four risk groups were defined from the four previous predictive factors and log-rank test showed statistical significance ( P < 0,001) of MVA occurrence rates between groups (See Fig. 1 ). The 4 risk factors (non-sustained ventricular tachycardia, LVEF < 45%, male sex and non-missense mutations) derived from a previous work showed good performance on predicting malignant ventricular arrhythmia on an external cohort. Further studies are needed to identify other potential risk factors that could be even more accurate to predict sudden cardiac death.

Dupuytren's and Ledderhose Diseases in a Family with LMNA-Related Cardiomyopathy and a Novel Variant in the ASTE1 Gene.

Dupuytren’s disease (palmar fibromatosis) involves nodules in fascia of the hand that leads to flexion contractures. Ledderhose disease (plantar fibromatosis) is similar with nodules of the foot. While clinical aspects are well-described, genetic mechanisms are unknown. We report a family with cardiac disease due to a heterozygous LMNA mutation (c.736C>T, p.Gln246Stop) with palmar/plantar fibromatosis and investigate the hypothesis that a second rare DNA variant increases the risk for fibrotic disease in LMNA mutation carriers. The proband and six family members were evaluated for the cardiac and hand/feet phenotypes and tested for the LMNA mutation. Fibroblast RNA studies revealed monoallelic expression of the normal LMNA allele and reduced lamin A/C mRNAs consistent with LMNA haploinsufficiency. A novel, heterozygous missense variant (c.230T>C, p.Val77Ala) in the Asteroid Homolog 1 (ASTE1) gene was identified as a potential risk factor in fibrotic disease using exome sequencing and family studies of five family members: four LMNA mutation carriers with fibromatosis and one individual without the LMNA mutation and no fibromatosis. With a possible role in epidermal growth factor receptor signaling, ASTE1 may contribute to the increased risk for palmar/plantar fibromatosis in patients with Lamin A/C haploinsufficiency.

1212Gene-based risk stratification for cardiac disorders in LMNA mutation carriers

1212Gene-based risk stratification for cardiac disorders in LMNA mutation carriers

Clinical disease presentation and ECG characteristics of LMNA mutation carriers

ObjectiveMutations in the LMNA gene encoding lamins A and C of the nuclear lamina are a frequent cause of cardiomyopathy accounting for 5–8% of familial dilated cardiomyopathy (DCM). Our aim...

Long-Term Arrhythmic and Nonarrhythmic Outcomes of Lamin A/C Mutation Carriers

BackgroundMutations in LMNA are variably expressed and may cause cardiomyopathy, atrioventricular block (AVB), or atrial arrhythmias (AAs) and ventricular arrhythmias (VA). Detailed natural history studies of LMNA-associated arrhythmic and nonarrhythmic outcomes are limited, and the prognostic significance of the index cardiac phenotype remains uncertain. ObjectivesThis study sought to describe the arrhythmic and nonarrhythmic outcomes of LMNA mutation carriers and to assess the prognostic significance of the index cardiac phenotype. MethodsThe incidence of AVB, AA, sustained VA, left ventricular systolic dysfunction (LVD) (= left ventricular ejection fraction ≤50%), and end-stage heart failure (HF) was retrospectively determined in 122 consecutive LMNA mutation carriers followed at 5 referral centers for a median of 7 years from first clinical contact. Predictors of VA and end-stage HF or death were determined. ResultsThe prevalence of clinical manifestations increased broadly from index evaluation to median follow-up: AVB, 46% to 57%; AA, 39% to 63%; VA, 16% to 34%; and LVD, 44% to 57%. Implantable cardioverter-defibrillators were placed in 59% of patients for new LVD or AVB. End-stage HF developed in 19% of patients, and 13% died. In patients without LVD at presentation, 24% developed new LVD, and 7% developed end-stage HF. Male sex (p = 0.01), nonmissense mutations (p = 0.03), and LVD at index evaluation (p = 0.004) were associated with development of VA, whereas LVD was associated with end-stage HF or death (p < 0.001). Mode of presentation (with isolated or combination of clinical features) did not predict sustained VA or end-stage HF or death. ConclusionsLMNA-related heart disease was associated with a high incidence of phenotypic progression and adverse arrhythmic and nonarrhythmic events over long-term follow-up. The index cardiac phenotype did not predict adverse events. Genetic diagnosis and subsequent follow-up, including anticipatory planning for therapies to prevent sudden death and manage HF, is warranted.

Genotype-phenotype associations in dilated cardiomyopathy: meta-analysis on more than 8000 individuals.

