The Experts below are selected from a list of 119301 Experts worldwide ranked by ideXlab platform

Cecile Julier - One of the best experts on this subject based on the ideXlab platform.

Marc Delepine - One of the best experts on this subject based on the ideXlab platform.

  • wolcott rallison syndrome clinical genetic and functional study of eif2ak3 mutations and suggestion of genetic heterogeneity
    Diabetes, 2004
    Co-Authors: Valérie Senée, Krishna M. Vattem, Lynn A. Rainbow, Annick Lecoq, Jean J. Robert, R. P. Rooman, Nick Shaw, Marc Delepine, Céline Haton, Catherine Diatloffzito
    Abstract:

    Wolcott-Rallison syndrome (WRS) is a rare autosomal-recessive disorder characterized by the association of permanent neonatal or early-infancy insulin-dependent diabetes, multiple epiphyseal dysplasia and growth retardation, and other variable multisystemic clinical manifestations. Based on genetic studies of two inbred families, we previously identified the gene responsible for this disorder as EIF2AK3 , the pancreatic eukaryotic initiation factor 2α (eIF2α) kinase. Here, we have studied 12 families with WRS, totalling 18 cases. With the exception of one case, all patients carried EIF2AK3 mutations resulting in truncated or missense versions of the protein. Exclusion of EIF2AK3 mutations in the one patient case was confirmed by both linkage and sequence data. The activities of missense versions of EIF2AK3 were characterized in vivo and in vitro and found to have a complete lack of activity in four mutant proteins and residual kinase activity in one. Remarkably, the onset of diabetes was relatively late (30 months) in the patient expressing the partially defective EIF2AK3 mutant and in the patient with no EIF2AK3 involvement (18 months) compared with other patients (<6 months). The patient with no EIF2AK3 involvement did not have any of the other variable clinical manifestations associated with WRS, which supports the idea that the genetic heterogeneity between this variant form of WRS and EIF2AK3 WRS correlates with some clinical heterogeneity.

  • wolcott rallison syndrome clinical genetic and functional study of eif2ak3 mutations and suggestion of genetic heterogeneity
    Diabetes, 2004
    Co-Authors: Valérie Senée, Krishna M. Vattem, Lynn A. Rainbow, Annick Lecoq, Jean J. Robert, R. P. Rooman, Nick Shaw, Marc Delepine, Céline Haton, Catherine Diatloffzito
    Abstract:

    Wolcott-Rallison syndrome (WRS) is a rare autosomal-recessive disorder characterized by the association of permanent neonatal or early-infancy insulin-dependent diabetes, multiple epiphyseal dysplasia and growth retardation, and other variable multisystemic clinical manifestations. Based on genetic studies of two inbred families, we previously identified the gene responsible for this disorder as EIF2AK3 , the pancreatic eukaryotic initiation factor 2α (eIF2α) kinase. Here, we have studied 12 families with WRS, totalling 18 cases. With the exception of one case, all patients carried EIF2AK3 mutations resulting in truncated or missense versions of the protein. Exclusion of EIF2AK3 mutations in the one patient case was confirmed by both linkage and sequence data. The activities of missense versions of EIF2AK3 were characterized in vivo and in vitro and found to have a complete lack of activity in four mutant proteins and residual kinase activity in one. Remarkably, the onset of diabetes was relatively late (30 months) in the patient expressing the partially defective EIF2AK3 mutant and in the patient with no EIF2AK3 involvement (18 months) compared with other patients (<6 months). The patient with no EIF2AK3 involvement did not have any of the other variable clinical manifestations associated with WRS, which supports the idea that the genetic heterogeneity between this variant form of WRS and EIF2AK3 WRS correlates with some clinical heterogeneity.

  • eif2ak3 encoding translation initiation factor 2 α kinase 3 is mutated in patients with wolcott rallison syndrome
    Nature Genetics, 2000
    Co-Authors: Marc Delepine, Marc Nicolino, M Golamaully, Cecile Julier, G. Mark Lathrop, Timothy Barrett
    Abstract:

    EIF2AK3 , encoding translation initiation factor 2-α kinase 3, is mutated in patients with Wolcott-Rallison syndrome

  • eif2ak3 encoding translation initiation factor 2 α kinase 3 is mutated in patients with wolcott rallison syndrome
    Nature Genetics, 2000
    Co-Authors: Marc Delepine, Marc Nicolino, M Golamaully, Cecile Julier, G. Mark Lathrop, Timothy Barrett
    Abstract:

    EIF2AK3 , encoding translation initiation factor 2-α kinase 3, is mutated in patients with Wolcott-Rallison syndrome

  • eif2ak3 encoding translation initiation factor 2 α kinase 3 is mutated in patients with wolcott rallison syndrome
    Nature Genetics, 2000
    Co-Authors: Marc Delepine, Marc Nicolino, M Golamaully, Cecile Julier, G. Mark Lathrop, Timothy Barrett
    Abstract:

