Low and High Expressing Alleles of the LMNA Gene: Implications for Laminopathy Disease Development

Today, there are at least a dozen different genetic disorders caused by mutations within the LMNA gene, and collectively, they are named laminopathies. Interestingly, the same mutation can cause phenotypes with different severities or even different disorders and might, in some cases, be asymptomatic. We hypothesized that one possible contributing mechanism for this phenotypic variability could be the existence of high and low expressing alleles in the LMNA locus. To investigate this hypothesis, we developed an allele-specific absolute quantification method for lamin A and lamin C transcripts using the polymorphic rs4641C/T LMNA coding SNP. The contribution of each allele to the total transcript level was investigated in nine informative human primary dermal fibroblast cultures from Hutchinson-Gilford progeria syndrome (HGPS) and unaffected controls. Our results show differential expression of the two alleles. The C allele is more frequently expressed and accounts for ∼70% of the lamin A and lamin C transcripts. Analysis of samples from six patients with Hutchinson-Gilford progeria syndrome showed that the c.1824C>T, p.G608G mutation is located in both the C and the T allele, which might account for the variability in phenotype seen among HGPS patients. Our method should be useful for further studies of human samples with mutations in the LMNA gene and to increase the understanding of the link between genotype and phenotype in laminopathies

Arrhythmias in Dilated Cardiomyopathy: Diagnosis and Treatment

In patients with dilated cardiomyopathy (DCM), it is possible to find a broad range of bradyrhythmias and tachyarrhythmias. Bradyrhythmias and supraventricular arrhythmias can frequently occur in some familial forms such as lamin A/C mutations. Nonsustained ventricular arrhythmias (VA) are observed in about 40% of patients with DCM, but their prognostic role is not clear, and conflicting data have been published in the last 30 years. Multiple mechanisms can explain atrial and ventricular tachyarrhythmias in DCM. Reentry is associated with slow conduction across surviving muscle bundles within regions of interstitial fibrosis, but other mechanisms can be involved, as nonuniform anisotropy of impulse propagation, ion channel dysfunction, and reduced gap junction function

La féminisation de la Fonction publique

Pascaud-Bécane Geneviève. La féminisation de la Fonction publique. In: Diplômées, n°93, 1975. pp. 6-21

High cardiovascular morbidity and mortality in myofibrillar myopathies due to DES gene mutations: a 10-year longitudinal study.

To determine incidence and type of major cardiac adverse events in patients with mutated desmin (DES) gene, we retrospectively reviewed baseline medical information, and examined the long-term outcomes of 28 DES patients (17 men, baseline mean age=37.7±14.4 years [min=9, max=71]) from 19 families. Baseline studies revealed skeletal muscle involvement in 21 patients and cardiac abnormalities in all but one patient. Over a mean follow-up of 10.4±9.4 years [min=1, max=35], cardiac death occurred in three patients, death due to cardiac comorbidities in two, one or more major cardiac adverse events in 13 patients. Among the 19 patients with mild conduction defects at baseline, eight developed high-degree conduction blocks requiring permanent pacing. Cardiac involvement was neither correlated with the type of DES mutation nor with the severity of skeletal muscle involvement. Our study underscores that in DES patients in-depth cardiac investigations are needed to prevent cardiac conduction system disease