Routine genetic testing in Dilated Cardiomyopathy (DCM) has recently become reality using Next-Generation Sequencing. Several studies have explored the relationship between genotypes and clinical phenotypes to support risk estimation and therapeutic decisions, however, most studies are small or restricted to a few genes. This study provides to our knowledge the first systematic meta-analysis on genotype-phenotype associations in DCM. We retrieved PubMed/Medline literature on genotype-phenotype associations in patients with DCM and mutations in LMNA, PLN, RBM20, MYBPC3, MYH7, TNNT2 and TNNI3. We summarized and extensively reviewed all studies that passed selection criteria and performed a meta-analysis on key phenotypic parameters. Together, 48 studies with 8097 patients were included. Furthermore, we reviewed recent studies investigating genotype-phenotype associations in DCM patients with TTN mutations. The average frequency of mutations in the investigated genes was between 1 and 5%. The mean age of DCM onset was the beginning of the fifth decade for all genes. Heart transplantation (HTx) rate was highest in LMNA mutation carriers (27%), while RBM20 mutation carriers were transplanted at a markedly younger age (mean 28.5years). While 73% of DCM patients with LMNA mutations showed cardiac conduction diseases, low voltage was the reported ECG hallmark in PLN mutation carriers. The frequency of ventricular arrhythmia in DCM patients with LMNA (50%) and PLN (43%) mutations was significantly higher. The penetrance of DCM phenotype in subjects with TTN truncating variants increased with age and reached 100% by age of 70. A pooled analysis of available genotype-phenotype data shows a higher prevalence of sudden cardiac death (SCD), cardiac transplantation, or ventricular arrhythmias in LMNA and PLN mutation carriers compared to sarcomeric gene mutations. This study will further support the clinical interpretation of genetic findings.

Proteomic identification of putative biomarkers for early detection of sudden cardiac death in a family with a LMNA gene mutation causing dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is a severe heart disease characterized by progressive ventricular dilation and impaired systolic function of the left ventricle. We recently identified a novel pathogenic mutation in the LMNA gene in a family affected by DCM showing sudden death background. We now aimed to identify potential biomarkers of disease status, as well as sudden death predictors, in members of this family. We analysed plasma samples from 14 family members carrying the mutation, four of which (with relevant clinical symptoms) were chosen for the proteomic analysis. Plasma samples from these four patients and from four sex- and age-matched healthy controls were processed for their enrichment in low- and medium-abundance proteins (ProteoMiner™) prior to proteomic analysis by 2D-DIGE and MS. 111 spots were found to be differentially regulated between mutation carriers and control groups, 83 of which were successfully identified by MS, corresponding to 41 different ORFs. Some proteins of interest were validated either by turbidimetry or western blot in family members and healthy controls. Actin, alpha-1-antytripsin, clusterin, vitamin-D binding protein and antithrombin-III showed increased levels in plasma from the diseased group. We suggest following these proteins as putative biomarkers for the evaluation of DCM status in LMNA mutation carriers. Biological significanceWe developed a proteomic analysis of plasma samples from a family showing history of dilated cardiomyopathy caused by a LMNA mutation, which may lead to premature death or cardiac transplant. We identified a number of proteins augmented in mutation carriers that could be followed as potential biomarkers for dilated cardiomyopathy on these patients.

Abstract 11990: LMNA Cardiomyopathy Mimicking Arrhythmogenic Right Ventricular Cardiomyopathy

