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1. Rotor Syndrome Presenting as Dubin-Johnson Syndrome

Author: Mariana Morais, Philippe Couvert, Isabelle Jéru, and Mariana Verdelho Machado
Subjects: conjugated hyperbilirubinemia, dubin-johnson syndrome, abcc2/mrp2, rotor syndrome, slco1b3/oatp1b, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract: A 42-year-old man with no relevant past medical history presented with intermittent mild icterus and no signs of chronic liver disease. Laboratory tests were notable for hyperbilirubinemia (total 7.97 mg/dL, direct 5.37 mg/dL), bilirubinuria, no signs of hemolysis, normal liver tests and lipids profile. Abdominal ultrasound was unremarkable. A panel of chronic liver diseases was negative except for increased serum (147.4 μg/dL) and urinary (179 μg/24 h) copper, with normal ceruloplasmin. No other Leipzig criteria for Wilson’s disease were found, including a negative test for ATP7B gene mutations (by exome sequencing). Total urinary coproporphyrin was normal with predominance of isomer I (86% of total urinary coproporphyrin output). Clinical and laboratorial profile was compatible with Dubin-Johnson syndrome; however, exome sequencing and search for deletions in the ABBC2 gene (encoding MRP2) only found a heterozygous potentially pathogenic variant (c.1483A>G – p.Lys495Glu). Additional extended molecular analysis of genes implicated in bilirubin metabolism found a homozygous deletion of a region encompassing exons 4–16 of SLCO1B3 gene (encoding OATP1B3) and all SLCO1B1 exons (encoding OATP1B1), thereby establishing Rotor syndrome diagnosis. Rotor and Dubin-Johnson syndromes are rare autosomal recessive liver diseases characterized by chronic conjugated hyperbilirubinemia, caused by the absence of the hepatic function OATP1B1/B3 (leading to impaired hepatic bilirubin reuptake and storage) and MRP2 transporters (leading to impaired hepatic bilirubin excretion), respectively. We report a case of compound hereditary hyperbilirubinemia with a misleading presentation with special focus on its diagnosis, particularly the advantage of extensive unbiased genetic testing by dedicated laboratories. With this case, we aim to highlight the necessity of establishing a diagnosis, reassuring the patient, and avoiding unnecessary invasive and costly diagnostic procedures.
Published: 2022
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2. Loss of thymidine phosphorylase activity disrupts adipocyte differentiation and induces insulin-resistant lipoatrophic diabetes

Author: Jérémie Gautheron, Lara Lima, Baris Akinci, Jamila Zammouri, Martine Auclair, Sema Kalkan Ucar, Samim Ozen, Canan Altay, Bridget E. Bax, Ivan Nemazanyy, Véronique Lenoir, Carina Prip-Buus, Cécile Acquaviva-Bourdain, Olivier Lascols, Bruno Fève, Corinne Vigouroux, Esther Noel, and Isabelle Jéru
Subjects: TP, Thymidine phosphorylase, Lipodystrophy, Insulin resistance, Mutation, Adipose stem cell, Medicine
Abstract: Abstract Background Thymidine phosphorylase (TP), encoded by the TYMP gene, is a cytosolic enzyme essential for the nucleotide salvage pathway. TP catalyzes the phosphorylation of the deoxyribonucleosides, thymidine and 2′-deoxyuridine, to thymine and uracil. Biallelic TYMP variants are responsible for Mitochondrial NeuroGastroIntestinal Encephalomyopathy (MNGIE), an autosomal recessive disorder characterized in most patients by gastrointestinal and neurological symptoms, ultimately leading to death. Studies on the impact of TYMP variants in cellular systems with relevance to the organs affected in MNGIE are still scarce and the role of TP in adipose tissue remains unexplored. Methods Deep phenotyping was performed in three patients from two families carrying homozygous TYMP variants and presenting with lipoatrophic diabetes. The impact of the loss of TP expression was evaluated using a CRISPR-Cas9-mediated TP knockout (KO) strategy in human adipose stem cells (ASC), which can be differentiated into adipocytes in vitro. Protein expression profiles and cellular characteristics were investigated in this KO model. Results All patients had TYMP loss-of-function variants and first presented with generalized loss of adipose tissue and insulin-resistant diabetes. CRISPR-Cas9-mediated TP KO in ASC abolished adipocyte differentiation and decreased insulin response, consistent with the patients’ phenotype. This KO also induced major oxidative stress, altered mitochondrial functions, and promoted cellular senescence. This translational study identifies a new role of TP by demonstrating its key regulatory functions in adipose tissue. Conclusions The implication of TP variants in atypical forms of monogenic diabetes shows that genetic diagnosis of lipodystrophic syndromes should include TYMP analysis. The fact that TP is crucial for adipocyte differentiation and function through the control of mitochondrial homeostasis highlights the importance of mitochondria in adipose tissue biology.
Published: 2022
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3. Editorial: Endocrine and metabolic diseases – genetic impact and therapies

Author: Isabelle Jéru, Bruno Fève, and Ralf Jockers
Subjects: endocrinology, metabolic diseases, genetics, gene, therapy, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Published: 2022
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4. The necroptosis-inducing pseudokinase mixed lineage kinase domain-like regulates the adipogenic differentiation of pre-adipocytes

Author: Julie Magusto, Carine Beaupère, Marta B. Afonso, Martine Auclair, Jean-Louis Delaunay, Pierre-Antoine Soret, Gilles Courtois, Tounsia Aït-Slimane, Chantal Housset, Isabelle Jéru, Bruno Fève, Vlad Ratziu, Cecilia M.P. Rodrigues, and Jérémie Gautheron
Subjects: Biological sciences, Molecular biology, Cell biology, Stem cells research, Science
Abstract: Summary: Receptor-interacting protein kinase-3 (RIPK3) and mixed lineage kinase domain-like (MLKL) proteins are key regulators of necroptosis, a highly pro-inflammatory mode of cell death, which has been involved in various human diseases. Necroptotic-independent functions of RIPK3 and MLKL also exist, notably in the adipose tissue but remain poorly defined. Using knock-out (KO) cell models, we investigated the role of RIPK3 and MLKL in adipocyte differentiation. Mlkl-KO abolished white adipocyte differentiation via a strong expression of Wnt10b, a ligand of the Wnt/β-catenin pathway, and a downregulation of genes involved in lipid metabolism. This effect was not recapitulated by the ablation of Ripk3. Conversely, Mlkl and Ripk3 deficiencies did not block beige adipocyte differentiation. These findings indicate that RIPK3 and MLKL have distinct roles in adipogenesis. The absence of MLKL blocks the differentiation of white, but not beige, adipocytes highlighting the therapeutic potential of MLKL inhibition in obesity.
Published: 2022
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5. Molecular and Cellular Bases of Lipodystrophy Syndromes

Author: Jamila Zammouri, Camille Vatier, Emilie Capel, Martine Auclair, Caroline Storey-London, Elise Bismuth, Héléna Mosbah, Bruno Donadille, Sonja Janmaat, Bruno Fève, Isabelle Jéru, and Corinne Vigouroux
Subjects: lipodystrophy, insulin resistance, diabetes, adipose tissue, genetics, senescence, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Lipodystrophy syndromes are rare diseases originating from a generalized or partial loss of adipose tissue. Adipose tissue dysfunction results from heterogeneous genetic or acquired causes, but leads to similar metabolic complications with insulin resistance, diabetes, hypertriglyceridemia, nonalcoholic fatty liver disease, dysfunctions of the gonadotropic axis and endocrine defects of adipose tissue with leptin and adiponectin deficiency. Diagnosis, based on clinical and metabolic investigations, and on genetic analyses, is of major importance to adapt medical care and genetic counseling. Molecular and cellular bases of these syndromes involve, among others, altered adipocyte differentiation, structure and/or regulation of the adipocyte lipid droplet, and/or premature cellular senescence. Lipodystrophy syndromes frequently present as systemic diseases with multi-tissue involvement. After an update on the main molecular bases and clinical forms of lipodystrophy, we will focus on topics that have recently emerged in the field. We will discuss the links between lipodystrophy and premature ageing and/or immuno-inflammatory aggressions of adipose tissue, as well as the relationships between lipomatosis and lipodystrophy. Finally, the indications of substitutive therapy with metreleptin, an analog of leptin, which is approved in Europe and USA, will be discussed.
Published: 2022
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6. Adherence with metreleptin therapy and health self-perception in patients with lipodystrophic syndromes

Author: Camille Vatier, Dina Kalbasi, Marie-Christine Vantyghem, Olivier Lascols, Isabelle Jéru, Anne Daguenel, Jean-François Gautier, Marion Buyse, and Corinne Vigouroux
Subjects: Lipodystrophic syndromes, Metreleptin therapy, Health self-perception, Adherence, Social interactions, Medicine
Abstract: Abstract Background Although metreleptin replacement therapy was shown to improve metabolic alterations in lipodystrophic syndromes, patients’ adherence and satisfaction with treatment have never been evaluated. The 20 patients with lipodystrophic syndromes participating in the French compassionate program of metreleptin therapy filled in a self-questionnaire including an Adherence Evaluation Test, the Treatment Satisfaction Questionnaire for Medication (TSQM®-vII), and items about physical appearance. Results 15 patients were women, median age was 32.5 years (IQT 25–75 (16.2;49.5), 18 had diabetes. Adherence with metreleptin (one daily subcutaneous injection) was poor in 25%, excellent in 25% and acceptable in 50% of patients. On a 0-to-100 scale, patients’ satisfaction scores reached 66.7 (52.1;81.2) for effectiveness, 55.6 (44.4;66.7) for ease/comfort of use, and 83.3 (52.1;83.3) for global satisfaction with metreleptin therapy. Self-reported side effects were frequent injection site reactions 100 (79.2;100). Satisfaction scores did not differ in patients with partial (n = 10) or generalized (n = 10) lipodystrophic syndromes, did not correlate with metabolic improvement, but were significantly higher in compliant patients with fewer side effects. Morphological appearance was reported improved under metreleptin therapy in 13 among 17 patients. Conclusions Metreleptin increases health self-perception and decreases morphotype-associated stigmatization in most patients with lipodystrophic syndromes, but poor comfort of use and local side effects weaken adherence.
Published: 2019
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7. Cytokine Signature in Schnitzler Syndrome: Proinflammatory Cytokine Production Associated to Th Suppression

Author: Marie Masson Regnault, Eric Frouin, Isabelle Jéru, Adriana Delwail, Sandrine Charreau, Sébastien Barbarot, Antoine Néel, Agathe Masseau, Xavier Puéchal, Xavier Kyndt, Stephane Gayet, François Lifermann, Bouchra Asli, Xavier Balguerie, Claire Blanchard-Delaunay, François Aubin, Rita Rizzi, Franco Rongioletti, Thierry Boyé, Laurence Gusdorf, Didier Bessis, Franck Morel, Ewa Hainaut, Dan Lipsker, and Jean-Claude Lecron
Subjects: Schnitzler syndrome, inflammasome, IL-1, IL-1 antagonist, cytokines, PBMC (peripheral blood mononuclear cells), Immunologic diseases. Allergy, RC581-607
Abstract: BackgroundSchnitzler syndrome (SchS) is a rare autoinflammatory disease characterized by urticarial exanthema, bone and joint alterations, fever and monoclonal IgM gammopathy. Overactivation of the interleukin(IL)-1 system is reported, even though the exact pathophysiological pathways remain unknown.ObjectiveTo determine ex vivo cytokine profiles of Peripheral Blood Mononuclear Cells (PBMCs) from SchS patients prior to treatment and after initiation of anti-IL-1 therapy (anakinra). The sera cytokine profile was studied in parallel.MethodsWe collected blood samples from thirty-six untreated or treated SchS. PBMCs were cultured with and without LPS or anti-CD3/CD28. Cytokine levels were evaluated in serum and cell culture supernatants using Luminex technology.ResultsSpontaneous TNFα, IL-6, IL-1β, IL-1α, and IL-1RA release by PBMCs of SchS patients were higher than in controls. LPS-stimulation further induced the secretion of these cytokines. In contrast, after T-cell stimulation, TNFα, IL-10, IFNγ, IL-17A, and IL-4 production decreased in SchS patients compared to healthy controls, but less in treated patients. Whereas IL-1β serum level was not detected in most sera, IL-6, IL-10, and TNFα serum levels were higher in patients with SchS and IFNγ and IL-4 levels were lower. Of note, IL-6 decreased after treatment in SchS (p = 0.04).ConclusionOur data strengthen the hypothesis of myeloid inflammation in SchS, mediated in particular by IL-1β, TNFα, and IL-6, associated with overproduction of the inhibitors IL-1RA and IL-10. In contrast, we observed a loss of Th1, Th2, and Th17 cell functionalities that tends to be reversed by anakinra.
Published: 2020
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8. Proceedings of the 23rd Paediatric Rheumatology European Society Congress: part three