    Wolcott-Rallison syndrome (WRS) is a rare, autosomal recessive disorder characterized by permanent neonatal or early infancy insulin-dependent diabetes. Epiphyseal dysplasia, osteoporosis and growth retardation occur at a later age. Other frequent multisystemic manifestations include hepatic and renal dysfunction, mental retardation and cardiovascular abnormalities1,2,3,4,5. On the basis of two consanguineous families, we mapped WRS to a region of less than 3 cM on chromosome 2p12, with maximal evidence of linkage and homozygosity at 4 microsatellite markers within an interval of approximately 1 cM. The gene encoding the eukaryotic translation initiation factor 2-α kinase 3 (EIF2AK3) resides in this interval; thus we explored it as a candidate. We identified distinct mutations of EIF2AK3 that segregated with the disorder in each of the families. The first mutation produces a truncated protein in which the entire catalytic domain is missing. The other changes an amino acid, located in the catalytic domain of the protein, that is highly conserved among kinases from the same subfamily. Our results provide evidence for the role of EIF2AK3 in WRS. The identification of this gene may provide insight into the understanding of the more common forms of diabetes and other pathologic manifestations of WRS.

David Montani - One of the best experts on this subject based on the ideXlab platform.

  • pulmonary vascular remodeling patterns and expression of general control nonderepressible 2 gcn2 in pulmonary veno occlusive disease
    Journal of Heart and Lung Transplantation, 2017
    Co-Authors: Esther J Nossent, Maria Rosa Ghigna, Fabrice Antigny, Melanie Lambert, Vincent Thomas De Montpreville, Xavier Jais, Harm Jan Bogaard, Barbara Girerd, David Montani, Laurent Savale
    Abstract:

    Background: Heritable pulmonary veno-occlusive disease (PVOD) is linked to mutations in the eukaryotic initiation factor 2 alpha kinase 4 (EIF2AK4) gene, leading to a loss of general control nonderepressible 2 (GCN2). The role of GCN2 expression in pulmonary vascular remodeling remains obscure. We sought to identify specific histologic and biologic features in heritable PVOD. Methods: Clinical data and lung histology of 24 PVOD patients (12 EIF2AK4 mutation carriers, 12 non-carriers) were submitted to systematic histologic analysis and semiautomated morphometry. GCN2 expression was quantified by Western blotting in 24 PVOD patients, 44 patients with pulmonary arterial hypertension (PAH; 23 bone morphogenetic protein receptor type II [. BMPR2] mutation carriers, 21 non-carriers), and 3 experimental pulmonary hypertension models. Results: PVOD patients showed a significant decrease of pulmonary arterial patency (p < 0.0001) compared with healthy controls. Histology of EIF2AK4 mutation carriers was distinctive from non-carriers regarding (1) arterial remodeling, with significantly more severe intimal fibrosis (p = 0.001), less severe medial hypertrophy (p = 0.001), and (2) stronger muscular hyperplasia of interlobular septal veins (p = 0.002). GCN2 expression was abolished in heritable PVOD (p < 0.0001), but also importantly decreased in sporadic PVOD (p = 0.03) as well as in heritable (p = 0.002) and idiopathic PAH (p = 0.003); moreover, GCN2 was abolished in 2 experimental pulmonary hypertension models and importantly decreased in 1 model (p < 0.0001 for all models). Conclusions: Pulmonary arterial remodeling in PVOD is present to an important extent. A significant decrease of GCN2 expression is a common denominator of all tested groups of PVOD and PAH, including their respective experimental models. Our results underline specific morphologic and biologic similarities between PAH and PVOD and let us consider both conditions rather in one large spectrum of disease than as two distinct and clear-cut entities.

  • Heritable pulmonary hypertension: from bench to bedside.
    European respiratory review : an official journal of the European Respiratory Society, 2017
    Co-Authors: Barbara Girerd, David Montani, Jason Weatherald, Marc Humbert
    Abstract:

    Mutations in the BMPR2 gene, and more rarely in ACVRL1, endoglin, caveolin-1, KCNK3 and TBX4 genes predispose to heritable pulmonary arterial hypertension, an autosomal dominant disease with incomplete penetrance. Bi-allelic mutations in the EIF2AK4 gene predispose to heritable pulmonary veno-occlusive disease/pulmonary capillary haemangiomatosis, an autosomal recessive disease with an unknown penetrance.In France, the national pulmonary hypertension referral centre offers genetic counselling and testing to adults and children. Predictive testing is also proposed to adult relatives at risk of carrying a predisposing mutation. In that context, we offer all asymptomatic BMPR2 mutation carriers a programme to detect pulmonary arterial hypertension at an early phase, as recommended by the 2015 European Society Society of Cardiology/European Respiratory Society pulmonary hypertension guidelines. Finally, pre-implantation genetic diagnosis has been conducted on five embryos from two couples in which the fathers were carriers of a pathogenic BMPR2 mutation.