Background and Objectives: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disease characterized by RV dilatation and ventricular arrhythmias. Desmosomal gene mutations are the major cause of ARVC. LMNA mutations have been known to lead dilated cardiomyopathy, other systemic diseases, and more recently, ARVC. In this study, we performed extensive genetic screening for LMNA in ARVC patients and assessed the clinical characteristics of patients with LMNA mutations. Methods: Study cohort consisted of 57 ARVC probands (definite; 45). Coding exons of LMNA, 4 desmosomal protein genes (PKP2, DSP, DSG2, DSC), and also 3 long QT syndrome related genes (KCNQ1, KCNH2, SCN5A) were amplified and sequenced by using illumina next generation sequencer. Clinical characteristics of LMNA mutation carriers and those of desmosomal mutation carriers were compared by using student t test. Results: Among 57 clinically-diagnosed ARVC probands, we identified desmosomal mutations in 32 probands (56.1%) and two LMNA mutations in two probands. The first LMNA mutation, p.M1K was detected in 62-year-old male, and the second one, p.W514X was in 70-year-old male. Both patients showed RV dilatation, non-sustained ventricular tachycardia, and complete atrioventricular block. His younger brother also died from ARVC. The proband’s daughter and son, who are currently in their 30s, have the same M1K mutation, however, have not had any signs of ARVC yet. In the family member with W514X mutant, the proband’s father suddenly died in his 40s and 45-year-old daughter who had the same W514X mutation, showed RV dilatation and brady-AF. In probands with LMNA mutations compared to those with desmosomal mutations, the age of onset was significantly older (38.6±18.1 vs 60.0±2.8), and their heart rate was significantly slower (61.1±12.5 vs 47±1.4). Both probands with LMNA mutations underwent pacemaker therapy, which is rare in patients with desmosomal mutations (2/2 vs 1/32 ). In family members with LMNA mutations, none of mutation carriers had showed ARVC until their 50s. Conclusion: Our patients with LMNA mutations developed ARVC with bradyarrhythmia after age of 50. Genetic screening for LMNA gene is important for ARVC, especially in cases with bradycardia.

0297: Risk stratification using CMR delayed enhancement in LMNA mutation carriers

Laminopathy is a frequent cause of familial dilated cardiomyopathy (DCM) associated with peripheral myopathy. The clinical cardiac manifestations are usually atrial fibrillation, atrio-ventricular blocks with a DCM. Myocardial delayed enhancement (DE) with cardiac magnetic resonance imaging (CMR) is known to be associated with a worse rhythmic prognosis in DCM. Determine if myocardial DE can be used as a risk stratification tool for cardiac prognosis in asymptomatic LMNA mutation carriers. Cohort study of 15 LMNA mutation carriers with left ventricular ejection fraction (LVEF) > 50% followed between 2009 et 2013 (10 DE+, 5 DE-). Primary endpoint was rythmic events uprise and secondary endpoint was LVEF evolution. Regarding patients with DE since 2009, 60% required pacemaker or implantable cardioverter-defibrillator (ICD) implantation for atrio-ventricular blocks, ventricular arrhythmias or left ventricular dysfunction whereas no patient with a normal CMR did (p = 0,027). In 2009, LVEF was similar in the two groups (LVEF = 68% DE+ group vs 65% DE- group, p = 0,18), whereas in 2013, DE group has a lower LVEF (LVEF = 53% DE+ group vs 65% DE- group, p = 0,009). Myocardial DE seems to be an early cardiac marker for PM or ICD implantation risk and left ventricular dysfunction in LMNA mutation carriers with normal LVEF.

Implantable cardioverter-defibrillators in lamin A/C mutation carriers with cardiac conduction disorders

Sudden cardiac death is frequent in patients with lamin A/C gene (LMNA) mutations and may be related to ventricular arrhythmias (VA). To evaluate a strategy of prophylactic implantable cardioverter-defibrillator (ICD) implantation in LMNA mutation carriers with significant cardiac conduction disorders. Forty-seven consecutive patients (mean age 38 ± 11 years; 26 men) were prospectively enrolled between March 1999 and April 2009. Prophylactic ICD implantation was performed in patients with significant cardiac conduction disorders: patients requiring permanent pacing for bradycardia or already implanted with a pacemaker at the initial presentation, or patients with a PR interval of >0.24 seconds and either complete left bundle branch block or nonsustained ventricular tachycardia. Twenty-one (45%) patients had significant conduction disorders and received a prophylactic ICD. Among ICD recipients, no patient died suddenly and 11 (52%) patients required appropriate ICD therapy during a median follow-up of 62 months. Left ventricular ejection fraction was ≥45% in 9 patients at the time of the event. Among the 10 patients without malignant VA, device memory recorded nonsustained ventricular tachycardia in 8 (80%). The presence of significant conduction disorders was the only factor related to the occurrence of malignant VA (hazard ratio 5.20; 95% confidence interval 1.14-23.53; P = .03). Life-threatening VAs are common in patients with LMNA mutations and significant cardiac conduction disorders, even if left ventricular ejection fraction is preserved. ICD is an effective treatment and should be considered in this patient population.