Author: Riccardo Papa, Alessandro Consolaro, Francesca Minoia, Roberta Caorsi, Gianmichele Magnano, Marco Gattorno, Angelo Ravelli, Paolo Picco, Roberto Pillon, Denise Pires Marafon, Lidia Meli, Claudia Bracaglia, Andrea Taddio, Fabrizio De Benedetti, Enes Turan, Sara Sebnem Kilic, Yasuhiko Itoh, Tomoko Shigemori, Shingo Yamanishi, Hidehiko Nagasaki, Ela Tarakci, Nilay Arman, Devrim Tarakci, Yusuf S. Akgul, Ozgur Kasapcopur, Emily Wilson, Hanna Lythgoe, Eve Smith, Jenny Preston, Michael W. Beresford, Lynn R. Spiegel, Jennifer Stinson, Mark Connelly, Adam Huber, Nadia Luca, Argerie Tsimicalis, Stephanie Luca, Naweed Tajuddin, Roberta Berard, Julie Barsalou, Sarah Campillo, Brian Feldman, Shirley Tse, Paul Dancey, Ciaran Duffy, Nicole Johnson, Patrick McGrath, Natalie Shiff, Lori Tucker, Charles Victor, Chitra Lalloo, Lauren Harris, Joseph Cafazzo, Kristin Houghton, Ronald Laxer, Madeleine Rooney, Roisin Campbell, Catherine Wright, Wineke Armbrust, Otto Lelieveld, Jolanda Tuinstra, Nico Wulffraat, Joyce Bos, Jeanette Cappon, Marion van Rossum, Mariët Hagedoorn, Anna Vermé, Ylva Lampela, Ayse Huri Ozdogan, S. Ugurlu, K. Barut, A. Androvic, O. Kasapçopu, Jody Etheridge, Katie Dobson, Sue Kemp, AnnaCarin Horne, Karin Palmblad, Malin Höglund, Natalia Stepanenko, Svetlana Salugina, Evgeny Fedorov, Irina Nikishina, Maria Kaleda, Kenan Barut, Amra Adrovic, Sezgin Sahin, Laurence Toumoulin, Johnny Frossard, Stephanie Archimbaut, Anne Paitier, Rolande Guastalli, Severine Guillaume Czitrom, Sirirat Charuvanij, Chollada Chaiyadech, Takako Miyamae, Hisashi Yamanaka, Cecile Picard, Guillaume Thouvenin, Caroline Kannengiesser, Jean-Christophe Dubus, Nadia Jeremiah, Frédéric Rieux-Laucat, Bruno Crestani, Véronique Secq, Christelle Ménard, Martine Reynaud-Gaubert, Françoise Thivolet-Bejui, Philippe Reix, Alexandre Belot, Ezgi Deniz Batu, Hafize Emine Sonmez, Abdulsamet Erden, Ekim Z. Taskiran, Omer Karadag, Umut Kalyoncu, İbrahim Oncel, Berkan Kaplan, Zehra Serap Arici, Cagri Mesut Temucin, Haluk Topaloglu, Yelda Bilginer, Mehmet Alikasifoglu, Seza Ozen, Lien Van Eyck, Ellen De Langhe, Isabelle Jéru, Erika Van Nieuwenhove, Vasiliki Lagou, Paul J. Baker, Jocelyn Garcia-Perez, James Dooley, Lien De Somer, Raf Sciot, Pierre-Yves Jeandel, Julia Ruuth-Praz, Bruno Copin, Myrna Medley-Hashim, Andre Megarbane, Sinisa Savic, An Goris, Serge Amselem, Adrian Liston, Seth Masters, Carine Wouters, Nami Okamoto, Yuko Sugita, Kousuke Shabana, Takuji Murata, Hiroshi Tamai, Juliana Ferenczová, Erika Banóova, Pavol Mrážik, Veronika Vargova, Dubravko Bajramovic, Ksenija Stekic Novacki, Kristina Potocki, Marijan Frkovic, Marija Jelusic, Olga Kostareva, Svetlana Arsenyeva, Anna Shapovalenko, Lennart Jans, Nele Herregods, Jacob Jaremko, Rik Joos, Joke Dehoorne, Xenofon Baraliakos, Sofia Ramiro, Julio C. Casasola-Vargas, Désirée van der Heijde, Robert Landewé, Ruben Burgos-Vargas, Shirley M. Tse, Gerd Horneff, Kristina Unnebrink, Jaclyn K. Anderson, Aysenur Paç Kisaarslan, Betül Sözeri, Zübeyde Gündüz, Gökmen Zararsız, Hakan Poyrazoğlu, Ruhan Düşünsel, Kazutaka Ouchi, Shinji Akioka, Hiroshi Kubo, Norio Nakagawa, Hajime Hosoi, Lovro Lamot, Fran Borovecki, Sanja Kapitanovic, Kristina Gotovac, Mandica Vidovic, Mirta Lamot, Edi Paleka Bosak, Miroslav Harjacek, Ricardo A. Russo, María M. Katsicas, Ruben Burgos Vargas, Ana L. Ortiz-Peyegahud, Zhang Pingping, Mou Yikun, Qi Jun, Jiang Yutong, Gu Jieruo, Mikhail M. Kostik, Shilova Ekaterina, Ilia Avrusin, Yuriy Korin, Olga Kopchak, Eugenia Isupova, Irina Chikova, Panova Tatyana, Margarita Dubko, Vera Masalova, Ludmila Snegireva, Tatyana Kornishina, Olga Kalashnikova, Vyacheslav Chasnyk, Tatyana Likhacheva, N. Ruperto, H. I. Brunner, P. Quartier, T. Constantin, E. Alexeeva, R. Schneider, I. Kone-Paut, K. Schikler, K. Marzan, N. Wulffraat, S. Padeh, V. Chasnyk, C. Wouters, J. B. Kuemmerle-Deschner, T. Kallinich, B. Lauwerys, E. Haddad, E. Nasonov, M. Trachana, O. Vougiouka, K. Leon, A. Speziale, K. Lheritier, E. Vritzali, A. Martini, D. Lovell, PRINTO/PRCSG, Nienke Ter Haar, Rianne Scholman, Wilco de Jager, Tamar Tak, Pieter Leliefeld, Bas Vastert, Sytze de Roock, Ariane de Ganck, Nadia Ryter, Miha Lavric, Dirk Foell, Renee F. Modica, Kathleen G. Lomax, Pamela Batzel, Armelle Cassanas, Melissa E. Elder, Rina Denisova, Ekaterina Alexeeva, Saniya Valieva, Tatyana Bzarova, Kseniya Isayeva, Tatyana Sleptsova, Olga Lomakina, Alexandra Chomahidze, Margarita Soloshenko, Meyry Shingarova, Elena Kachshenko, Wilco De Jager, Sebastiaan J. Vastert, Gerdien Mijnheer, Berent J. Prakken, Nico M. Wulffraat, Hafize E. Sönmez, Asuman N. Karhan, Ezgi D. Batu, Zehra S. Arıcı, Ersin Gümüş, Hülya Demir, Aysel Yüce, Seza Özen, Jasmina Ahluwalia, Bhavneet Bharti, Sweta Rajpal, Varun Uppal, Alaknanda Walia, Surjit S. Samlok, Narender Kumar, Clarissa C. Valões, Beatriz C. Molinari, Ana Claudia G. Pitta, Natali W. Gormezano, Sylvia C. Farhat, Kátia Kozu, Adriana M. Sallum, Simone Appenzeller, Ana Paula Sakamoto, Maria T. Terreri, Rosa M. Pereira, Claudia S. Magalhães, Cássia Maria Barbosa, Francisco Hugo Gomes, Eloisa Bonfá, Clovis A. Silva, Kubra Ozturk, Zelal Ekinci, Maie Helal, Natalia Cabrera, Jean Christophe Lega, Jocelyne Drai, Rene Ecochard, O. V. Shpitonkova, N. S. Podchernyaeva, Y. O. Kostina, N. G. Dashkova, M. K. Osminina, Gozde Yucel, Ahmet Arvas, Nandini Moorthy, Paraskevi Dimou, Angela Midgley, Matthew Peak, Simon C. Satchell, Rachael D. Wright, Rachel Corkhill, Eve M. Smith, Sagar Bhattad, Amit Rawat, Surjit Singh, Anju Gupta, Deepti Suri, Martin de Boer, Taco Kuijpers, Vignesh Pandiarajan, Sapna Sandal, Sebastian Giraldo, Roy Sanguino, Adriana S. Diaz, Selcuk Uzuner, Gizem Durcan, Ali Guven Kilicoglu, Ayhan Bilgic, Kayhan Bahali, Sinem Durmus, Hafize Uzun, Nur Canpolat, Salim Caliskan, Lale Sever, Tomomi Sato, Fuminori Kimura, Wafaa Suwairi, Reem Abdwani, Abdulaziz Al Rowais, Jubran Al qanatish, Abdulrahman Al Asiri, Ekaterina Gaidar, Mikhail Kostik, Elena Serogodskaya, Tatyana Nikitina, Evgenia Isupova, Elham Sardar, Perrine Dusser, Antoine Rousseau, Marc Labetoulle, Emanuel Barreau, Bahram Bodaghi, Isabelle Kone-Paut, Ivan Foeldvari, Jordi Anton, Rosa Bou, Sheila Angeles-Han, Regitze Bangsgaard, Gabriele Brumm, Tamas Constantin, Clive Edelsten, Jens Klotsche, Kirsten Minden, Elisabetta Miserocchi, Susan Nielsen, Gabriele Simonini, Arnd Heiligenhaus, Juan Manuel Mosquera Angarita, Carmen Garcia de Vicuña, Maria Victoria Hernandez, Alfredo Adan, Victor Llorens, Rosa Alcobendas, Susana Noval, Juan Carlos Lopez Robledillo, Isabel Valls, Mari Carmen Pinedo, Alejandro Fonollosa, Jaime de Inocencio, Pilar Tejada, Beatriz Bravo, Manuel Torribio, María Jesús García de Yebenes, Jordi Antón, Uveitis Working Group of the Spanish Pediatric Rheumatology Society, Lorenza Maria Argolini, Irene Pontikaki, Maria Orietta Borghi, Laura Cesana, Barbara Castiglioni, Maurizio Gattinara, Pierluigi Meroni, Pierre Quartier, Veronique Despert, Sylvaine Poignant, Amandine Baptiste, Caroline Elie, Laurent Kodjikian, Dominique Monnet, Michel Weber, Laura Moal, LuuLy Pham, Emmanuel Barreau, Cherif Titah, Pascal Dureau, Vanessa Cecchin, Maria Elisabetta Zannin, Daniele Ferrari, Francesco Comacchio, Rolando Cimaz, Fernanda Falcini, Antonella Petaccia, Stefania Viola, Luciana Breda, Francesco La Torre, Fabio Vittadello, Giorgia Martini, Francesco Zulian, Caroline Galeotti, Guillaume Sarrabay, Olivier Fogel, Isabelle Touitou, Corinne Miceli-Richard, Isabelle Koné-Paut, Hala Etayari, Hashad Soad, Ihab El Kadry, Habibullah Eatamadi, Kais AlAlgawi, Mustafa Al Maini, Khulood Khawaja, Sophie Van den Berghe, Ilse de Schryver, Ann Raes, Lídia L. C. Teixeira, Ana Duarte, Sandra Sousa, Filipe Vinagre, Maria J. Santos, Nataly S. Shevchenko, Ludmila F. Bogmat, Marina V. Demyanenko, Navdha R. Ramchurn, Mark Friswell, Rebecca A. James, Lucy R. Wedderburn, Reshma Pattani, Clarissa A. Pilkington, Sandrine Compeyrot-Lacassagne, Ana V. Villarreal, Nydia Acevedo, Enrique Faugier, Rocio Maldonado, Dilek Yılmaz, Hilal Bektaş Uysal, Elena Kamenets, Ekaterina Zaharova, Stefka Radenska-Lopovok, Joao Nascimento, Helena Sofia, Carla Zilhão, Rui Almeida, Margarida Guedes, Murat Deveci, Svetlana Rodionovskaya, Vera Vinnikova, Irina Tsymbal, Edyta Olesińska, Jacek Postępski, Agnieszka Mroczkowska-Juchkiewicz, Agnieszka Pawłowska-Kamieniak, Beata Chrapko, Damjana Ključevšek, Nina Emeršič, Nataša Toplak, Tadej Avčin, Faina Rokhlina, Galina Glazyrina, Natalia Kolyadina, Kwangnam Kim, Sinae Eom, Daeyoung Kim, Jungwoo Rhim, Francesca Ricci, Paola Montesano, Barbara Bonafini, Veronica Medeghini, Ilaria Parissenti, Antonella Meini, Marco Cattalini, Paolo Airò, Nataliya Panko, Nataliya Shevchenko, Iryna Lebec, Yevgeniya Zajceva, Sara Rostlund, Marie André, Takuma Hara, Takayuki Kishi, Yumi Tani, Aki Hanaya, Satoru Nagata, Velma Selmanovic, Aida Omercahic-Dizdarevic, Adisa Cengic, Almira Cosickic, Aida Omerčahić Dizdarević, Gemma Lepri, Clara Malattia, Eleonora Bellucci, Marco Matucci-Cerinic, Anton Solovyev, Elena Fedotova, Ana Victoria Villarreal, Talia Diaz, Yuridiana Ramirez, Teresa Giani, Achille Marino, Daniel Hunt, Muthana Al Obaidi, Veli Veli, Charalampia Papadopoulou, Jochen Kammermeier, Anna Poluha, Gangadhara C. Bharmappanavara, Alison Kelly, Lindsay Shaw, Giovanna Ferrara, Michele Luzzati, Mattia Giovannini, Liliana Jurado, Juliana Chamorro, Lorena Sarmiento, Ester Conversano, Maria Francesca Gicchino, Giulia Macchini, Carmela Granato, Assunta Tirelli, Alma N. Olivieri, Marija Perica, Lana Tambić Bukovac, Reza Sinaei, Vadood Javadi Parvaneh, Reza Shiari, Khosro Rahmani, Fatemeh F. Mehregan, Mehrnoush Hassas Yeganeh, Inmaculada Calvo Penadés, Berta López Montesinos, Ma Isabel González Fernández, Adriana Rodríguez Vidal, Anand Prahalad Rao, Ayesha Romana, Jyothi Raghuram, Ankur Kumar, Vishali Gupta, Elif Comak, Gülşah Kaya Aksoy, Aygen Yılmaz, Atike Atalay, Mustafa Koyun, Reha Artan, Sema Akman, Maria I. Kaleda, Irina P. Nikishina, Sergei K. Soloviev, Victor A. Malievsky, Ekaterina V. Nikolaeva, Agnieszka Gazda, Beata Kołodziejczyk, Lidia Rutkowska-Sak, Angela Mauro, Pierluigi Marzuillo, Stefano Guarino, and Angela La Manna
Subjects: Pediatrics, RJ1-570, Diseases of the musculoskeletal system, RC925-935
Published: 2017
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9. Congenital Generalized Lipoatrophy (Berardinelli-Seip Syndrome) Type 1: Description of Novel AGPAT2 Homozygous Variants Showing the Highly Heterogeneous Presentation of the Disease

Author: Giovanni Ceccarini, Silvia Magno, Caterina Pelosini, Federica Ferrari, Maria Rita Sessa, Gaia Scabia, Margherita Maffei, Isabelle Jéru, Olivier Lascols, Corinne Vigouroux, and Ferruccio Santini
Subjects: lipodystrophy, Berardinelli-Seip syndrome, BSCL1, AGPAT2, leptin, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Berardinelli-Seip congenital lipoatrophy (BSCL) is characterized by near total fat atrophy, associated with the progressive development of metabolic complications. BSCL type 1 (BSCL1) is caused by mutations in AGPAT2, encoding 1-acylglycerol-3phosphate-O-acyltransferase β (recently renamed lysophosphatidic acid acyltransferase beta), which catalyzes the transformation of lysophosphatidic acid in phosphatidic acid, the precursor of glycerophospholipids and triglycerides. BSCL1 is an autosomal recessive disease due to AGPAT2 pathogenic variants leading to a depletion of triglycerides inside the adipose organ, and to a defective signaling of key elements involved in proper adipogenesis. We herein investigated the characteristics of two AGPAT2 variants in Caucasian Italian patients with Berardinelli-Seip congenital lipoatrophy. The first patient exhibited a novel homozygous nonsense c.430 C > T AGPAT2 mutation (p.Gln144*) predicting the synthesis of a truncated enzyme of approximately half of the proper size. The second patient harbored a homozygous AGPAT2 missense variant (p.Arg159Cys), never described previously in BSCL1 patients: the segregation of the disease with the mutation in the pedigree of the family and the in silico analysis are compatible with a causative role of the p.Arg159Cys variant. We remark that BSCL1 can be clinically very heterogeneous at presentation and that the associated complications, occurring in the natural history of the disease, reduce life-expectancy. We point to the necessity for medical treatments capable of reducing the risk of cardiovascular death. In BSCL1 patients, the assessment of cardiovascular disease with conventional diagnostic means maybe particularly challenging.
Published: 2020
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10. Looking at New Unexpected Disease Targets in LMNA-Linked Lipodystrophies in the Light of Complex Cardiovascular Phenotypes: Implications for Clinical Practice

Author: Héléna Mosbah, Camille Vatier, Franck Boccara, Isabelle Jéru, Olivier Lascols, Marie-Christine Vantyghem, Bruno Fève, Bruno Donadille, Elisabeth Sarrazin, Sophie Benabbou, Jocelyn Inamo, Stéphane Ederhy, Ariel Cohen, Barbara Neraud, Pascale Richard, Fabien Picard, Sophie Christin-Maitre, Alban Redheuil, Karim Wahbi, and Corinne Vigouroux
Subjects: lipodystrophy, lmna, cardiovascular disease, Cytology, QH573-671
Abstract: Variants in LMNA, encoding A-type lamins, are responsible for laminopathies including muscular dystrophies, lipodystrophies, and progeroid syndromes. Cardiovascular laminopathic involvement is classically described as cardiomyopathy in striated muscle laminopathies, and arterial wall dysfunction and/or valvulopathy in lipodystrophic and/or progeroid laminopathies. We report unexpected cardiovascular phenotypes in patients with LMNA-associated lipodystrophies, illustrating the complex multitissular pathophysiology of the disease and the need for specific cardiovascular investigations in affected patients. A 33-year-old woman was diagnosed with generalized lipodystrophy and atypical progeroid syndrome due to the newly identified heterozygous LMNA p.(Asp136Val) variant. Her complex cardiovascular phenotype was associated with atherosclerosis, aortic valvular disease and left ventricular hypertrophy with rhythm and conduction defects. A 29-year-old woman presented with a partial lipodystrophy syndrome and a severe coronary atherosclerosis which required a triple coronary artery bypass grafting. She carried the novel heterozygous p.(Arg60Pro) LMNA variant inherited from her mother, affected with partial lipodystrophy and dilated cardiomyopathy. Different lipodystrophy-associated LMNA pathogenic variants could target cardiac vasculature and/or muscle, leading to complex overlapping phenotypes. Unifying pathophysiological hypotheses should be explored in several cell models including adipocytes, cardiomyocytes and vascular cells. Patients with LMNA-associated lipodystrophy should be systematically investigated with 24-h ECG monitoring, echocardiography and non-invasive coronary function testing.
Published: 2020
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11. The risk of familial Mediterranean fever in MEFV heterozygotes: a statistical approach.