High Risk of Fatal and Nonfatal Venous Thromboembolism in Myotonic Dystrophy

International audienceMyotonic dystrophy (MD), the most common inherited myopathy, is associated with high cardiovascular mortality 1. A preliminary analysis of the DM1 Heart Registry (URL: ClinicalTrials.gov. Unique identifier: NCT01136330), a comprehensive database that captures information relative to the cardiac management of adults presenting to our center with MD 2 , revealed a high prevalence of venous thromboembolism (VTE). We designed this study to estimate the risk of VTE in MD and its survival consequences. We retrospectively analyzed the data relative to patients referred to our center between January 2000 and January 2015, including 1148 with MD and 1662 with other inherited myopathies (facioscapulohumeral, dystrophinopathy, mitochondrial, glycogen-and lipid-storage diseases, limb-girdle muscular dystrophies, nucleopathies, collagen VI-related disorders, myofibrillar, and congenital). This study was approved by our local Ethics Committee, and all patients granted their written informed consent to participate. We compared patient baseline characteristics using Wilcoxon rank-sum or Fisher exact tests as appropriate. VTE, defined as ≥1 episode of deep vein thrombosis or pulmonary embolism, was analyzed in a competing-risks framework, with death as a competing event. Cumulative incidences (probability of occurrence over follow-up), hazard ratios (HRs), and cumulative hazards of VTE were estimated. We searched for predictors of the hazard of VTE using Cox proportional hazards models for the cause-specific hazards on the time of study scale, with follow-up beginning on the date of inclusion in the study until the occurrence of VTE, death, or last follow-up, whichever occurred first. All patient characteristics described in the results were included in this analysis, including all variables from our database that represent known VTE risk factors. At first presentation, patients with MD, compared with others, were older (40 [29-51] years versus 39 [25-52] years; P=0.029); had a lower proportion of men (556 [48.4%] versus 990 [59.6%]; P<0.0001); had a more frequent personal history of VTE (40 [3.5%] versus 9 [0.5%]; P<0.0001), heart failure (12 [1.0%] versus 128 [7.7%]; P<0.0001), and conduction disease (461 [40.2%] versus 195 [11.7%]; P<0.0001); were treated with vitamin K antagonists (32 [3.0%] versus 25 [1.5%], P=0.009) and estrogen contraceptives (137 [11.9%] versus 140 [8.4%], P=0.002); and had a lower Walton score 3 (1 [0-3] versus 3 [1-6]; P<0.0001) and less frequent ambulation loss (80 [6.9%] versus 405 [24.4%], P<0.0001). A similar prevalence was observed for obesity (123 [10.9%] versus 183 [11.2%]; P=0.85), respiratory failure (133 [13.2%] versus 257 [15.8%]; P=0.071), and cancer (31 [2.8%] versus 33 [1.9%]; P=0.25). VT

0457: Atrial flutter in myotonic dystrophy type 1: patient characteristics and clinical outcome

BackgroundThe characteristics of DM1 patients with atrial flutter (AFL) and their clinical outcome are unknown.MethodsWe retrospectively included the patients≥18 years of age with DM1 who were admitted in our institutions with AFL between January 2000 and September 2013 and analyzed their clinical outcome. We compared the incidence of AFL recurrences in patients who were treated with versus without radiofrequency (RF) ablation. Single and multiple variable analyses were performed to identify predictors of AFL recurrences.ResultsWe included 60 consecutive patients (age=41±13 years, male=34), including 55 with persistent, 2 with paroxysmal, and 3 permanent AFL. Over a 53±28 months mean follow-up duration, AFL recurrence occurred in 12 patients (24%), atrial fibrillation in 13 (26%), ischemic stroke in 2 (3%), cerebral hemorrhage in 1 (2%) and sinus node dysfunction in 4 (7%). Patients treated by RF ablation were significantly more frequently free of AFL recurrences by Kaplan Meier analysis (95% vs. 61%, HR=0.17, 95% CI 0.08 to 0.97, p=0.04). By multivariate analyses, RF ablation was the only parameter significantly associated with absence of AFL recurrence (p=0.01).ConclusionsPatients with DM1 presenting with AFL are exposed to stroke, severe sinus node dysfunction and cerebral hemorrhage. RF catheter ablation is associated with a lower risk for AFL recurrences and may limit iatrogenic complications associated with pharmacological treatments