Genetic analysis in 418 index patients with idiopathic dilated cardiomyopathy: overview of 10 years' experience

With more than 40 dilated cardiomyopathy (DCM)-related genes known, genetic analysis of patients with idiopathic DCM is costly and time-consuming. We describe the yield from genetic analysis in DCM patients in a large Dutch cohort. We collected cardiological and neurological evaluations, family screenings, and genetic analyses for 418 index patients with idiopathic DCM. We identified 35 (putative) pathogenic mutations in 82 index patients (20%). The type of DCM influenced the yield, with mutations found in 25% of familial DCM cases, compared with 8% of sporadic DCM cases and 62% of cases where DCM was accompanied by neuromuscular disease. A PLN founder mutation (43 cases) and LMNA mutations (19 cases, 16 different mutations) were most prevalent and often demonstrated a specific phenotype. Other mutations were found in: MYH7, DES, TNNT2, DMD, TPM1, DMPK, SCN5A, SGCB (homozygous), and TNNI3. After a median follow-up of 40 months, the combined outcome of death from any cause, heart transplantation, or malignant ventricular arrhythmias in patients with a mutation was worse than in those without an identified mutation (hazard ratio 2.0, 95% confidence interval 1.4-3.0). This seems to be mainly attributable to a high prevalence of malignant ventricular arrhythmias and end-stage heart failure in LMNA and PLN mutation carriers. The yield of identified mutations in DCM index patients with clinical clues, such as associated neuromuscular disease or familial occurrence, is higher compared with those without these clues. For sporadic DCM, specific clinical characteristics may be used to select cases for DNA analysis.

LMNA mutations in Polish patients with dilated cardiomyopathy: prevalence, clinical characteristics, and in vitro studies

BackgroundLMNA mutations are most frequently involved in the pathogenesis of dilated cardiomyopathy with conduction disease. The goal of this study was to identify LMNA mutations, estimate their frequency among Polish dilated cardiomyopathy patients and characterize their effect both in vivo and in vitro.MethodsBetween January, 2008 and June, 2012 two patient populations were screened for the presence of LMNA mutations by direct sequencing: 66 dilated cardiomyopathy patients including 27 heart transplant recipients and 39 dilated cardiomyopathy patients with heart failure referred for heart transplantation evaluation, and 44 consecutive dilated cardiomyopathy patients, referred for a family evaluation and mutation screening.ResultsWe detected nine non-synonymous mutations including three novel mutations: p.Ser431*, p.Val256Gly and p.Gly400Argfs*11 deletion. There were 25 carriers altogether in nine families. The carriers were mostly characterized by dilated cardiomyopathy and heart failure with conduction system disease and/or complex ventricular arrhythmia, although five were asymptomatic. Among the LMNA mutation carriers, six underwent heart transplantation, fourteen ICD implantation and eight had pacemaker. In addition, we obtained ultrastructural images of cardiomyocytes from the patient carrying p.Thr510Tyrfs*42. Furthermore, because the novel p.Val256Gly mutation was found in a sporadic case, we verified its pathogenicity by expressing the mutation in a cellular model.ConclusionsIn conclusion, in the two referral centre populations, the screening revealed five mutations among 66 heart transplant recipients or patients referred for heart transplantation (7.6%) and four mutations among 44 consecutive dilated cardiomyopathy patients referred for familial evaluation (9.1%). Dilated cardiomyopathy patients with LMNA mutations have poor prognosis, however considerable clinical variability is present among family members.

Gender‐specific differences in major cardiac events and mortality in lamin A/C mutation carriers

Mutations in the lamin A/C gene (LMNA) cause a variety of clinical phenotypes, including dilated cardiomyopathy. LMNA is one of the most prevalent mutated genes in dilated cardiomyopathy, and is associated with a high risk of arrhythmias, sudden cardiac death, and heart failure. There are few data on the impact of age and gender on cardiac disease penetrance and mortality. In a multicentre cohort of 269 LMNA mutation carriers, we evaluated gender-specific penetrance of cardiac involvement and major cardiac events. All-cause mortality of mutation carriers [standardized mortality ratio (SMR)] was determined. Cardiac disease penetrance was age dependent and almost complete at the age of 70 years. The presence of an LVEF ≤45% was significantly higher in men (P < 0.001). However, there was no difference between genders in the prevalence of atrioventricular block, atrial tachyarrhythmias, and non-sustained ventricular tachycardia. Malignant ventricular arrhythmias (26% vs. 8%) and end-stage heart failure (28% vs. 14%) were more common in men than in women (P < 0.001 and P = 0.006, respectively). All-cause mortality of mutation carriers was significantly increased [SMR 4.0, 95% confidence interval (CI) 2.8-5.2] between the ages of 15 and 75 years. Mortality in men was higher than in women (hazard ratio 2.2, 95% CI 1.2-4.3). This large cohort of LMNA mutation carriers demonstrates a high cardiac disease penetrance and a high mortality in mutation carriers. Male mutation carriers have a worse prognosis due to a higher prevalence of malignant ventricular arrhythmias and end-stage heart failure.