  • clinical phenotypes and outcomes of heritable and sporadic pulmonary veno occlusive disease a population based study
    The Lancet Respiratory Medicine, 2017
    Co-Authors: David Montani, Laurent Savale, Xavier Jais, Andrei Seferian, Barbara Girerd, Peter Dorfmüller, Edmund M T Lau, Marilyne Levy, David Amar, Melanie Eyries
    Abstract:

    Background Bi-allelic mutations of the EIF2AK4 gene cause heritable pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis (PVOD/PCH). We aimed to assess the eff ect of EIF2AK4 mutations on the clinical phenotypes and outcomes of PVOD/PCH. Methods We did a population-based study using clinical, functional, and haemodynamic data from the registry of the French Pulmonary Hypertension Network. We reviewed the clinical data and outcomes from all patients referred to the French Referral Centre (Pulmonary Department, Hospital Kremlin-Bicetre, University Paris-Sud) with either confi rmed or highly probable PVOD/PCH with DNA available for mutation screening (excluding patients with other risk factors of pulmonary hypertension, such as chronic respiratory diseases). We sequenced the coding sequence and intronic junctions of the EIF2AK4 gene, and compared clinical characteristics and outcomes between EIF2AK4 mutation carriers and non-carriers. Medical therapies approved for pulmonary arterial hypertension (prostacyclin derivatives, endothelin receptor antagonists and phosphodiesterase type-5 inhibitors) were given to patients according to the clinical judgment and discretion of treating physicians. The primary outcome was the event-free survival (death or transplantation). Secondary outcomes included response to therapies for pulmonary arterial hypertension and survival after lung transplantation. A satisfactory clinical response to specifi c therapy for pulmonary arterial hypertension was defi ned by achieving New York Heart Association functional class I or II, a 6-min walk distance of more than 440 m, and a cardiac index greater than 2·5 L/min per m² at the fi rst reassessment after initiation of specifi c therapy for pulmonary arterial hypertension. Findings We obtained data from Jan 1, 2003, to June 1, 2016, and identifi ed 94 patients with sporadic or heritable PVOD/PCH (confi rmed or highly probable). 27 (29%) of these patients had bi-allelic EIF2AK4 mutations. PVOD/ PCH due to EIF2AK4 mutations occurred from birth to age 50 years, and these patients were younger at presentation than non-carriers (median 26·0 years [range 0–50.3] vs 60·0 years [6·7–81·4] years; p<0·0001). At diagnosis, both mutations carriers and non-carriers had similarly severe precapillary pulmonary hypertension and functional impairment. 22 (81%) of mutations carriers and 63 (94%) of non-carriers received therapy approved for pulmonary arterial hypertension. Drug-induced pulmonary oedema occurred in fi ve (23%) of treated EIF2AK4 mutations carriers and 13 (21%) of treated non-carriers. Follow-up assessment after initiation of treatment showed that only three (4%) patients with PVOD/PCH reached the predefi ned criteria for satisfactory clinical response. The probabilities of event-free survival (death or transplantation) at 1 and 3 years were 63% and 32% in EIF2AK4 mutations carriers, and 75% and 34% in non-carriers. No signifi cant diff erences occurred in event-free survival between the 2 groups (p=0·38). Among the 33 patients who had lung transplantation, estimated posttransplantation survival rates at 1, 2, and 5 years were 84%, 81%, and 73%, respectively. Interpretation Heritable PVOD/PCH due to bi-allelic EIF2AK4 mutations is characterised by a younger age at diagnosis but these patients display similar disease severity compared with mutation non-carriers. Response to therapy approved for pulmonary arterial hypertension in PVOD/PCH is rare. PVOD/PCH is a devastating condition and lung transplantation should be considered for eligible patients.

  • caracteristiques des patients atteints de maladie veino occlusive porteurs de mutations du gene EIF2AK4
    Revue Des Maladies Respiratoires, 2016
    Co-Authors: David Montani, Laurent Savale, Andrei Seferian, Barbara Girerd, Florent Soubrier, D Amar, X Jais, F Parent, E Fadel, O Sitbon
    Abstract:

    Introduction Le gene EIF2AK4  a recemment ete decouvert comme le gene de predisposition a la maladie veino-occlusive pulmonaire (MVO). La MVO heritable se transmet sur le mode autosomique recessif. Methodes Les donnees cliniques et de survie des patients porteurs de mutations bi-alleliques du gene EIF2AK4  et suivis dans le centre de reference de l’hypertension pulmonaire severe, ont ete recuperees. Resultats Vingt-quatre patients porteurs de mutations bi-alleliques du gene EIF2AK4  ont ete identifies (13 femmes, âge 26,4 ± 8,7 ans). Au diagnostic, les patients etaient majoritairement en classe fonctionnelle NYHA III (71 %) ou IV (21 %). La distance parcourue au test de marche de 6 min etait de 365 ± 168 m. Les patients etaient hypoxemiques (9,5 ± 1,9 kPa) avec une DLCO basse (30 ± 7 %) et presentaient une hypertension pulmonaire precapillaire severe (PAPmoyenne : 51 ± 12 mmHg, PAP d’occlusion : 8 ± 4 mmHg, index cardiaque : 2,53 ± 0,89 L/min/m 2 , et resistances vasculaires pulmonaires : 12,5 ± 6,6 UW). Le scanner thoracique revelait des lignes septales, des nodules flous, et des adenopathies mediastinales chez 100 %, 96 % et 83 % des patients, respectivement. Aucune reponse clinique a long terme n’a ete observee chez les patients recevant un traitement de l’HTAP ( n  = 21) et 5 patients ont developpe un œdeme pulmonaire. Quatre patients sont decedes durant le suivi et 18 ont beneficie d’une transplantation pulmonaire. La survie sans evenement (deces ou transplantation) a 1, 2 et 3 ans etait de 63 %, 54 % et 32 %. Conclusion La MVO heritable associee a des mutations bi-alleliques du gene EIF2AK4  est caracterisee par un jeune âge au diagnostic et une severite clinique, fonctionnelle et hemodynamique. Le pronostic est sombre et la transplantation pulmonaire reste le traitement de reference.