High Risk of Fatal and Nonfatal Venous Thromboembolism in Myotonic Dystrophy

International audienceMyotonic dystrophy (MD), the most common inherited myopathy, is associated with high cardiovascular mortality 1. A preliminary analysis of the DM1 Heart Registry (URL: ClinicalTrials.gov. Unique identifier: NCT01136330), a comprehensive database that captures information relative to the cardiac management of adults presenting to our center with MD 2 , revealed a high prevalence of venous thromboembolism (VTE). We designed this study to estimate the risk of VTE in MD and its survival consequences. We retrospectively analyzed the data relative to patients referred to our center between January 2000 and January 2015, including 1148 with MD and 1662 with other inherited myopathies (facioscapulohumeral, dystrophinopathy, mitochondrial, glycogen-and lipid-storage diseases, limb-girdle muscular dystrophies, nucleopathies, collagen VI-related disorders, myofibrillar, and congenital). This study was approved by our local Ethics Committee, and all patients granted their written informed consent to participate. We compared patient baseline characteristics using Wilcoxon rank-sum or Fisher exact tests as appropriate. VTE, defined as ≥1 episode of deep vein thrombosis or pulmonary embolism, was analyzed in a competing-risks framework, with death as a competing event. Cumulative incidences (probability of occurrence over follow-up), hazard ratios (HRs), and cumulative hazards of VTE were estimated. We searched for predictors of the hazard of VTE using Cox proportional hazards models for the cause-specific hazards on the time of study scale, with follow-up beginning on the date of inclusion in the study until the occurrence of VTE, death, or last follow-up, whichever occurred first. All patient characteristics described in the results were included in this analysis, including all variables from our database that represent known VTE risk factors. At first presentation, patients with MD, compared with others, were older (40 [29-51] years versus 39 [25-52] years; P=0.029); had a lower proportion of men (556 [48.4%] versus 990 [59.6%]; P<0.0001); had a more frequent personal history of VTE (40 [3.5%] versus 9 [0.5%]; P<0.0001), heart failure (12 [1.0%] versus 128 [7.7%]; P<0.0001), and conduction disease (461 [40.2%] versus 195 [11.7%]; P<0.0001); were treated with vitamin K antagonists (32 [3.0%] versus 25 [1.5%], P=0.009) and estrogen contraceptives (137 [11.9%] versus 140 [8.4%], P=0.002); and had a lower Walton score 3 (1 [0-3] versus 3 [1-6]; P<0.0001) and less frequent ambulation loss (80 [6.9%] versus 405 [24.4%], P<0.0001). A similar prevalence was observed for obesity (123 [10.9%] versus 183 [11.2%]; P=0.85), respiratory failure (133 [13.2%] versus 257 [15.8%]; P=0.071), and cancer (31 [2.8%] versus 33 [1.9%]; P=0.25). VT

High Risk of Fatal and Non-Fatal Venous Thromboembolism in Myotonic Dystrophy

International audienceBackground: The risk of venous thromboembolism (VTE), defined as deep vein thrombosis, pulmonany embolism (PE), or both, in myotonic dystrophy (DM) is unknown. Our objective was to estimate the risk of VTE in DM and its impact on all-cause and cardiovascular mortality. Methods: In 1,148 retrospectively studied adults (592 women) suffering from DM, referred between January 2000 and January 2015, we estimated the cumulative incidence of VTE and proportion of all- cause and cardiovascular deaths, and compared the incidence of VTE with that in patients with other inherited myopathies followed at our center, and with a community-based French population. Results: Among all patients with DM (mean age=40.6#14.3; 592 women), 82 developed VTE over a 10.9-year follow-up (95% CI 2.4 to 14.7), representing a 10.3% cumulative incidence (95% CI 7.8 to 12.7%), and 253 died, 83 of a cardiovascular cause. In patients with DM, the incidence of VTE was higher than a) in 1,662 patients (mean age=39.7+16.2; 989 women) with other inherited myopathies (mean age=39.7+16.2), in whom the cumulative incidence was 2.2% (95% Cl 1.1 to 3.3) and hazard ratio (HR) 4.63 (95% CI 2.63 to 8.18; p<0.0001), and b) in a community-based population with a standardized rate ratio of 7.53 (95% CI 6.02 to 9.28; p<0.0001). VTE was independently predicted by age (HR=1.02; 95% CI 1.00 to 1.04; p=0.041), personal history of VTE (HR=4.71; 95% CI 2.20 to 10.1; p<0.0001), obesity (HR=2.31; 95% CI 1.30 to 4.08; p=0.004), loss of ambulation (HR=4.57;95% C| 2.12 to9.87; p=0.0001) and history of cancer (HR=3.89; 95% CI 1.62 to 9.32; p=0.002). The 26 deaths from PE in patients with DM represented 10.3% of all deaths and 31.3% of cardiovascular deaths. Conclusion: The risk of fatal and non-fatal VTE in patients with DM was high