Lamin A/C mutation is independently associated with an increased risk of arterial and venous thromboembolic complications

BackgroundLamin A/C (LMNA) mutation carriers suffer from a variety of clinical phenotypes, including dilated cardiomyopathy (DCM). Although it has been suggested that carriers are at risk for thromboembolic complications, it is unknown whether this risk is higher than can be expected from the underlying cardiac abnormalities. The purpose of this study was to determine whether a LMNA mutation is associated with an increased risk of thromboembolic complications. MethodsWe compared a cohort of 76 LMNA mutation carriers with a cohort of 224 idiopathic DCM patients without a LMNA mutation, with respect to the prevalence of arterial and venous thromboembolic complications. Furthermore, we carried out a case–control study to explore whether a prothrombotic phenotype was present in LMNA mutation carriers without DCM or atrial tachyarrhythmias (n=14) and compared this with mutation negative relatives (n=13). ResultsThe prevalence of thromboembolic complications was higher in the cohort of LMNA mutation carriers than in DCM patients (22 vs 11%; p<0.05), after respectively mean follow-up of 42±12 and 49±12years. After adjustment for possible confounders, including atrial tachyarrhythmias and left ventricular ejection fraction, LMNA mutation carriership was independently associated with an increased risk of thromboembolic complications (HR 4.8, 95% CI: 2.2–10.6). The results of the case–control study suggested a prothrombotic phenotype in LMNA mutation carriers, as reflected by an altered platelet function and increased thrombin generation. ConclusionsLMNA mutation is independently associated with an increased risk of arterial and venous thromboembolic complications. Laboratory research in LMNA mutation carriers without severe cardiac abnormalities suggests a prothrombotic phenotype.

Protein profiling reveals energy metabolism and cytoskeletal protein alterations in LMNA mutation carriers

Nuclear envelope-related muscular dystrophies, in particular those referred to as laminopathies, are relatively novel and unclear diseases, also considering the increasing number of mutations identified so far in genes of the nuclear envelope. As regard LMNA gene, only tentative relations between phenotype, type and localization of the mutations have been established in striated muscle diseases, while laminopathies affecting adipose tissue, peripheral nerves or progerioid syndromes could be linked to specific genetic variants. This study describes the biochemical phenotype of neuromuscular laminopathies in samples derived from LMNA mutant patients. Since it has been reported that nuclear alterations, due to LMNA defects, are present also in fibroblasts from Emery–Dreifuss muscular dystrophy and familial partial lipodystrophy patients, we analyzed 2D-maps of skin fibroblasts of patients carrying 12 different LMNA mutations spread along the entire gene. To recognize distinctive proteins underlying affected biochemical pathways, we compared them with fibroblasts from healthy controls and, more importantly, fibroblasts from patients with non-lamin related neuromuscular disorders. We found less abundance of cytoskeletal/structural proteins, confirming a dominant role for Lamin A/C in structural support of nuclear architecture. Interestingly, we also established significant changes in the expression of proteins involved in cellular energy production and oxidative stress response. To our knowledge, this is the first report where proteomics was applied to characterize ex-vivo cells from LMNA patients, suggesting that this may represent a new approach to better understand the molecular mechanisms of these rare diseases and facilitate the development of novel therapeutic treatments.

Identification of Novel Mutations inLMNAAssociated with Familial Forms of Dilated Cardiomyopathy

The lamin A/C proteins are major structural and functional components of the nuclear lamina. Mutations identified in LMNA encoding lamin A/C belong to the most frequently described causes for inherited forms of dilated cardiomyopathy (DCM). To elucidate the clinical characteristics of LMNA mutation carriers we performed genetic analysis of LMNA in 20 unrelated patients with DCM and cardiac conduction disease. In six small nuclear families heterozygous mutations in LMNA were identified. Two missense mutations led to the substitution of highly conserved amino acid residues within the rod domain of lamin A/C and four not-yet-described nonsense mutations cause the formation of predicted truncated lamin A/C missing parts of the tail domain. DCM was the most prominent clinical characteristic of the affected family members with a high degree of involvement of conduction system defects and less often accompanied by muscular dystrophy. The cardiac phenotype of the affected family members was severe and progressive with age, indicating the necessity for a genetic testing for LMNA mutations in patients with familial DCM and early onset of conduction disorders.