  • occupational exposure to organic solvents a risk factor for pulmonary veno occlusive disease
    European Respiratory Journal, 2015
    Co-Authors: David Montani, Laurent Savale, Xavier Jais, Lynda Bensefacolas, Ines Zendah, Jerome Le Pavec, Pascal Andujar, Barbara Girerd, Alexis Descatha, Andrei Seferian
    Abstract:

    Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension characterised by predominant remodelling of pulmonary venules. Bi-allelic mutations in the eukaryotic translation initiation factor 2α kinase 4 ( EIF2AK4 ) gene were recently described as the major cause of heritable PVOD, but risk factors associated with PVOD remain poorly understood. Occupational exposures have been proposed as a potential risk factor for PVOD, but epidemiological studies are lacking. A case–control study was conducted in consecutive PVOD (cases, n=33) and pulmonary arterial hypertension patients (controls, n=65). Occupational exposure was evaluated via questionnaire interview with blinded assessments using an expert consensus approach and a job exposure matrix (JEM). Using the expert consensus approach, PVOD was significantly associated with occupational exposure to organic solvents (adjusted OR 12.8, 95% CI 2.7–60.8), with trichloroethylene being the main agent implicated (adjusted OR 8.2, 95% CI 1.4–49.4). JEM analysis independently confirmed the association between PVOD and trichloroethylene exposure. Absence of significant trichloroethylene exposure was associated with a younger age of disease (54.8±21.4 years, p=0.037) and a high prevalence of harbouring bi-allelic EIF2AK4 mutations (41.7% versus 0%, p=0.015). Occupational exposure to organic solvents may represent a novel risk factor for PVOD. Genetic background and environmental exposure appear to influence the phenotypic expression of the disease.

Barbara Girerd - One of the best experts on this subject based on the ideXlab platform.

  • pulmonary vascular remodeling patterns and expression of general control nonderepressible 2 gcn2 in pulmonary veno occlusive disease
    Journal of Heart and Lung Transplantation, 2017
    Co-Authors: Esther J Nossent, Maria Rosa Ghigna, Fabrice Antigny, Melanie Lambert, Vincent Thomas De Montpreville, Xavier Jais, Harm Jan Bogaard, Barbara Girerd, David Montani, Laurent Savale
    Abstract:

    Background: Heritable pulmonary veno-occlusive disease (PVOD) is linked to mutations in the eukaryotic initiation factor 2 alpha kinase 4 (EIF2AK4) gene, leading to a loss of general control nonderepressible 2 (GCN2). The role of GCN2 expression in pulmonary vascular remodeling remains obscure. We sought to identify specific histologic and biologic features in heritable PVOD. Methods: Clinical data and lung histology of 24 PVOD patients (12 EIF2AK4 mutation carriers, 12 non-carriers) were submitted to systematic histologic analysis and semiautomated morphometry. GCN2 expression was quantified by Western blotting in 24 PVOD patients, 44 patients with pulmonary arterial hypertension (PAH; 23 bone morphogenetic protein receptor type II [. BMPR2] mutation carriers, 21 non-carriers), and 3 experimental pulmonary hypertension models. Results: PVOD patients showed a significant decrease of pulmonary arterial patency (p < 0.0001) compared with healthy controls. Histology of EIF2AK4 mutation carriers was distinctive from non-carriers regarding (1) arterial remodeling, with significantly more severe intimal fibrosis (p = 0.001), less severe medial hypertrophy (p = 0.001), and (2) stronger muscular hyperplasia of interlobular septal veins (p = 0.002). GCN2 expression was abolished in heritable PVOD (p < 0.0001), but also importantly decreased in sporadic PVOD (p = 0.03) as well as in heritable (p = 0.002) and idiopathic PAH (p = 0.003); moreover, GCN2 was abolished in 2 experimental pulmonary hypertension models and importantly decreased in 1 model (p < 0.0001 for all models). Conclusions: Pulmonary arterial remodeling in PVOD is present to an important extent. A significant decrease of GCN2 expression is a common denominator of all tested groups of PVOD and PAH, including their respective experimental models. Our results underline specific morphologic and biologic similarities between PAH and PVOD and let us consider both conditions rather in one large spectrum of disease than as two distinct and clear-cut entities.