Author: Isabelle Jéru, Véronique Hentgen, Emmanuelle Cochet, Philippe Duquesnoy, Gaëlle Le Borgne, Emmanuel Grimprel, Katia Stankovic Stojanovic, Sonia Karabina, Gilles Grateau, and Serge Amselem
Subjects: Medicine, Science
Abstract: Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disorder due to MEFV mutations and one of the most frequent Mediterranean genetic diseases. The observation of many heterozygous patients in whom a second mutated allele was excluded led to the proposal that heterozygosity could be causal. However, heterozygosity might be coincidental in many patients due to the very high rate of mutations in Mediterranean populations.To better delineate the pathogenicity of heterozygosity in order to improve genetic counselling and disease management.Complementary statistical approaches were used: estimation of FMF prevalence at population levels, genotype comparison in siblings from 63 familial forms, and genotype study in 557 patients from four Mediterranean populations.At the population level, we did not observe any contribution of heterozygosity to disease prevalence. In affected siblings of patients carrying two MEFV mutations, 92% carry two mutated alleles, whereas 4% are heterozygous with typical FMF diagnosis. We demonstrated statistically that patients are more likely to be heterozygous than healthy individuals, as shown by the higher ratio heterozygous carriers/non carriers in patients (p
Published: 2013
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12. Involvement of the same TNFR1 residue in mendelian and multifactorial inflammatory disorders.

Author: Isabelle Jéru, Serge Charmion, Emmanuelle Cochet, Bruno Copin, Philippe Duquesnoy, Maria Teresa Mitjavila Garcia, Gaëlle Le Borgne, Pascal Cathebras, Jacques Gaillat, Sonia Karabina, Catherine Dodé, Peter Lohse, Véronique Hentgen, and Serge Amselem
Subjects: Medicine, Science
Abstract: OBJECTIVES: TNFRSF1A is involved in an autosomal dominant autoinflammatory disorder called TNFR-associated periodic syndrome (TRAPS). Most TNFRSF1A mutations are missense changes and, apart from those affecting conserved cysteines, their deleterious effect remains often questionable. This is especially true for the frequent R92Q mutation, which might not be responsible for TRAPS per se but represents a susceptibility factor to multifactorial inflammatory disorders. This study investigates TRAPS pathophysiology in a family exceptional by its size (13 members) and compares the consequences of several mutations affecting arginine 92. METHODS: TNFRSF1A screening was performed by PCR-sequencing. Comparison of the 3-dimensional structure and electrostatic properties of wild-type and mutated TNFR1 proteins was performed by in silico homology modeling. TNFR1 expression was assessed by FACS analysis, western blotting and ELISA in lysates and supernatants of HEK293T cells transiently expressing wild-type and mutated TNFR1. RESULTS: A TNFRSF1A heterozygous missense mutation, R92W (c.361C>T), was shown to perfectly segregate with typical TRAPS manifestations within the family investigated (p
Published: 2013
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13. Involvement of the modifier gene of a human Mendelian disorder in a negative selection process.

Author: Isabelle Jéru, Hasmik Hayrapetyan, Philippe Duquesnoy, Emmanuelle Cochet, Jean-Louis Serre, Josué Feingold, Gilles Grateau, Tamara Sarkisian, Marc Jeanpierre, and Serge Amselem
Subjects: Medicine, Science
Abstract: BACKGROUND:Identification of modifier genes and characterization of their effects represent major challenges in human genetics. SAA1 is one of the few modifiers identified in humans: this gene influences the risk of renal amyloidosis (RA) in patients with familial Mediterranean fever (FMF), a Mendelian autoinflammatory disorder associated with mutations in MEFV. Indeed, the SAA1 alpha homozygous genotype and the p.Met694Val homozygous genotype at the MEFV locus are two main risk factors for RA. METHODOLOGY/PRINCIPAL FINDINGS:HERE, WE INVESTIGATED ARMENIAN FMF PATIENTS AND CONTROLS FROM TWO NEIGHBORING COUNTRIES: Armenia, where RA is frequent (24%), and Karabakh, where RA is rare (2.5%). Sequencing of MEFV revealed similar frequencies of p.Met694Val homozygotes in the two groups of patients. However, a major deficit of SAA1 alpha homozygotes was found among Karabakhian patients (4%) as compared to Armenian patients (24%) (p = 5.10(-5)). Most importantly, we observed deviations from Hardy-Weinberg equilibrium (HWE) in the two groups of patients, and unexpectedly, in opposite directions, whereas, in the two control populations, genotype distributions at this locus were similar and complied with (HWE). CONCLUSIONS/SIGNIFICANCE:The excess of SAA1alpha homozygotes among Armenian patients could be explained by the recruitment of patients with severe phenotypes. In contrast, a population-based study revealed that the deficit of alpha/alpha among Karabakhian patients would result from a negative selection against carriers of this genotype. This study, which provides new insights into the role of SAA1 in the pathophysiology of FMF, represents the first example of deviations from HWE and selection involving the modifier gene of a Mendelian disorder.
Published: 2009
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14. Perinatal, metabolic, and reproductive features inPPARG-related lipodystrophy

Author: Camille Gosseaume, Thierry Fournier, Isabelle Jéru, Marie-Léone Vignaud, Isabelle Missotte, Françoise Archambeaud, Xavier Debussche, Céline Droumaguet, Bruno Fève, Sophie Grillot, Bruno Guerci, Sylvie Hieronimus, Yves Horsmans, Estelle Nobécourt, Catherine Pienkowski, Christine Poitou, Jean-Paul Thissen, Olivier Lascols, Séverine Degrelle, Vassilis Tsatsaris, Corinne Vigouroux, and Camille Vatier
Subjects: Endocrinology, Endocrinology, Diabetes and Metabolism, General Medicine
Abstract: ObjectiveThe adipogenic PPARG-encoded PPARγ nuclear receptor also displays essential placental functions. We evaluated the metabolic, reproductive, and perinatal features of patients with PPARG-related lipodystrophy.MethodsCurrent and retrospective data were collected in patients referred to a National Rare Diseases Reference Centre.Results26 patients from 15 unrelated families were studied (18 women, median age 43 years). They carried monoallelic PPARG variants except a homozygous patient with congenital generalized lipodystrophy. Among heterozygous patients aged 16 or more (n = 24), 92% had diabetes, 96% partial lipodystrophy (median age at diagnosis 24 and 37 years), 78% hypertriglyceridaemia, 71% liver steatosis, and 58% hypertension. The mean BMI was 26 ± 5.0 kg/m2. Women (n = 16) were frequently affected by acute pancreatitis (n = 6) and/or polycystic ovary syndrome (n = 12). Eleven women obtained one or several pregnancies, all complicated by diabetes (n = 8), hypertension (n = 4), and/or hypertriglyceridaemia (n = 10). We analysed perinatal data of patients according to the presence (n = 8) or absence (n = 9) of a maternal dysmetabolic environment. The median gestational age at birth was low in both groups (37 and 36 weeks of amenorrhea, respectively). As expected, the birth weight was higher in patients exposed to a foetal dysmetabolic environment of maternal origin. In contrast, 85.7% of non-exposed patients, in whom the variant is, or is very likely to be, paternally-inherited, were small for gestational age.ConclusionsLipodystrophy-related PPARG variants induce early metabolic complications. Our results suggest that placental expression of PPARG pathogenic variants carried by affected foetuses could impair prenatal growth and parturition. This justifies careful pregnancy monitoring in affected families.
Published: 2023
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15. Therapeutic indications and metabolic effects of metreleptin in patients with lipodystrophy syndromes: Real‐life experience from a national reference network

Author: Héléna Mosbah, Marie‐Christine Vantyghem, Estelle Nobécourt, Fabrizio Andreelli, Francoise Archambeaud, Elise Bismuth, Claire Briet, Maryse Cartigny, Benjamin Chevalier, Bruno Donadille, Anne Daguenel, Mathilde Fichet, Jean‐François Gautier, Sonja Janmaat, Isabelle Jéru, Carole Legagneur, Lysiane Leguier, Julie Maitre, Elise Mongeois, Christine Poitou, Eric Renard, Yves Reznik, Anne Spiteri, Florence Travert, Bruno Vergès, Jamila Zammouri, Corinne Vigouroux, Camille Vatier, Recherche translationnelle sur le diabète - U 1190 (RTD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Nutrition et obésités: approches systémiques (UMR-S 1269) (Nutriomics), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CRSA), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)
Subjects: Adult, Leptin, Adolescent, Lipodystrophy, Endocrinology, Diabetes and Metabolism, Syndrome, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Middle Aged, Young Adult, Endocrinology, Lipodystrophy, Congenital Generalized, Internal Medicine, Humans, Retrospective Studies
Abstract: International audience; Aims: To describe baseline characteristics and follow-up data in patients with lipodystrophy syndromestreated with metreleptin in a national reference network, in a real-life setting.Patients and Methods: Clinical and metabolic data from patients receiving metreleptin in France wereretrospectively collected, at baseline, one year and at the latest follow-up during treatment.Results: Forty-seven patients with lipodystrophy including generalized lipodystrophy (GLD, n=28) andpartial lipodystrophy (PLD, n=19) received metreleptin over the last decade. At baseline, age was 29.3[16.6-47.6] (years, median [interquartile range]); BMI 23.8 kg/m2 [21.2-25.7]; serum leptin 3.2 [1.0-4.9] ng/mL); 94% of patients had diabetes (66% insulin-treated), 53% hypertension, and 87%dyslipidemia. Metreleptin therapy, administered during 31.7 [14.2-76.0] months, was ongoing in 77%of patients at the latest follow-up. In patients with GLD, HbA1c (%) and fasting triglycerides (mmol/L)significantly decreased from baseline to one year-metreleptin treatment, from 8.4 [6.5-9.9] to 6.8 [5.6-7.4], and 3.6 [1.7-8.5] to 2.2 [1.1-3.7] respectively (p
Published: 2022
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16. Proceedings of the annual meeting of the European Consortium of Lipodystrophies (ECLip) Cambridge, UK, 7-8 April 2022

Author: Héléna Mosbah, Baris Akinci, David Araújo-Vilar, Juan Carrion Tudela, Giovanni Ceccarini, Philippe Collas, I. Sadaf Farooqi, Antía Fernández-Pombo, Isabelle Jéru, Fredrik Karpe, Kerstin Krause, Margherita Maffei, Konstanze Miehle, Elif Oral, Naca Perez de Tudela, Xavier Prieur, Justin Rochford, Rebecca Sanders, Ferruccio Santini, David B. Savage, Julia von Schnurbein, Robert Semple, Anna Stears, Ekaterina Sorkina, Marie-Christine Vantyghem, Camille Vatier, Antonio Vidal-Puig, Corinne Vigouroux, and Martin Wabitsch
Subjects: Endocrinology, Endocrinology, Diabetes and Metabolism, General Medicine
Abstract: Lipodystrophy syndromes are rare diseases with defects in the development or maintenance of adipose tissue, frequently leading to severe metabolic complications. They may be genetic or acquired, with variable clinical forms, and are largely underdiagnosed. The European Consortium of Lipodystrophies, ECLip, is a fully functional non-profit network of European centers of excellence working in the field of lipodystrophies. It provides a favorable environment to promote large Europe-wide and international collaborations to increase the basic scientific understanding and clinical management of these diseases. It works with patient advocacy groups to increase public awareness. The network also promotes a European Patient Registry of lipodystrophies, as a collaborative research platform for consortium members. The annual congress organized gives an update of the findings of network research groups, highlighting clinical and fundamental aspects. The talks presented during the meeting in Cambridge, UK, in 2022 are summarized in these minutes.
Published: 2022

17. Lessons from the impact of COVID-19 on medical educational continuity and practices

Author: Alexandre Hertig, Alain Carrié, Noémie Simon-Tillaux, Marie-Christine Renaud, Isabelle Jéru, and Camille Vatier
Subjects: 020205 medical informatics, Physiology, Distance education, Curriculum Development and Assessment, 02 engineering and technology, Computer-assisted web interviewing, Education, Digital media, Likert scale, 03 medical and health sciences, 0302 clinical medicine, 0202 electrical engineering, electronic engineering, information engineering, ComputingMilieux_COMPUTERSANDEDUCATION, 030212 general & internal medicine, Set (psychology), Curriculum, Multiple choice, Medical education, teachers, business.industry, COVID-19, General Medicine, undergraduate student, Scale (social sciences), digital resources, business, Psychology, remote learning
Abstract: The COVID-19 crisis necessitated abrupt transition to remote learning in medical schools. We aimed to assess the impact of COVID-19 on French undergraduate students and teachers, to identify practice changes, and to evaluate successes and areas for improvement of this remote learning experience. Data from 2 online questionnaires were analyzed with 509 participants among students and 189 among teachers from Sorbonne University. Responses to multiple choice, Likert response scale, and open-ended questions were evaluated. COVID-19 had negative impact on teaching continuity. Sixty-seven percent of students were in a dropout situation, and many suffered from psychological stress, leading to set up of a psychological support unit. Although most teachers (81%) and students (72%) had limited knowledge of digital resources, distance learning was quickly implemented, with a predominant use of Zoom. The analysis of several parameters revealed that students were significantly more satisfied than teachers by remote learning. Nevertheless, both students and teachers agreed to replace classical lectures by digital media and to promote in-person teaching in small interactive groups. This paper shares tips for faculty rapidly establishing remote learning. This comparative study of the students’ and teachers’ points of view underlines that new medical curricula should include more digital contents. We make recommendations regarding general university organization, equipment, and curricular development for long-term implementation of digital resources with reinforced relationships between faculty and students.
Published: 2021