  • Heritable pulmonary hypertension: from bench to bedside.
    European respiratory review : an official journal of the European Respiratory Society, 2017
    Co-Authors: Barbara Girerd, David Montani, Jason Weatherald, Marc Humbert
    Abstract:

    Mutations in the BMPR2 gene, and more rarely in ACVRL1, endoglin, caveolin-1, KCNK3 and TBX4 genes predispose to heritable pulmonary arterial hypertension, an autosomal dominant disease with incomplete penetrance. Bi-allelic mutations in the EIF2AK4 gene predispose to heritable pulmonary veno-occlusive disease/pulmonary capillary haemangiomatosis, an autosomal recessive disease with an unknown penetrance.In France, the national pulmonary hypertension referral centre offers genetic counselling and testing to adults and children. Predictive testing is also proposed to adult relatives at risk of carrying a predisposing mutation. In that context, we offer all asymptomatic BMPR2 mutation carriers a programme to detect pulmonary arterial hypertension at an early phase, as recommended by the 2015 European Society Society of Cardiology/European Respiratory Society pulmonary hypertension guidelines. Finally, pre-implantation genetic diagnosis has been conducted on five embryos from two couples in which the fathers were carriers of a pathogenic BMPR2 mutation.

  • clinical phenotypes and outcomes of heritable and sporadic pulmonary veno occlusive disease a population based study
    The Lancet Respiratory Medicine, 2017
    Co-Authors: David Montani, Laurent Savale, Xavier Jais, Andrei Seferian, Barbara Girerd, Peter Dorfmüller, Edmund M T Lau, Marilyne Levy, David Amar, Melanie Eyries
    Abstract:

    Background Bi-allelic mutations of the EIF2AK4 gene cause heritable pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis (PVOD/PCH). We aimed to assess the eff ect of EIF2AK4 mutations on the clinical phenotypes and outcomes of PVOD/PCH. Methods We did a population-based study using clinical, functional, and haemodynamic data from the registry of the French Pulmonary Hypertension Network. We reviewed the clinical data and outcomes from all patients referred to the French Referral Centre (Pulmonary Department, Hospital Kremlin-Bicetre, University Paris-Sud) with either confi rmed or highly probable PVOD/PCH with DNA available for mutation screening (excluding patients with other risk factors of pulmonary hypertension, such as chronic respiratory diseases). We sequenced the coding sequence and intronic junctions of the EIF2AK4 gene, and compared clinical characteristics and outcomes between EIF2AK4 mutation carriers and non-carriers. Medical therapies approved for pulmonary arterial hypertension (prostacyclin derivatives, endothelin receptor antagonists and phosphodiesterase type-5 inhibitors) were given to patients according to the clinical judgment and discretion of treating physicians. The primary outcome was the event-free survival (death or transplantation). Secondary outcomes included response to therapies for pulmonary arterial hypertension and survival after lung transplantation. A satisfactory clinical response to specifi c therapy for pulmonary arterial hypertension was defi ned by achieving New York Heart Association functional class I or II, a 6-min walk distance of more than 440 m, and a cardiac index greater than 2·5 L/min per m² at the fi rst reassessment after initiation of specifi c therapy for pulmonary arterial hypertension. Findings We obtained data from Jan 1, 2003, to June 1, 2016, and identifi ed 94 patients with sporadic or heritable PVOD/PCH (confi rmed or highly probable). 27 (29%) of these patients had bi-allelic EIF2AK4 mutations. PVOD/ PCH due to EIF2AK4 mutations occurred from birth to age 50 years, and these patients were younger at presentation than non-carriers (median 26·0 years [range 0–50.3] vs 60·0 years [6·7–81·4] years; p<0·0001). At diagnosis, both mutations carriers and non-carriers had similarly severe precapillary pulmonary hypertension and functional impairment. 22 (81%) of mutations carriers and 63 (94%) of non-carriers received therapy approved for pulmonary arterial hypertension. Drug-induced pulmonary oedema occurred in fi ve (23%) of treated EIF2AK4 mutations carriers and 13 (21%) of treated non-carriers. Follow-up assessment after initiation of treatment showed that only three (4%) patients with PVOD/PCH reached the predefi ned criteria for satisfactory clinical response. The probabilities of event-free survival (death or transplantation) at 1 and 3 years were 63% and 32% in EIF2AK4 mutations carriers, and 75% and 34% in non-carriers. No signifi cant diff erences occurred in event-free survival between the 2 groups (p=0·38). Among the 33 patients who had lung transplantation, estimated posttransplantation survival rates at 1, 2, and 5 years were 84%, 81%, and 73%, respectively. Interpretation Heritable PVOD/PCH due to bi-allelic EIF2AK4 mutations is characterised by a younger age at diagnosis but these patients display similar disease severity compared with mutation non-carriers. Response to therapy approved for pulmonary arterial hypertension in PVOD/PCH is rare. PVOD/PCH is a devastating condition and lung transplantation should be considered for eligible patients.