18. Lipodystrophies génétiques partielles, de la physiopathologie à la prise en charge

Author: Corinne Vigouroux, Héléna Mosbah, Marie-Christine Vantyghem, Camille Vatier, B. Donadille, Sonja Janmaat, and Isabelle Jéru
Subjects: 03 medical and health sciences, 0302 clinical medicine, Nutrition and Dietetics, Endocrinology, Diabetes and Metabolism, Internal Medicine, 030209 endocrinology & metabolism, 030204 cardiovascular system & hematology, Cardiology and Cardiovascular Medicine
Abstract: Resume Les lipodystrophies partielles d’origine genetique sont des maladies rares caracterisees par un deficit selectif de tissu adipeux (TA). Leur diagnostic est complexe et leur prevalence est sous-estimee du fait de leur proximite clinique avec le syndrome metabolique. Le diagnostic repose sur la mise en evidence d’une lipoatrophie partielle et sur l’existence de complications metaboliques en lien avec l’absence de TA. Plusieurs genes sont impliques dans ces maladies, bien que dans plus de 50 % des cas on ne retrouve pas d’etiologie moleculaire apres analyse des genes connus. Les proteines correspondantes exercent des roles divers necessaires au fonctionnement adipocytaire. Le traitement des lipodystrophies est, d’une part, celui des complications metaboliques associees avec, dans certains cas, une indication a un traitement par leptine recombinante et, d’autre part, des comorbidites specifiques, en particulier cardiovasculaires, dans certaines formes cliniques.
Published: 2021
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19. Lipoatrophic diabetes in familial partial lipodystrophy type 2: From insulin resistance to diabetes

Author: Guillaume Treiber, Alice Guilleux, Kevin Huynh, Oriane Bonfanti, Ania Flaus–Furmaniuk, David Couret, Natalie Mellet, Céline Bernard, Nathalie Le-Moullec, Berenice Doray, Isabelle Jéru, Jean-Christophe Maiza, Bhoopendrasing Domun, Muriel Cogne, Olivier Meilhac, Corinne Vigouroux, Peter J Meikle, and Estelle Nobécourt
Subjects: Endocrinology, Endocrinology, Diabetes and Metabolism, Internal Medicine, General Medicine
Abstract: Subjects with Familial Partial Lipodystrophy type 2 (FPLD2) are at high risk to develop diabetes. To better understand the natural history and variability of this disease, we studied glucose tolerance, insulin response to an oral glucose load, and metabolic markers in the largest cohort to date of subjects with FPLD2 due to the same LMNA variant.A total of 102 patients aged18 years, with FPLD2 due to the LMNA 'Reunionese' variant p.(Thr655Asnfs*49) and 22 unaffected adult relatives with normal glucose tolerance (NGT) were enrolled. Oral Glucose Tolerance Tests (OGTT) with calculation of derived insulin sensitivity and secretion markers, and measurements of HbA1c, C-reactive protein, leptin, adiponectin and lipid profile were performed.In patients with FPLD2: 65% had either diabetes (41%) or prediabetes (24%) despite their young age (median: 39.5 years IQR 29.0-50.8) and close-to-normal BMI (median: 25.5 kg/mOGTT reveals early alterations of glucose and insulin metabolism in patients with FPLD2, and should be systematically performed before excluding a diagnosis of prediabetes or diabetes to adapt medical care. Decreased adiponectin is an early marker of the disease. Adiponectin replacement therapy warrants further study in FPLD2.
Published: 2022

20. Discovery and functional analysis of a novel ALPK1 variant in ROSAH syndrome

Author: Tom Snelling, Leo O. Garnotel, Isabelle Jeru, Maud Tusseau, Laurence Cuisset, Antoinette Perlat, Geoffrey Minard, Thibaut Benquey, Yann Maucourant, Nicola T. Wood, Philip Cohen, and Alban Ziegler
Subjects: ADP-heptose, ALPK1, nucleotide sugar, UDP-mannose, ROSAH, TIFA, Biology (General), QH301-705.5
Abstract: Retinal dystrophy, optic nerve oedema, splenomegaly, anhidrosis and migraine headache (ROSAH) syndrome is an autosomal dominant disorder and to date is known to be caused by either the Thr237Met or Tyr254Cys variant in the protein kinase ALPK1. Here, we identify a family in which ROSAH syndrome is caused by a novel variant in which Ser277 is changed to Phe. All six patients examined display ocular inflammation and optic nerve elevation, four have retinal degeneration and four are registered blind. In contrast to wild-type ALPK1, which is activated specifically by bacterial ADP-heptose, ALPK1[Ser277Phe] is also activated by the human metabolites UDP-mannose and ADP-ribose and more strongly than the most frequent ROSAH-causing variant (ALPK1[Thr237Met]) but, unlike ALPK1[Thr237Met], ALPK1[Ser277Phe] is also activated by GDP-mannose. These observations can explain why ALPK1 variants causing ROSAH syndrome display constitutive activity in human cells. The side chains of Ser277 and Tyr254 interact in the crystal structure of ALPK1, but mutational analysis established that it is not the loss of this hydrogen bond between Ser277 and Tyr254 that alters the specificity of the ADP-heptose-binding pocket in the Ser277Phe and Tyr254Cys variants. The characterization of ALPK1 variants that cause ROSAH syndrome suggests ways in which drugs that selectively inhibit these disease-causing variants may be developed.
Published: 2024
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21. <scp>RIPK3</scp> dampens mitochondrial bioenergetics and lipid droplet dynamics in metabolic liver disease

Author: Marta B. Afonso, Tawhidul Islam, Julie Magusto, Ricardo Amorim, Véronique Lenoir, Rui F. Simões, José Teixeira, Liana C. Silva, Dominique Wendum, Isabelle Jéru, Corinne Vigouroux, Rui E. Castro, Paulo J. Oliveira, Carina Prip‐Buus, Vlad Ratziu, Jérémie Gautheron, Cecília M. P. Rodrigues, Prip-Buus, Carina, Universidade de Lisboa, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Coimbra [Portugal] (UC), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre de Référence des Maladies Rares - Maladies Inflammatoires des Voies Biliaires et Service d’Hépatologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre National de Référence des Pathologies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité [CHu Saint-Antoine] (PRISIS), CHU Saint-Antoine [AP-HP], [Institut Cochin] Département Endocrinologie, métabolisme, diabète (EMD) (EMD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)
Subjects: [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Hepatology, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology
Abstract: International audience; Background and aims: Receptor-interacting protein kinase 3 (RIPK3) mediates NAFLD progression, but its metabolic function is unclear. Here, we aimed to investigate the role of RIPK3 in modulating mitochondria function, coupled with lipid droplet (LD) architecture in NAFLD.Approach and results: Functional studies evaluating mitochondria and LD biology were performed in wild-type (WT) and Ripk3-/- mice fed a choline-deficient, amino acid-defined (CDAA) diet for 32 and 66 weeks and in CRISPR-Cas9 Ripk3-null fat-loaded immortalized hepatocytes. The association between hepatic perilipin (PLIN) 1 and 5, RIPK3, and disease severity was also addressed in a cohort of patients with NAFLD and in PLIN1-associated familial partial lipodystrophy. Ripk3 deficiency rescued impairment in mitochondrial biogenesis, bioenergetics, and function in CDAA diet-fed mice and fat-loaded hepatocytes. Ripk3 deficiency was accompanied by a strong upregulation of antioxidant systems, leading to diminished oxidative stress upon fat loading both in vivo and in vitro. Strikingly, Ripk3-/- hepatocytes displayed smaller size LD in higher numbers than WT cells after incubation with free fatty acids. Ripk3 deficiency upregulated adipocyte and hepatic levels of LD-associated proteins PLIN1 and PLIN5. PLIN1 upregulation controlled LD structure and diminished mitochondrial stress upon free fatty acid overload in Ripk3-/- hepatocytes and was associated with diminished human NAFLD severity. Conversely, a pathogenic PLIN1 frameshift variant was associated with NAFLD and fibrosis, as well as with increased hepatic RIPK3 levels in familial partial lipodystrophy.Conclusions: Ripk3 deficiency restores mitochondria bioenergetics and impacts LD dynamics. RIPK3 inhibition is promising in ameliorating NAFLD.
Published: 2022
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22. Reply to Morje et al

Author: Camille Vatier, Marie-Christine Renaud, Isabelle Jéru, Alexandre Hertig, Alain Carrié, and Noémie Simon-Tillaux
Subjects: 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), Physiology, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), General Medicine, Sociology, Virology, Letter to the Editor, Education
Published: 2021

23. Biallelic CAV1 null variants induce congenital generalized lipodystrophy with achalasia

Author: Olivier Lascols, Asuman Nur Karhan, Jamila Zammouri, Jocelyne Magré, Isabelle Jéru, Fehmi Ates, Marie-Christine Verpont, Bruno Fève, Martine Auclair, Yusuf Usta, E. Capel, Feramuz Demir Apaydin, and Corinne Vigouroux
Subjects: Male, medicine.medical_specialty, Adolescent, Endocrinology, Diabetes and Metabolism, Caveolin 2, Caveolin 1, 030209 endocrinology & metabolism, Caveolae, Asymptomatic, Neonatal Progeroid Syndrome, Congenital generalized lipodystrophy, 03 medical and health sciences, Consanguinity, 0302 clinical medicine, Endocrinology, Insulin resistance, Lipodystrophy, Congenital Generalized, Microscopy, Electron, Transmission, Internal medicine, Retinitis pigmentosa, medicine, Humans, Child, Index case, Cellular Senescence, 030304 developmental biology, Dyslipidemias, 0303 health sciences, business.industry, Generalized lipodystrophy, Homozygote, Infant, RNA-Binding Proteins, General Medicine, Fibroblasts, medicine.disease, 3. Good health, Pedigree, Esophageal Achalasia, Oxidative Stress, Child, Preschool, Female, medicine.symptom, business
Abstract: Objective CAV1 encodes caveolin-1, a major protein of plasma membrane microdomains called caveolae, involved in several signaling pathways. Caveolin-1 is also located at the adipocyte lipid droplet. Heterozygous pathogenic variants of CAV1 induce rare heterogeneous disorders including pulmonary arterial hypertension and neonatal progeroid syndrome. Only one patient was previously reported with a CAV1 homozygous pathogenic variant, associated with congenital generalized lipodystrophy (CGL3). We aimed to further delineate genetic transmission, clinical, metabolic, and cellular characteristics of CGL3. Design/Methods In a large consanguineous kindred referred for CGL, we performed next-generation sequencing, as well as clinical, imagery, and metabolic investigations. We studied skin fibroblasts from the index case and the previously reported patient with CGL3. Results Four patients, aged 8 months to 18 years, carried a new homozygous p.(His79Glnfs*3) CAV1 variant. They all displayed generalized lipodystrophy since infancy, insulin resistance, low HDL-cholesterol, and/or high triglycerides, but no pulmonary hypertension. Two patients also presented at the age of 15 and 18 years with dysphagia due to achalasia, and one patient had retinitis pigmentosa. Heterozygous parents and relatives (n = 9) were asymptomatic, without any metabolic abnormality. Patients’ fibroblasts showed a complete loss of caveolae and no protein expression of caveolin-1 and its caveolin-2 and cavin-1 partners. Patients’ fibroblasts also displayed insulin resistance, increased oxidative stress, and premature senescence. Conclusions The CAV1 null variant investigated herein leads to an autosomal recessive congenital lipodystrophy syndrome. Loss of caveolin-1 and/or caveolae induces specific manifestations including achalasia which requires specific management. Overlapping phenotypic traits between the different CAV1-related diseases require further studies.
Published: 2021

24. Genetic contribution of ABCC2 to Dubin‐Johnson syndrome and inherited cholestatic disorders

Author: Muriel Girard, Yves Chretien, Bertrand Roquelaure, Olivier Chazouillères, Catherine Dong, Véronique Barbu, Christophe Corpechot, Isabelle Jéru, Pierre Broué, Chantal Housset, and Olivier Lascols
Subjects: Adult, Male, Heterozygote, medicine.medical_specialty, Adolescent, DNA Copy Number Variations, Benign Recurrent Intrahepatic Cholestasis, Population, Cholestasis, Intrahepatic, Gastroenterology, Liver disorder, Cohort Studies, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Dubin–Johnson syndrome, Cholestasis, Pregnancy, Internal medicine, medicine, Humans, Neonatal cholestasis, Child, education, Genetic testing, education.field_of_study, Hepatology, medicine.diagnostic_test, Jaundice, Chronic Idiopathic, business.industry, Infant, Middle Aged, medicine.disease, Multidrug Resistance-Associated Protein 2, Pregnancy Complications, Child, Preschool, 030220 oncology & carcinogenesis, Mutation, Female, 030211 gastroenterology & hepatology, France, Multidrug Resistance-Associated Proteins, business, Cholestasis of pregnancy
Abstract: Background and aims The ABCC2 gene is implicated in Dubin-Johnson syndrome (DJS), a rare autosomal recessive liver disorder. The primary aim of this study was to determine the diagnostic value of ABCC2 genetic testing in the largest cohort of DJS reported to date. The high number of patients with cholestatic manifestations in this series prompted us to evaluate the genetic contribution of rare, potentially pathogenic ABCC2 variants to other inherited cholestatic disorders. Methods The cohort study included 32 patients with clinical DJS diagnosis, and 372 patients referred for the following disorders: low phospholipid-associated cholelithiasis (LPAC) syndrome, intrahepatic cholestasis of pregnancy (ICP) and benign recurrent intrahepatic cholestasis (BRIC). ABCC2 was screened by next-generation sequencing. Results Most patients with clinical DJS had positive genetic diagnosis (n = 30; 94%), with a great diversity of point mutations and copy number variations in ABCC2. Strikingly, eight (27%) of these patients showed transient cholestatic features at presentation: four neonatal cholestasis, two ICP, one contraceptive-induced cholestasis and one sporadic cholestasis. Conversely, the frequency of rare, heterozygous, potentially pathogenic ABCC2 variants in patients with LPAC, ICP or BRIC did not differ significantly from that of the general population. Conclusions This large series reveals that DJS is a highly homogeneous Mendelian disorder involving a large spectrum of ABCC2 variants. Genetic testing is crucial to establish early DJS diagnosis in patients with atypical presentations, such as neonatal cholestasis. This study also provides no evidence for the contribution of rare, potentially pathogenic ABCC2 variants to other inherited cholestatic disorders.
Published: 2019
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25. Development and Validation of a New Risk Prediction Score for Life-Threatening Ventricular Tachyarrhythmias in Laminopathies

Author: Mélanie Fradin, Nicolas Sadoul, Xavier Waintraub, Didier Klug, Albert Hagège, Pascal Sabouraud, Arnaud Isapof, Julien Durigneux, Olivier Lascols, Pascal Laforêt, Armelle Magot, Ivana Dabaj, Eloi Marijon, Camille Vatier, Pascal Cintas, Emmanuelle Salort, Bénédicte Gaborit, Antoine Muchir, Xavier Ferrer, Pascale Richard, Corinne Metay, Stéphane Boulé, Sarah Leonard-Louis, Philippe Mabo, V. Tiffreau, Caroline Stalens, Jitendra K. Vohra, Stéphane Schaeffer, Khadija Chikhaoui, Eric Bieth, Sandra Mercier, Pierre Ambrosi, Aleksandra Nadaj-Pakleza, Michèle Mayer, Katja Zeppenfeld, Gisèle Bonne, Véronique Manel, Jean-Marc Davy, Guilhem Sole, Ghassan Moubarak, Nicolas Lamblin, Klaus Dieterich, Christophe Meune, Abdallah Fayssoil, Arnaud Lazarus, Philippe Maury, Karim Wahbi, Philippe Petiot, Isabelle Jéru, Annick Toutain, Corinne Vigouroux, Ana Ferreiro, Maud Michaud, H.M. Bécane, Bruno Eymard, Thomas D. Gossios, Marie-Christine Vantyghem, Saurabh Kumar, Estelle Gandjbakhch, Yann Péréon, T. Thompson, Marie-Christine Minot-Myhié, Anthony Behin, Frédéric Sacher, Philippe Charron, Nicolas Combes, Julien Praline, Dominique Babuty, Emmanuelle Lagrue, Usha B. Tedrow, Jean-Marc Sellal, Florence Petit, Perry M. Elliott, Frédéric Anselme, Philippe Chevalier, Frederic Taithe, Christine Barnerias, Vincent Laugel, Andoni Echaniz-Laguna, Raphaël P. Martins, Alexander F.A. Androulakis, Rabah Ben Yaou, Franck Boccara, Ulrike Walther-Louvier, Tanya Stojkovic, Françoise Bouhour, Annachiara De Sandre-Giovannoli, Susana Quijano-Roy, Françoise Chapon, Jean-Noël Trochu, Céline Tard, Anne Rollin, Jean-Marie Cuisset, Denis Duboc, Raphaël Porcher, Catherine Sarret, Jonathan M. Kalman, Florence Demurger, Damien Bonnet, Christine Francannet, Neal K. Lakdawala, Romain Eschalier, Fabien Labombarda, Kostantinos Savvatis, Raul Juntas Morales, Isabelle Desguerre, Nicolas Lévy, Anne-Claire Brehin, Service de Cardiologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Rouen, Normandie Université (NU), St Bartholomew's Hospital (London), Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Association française contre les myopathies (AFM-Téléthon), IHU-LIRYC, Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux], Service de Cardiologie B, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Hôpital Ambroise Paré [AP-HP], William Harvey Research Institute, Barts and the London Medical School, Biostatistique et épidemiologie clinique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de cardiologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Filière Neuromusculaire (FILNEMUS), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Université de Caen Normandie (UNICAEN), Laboratoire d'Informatique Scientifique et Industrielle (LISI), Université de Poitiers-Ecole Nationale Supérieure de Mécanique et d'Aérotechnique [Poitiers] (ISAE-ENSMA), Hôpital Raymond Poincaré [AP-HP], CHU Lille, Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Aix Marseille Université (AMU), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut de cardiologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de cardiologie et maladies vasculaires [Rennes] = Cardiac, Thoracic, and Vascular Surgery [Rennes], CHU Pontchaillou [Rennes], Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Clinique Pasteur [Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Imagerie Adaptative Diagnostique et Interventionnelle (IADI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), The Royal Melbourne Hospital, Leiden University Medical Center (LUMC), Universiteit Leiden, Service de neurologie pédiatrique [CHU Necker], Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Antoine [AP-HP], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Necker - Enfants Malades [AP-HP], Hôpital Privé Le Bois Ramsay Santé [Lille], Service de génétique [Rouen], Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Hôpital Côte de Nacre [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Mobilités : Vieillissement, Pathologie, Santé (COMETE), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Roger Salengro [Lille], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de ressources biologiques Tissus ADN Cellules [Hôpital de la Timone - APHM] (CRB TAC), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Cytogénétique et de Biologie Cellulaire, Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Centre Hospitalier Universitaire [Grenoble] (CHU), [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Les Hôpitaux Universitaires de Strasbourg (HUS), CHU Clermont-Ferrand, Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de neurologie [Bordeaux], Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de chirurgie cadiovasculaire et thoracique [Rouen], Hôpital Charles Nicolle [Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Service de cardiologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CHU Trousseau [APHP], Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Strasbourg, Clinique Ambroise Paré [Centres Médico-Chirurgicaux Ambroise Pré, Pierre Cherest, Hartmann], Hôpital Cochin [AP-HP], Hospices Civils de Lyon (HCL), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université de Lorraine (UL), Service de neurologie [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Centre Hospitalier Universitaire de Reims (CHU Reims), Institut Pascal (IP), SIGMA Clermont (SIGMA Clermont)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de Neurologie [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Laboratoire d'étude de la motricité humaine - EA 3608 (LEMH), Université de Lille, Droit et Santé, Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Physiopathologie et thérapie du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Montréal (UdeM), Laboratoire Génie des procédés papetiers (LGP2 ), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS), The Heart Hospital [London], University College of London [London] (UCL), This study was funded by grants from the AFM-Téléthon (French Alliance against Myopathies), which was not involved in the design and conduct of the study, collection, management, analysis, and interpretation of the data, preparation, review, or approval of the manuscript, and decision to submit the manuscript for publication. Some of this work was undertaken at University College London (United Kingdom) and St. Bartholomew’s Hospital (London, United Kingdom), which received a portion of funding from the United Kingdom Department of Health’s National Institute for Health Research Biomedical Research Centres funding scheme., Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], Centre de recherche en myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP], CHU Bordeaux [Bordeaux]-Université Bordeaux Segalen - Bordeaux 2, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-CHU Trousseau [APHP], unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de cardiologie et maladies vasculaires, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], CHU Pitié-Salpêtrière [APHP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Unit of Neuromuscular Morphology [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [APHP]-Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de référence des maladies rares neuromusculaires Aquitaine-Grand Sud Ouest, CHU Bordeaux [Bordeaux], Laboratoire d'Informatique Scientifique et Industrielle (LISI / ENSMA), LISI-ENSMA, Service de Biochimie-Génétique [Béclère], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Thérapie des maladies du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Cardiologie A, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'Endocrinologie et Métabolisme, Unité de Cardiologie et Soins Intensifs, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse], CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Service de Génétique [Purpan], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], Centre de Référence M3C Malformations Cardiaques Congénitales Complexes, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-CHU Necker - Enfants Malades [AP-HP], Hôpital neurologique, Centre Hospitalier Universitaire de Lille (CHU de Lille), Service Neurologie Pédiatrique, Service de Neuropédiatrie, INSERM U836, équipe 4, Muscles et pathologies, Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Département de Neurologie, Hôpital Civil de Strasbourg, Groupe Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique médicale, CHU - HÔTEL-DIEU Clermont-Ferrand, CLAD Ouest, Centre Hospitalier Universitaire [Rennes], Centre recherche en CardioVasculaire et Nutrition (C2VN), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de Neuropédiatrie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie et cerveau, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement (Inserm U1167 - RID-AGE - Institut Pasteur), Clinique Ambroise Paré, CHU Cochin [AP-HP], Epilepsie, sommeil et explorations fonctionnelles neuropédiatriques, Hospices Civils de Lyon (HCL)-Hopital Neurologique-Hôpital Femme Mère Enfant, Department of Medicine, Columbia University [New York]-College of Physicians and Surgeons, Service de neurologie, Hospices Civils de Lyon (HCL)-Hôpital de la Croix-Rousse [CHU - HCL], Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U837 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, Hôpital de Rangueil, Institut Pascal - Clermont Auvergne (IP), Sigma CLERMONT (Sigma CLERMONT)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), laboratoire d'étude de la motricité humaine (LEMH EA3608), Université de Montréal - UdeM (CANADA), Laboratoire Génie des procédés papetiers (LGP2), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche en Myologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-CHU Necker - Enfants Malades [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Sorbonne Université, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), European Genomic Institute for Diabetes - FR 3508 (EGID), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Hôpital Purpan [Toulouse], Hôpital Charles Nicolle [Rouen]-CHU Rouen, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Hôpital Gui de Chauliac [Montpellier]-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), SIGMA Clermont (SIGMA Clermont)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut de Myologie, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, Male, Tachycardia, medicine.medical_specialty, implantable, Accurate estimation, Ventricular Tachyarrhythmias, Validation Studies as Topic, 030204 cardiovascular system & hematology, tachycardia, Sudden death, LMNA, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, death, Physiology (medical), Internal medicine, defibrillators, medicine, Humans, In patient, 030212 general & internal medicine, sudden, [SDV.GEN]Life Sciences [q-bio]/Genetics, Prediction score, business.industry, Defibrillators, Implantable, ventricular, Tachycardia, Ventricular, Cardiology, Female, medicine.symptom, Cardiomyopathies, Cardiology and Cardiovascular Medicine, business
Abstract: Background: An accurate estimation of the risk of life-threatening (LT) ventricular tachyarrhythmia (VTA) in patients with LMNA mutations is crucial to select candidates for implantable cardioverter-defibrillator implantation. Methods: We included 839 adult patients with LMNA mutations, including 660 from a French nationwide registry in the development sample, and 179 from other countries, referred to 5 tertiary centers for cardiomyopathies, in the validation sample. LTVTA was defined as (1) sudden cardiac death or (2) implantable cardioverter defibrillator–treated or hemodynamically unstable VTA. The prognostic model was derived using the Fine-Gray regression model. The net reclassification was compared with current clinical practice guidelines. The results are presented as means (SD) or medians [interquartile range]. Results: We included 444 patients, 40.6 (14.1) years of age, in the derivation sample and 145 patients, 38.2 (15.0) years, in the validation sample, of whom 86 (19.3%) and 34 (23.4%) experienced LTVTA over 3.6 [1.0–7.2] and 5.1 [2.0–9.3] years of follow-up, respectively. Predictors of LTVTA in the derivation sample were: male sex, nonmissense LMNA mutation, first degree and higher atrioventricular block, nonsustained ventricular tachycardia, and left ventricular ejection fraction (https://lmna-risk-vta.fr). In the derivation sample, C-index (95% CI) of the model was 0.776 (0.711–0.842), and the calibration slope 0.827. In the external validation sample, the C-index was 0.800 (0.642–0.959), and the calibration slope was 1.082 (95% CI, 0.643–1.522). A 5-year estimated risk threshold ≥7% predicted 96.2% of LTVTA and net reclassified 28.8% of patients with LTVTA in comparison with the guidelines-based approach. Conclusions: In comparison with the current standard of care, this risk prediction model for LTVTA in laminopathies significantly facilitated the choice of candidates for implantable cardioverter defibrillators. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03058185.
Published: 2019
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26. Cardiovascular complications of lipodystrophic syndromes – focus on laminopathies

Author: Isabelle Jéru, Marie-Christine Vantyghem, Héléna Mosbah, Karim Wahbi, Camille Vatier, B. Donadille, Corinne Vigouroux, Franck Boccara, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Recherche translationnelle sur le diabète - U 1190 (RTD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Filière Neuromusculaire (FILNEMUS), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service de Cardiologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Service d'Endocrinologie, diabétologie et endocrinologie de la reproduction [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre National de Référence des Pathologies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité [CHu Saint-Antoine] (PRISIS), Service de Cardiologie [CHU Saint-Antoine], Laboratoire commun de biologie et génétique moléculaires [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and Gestionnaire, Hal Sorbonne Université
Subjects: medicine.medical_specialty, Lipodystrophy, Endocrinology, Diabetes and Metabolism, LMNA, MESH: Laminopathies, MESH: Phenotype, Electrocardiography, Endocrinology, MESH: Lipodystrophy, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, medicine, Humans, Cardiovascular complications, MESH: Syndrome, Intensive care medicine, ComputingMilieux_MISCELLANEOUS, Focus (computing), MESH: Humans, business.industry, Laminopathies, MESH: Cardiovascular Diseases, General Medicine, Syndrome, medicine.disease, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, MESH: Electrocardiography, Phenotype, Cardiovascular Diseases, business
Abstract: International audience
Published: 2021
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27. Genetics of lipodystrophy syndromes

Author: Isabelle Jéru
Subjects: Proteasome Endopeptidase Complex, Mitochondrial Diseases, Lipodystrophy, Mitochondrial disease, Bioinformatics, GTP Phosphohydrolases, Mitochondrial Proteins, GTP-Binding Protein gamma Subunits, medicine, Adipocytes, Humans, Genetic Testing, Exome, Inflammation, Adipogenesis, business.industry, Genetic heterogeneity, Organ dysfunction, Genetic data, High-Throughput Nucleotide Sequencing, General Medicine, Syndrome, medicine.disease, Lamin Type A, PPAR gamma, Lipomatosis, Multiple Symmetrical, Identification (biology), Personalized medicine, medicine.symptom, business, Acyltransferases
Abstract: Summary Lipodystrophic syndromes (LS) constitute a clinically and genetically heterogeneous group of diseases characterized by a loss of adipose tissue. These syndromes are usually associated with metabolic complications, which are determinant for morbidity and mortality. The classical forms of LS include partial, generalized, and progeroid lipodystrophies. They are usually due to defects in proteins playing a key role in adipogenesis and adipocyte functions. More recently, systemic disorders combining lipodystrophy and multiple organ dysfunction have been described, including autoinflammatory syndromes, mitochondrial disorders, as well as other complex entities. To date, more than thirty genes have been implicated in the monogenic forms of LS, but the majority of them remain genetically-unexplained. The associated pathophysiological mechanisms also remain to be clarified in many instances. Next generation sequencing-based approaches allow simultaneous testing of multiple genes and have become crucial to speed up the identification of new disease-causing genes. The challenge for geneticists is now the interpretation of the amount of available genetic data, generated especially by exome and whole-genome sequencing. International recommendations on the interpretation and classification of variants have been set up and are regularly reassessed. Very close collaboration between geneticists, clinicians, and researchers will be necessary to make rapid progress in understanding the molecular and cellular basis of these diseases, and to promote personalized medicine.
Published: 2021

28. Indications thérapeutiques et effets métaboliques de la métréleptine chez les patients atteints de lipodystrophie : données de vie réelle du registre français