  • caracteristiques des patients atteints de maladie veino occlusive porteurs de mutations du gene EIF2AK4
    Revue Des Maladies Respiratoires, 2016
    Co-Authors: David Montani, Laurent Savale, Andrei Seferian, Barbara Girerd, Florent Soubrier, D Amar, X Jais, F Parent, E Fadel, O Sitbon
    Abstract:

    Introduction Le gene EIF2AK4  a recemment ete decouvert comme le gene de predisposition a la maladie veino-occlusive pulmonaire (MVO). La MVO heritable se transmet sur le mode autosomique recessif. Methodes Les donnees cliniques et de survie des patients porteurs de mutations bi-alleliques du gene EIF2AK4  et suivis dans le centre de reference de l’hypertension pulmonaire severe, ont ete recuperees. Resultats Vingt-quatre patients porteurs de mutations bi-alleliques du gene EIF2AK4  ont ete identifies (13 femmes, âge 26,4 ± 8,7 ans). Au diagnostic, les patients etaient majoritairement en classe fonctionnelle NYHA III (71 %) ou IV (21 %). La distance parcourue au test de marche de 6 min etait de 365 ± 168 m. Les patients etaient hypoxemiques (9,5 ± 1,9 kPa) avec une DLCO basse (30 ± 7 %) et presentaient une hypertension pulmonaire precapillaire severe (PAPmoyenne : 51 ± 12 mmHg, PAP d’occlusion : 8 ± 4 mmHg, index cardiaque : 2,53 ± 0,89 L/min/m 2 , et resistances vasculaires pulmonaires : 12,5 ± 6,6 UW). Le scanner thoracique revelait des lignes septales, des nodules flous, et des adenopathies mediastinales chez 100 %, 96 % et 83 % des patients, respectivement. Aucune reponse clinique a long terme n’a ete observee chez les patients recevant un traitement de l’HTAP ( n  = 21) et 5 patients ont developpe un œdeme pulmonaire. Quatre patients sont decedes durant le suivi et 18 ont beneficie d’une transplantation pulmonaire. La survie sans evenement (deces ou transplantation) a 1, 2 et 3 ans etait de 63 %, 54 % et 32 %. Conclusion La MVO heritable associee a des mutations bi-alleliques du gene EIF2AK4  est caracterisee par un jeune âge au diagnostic et une severite clinique, fonctionnelle et hemodynamique. Le pronostic est sombre et la transplantation pulmonaire reste le traitement de reference.

  • occupational exposure to organic solvents a risk factor for pulmonary veno occlusive disease
    European Respiratory Journal, 2015
    Co-Authors: David Montani, Laurent Savale, Xavier Jais, Lynda Bensefacolas, Ines Zendah, Jerome Le Pavec, Pascal Andujar, Barbara Girerd, Alexis Descatha, Andrei Seferian
    Abstract:

    Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension characterised by predominant remodelling of pulmonary venules. Bi-allelic mutations in the eukaryotic translation initiation factor 2α kinase 4 ( EIF2AK4 ) gene were recently described as the major cause of heritable PVOD, but risk factors associated with PVOD remain poorly understood. Occupational exposures have been proposed as a potential risk factor for PVOD, but epidemiological studies are lacking. A case–control study was conducted in consecutive PVOD (cases, n=33) and pulmonary arterial hypertension patients (controls, n=65). Occupational exposure was evaluated via questionnaire interview with blinded assessments using an expert consensus approach and a job exposure matrix (JEM). Using the expert consensus approach, PVOD was significantly associated with occupational exposure to organic solvents (adjusted OR 12.8, 95% CI 2.7–60.8), with trichloroethylene being the main agent implicated (adjusted OR 8.2, 95% CI 1.4–49.4). JEM analysis independently confirmed the association between PVOD and trichloroethylene exposure. Absence of significant trichloroethylene exposure was associated with a younger age of disease (54.8±21.4 years, p=0.037) and a high prevalence of harbouring bi-allelic EIF2AK4 mutations (41.7% versus 0%, p=0.015). Occupational exposure to organic solvents may represent a novel risk factor for PVOD. Genetic background and environmental exposure appear to influence the phenotypic expression of the disease.

Laurent Savale - One of the best experts on this subject based on the ideXlab platform.

  • pulmonary vascular remodeling patterns and expression of general control nonderepressible 2 gcn2 in pulmonary veno occlusive disease
    Journal of Heart and Lung Transplantation, 2017
    Co-Authors: Esther J Nossent, Maria Rosa Ghigna, Fabrice Antigny, Melanie Lambert, Vincent Thomas De Montpreville, Xavier Jais, Harm Jan Bogaard, Barbara Girerd, David Montani, Laurent Savale
    Abstract:

    Background: Heritable pulmonary veno-occlusive disease (PVOD) is linked to mutations in the eukaryotic initiation factor 2 alpha kinase 4 (EIF2AK4) gene, leading to a loss of general control nonderepressible 2 (GCN2). The role of GCN2 expression in pulmonary vascular remodeling remains obscure. We sought to identify specific histologic and biologic features in heritable PVOD. Methods: Clinical data and lung histology of 24 PVOD patients (12 EIF2AK4 mutation carriers, 12 non-carriers) were submitted to systematic histologic analysis and semiautomated morphometry. GCN2 expression was quantified by Western blotting in 24 PVOD patients, 44 patients with pulmonary arterial hypertension (PAH; 23 bone morphogenetic protein receptor type II [. BMPR2] mutation carriers, 21 non-carriers), and 3 experimental pulmonary hypertension models. Results: PVOD patients showed a significant decrease of pulmonary arterial patency (p < 0.0001) compared with healthy controls. Histology of EIF2AK4 mutation carriers was distinctive from non-carriers regarding (1) arterial remodeling, with significantly more severe intimal fibrosis (p = 0.001), less severe medial hypertrophy (p = 0.001), and (2) stronger muscular hyperplasia of interlobular septal veins (p = 0.002). GCN2 expression was abolished in heritable PVOD (p < 0.0001), but also importantly decreased in sporadic PVOD (p = 0.03) as well as in heritable (p = 0.002) and idiopathic PAH (p = 0.003); moreover, GCN2 was abolished in 2 experimental pulmonary hypertension models and importantly decreased in 1 model (p < 0.0001 for all models). Conclusions: Pulmonary arterial remodeling in PVOD is present to an important extent. A significant decrease of GCN2 expression is a common denominator of all tested groups of PVOD and PAH, including their respective experimental models. Our results underline specific morphologic and biologic similarities between PAH and PVOD and let us consider both conditions rather in one large spectrum of disease than as two distinct and clear-cut entities.

  • clinical phenotypes and outcomes of heritable and sporadic pulmonary veno occlusive disease a population based study
    The Lancet Respiratory Medicine, 2017
    Co-Authors: David Montani, Laurent Savale, Xavier Jais, Andrei Seferian, Barbara Girerd, Peter Dorfmüller, Edmund M T Lau, Marilyne Levy, David Amar, Melanie Eyries
    Abstract:

    Background Bi-allelic mutations of the EIF2AK4 gene cause heritable pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis (PVOD/PCH). We aimed to assess the eff ect of EIF2AK4 mutations on the clinical phenotypes and outcomes of PVOD/PCH. Methods We did a population-based study using clinical, functional, and haemodynamic data from the registry of the French Pulmonary Hypertension Network. We reviewed the clinical data and outcomes from all patients referred to the French Referral Centre (Pulmonary Department, Hospital Kremlin-Bicetre, University Paris-Sud) with either confi rmed or highly probable PVOD/PCH with DNA available for mutation screening (excluding patients with other risk factors of pulmonary hypertension, such as chronic respiratory diseases). We sequenced the coding sequence and intronic junctions of the EIF2AK4 gene, and compared clinical characteristics and outcomes between EIF2AK4 mutation carriers and non-carriers. Medical therapies approved for pulmonary arterial hypertension (prostacyclin derivatives, endothelin receptor antagonists and phosphodiesterase type-5 inhibitors) were given to patients according to the clinical judgment and discretion of treating physicians. The primary outcome was the event-free survival (death or transplantation). Secondary outcomes included response to therapies for pulmonary arterial hypertension and survival after lung transplantation. A satisfactory clinical response to specifi c therapy for pulmonary arterial hypertension was defi ned by achieving New York Heart Association functional class I or II, a 6-min walk distance of more than 440 m, and a cardiac index greater than 2·5 L/min per m² at the fi rst reassessment after initiation of specifi c therapy for pulmonary arterial hypertension. Findings We obtained data from Jan 1, 2003, to June 1, 2016, and identifi ed 94 patients with sporadic or heritable PVOD/PCH (confi rmed or highly probable). 27 (29%) of these patients had bi-allelic EIF2AK4 mutations. PVOD/ PCH due to EIF2AK4 mutations occurred from birth to age 50 years, and these patients were younger at presentation than non-carriers (median 26·0 years [range 0–50.3] vs 60·0 years [6·7–81·4] years; p<0·0001). At diagnosis, both mutations carriers and non-carriers had similarly severe precapillary pulmonary hypertension and functional impairment. 22 (81%) of mutations carriers and 63 (94%) of non-carriers received therapy approved for pulmonary arterial hypertension. Drug-induced pulmonary oedema occurred in fi ve (23%) of treated EIF2AK4 mutations carriers and 13 (21%) of treated non-carriers. Follow-up assessment after initiation of treatment showed that only three (4%) patients with PVOD/PCH reached the predefi ned criteria for satisfactory clinical response. The probabilities of event-free survival (death or transplantation) at 1 and 3 years were 63% and 32% in EIF2AK4 mutations carriers, and 75% and 34% in non-carriers. No signifi cant diff erences occurred in event-free survival between the 2 groups (p=0·38). Among the 33 patients who had lung transplantation, estimated posttransplantation survival rates at 1, 2, and 5 years were 84%, 81%, and 73%, respectively. Interpretation Heritable PVOD/PCH due to bi-allelic EIF2AK4 mutations is characterised by a younger age at diagnosis but these patients display similar disease severity compared with mutation non-carriers. Response to therapy approved for pulmonary arterial hypertension in PVOD/PCH is rare. PVOD/PCH is a devastating condition and lung transplantation should be considered for eligible patients.