Author: J.F. Gautier, A. DaguenelNguyen, M. Fichet, J. Maitre, Yves Reznik, E. Bismuth, Corinne Vigouroux, F. Travert, A. Spiteri, Eric Renard, Camille Vatier, Sonja Janmaat, Claire Briet, J. Zammouri, A. Guilleux, C. Legagneur, M. Cartigny, Marie-Christine Vantyghem, E. Mongeois, Héléna Mosbah, B. Donadille, Christine Poitou, F. Archambeaud, Isabelle Jéru, Fabrizio Andreelli, B. Vergès, and E. Nobecourt
Subjects: Endocrinology, Endocrinology, Diabetes and Metabolism, General Medicine
Published: 2021
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29. Impact of pathogenic PPARG variants on pregnancy outcomes and in utero development

Author: Xavier Debussche, Camille Gosseaume, Isabelle Jéru, Corinne Vigouroux, Estelle Nobecourt, Françoise Archambeaud, Camille Vatier, Catherine Pienkowski, Isabelle Missotte, Olivier Lascols, Thierry Fournier, Bruno Guerci, Jean-Paul Thissen, and Séverine A. Degrelle
Subjects: Peroxisome proliferator-activated receptor gamma, Reproductive Medicine, In utero, business.industry, Obstetrics and Gynecology, Medicine, Pregnancy outcomes, Bioinformatics, business, Developmental Biology
Published: 2021
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30. LIPE-related lipodystrophic syndrome: clinical features and disease modeling using adipose stem cells

Author: Eric Renard, Corinne Vigouroux, Emilie Capel, Caroline Aguilhon, Roberto Motterlini, Camille Sollier, Claire Douillard, Isabelle Jéru, Laura Braud, Camille Vatier, Vasily Smirnov, Olivier Lascols, S. Defoort-Dhellemmes, Jennifer Gorwood, Martine Auclair, Miriam Ladsous, Vigouroux, Corinne, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Département Endocrinologie-Diabétologie-Nutrition [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Service d’Exploration de la Vision et Neuro-ophtalmologie [CHU Lille], Hôpital Roger Salengro [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Faculté de Médecine Henri Warembourg - Université de Lille, Service Endocrinologie, diabétologie, maladies métaboliques et nutrition (LILLE - Endocrino), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Référence des Maladies Héréditaires du Métabolisme [Lille], Hôpital Jeanne de Flandre [Lille]-Clinique de Pédiatrie (Gastro-entérologie, hépatologie et nutrition)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CH de Valenciennes, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre National de Référence des Pathologies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité [CHu Saint-Antoine] (PRISIS), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire commun de biologie et génétique moléculaires [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Université Lille 2 - Faculté de Médecine, Service Endocrinologie Diabétologie et Métabolisme (LILLE - Endocrino), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10
Subjects: medicine.medical_specialty, Lipodystrophy, Endocrinology, Diabetes and Metabolism, Lipomatosis, Adipose tissue, 030209 endocrinology & metabolism, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Insulin resistance, Adipocyte, Internal medicine, Diabetes mellitus, Adipocytes, Humans, Medicine, Lipoatrophy, Alleles, Aged, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Models, Genetic, business.industry, Stem Cells, Partial Lipodystrophy, Genetic Variation, Cell Differentiation, Syndrome, General Medicine, Middle Aged, Sterol Esterase, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, 3. Good health, Phenotype, Adipose Tissue, chemistry, 030220 oncology & carcinogenesis, Lipomatosis, Multiple Symmetrical, Female, business
Abstract: Objective The term Multiple Symmetric Lipomatosis (MSL) describes a heterogeneous group of rare monogenic disorders and multifactorial conditions, characterized by upper-body adipose masses. Biallelic variants in LIPE encoding hormone-sensitive lipase (HSL), a key lipolytic enzyme, were implicated in three families worldwide. We aimed to further delineate LIPE-related clinical features and pathophysiological determinants. Methods A gene panel was used to identify pathogenic variants. The disease features were reviewed at the French lipodystrophy reference center. The immunohistological, ultrastructural, and protein expression characteristics of lipomatous tissue were determined in surgical samples from one patient. The functional impact of variants was investigated by developing a model of adipose stem cells (ASCs) isolated from lipomatous tissue. Results We identified new biallelic LIPE null variants in three unrelated patients referred for MSL and/or partial lipodystrophy. The hallmarks of the disease, appearing in adulthood, included lower-limb lipoatrophy, upper-body and abdominal pseudo-lipomatous masses, diabetes and/or insulin resistance, hypertriglyceridemia, liver steatosis, high blood pressure, and neuromuscular manifestations. Ophthalmological investigations revealed numerous auto-fluorescent drusen-like retinal deposits in all patients. Lipomatous tissue and patient ASCs showed loss of HSL and decreased expression of adipogenic and mature adipocyte markers. LIPE-mutated ASCs displayed impaired adipocyte differentiation, decreased insulin response, defective lipolysis, and mitochondrial dysfunction. Conslusions Biallelic LIPE null variants result in a multisystemic disease requiring multidisciplinary care. Loss of HSL expression impairs adipocyte differentiation, consistent with the lipodystrophy/MSL phenotype and associated metabolic complications. Detailed ophthalmological examination could reveal retinal damage, further pointing to the nervous tissue as an important disease target.
Published: 2021
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31. Lipodystrophie et lipoatrophie

Author: Sonja Janmaat, Héléna Mosbah, Isabelle Jéru, B. Fève, Olivier Lascols, J. Zammouri, B. Donadille, C. Vatier, and C. Vigouroux
Subjects: business.industry, Medicine, business
Published: 2021
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32. Collaborateurs

Author: Amar Abderrhamani, Najate Achamrah, Benjamin Allès, Maud Alligier, Chloé Amouyal, Sébastien André, Fabrizio Andreelli, Barbara Antuna-Puente, Gérard Apfeldorfer, Roberto Arienzo, Isabelle Arnulf, Judith Aron-Wisnewski, Estelle Aubry, Antoine Avignon, Anne Bachelot, Pascal Barat, Robert Barouki, Jean-Philippe Bastard, Marie Bastin, Thibaut Batisse, Bernard Bauduceau, Catherine Bauters, Pierre Bel Lassen, Alice Bellicha, Audrey Bergouignan, Rebecca Bienvenot, Philip Böhme, Amélie Bonnefond, Lyse Bordier, Yves Boirie, Anne-Laure Borel, Philippe Bouchard, Jean-Luc Bouillot, Marie-Christine Boutron-Ruault, Édith Brot-Laroche, Robert Caiazzo, Claire Carette, Caroline Carriere, Audrey Carriere-Pazat, Louis Casteilla, Dominique-Adèle Cassuto, Marie-Aline Charles, Didier Chapelot, Hélène Charreire, Nicolas Chevalier, Jean-Marc Chevallier, Cécile Ciangura, Karine Clément, Moïse Coëffier, Philippe Cornet, Christine Cortet, Muriel Coupaye, Sébastien Czernichow, Jérôme Dargent, Nathalie Delzenne, Philippe Deruelle, Jean-Claude Desport, Magalie Desseigne, Bruno Detournay, Sébastien Dharancy, Emmanuel Disse, Bruno Donadille, Claire Douillard, Béatrice Dubern, Sophie Dubreuil, Martine Duclos, Hélène Duez, Sophie Dunoyer, Charlotte Dupont, Vincent Durlach, Dominique Durrer-Schutz, Sophie Duverne, Harold Eburdery, Stéphanie Espiard, Nathalie Esser, Amandine Everard, Pauline Faucher, Philippe Fayemendy, Soraya Fellahi, Bruno Fève, Alicia Fillon, Vanessa Folope, Isabelle Fontanille, Marie-Laure Frelut, Philippe Froguel, Bénédicte Gaborit, Blandine Gatta-Cherifi, Christelle Guillet, Laurent Grange, Catherine Grangeard, Iva Gueorguieva, Serge Halimi, Hélène Hanaire, Solveig Heide, Barbara Heude, Sylvain Iceta, Sonja Janmaat, Isabelle Jéru, Pierre Jésus, Anne-Sophie Joly, Béatrice Jouret, Chantal Julia, Sabrina Julien-Sweerts, Min Ji Kim, Miriam Ladsous, Jean-Daniel Lalau, Dominique Langin, Olivier Lascols, Guillaume Lassailly, Claire de La Serre, Martine Laville, Sophie Laye, Jean-Michel Lecerf, Armelle Leturque, Rachel Lévy, Yasmine Lienard, Guillaume Losserand, Aïcha Maghroudi, Christophe Magnan, Geneviève Marcelin, Camille Marciniak, Philippe Marre, Lucile Marty, Philippe Mathurin, Joane Matta, Matthieu Mencia-Huerta, Andréanne Michaud, Vincent Miramont, Caroline Mocquot, Sandrine Monnery-Patris, Émilie Montastier, Pauline Morigny, Héléna Mosbah, Nathalie Negro, Audrey Neyrinck, Jean-Michel Oppert, Naïma Oukhouya Daoud, Filippo Pacini, Julien Paccou, Nicolas Paquot, François Pattou, Soazig Péron-Le Lay, Pierre Peuteuil, Tigran Poghosyan, Christine Poitou, Jean-Pierre Poulain, Guillaume Pourcher, Didier Quilliot, Jocelyne Raison, Marc Raucoules-Aimé, Gérard Ribes, Nathalie Rigal, Patrick Ritz, Claire Rives-Lange, Pauline Riviere, Maud Robert, Julie Rodriguez, Monique Romon, Cindy Rose, Romain Rozier, Thibault de Saint Pol, Frédéric Sanguignol, André Scheen, Jean-Louis Schlienger, Nathalie Sermondade, Yasmine Sebti, Chantal Simon, Luc Tappy, Maïté Tauber, Hélène Thibault, David Thivel, Philippe Valet, Marie-Christine Vantyghem, Camille Vatier, Bruno Verges, Hélène Verkindt, Bernard Vialettes, Corinne Vigouroux, Stéphane Walrand, Bernard Waysfeld, Jamila Zammouri, Jean-Philippe Zermati, Olivier Ziegler, and Jean-Daniel Zucker
Published: 2021
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33. Looking at New Unexpected Disease Targets in LMNA-Linked Lipodystrophies in the Light of Complex Cardiovascular Phenotypes: Implications for Clinical Practice

Author: Stéphane Ederhy, Elisabeth Sarrazin, B. Donadille, Olivier Lascols, Fabien Picard, Bruno Fève, Isabelle Jéru, Corinne Vigouroux, Karim Wahbi, Camille Vatier, Ariel Cohen, Héléna Mosbah, Sophie Benabbou, Pascale Richard, Sophie Christin-Maitre, Marie-Christine Vantyghem, B. Neraud, Alban Redheuil, Jocelyn Inamo, Franck Boccara, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Recherche translationnelle sur le diabète - U 1190 (RTD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU de la Martinique [Fort de France], Hôpital Pierre Zobda-Quitman [CHU de la Martinique], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Hôpital Foch [Suresnes], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Filière Neuromusculaire (FILNEMUS), Institut de cardiologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire d'Imagerie Biomédicale [Paris] (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-CHU Saint-Antoine [AP-HP], Service d'Endocrinologie, diabétologie et endocrinologie de la reproduction [CHU Saint-Antoine], Service de Cardiologie [CHU Saint-Antoine], Laboratoire commun de biologie et génétique moléculaires [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité Fonctionnelle de Cardiogénétique et Myogénétique Moléculaire et Cellulaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Service de Biochimie Métabolique [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire d'Imagerie Biomédicale (LIB), Service de radiologie cardiovasculaire et interventionnelle [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Gestionnaire, Hal Sorbonne Université, and Service de Radiologie cardiovasculaire et interventionnelle [CHU Pitié-Salpêtrière]
Subjects: 0301 basic medicine, medicine.medical_specialty, lipodystrophy, [SDV]Life Sciences [q-bio], Cardiomyopathy, LMNA, 030204 cardiovascular system & hematology, Progeroid syndromes, 03 medical and health sciences, 0302 clinical medicine, lmna, cardiovascular disease, Internal medicine, medicine, lcsh:QH301-705.5, Coronary atherosclerosis, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Generalized lipodystrophy, Partial Lipodystrophy, Dilated cardiomyopathy, General Medicine, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, lcsh:Biology (General), Cardiology, Lipodystrophy, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Variants in LMNA, encoding A-type lamins, are responsible for laminopathies including muscular dystrophies, lipodystrophies, and progeroid syndromes. Cardiovascular laminopathic involvement is classically described as cardiomyopathy in striated muscle laminopathies, and arterial wall dysfunction and/or valvulopathy in lipodystrophic and/or progeroid laminopathies. We report unexpected cardiovascular phenotypes in patients with LMNA-associated lipodystrophies, illustrating the complex multitissular pathophysiology of the disease and the need for specific cardiovascular investigations in affected patients. A 33-year-old woman was diagnosed with generalized lipodystrophy and atypical progeroid syndrome due to the newly identified heterozygous LMNA p.(Asp136Val) variant. Her complex cardiovascular phenotype was associated with atherosclerosis, aortic valvular disease and left ventricular hypertrophy with rhythm and conduction defects. A 29-year-old woman presented with a partial lipodystrophy syndrome and a severe coronary atherosclerosis which required a triple coronary artery bypass grafting. She carried the novel heterozygous p.(Arg60Pro) LMNA variant inherited from her mother, affected with partial lipodystrophy and dilated cardiomyopathy. Different lipodystrophy-associated LMNA pathogenic variants could target cardiac vasculature and/or muscle, leading to complex overlapping phenotypes. Unifying pathophysiological hypotheses should be explored in several cell models including adipocytes, cardiomyocytes and vascular cells. Patients with LMNA-associated lipodystrophy should be systematically investigated with 24-h ECG monitoring, echocardiography and non-invasive coronary function testing.
Published: 2020
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34. Lipodystrophic syndromes due toLMNAmutations: recent developments on biomolecular aspects, pathophysiological hypotheses and therapeutic perspectives

Author: Caroline Le Dour, Corinne Vigouroux, Pauline Afonso, Véronique Béréziat, Guillaume Bidault, Olivier Lascols, Anne-Claire Guenantin, Camille Vatier, Jacqueline Capeau, Isabelle Jéru, Emilie Capel, Nolwenn Briand, Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire commun de biologie et génétique moléculaires [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), The Wellcome Trust Sanger Institute [Cambridge], Metabolic Research Laboratories [Cambridge, UK] (University of Cambridge), Wellcome Trust - MRC Cambridge-Addenbrooke’s Hospital [Cambridge, UK], Department of Molecular Medicine [Oslo], Institute of Basic Medical Sciences [Oslo], Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO)-Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO), The authors thank Sorbonne Université, former Université Pierre and Marie Curie (UPMC), Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Cardio Metabolism (ICAN), ANRS (France REcherche Nord&Sud Sidahiv Hépatites), Région Ile-de-France STEM-Pole, Association Française d’Etude et de Recherche sur l’Obésité (AFERO), Fondation de France, Fondation pour la Recherche Médicale, Société Francophone du Diabète (SFD), for the financial support to our research team at Saint Antoine Research Centre, Paris, France., and Vigouroux, Corinne
Subjects: 0301 basic medicine, Senescence, lipodystrophy, senescence, induced pluripotent stem cells, extracellular matrix, Adipose tissue, Biology, Bioinformatics, LMNA, 03 medical and health sciences, Metreleptin, chemistry.chemical_compound, 0302 clinical medicine, medicine, Humans, Epigenetics, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Lamin A/C, epigenetics, integumentary system, Laminopathies, differentiation, Cell Biology, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Lamin Type A, medicine.disease, adipose tissue, 3. Good health, 030104 developmental biology, chemistry, metreleptin, 030220 oncology & carcinogenesis, Mutation, Anticipation (genetics), anticipation, Lipodystrophy, Lamin
Abstract: International audience; Mutations in LMNA, encoding A-type lamins, are responsible for laminopathies including musculardystrophies, lipodystrophies, and premature ageing syndromes. LMNA mutations have been shownto alter nuclear structure and stiffness, binding to partners at the nuclear envelope or within thenucleoplasm, gene expression and/or prelamin A maturation. LMNA-associated lipodystrophicfeatures, combining generalized or partial fat atrophy and metabolic alterations associated withinsulin resistance, could result from altered adipocyte differentiation or from altered fat structure.Recent studies shed some light on how pathogenic A-type lamin variants could triggerlipodystrophy, metabolic complications, and precocious cardiovascular events. Alterations inadipose tissue extracellular matrix and TGF-beta signaling could initiate metabolic inflexibility.Premature senescence of vascular cells could contribute to cardiovascular complications. Inaffected families, metabolic alterations occur at an earlier age across generations, which couldresult from epigenetic deregulation induced by LMNA mutations. Novel cellular modelsrecapitulating adipogenic developmental pathways provide scalable tools for disease modelingand therapeutic screening.
Published: 2018
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35. Les mutations d’EPHX1 sont responsables de diabète lipoatrophique, consécutif à une altération de l’hydrolyse des époxydes et à une sénescence cellulaire accrue

Author: B. Cerame, C. Morisseau, F. Phan, J. Zammouri, Fabrizio Andreelli, W. Chung, B. Fève, E. Capel, G. Baujat, Corinne Vigouroux, C. Moulin, Y. Wang, J. Gautheron, J. Yang, Martine Auclair, Isabelle Jéru, and B. Hammock
Subjects: Endocrinology, Endocrinology, Diabetes and Metabolism, General Medicine
Published: 2021
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36. LMNA-associated partial lipodystrophy: anticipation of metabolic complications

Author: Camille Vatier, Isabelle Jéru, Marie-Christine Vantyghem, Corinne Vigouroux, and Olivier Lascols
Subjects: 0301 basic medicine, Pediatrics, medicine.medical_specialty, business.industry, Partial Lipodystrophy, Retrospective cohort study, Familial partial lipodystrophy, medicine.disease, LMNA, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Endocrinology, Diabetes mellitus, Internal medicine, Anticipation (genetics), Genetics, medicine, Lipodystrophy, business, Body mass index, 030217 neurology & neurosurgery, Genetics (clinical)
Abstract: BackgroundType-2 familial partial lipodystrophy (FPLD2) is a rare autosomal dominant lipodystrophic disorder due to mutations inLMNAencoding lamin A/C, a key epigenetic regulator. FPLD2 severity is determined by the occurrence of metabolic complications, especially diabetes and hypertriglyceridaemia. We evaluated the disease history and severity over generations.MethodsThis retrospective study of the largest cohort of patients with FPLD2 reported to date investigates 85 patients from 24 families comprising three generations (G1: n=39; G2: n=41; G3: n=5).ResultsLipodystrophy appears with the same characteristics and at the same age in first generation (G1;18.6±1.5 years) and second generation (G2;15.9±0.8 years). Despite similar body mass index (23.7±0.6 vs 23.8±0.6 kg/m2), the mean delay between the onset of lipodystrophy and diabetes was far shorter in G2 (10.5±2.4 years) than in G1 (29.0±3.5 years) (p=0.0002). The same is true for the delay preceding hypertriglyceridaemia (G2: 4.5±1.4; G1: 19.3±3.2 years) (p=0.002), revealing an anticipation phenomenon. Observations in G3, and analysis within each family of disease history and diagnostic procedures, confirmed this result.ConclusionsThis study is a rare example of anticipation unrelated to a trinucleotide expansion. Discovery of this early occurrence of metabolic complications in young generations underlines the utility of presymptomatic genetic diagnosis, with careful metabolic screening and preventive lifestyle in all at-risk individuals.
Published: 2017
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37. European lipodystrophy registry: background and structure

Author: David B. Savage, Alessandra Gambineri, Raoul C.M. Hennekam, Claire Adams, Paolo Sbraccia, Jannik Schaaf, Julia von Schnurbein, David Araújo-Vilar, Camille Vatier, Giovanna Lattanzi, Konstanze Miehle, Baris Akinci, Giuseppe Novelli, Giovanni Ceccarini, Isabelle Jéru, Maria Rosaria D'Apice, Ferruccio Santini, Gabriele Nagel, Elena Vorona, Ekaterina Sorkina, George A. Tanteles, Martin Wabitsch, Corinne Vigouroux, Marie-Christine Vantyghem, Ermelinda Santos Silva, von Schnurbein, Julia [0000-0001-9918-664X], Apollo - University of Cambridge Repository, General Paediatrics, APH - Quality of Care, Von Schnurbein J., Adams C., Akinci B., Ceccarini G., D'Apice M.R., Gambineri A., Hennekam R.C.M., Jeru I., Lattanzi G., Miehle K., Nagel G., Novelli G., Santini F., Santos Silva E., Savage D.B., Sbraccia P., Schaaf J., Sorkina E., Tanteles G., Vantyghem M.-C., Vatier C., Vigouroux C., Vorona E., Araujo-Vilar D., and Wabitsch M.
Subjects: medicine.medical_specialty, Registry, Lipodystrophy, Catabolic state, Pharmacology toxicology, lcsh:Medicine, Adipose tissue, 030209 endocrinology & metabolism, Signs and symptoms, Settore MED/09, Rare diseases, 03 medical and health sciences, 0302 clinical medicine, 0502 economics and business, medicine, Humans, Pharmacology (medical), Registries, ddc:610, Genetics (clinical), Rare endocrinological diseases, User authentication, business.industry, Research, 05 social sciences, lcsh:R, General Medicine, medicine.disease, 3. Good health, Open source, Settore MED/03, Family medicine, General Data Protection Regulation, 050211 marketing, business, Rare disease, Software
Abstract: ClinicalTrials.gov (NCT03553420). Registered 14 March 2018, retrospectively registered Background: Lipodystrophy syndromes comprise a group of extremely rare and heterogeneous diseases characterized by a selective loss of adipose tissue in the absence of nutritional deprivation or catabolic state. Because of the rarity of each lipodystrophy subform, research in this area is difficult and international co-operation mandatory. Therefore, in 2016, the European Consortium of Lipodystrophies (ECLip) decided to create a registry for patients with lipodystrophy. Results: The registry was build using the information technology Open Source Registry System for Rare Diseases in the EU (OSSE), an open-source software and toolbox. Lipodystrophy specific data forms were developed based on current knowledge of typical signs and symptoms of lipodystrophy. The platform complies with the new General Data Protection Regulation (EU) 2016/679 by ensuring patient pseudonymization, informational separation of powers, secure data storage and security of communication, user authentication, person specific access to data, and recording of access granted to any data. Inclusion criteria are all patients with any form of lipodystrophy (with the exception of HIV-associated lipodystrophy). So far 246 patients from nine centres (Amsterdam, Bologna, Izmir, Leipzig, Münster, Moscow, Pisa, Santiago de Compostela, Ulm) have been recruited. With the help from the six centres on the brink of recruitment (Cambridge, Lille, Nicosia, Paris, Porto, Rome) this number is expected to double within the next one or 2 years. Conclusions: A European registry for all patients with lipodystrophy will provide a platform for improved research in the area of lipodystrophy. All physicians from Europe and neighbouring countries caring for patients with lipodystrophy are invited to participate in the ECLip Registry. E.S. has funding for lipodystrophy studies by the Russian Science Foundation,grantNo17–75-30035C.Vi. and C.Va. received funding by the French Ministry of Solidarity andHealth, Assistance-Publique Hôpitaux de Paris, Sorbonne Université, the Insti-tut National de la Santé et de la Recherche Médicale (Inserm), and CardioMe-tabolism and Nutrition University Hospital Institute (ICAN), grant ANR-10-IAHU, FranceD.B.S. is supported by the Wellcome Trust (WT 107064), the MRC MetabolicDisease Unit (MRC_MC_UU_12012/2), and The National Institute for HealthResearch (NIHR) Cambridge Biomedical Research Centre and NIHR RareDisease Translational Research Collaboration.D.A.-V. received funding by the Instituto de Salud Carlos III and the EuropeanRegional Development Fund, FEDER (grant number PI18/01890), by theConsellería de Industria, Xunta de Galicia (grant number ED341b 2017/19),and by Fundación Mutua Madrileña (Call 2015).E.S.-S. work was supported by Applied Molecular Biosciences Unit (UCIBIO),which is financed by national funds from FCT/MCTES (UID/MULTI/04378/2019). info:eu-repo/semantics/publishedVersion
Published: 2020

38. Diagnostic Challenge in PLIN1-Associated Familial Partial Lipodystrophy

Author: Marie-Christine Vantyghem, Martine Auclair, Olivier Lascols, David B. Savage, Camille Vatier, Elise Bismuth, Isabelle Jéru, Sara Barraud, Pascale Cervera, Corinne Vigouroux, Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université Sorbonne Paris Cité (USPC), Université Pierre et Marie Curie - Paris 6 (UPMC), Pathologie de l'Adipocyte et des Cellules Hepatiques, University of Cambridge [UK] (CAM), and Barraud, Sara
Subjects: 0301 basic medicine, Male, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, DNA Mutational Analysis, Case Report, Bioinformatics, Biochemistry, 0302 clinical medicine, Endocrinology, Hyperinsulinemia, Frameshift Mutation, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, education.field_of_study, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Polycystic ovary, 3. Good health, Lipodystrophy, Familial Partial, Pedigree, Phenotype, Molecular Diagnostic Techniques, Female, Lipodystrophy, Adult, medicine.medical_specialty, Perilipin-1, Population, 030209 endocrinology & metabolism, Frameshift mutation, Diagnosis, Differential, 03 medical and health sciences, Young Adult, Insulin resistance, Diabetes mellitus, Internal medicine, medicine, Humans, Family, education, Aged, business.industry, Biochemistry (medical), Sequence Analysis, DNA, medicine.disease, Familial partial lipodystrophy, 030104 developmental biology, Insulin Resistance, business
Abstract: Context Heterozygous frameshift variants in PLIN1 encoding perilipin-1, a key protein for lipid droplet formation and triglyceride metabolism, have been implicated in familial partial lipodystrophy type 4 (FPLD4), a rare entity with only six families reported worldwide. The pathogenicity of other PLIN1 null variants identified in patients with diabetes and/or hyperinsulinemia was recently questioned because of the absence of lipodystrophy in these individuals and the elevated frequency of PLIN1 null variants in the general population. Objectives To reevaluate the pathogenicity of PLIN1 frameshift variants owing to new data obtained in the largest series of patients with FPLD4. Methods We performed histological and molecular studies for patients referred to our French National Reference Center for Rare Diseases of Insulin Secretion and Insulin Sensitivity for lipodystrophy and/or insulin resistance and carrying PLIN1 frameshift variants. Results We identified two heterozygous PLIN1 frameshift variants segregating with the phenotype in nine patients from four unrelated families. The FPLD4 stereotypical signs included postpubertal partial lipoatrophy of variable severity, muscular hypertrophy, acromegaloid features, polycystic ovary syndrome and/or hirsutism, metabolic complications (e.g., hypertriglyceridemia, liver steatosis, insulin resistance, diabetes), and disorganized subcutaneous fat lobules with fibrosis and macrophage infiltration. Conclusions These data suggest that some FPLD4-associated PLIN1 variants are deleterious. Thus, the evidence for the pathogenicity of each variant ought to be carefully considered before genetic counseling, especially given the importance of an early diagnosis for optimal disease management. Thus, we recommend detailed familial investigation, adipose tissue-focused examination, and follow-up of metabolic evolution.
Published: 2019
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39. Update on the Genetics of Autoinflammatory Disorders

Author: Isabelle Jéru
Subjects: Pulmonary and Respiratory Medicine, Genetics, Epigenomics, Immunology, Hereditary Autoinflammatory Diseases, Genetic data, Biology, Autoimmune Diseases, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, Somatic mosaicism, Immunology and Allergy, Humans, Routine clinical practice, Identification (biology), Epigenetics, 030223 otorhinolaryngology, Autoinflammatory Disorders
Abstract: This review aims at presenting the most significant data obtained in the field of the genetics of autoinflammatory disorders (AID) over the last past 5 years. More than 15 genes have been implicated in AID since 2014, unveiling new pathogenic pathways. Recent data have revealed atypical modes of transmission in several inherited AID, such as somatic mosaicism and digenism. First pieces of evidence showing an involvement of epigenetic modifications in the pathogenesis of AID have also been brought to light. Novel genetic data have been obtained on the molecular bases of genetically complex AID. The development of next-generation sequencing in routine clinical practice has led to an explosion in the identification of new AID genes. Advances in the knowledge of AID further blur the limits between monogenic and multifactorial forms of these syndromes, and between autoinflammatory and autoimmune conditions.
Published: 2019

40. Lipodystrophic syndromes: From diagnosis to treatment

Author: Corinne Vigouroux, Emilie Capel, Camille Vatier, Isabelle Jéru, Olivier Lascols, Bruno Fève, Camille Sollier, Sonja Janmaat, Martine Auclair, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre National de Référence des Pathologies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité [CHu Saint-Antoine] (PRISIS), CHU Saint-Antoine [AP-HP], Laboratoire commun de biologie et génétique moléculaires [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service d'Endocrinologie, diabétologie et endocrinologie de la reproduction [CHU Saint-Antoine], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Vigouroux, Corinne
Subjects: Adult, Lipodystrophy, Endocrinology, Diabetes and Metabolism, Genetic counseling, Adipose tissue, Lipodystrophie, 030209 endocrinology & metabolism, Context (language use), Comorbidity, Bioinformatics, Hypertriglycéridémie, Metreleptin, Diagnostic Techniques, Endocrine, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Insulin resistance, Endocrinology, Adipocyte, Genetics, Medicine, Humans, Genetic Predisposition to Disease, Génétique, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Hypertriglyceridemia, business.industry, Leptin, General Medicine, Syndrome, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, Métréleptine, 3. Good health, Insulino-résistance, chemistry, 030220 oncology & carcinogenesis, business
Abstract: International audience; Lipodystrophic syndromes are acquired or genetic rare diseases, characterised by a generalised or partial lack of adipose tissue leading to metabolic alterations linked to strong insulin resistance. They encompass a variety of clinical entities due to primary defects in adipose differentiation, in the structure and/or regulation of the adipocyte lipid droplet, or due to immune-inflammatory aggressions, chromatin deregulations and/or mitochondrial dysfunctions affecting adipose tissue. Diagnosis is based on clinical examination, pathological context and comorbidities, and on results of metabolic investigations and genetic analyses, which together determine management and genetic counselling. Early lifestyle and dietary measures focusing on regular physical activity and avoiding excess energy intake are crucial. They are accompanied by multidisciplinary follow-up adapted to each clinical form. In case of hyperglycemia, antidiabetic medications, with metformin as a first-line therapy in adults, are used in addition to lifestyle and dietary modifications. When standard treatments have failed to control metabolic disorders, the orphan drug metreleptin, an analog of leptin, can be effective in certain forms of lipodystrophy syndrome. Metreleptin therapy indications, prescription and monitoring were recently defined in France, representing a major improvement in patient care.
Published: 2019
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41. SUN-037 Diagnosis Challenge in Type 4 Familial Partial Lipodystrophic Syndrome