  • caracteristiques des patients atteints de maladie veino occlusive porteurs de mutations du gene EIF2AK4
    Revue Des Maladies Respiratoires, 2016
    Co-Authors: David Montani, Laurent Savale, Andrei Seferian, Barbara Girerd, Florent Soubrier, D Amar, X Jais, F Parent, E Fadel, O Sitbon
    Abstract:

    Introduction Le gene EIF2AK4  a recemment ete decouvert comme le gene de predisposition a la maladie veino-occlusive pulmonaire (MVO). La MVO heritable se transmet sur le mode autosomique recessif. Methodes Les donnees cliniques et de survie des patients porteurs de mutations bi-alleliques du gene EIF2AK4  et suivis dans le centre de reference de l’hypertension pulmonaire severe, ont ete recuperees. Resultats Vingt-quatre patients porteurs de mutations bi-alleliques du gene EIF2AK4  ont ete identifies (13 femmes, âge 26,4 ± 8,7 ans). Au diagnostic, les patients etaient majoritairement en classe fonctionnelle NYHA III (71 %) ou IV (21 %). La distance parcourue au test de marche de 6 min etait de 365 ± 168 m. Les patients etaient hypoxemiques (9,5 ± 1,9 kPa) avec une DLCO basse (30 ± 7 %) et presentaient une hypertension pulmonaire precapillaire severe (PAPmoyenne : 51 ± 12 mmHg, PAP d’occlusion : 8 ± 4 mmHg, index cardiaque : 2,53 ± 0,89 L/min/m 2 , et resistances vasculaires pulmonaires : 12,5 ± 6,6 UW). Le scanner thoracique revelait des lignes septales, des nodules flous, et des adenopathies mediastinales chez 100 %, 96 % et 83 % des patients, respectivement. Aucune reponse clinique a long terme n’a ete observee chez les patients recevant un traitement de l’HTAP ( n  = 21) et 5 patients ont developpe un œdeme pulmonaire. Quatre patients sont decedes durant le suivi et 18 ont beneficie d’une transplantation pulmonaire. La survie sans evenement (deces ou transplantation) a 1, 2 et 3 ans etait de 63 %, 54 % et 32 %. Conclusion La MVO heritable associee a des mutations bi-alleliques du gene EIF2AK4  est caracterisee par un jeune âge au diagnostic et une severite clinique, fonctionnelle et hemodynamique. Le pronostic est sombre et la transplantation pulmonaire reste le traitement de reference.

  • occupational exposure to organic solvents a risk factor for pulmonary veno occlusive disease
    European Respiratory Journal, 2015
    Co-Authors: David Montani, Laurent Savale, Xavier Jais, Lynda Bensefacolas, Ines Zendah, Jerome Le Pavec, Pascal Andujar, Barbara Girerd, Alexis Descatha, Andrei Seferian
    Abstract:

    Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension characterised by predominant remodelling of pulmonary venules. Bi-allelic mutations in the eukaryotic translation initiation factor 2α kinase 4 ( EIF2AK4 ) gene were recently described as the major cause of heritable PVOD, but risk factors associated with PVOD remain poorly understood. Occupational exposures have been proposed as a potential risk factor for PVOD, but epidemiological studies are lacking. A case–control study was conducted in consecutive PVOD (cases, n=33) and pulmonary arterial hypertension patients (controls, n=65). Occupational exposure was evaluated via questionnaire interview with blinded assessments using an expert consensus approach and a job exposure matrix (JEM). Using the expert consensus approach, PVOD was significantly associated with occupational exposure to organic solvents (adjusted OR 12.8, 95% CI 2.7–60.8), with trichloroethylene being the main agent implicated (adjusted OR 8.2, 95% CI 1.4–49.4). JEM analysis independently confirmed the association between PVOD and trichloroethylene exposure. Absence of significant trichloroethylene exposure was associated with a younger age of disease (54.8±21.4 years, p=0.037) and a high prevalence of harbouring bi-allelic EIF2AK4 mutations (41.7% versus 0%, p=0.015). Occupational exposure to organic solvents may represent a novel risk factor for PVOD. Genetic background and environmental exposure appear to influence the phenotypic expression of the disease.

  • mitomycin induced pulmonary veno occlusive disease evidence from human disease and animal models
    Circulation, 2015
    Co-Authors: Frederic Perros, Fabrice Antigny, Peter Dorfmüller, Sven Gunther, Benoit Ranchoux, Laurent Godinas, Mariecamille Chaumais, Aurelie Hautefort, Nicolas Raymond, Laurent Savale
    Abstract:

    Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension characterized by the obstruction of small pulmonary veins and a dismal prognosis. PVOD may be sporadic or heritable because of biallelic mutations of the EIF2AK4 gene coding for GCN2. Isolated case reports suggest that chemotherapy may be a risk factor for PVOD.