Author: Camille Vatier, David B Savage, Marie-Christine Vantyghem, Isabelle Jéru, Corinne Vigouroux, Martine Auclair, Brigitte Delemer, Olivier Lascols, Hilary Meggison, and Elise Bismuth
Subjects: medicine.medical_specialty, How Genetics and Development Impact the Endocrine System, Type (biology), Text mining, business.industry, Endocrinology, Diabetes and Metabolism, medicine, business, Dermatology, Genetics and Development (including Gene Regulation)
Abstract: Introduction: Type 4 familial partial lipodystrophic syndrome (FPLD4) is an autosomal dominant disease due to frameshift variants of PLIN1 gene. This gene encodes perilipin 1, a protein playing a key role in the structure of the adipocyte lipid droplet and in the regulation of lipolysis. Only 6 independent families with FPLD4 have been described. The aim of this work was to identify the major signs of the disease in the largest cohort of FPLD4 patients reported to date. Patients and Methods: Clinical and biological phenotype of 11 new patients with a family history of lipodystrophic syndrome and bearing a frameshift variant of PLIN1 gene, were investigated after written informed consent. Histological examination, and perilipin 1 protein expression analyses by western blot on whole cell extracts were performed on biopsies of adipose tissue in 2 patients. Results: We identified 3 heterozygous frameshift variants of PLIN1, segregating with the disease in 11 patients from 5 independent families. Our team had already described the p.Val398Glyfs*167 variant, and 2 new variants p.Gly362Glyfs*63 and p.Pro403Argfs*164 were identified. In all patients next generation sequencing (NGS) excluded any other molecular defect known to be responsible for lipodystrophy. On the studied adipose tissue samples, the PLIN1 variant leads to an abnormal longer form of perilipin 1 with fat fibrosis. The main signs of FPLD4 associate a partial, but also sometimes generalized lipoatrophy of post-pubertal occurrence and a phenotype of variable severity including muscular hypertrophy, acromegaloid facies, hirsutism, and metabolic complications (hypertriglyceridemia, insulin-resistance, diabetes, liver steatosis). Lipoatrophy might be missing or difficult to identify in men and youth. Leptin level was low or inappropriate to BMI, which was below 30 but not always very low. Conclusion: The clinical phenotype of FPLD4 is quite homogeneous, but the clinical diagnosis requires a careful clinical examination and/or an expert advice. An early genetic diagnosis is recommended to confirm the disease and prevent metabolic complications.
Published: 2019
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42. Cytokine signatures in hereditary fever syndromes (HFS)

Author: Isabelle Jéru, Jose Noel Ibrahim, Jean-Claude Lecron, and Myrna Medlej-Hashim
Subjects: Lipopolysaccharides, 0301 basic medicine, Inflammasomes, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Interleukin-1beta, Immunology, Familial Mediterranean fever, Inflammation, Biology, General Biochemistry, Genetics and Molecular Biology, Mice, 03 medical and health sciences, AIM2, Muckle–Wells syndrome, 0302 clinical medicine, medicine, Animals, Humans, Immunology and Allergy, Cells, Cultured, 030203 arthritis & rheumatology, Mevalonate kinase deficiency, integumentary system, Hereditary Autoinflammatory Diseases, NOD-like receptor, Cryopyrin-associated periodic syndrome, medicine.disease, Cryopyrin-Associated Periodic Syndromes, Immunity, Innate, Familial Mediterranean Fever, 030104 developmental biology, Cytokine, Leukocytes, Mononuclear, Cytokines, Mevalonate Kinase Deficiency, medicine.symptom
Abstract: Hereditary fever syndromes (HFS) include a group of disorders characterized by recurrent self-limited episodes of fever accompanied by inflammatory manifestations occurring in the absence of infection or autoimmune reaction. Advances in the genetics of HFS have led to the identification of new gene families and pathways involved in the regulation of inflammation and innate immunity. The key role of several cytokine networks in the pathogenesis of HFS has been underlined by several groups, and supported by the rapid response of patients to targeted cytokine blocking therapies. This can be due to the direct effect of cytokine overproduction or to an absence of receptor antagonist resulting in dysbalance of downstream pro- and anti-inflammatory cytokine networks. The aim of this study was to present an overview and to discuss the major concepts regarding the cellular and molecular immunology of HFS, with a particular focus on their specific cytokine signatures and physiopathological implications. Based on their molecular and cellular mechanisms, HFS have been classified into intrinsic and extrinsic IL-1β activation disorders or inflammasomopathies, and protein misfolding disorders. This review integrates all recent data in an updated classification of HFS.
Published: 2017
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43. Conséquences des variants pathogènes de PPARG responsables de lipodystrophie familiale partielle de type 3 (FPLD3) sur le déroulement de la grossesse et le développement in utero

Author: Thierry Fournier, Isabelle Jéru, E. Nobecourt, O. Lascols, I. Missotte, Bruno Guerci, Corinne Vigouroux, C. Gosseaume, F. Archambeaud, J.P. Thissen, C. Pienkowski, X. Debussche, Camille Vatier, and Séverine A. Degrelle
Subjects: Endocrinology, Endocrinology, Diabetes and Metabolism, General Medicine
Abstract: Contexte PPARγ est un recepteur nucleaire essentiel a la differenciation adipocytaire et au developpement trophoblastique. Certains variants de PPARG sont responsables du syndrome lipodystrophique familial partiel-type 3 (FPLD3) avec anomalies adipocytaires et insulino-resistance. Ces variants pourraient aussi affecter le developpement in utero, comme le suggere le cas d’une patiente dont la grossesse s’est compliquee de mort neonatale dans un contexte de prematurite et d’anomalies placentaires vasculaires associees a un variant PPARG-FPLD3. Objectif Etudier le phenotype metabolique et le developpement foetal des patients porteurs de variants pathogenes de PPARG. Patients et methodes Etudes transversale et retrospective de patients avec un variant pathogene PPARG-FPLD3. Resultats 22 patients issus de 13 familles ont ete etudies. L’âge median au diagnostic etait de 36 ans. A l’inclusion, 90 % des patients de plus de 15 ans presentaient un diabete (n = 19/21), 58 % une HTA (n = 12/21), 80 % une hypertriglyceridemie (n = 17/21), 76 % une steatose hepatique (n = 16/21), avec une obesite ou un surpoids dans 62 % des cas (n = 13/21). L’âge moyen au diagnostic de diabete et d’HTA de 22 et 28 ans respectivement. Neuf patients (9/16, 56 %) etaient nes prematures et 50 % (n = 7/14) avaient un retard de croissance intra-uterin (RCIU). Tous les patients dont le variant PPARG etait herite du pere (i.e placenta porteur du variant, mere indemne de FPLD3), presentaient une prematurite et un RCIU. Conclusion Ces resultats suggerent que les variants pathogenes de PPARG responsables de FPLD3 pourraient induire des anomalies placentaires specifiques. Des etudes in vitro sont en cours pour en etudier les mecanismes.
Published: 2020
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44. Des variants pathogènes du gène de la lipase hormono-sensible sont responsables d’un syndrome associant lipodystrophie partielle et lipomatose de Launois-Bensaude

Author: Eric Renard, Martine Auclair, O. Lascols, Isabelle Jéru, Camille Sollier, C. Aguilhon, Corinne Vigouroux, E. Capel, and M. Ladsous
Subjects: Endocrinology, Endocrinology, Diabetes and Metabolism, General Medicine
Abstract: Introduction Les lipodystrophies partielles familiales (FPLD) sont des maladies rares et heterogenes. Nous avons montre que le gene codant la mitofusine-2, une proteine controlant la fusion mitochondriale, est implique dans un syndrome associant des masses lipomateuses de la partie superieure du corps (lipomatose de Launois-Bensaude, LLB) et une lipodystrophie partielle (FPLD) avec troubles metaboliques. Ce phenotype reste neanmoins le plus souvent inexplique. Objectif Caracteriser les bases moleculaires du syndrome LLB/FPLD et analyser les consequences des variants pathogenes sur le phenotype clinique, le tissu adipeux, la differenciation et les fonctions adipocytaires in vitro. Methodes La recherche de l’etiologie moleculaire chez les patients atteints d’un phenotype mixte LLB/FPLD a ete realisee par sequencage d’un panel de genes. Nous avons isole les cellules souches adipocytaires (ASC) du tissu pseudo-lipomateux d’une patiente et analyse leur differenciation, insulino-sensibilite, capacite de lipolyse, et expression genique et proteique. Resultats Nous avons identifie de nouveaux variants bialleliques frameshift de LIPE codant la lipase hormono-sensible (LHS), enzyme-cle de la lipolyse, chez deux patientes. Elles presentaient des masses pseudo-lipomateuses, une lipoatrophie distale, une insulino-resistance avec steatose hepatique et hypertriglyceridemie. L’expression de la LHS etait abolie dans le tissu adipeux. Comparees a des ASC temoins, les ASC de la patiente montrent un defaut de differenciation adipocytaire, un defaut de lipolyse et une insulino-resistance. Discussion Certains variants bialleliques de LIPE entrainent un phenotype mixte LLB/FPLD, permettant d’enrichir la nosologie des lipodystrophies genetiques et de re-evaluer le role de la LHS dans la differenciation et les fonctions adipocytaires.
Published: 2020
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45. Other Rare Monogenic Autoinflammatory Diseases

Author: Isabelle Jéru, Eric P. Hanson, and Scott W. Canna
Subjects: Rapid identification, business.industry, Medicine, Identification (biology), In patient, business, Bioinformatics, Autoinflammatory Disorders
Abstract: Over the past decade, major advances have been m`ade in understanding the molecular and cellular bases leading to autoinflammatory diseases, and a number of very rare entities have been described. Next-generation sequencing technologies led to the rapid identification of a number of additional genes responsible for syndromes observed in only a very small number of families or in sporadic cases. The identification of all these new genes and associated molecular pathways underlines that activation of interleukin (IL)-1β signaling is far from being the only pathogenic process involved in autoinflammatory disorders. Genetic defects found in patients with rare monogenic autoinflammatory diseases might also facilitate the study of common autoinflammatory diseases with a genetic component. Since these disorders affect multiple organs with potentially severe complications, management of patients is complex and warrants a multidisciplinary approach. Finally, it is necessary to translate discoveries of the pathophysiology of these conditions into more effective therapies, since the choice of therapeutic options often remains empirical.
Published: 2019
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46. Monogenic forms of lipodystrophic syndromes - diagnosis, detection, and practical management considerations from clinical cases

Author: Corinne Vigouroux, Marie-Christine Vantyghem, Camille Vatier, Jean-Claude Carel, Sophie Christin-Maitre, Bruno Fève, Isabelle Jéru, Jacques Beltrand, Olivier Lascols, Caroline Storey, Elise Bismuth, Service d'Endocrinologie, diabétologie et endocrinologie de la reproduction [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-CHU Saint-Antoine [AP-HP], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Sorbonne Paris Cité (USPC), Laboratoire commun de biologie et génétique moléculaires [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'endocrinologie, gynécologie et diabétologie pédiatriques [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'endocrinologie, diabétologie et nutrition, Centre de Recherche en Nutrition Humaine - Ile de France (CRNH - IDF)-Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13), Gestionnaire, Hal Sorbonne Université, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Sorbonne Paris Cité (USPC)-Hôpital Jean Verdier [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre de Recherche en Nutrition Humaine - Ile de France (CRNH - IDF)
Subjects: Adult, Male, Pediatrics, medicine.medical_specialty, Lipodystrophy, Familial partial lipodystrophy, Berardinelli-Seip congenital lipodystrophy, Early detection, Consanguinity, 030204 cardiovascular system & hematology, Metreleptin, Congenital generalized lipodystrophy, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, GTP-Binding Protein gamma Subunits, medicine, Humans, 030212 general & internal medicine, Aged, Metabolic Syndrome, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, business.industry, Infant, General Medicine, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, 3. Good health, Fatty Liver, chemistry, Mutation, Berardinelli-Seip Congenital Lipodystrophy, Female, business, Acyltransferases
Abstract: International audience; BACKGROUND: Lipodystrophic syndromes are rare diseases of genetic or acquired origin characterized by partial or generalized lack of body fat. Early detection and diagnosis are crucial to prevent and manage associated metabolic dysfunctions, i.e. insulin resistance, dyslipidemia, fatty liver, and diabetes, and to provide appropriate genetic counseling. By means of several representative case studies, this article illustrates the diagnostic and management challenges of lipodystrophic syndromes.REVIEW: Berardinelli-Seip congenital lipodystrophy (BSCL) is typically diagnosed at birth, or soon thereafter, with generalized lipoatrophy and hepatomegaly secondary to hepatic steatosis. Physicians must also consider this diagnosis in adults with atypical non-autoimmune diabetes, hypertriglyceridemia, and a lean and muscular phenotype. The BSCL1 subtype due to mutations in the AGPAT2 gene can have an unusual presentation, especially in neonates and infants. Particular attention should be paid to infants presenting failure to thrive who also have hepatomegaly and metabolic derangements. The BSCL2 sub-type due to mutations in the BSCL gene tends to be more severe than BSCL1, and is characterized by greater fat loss, mild intellectual disability, earlier onset of diabetes, and higher incidence of premature death. Effective management from an earlier age may moderate the natural disease course. Partial lipodystrophies may easily be confused with common central obesity and/or metabolic syndrome. In patients with unexplained pancreatitis and hypertriglyceridemia, lipodystrophies such as familial partial lipodystrophy type 2 (FPLD2; Dunnigan type, due to LMNA mutations) should be considered. Oral combined contraceptives, which can reveal the disease by inducing severe hypertriglyceridemia, are contraindicated. Endogenous estrogens may also lead to "unmasking" of the FPLD2 phenotype, which often appears at puberty, and is more severe in females than males.CONCLUSIONS: Diet and exercise, adapted to age and potential comorbidities, are essential prerequisites for therapeutic management of lipodystrophic syndromes. Metreleptin therapy can be useful to manage lipodystrophy-related metabolic complications
Published: 2019
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47. MFN2-associated lipomatosis: Clinical spectrum and impact on adipose tissue

Author: Corinne Vigouroux, Philippe Froguel, Olivier Lascols, Emmanuel Disse, Sara Barraud, Emilie Capel, Anne Miquel, J.J. Robert, Martine Laville, Héléna Mosbah, Isabelle Jéru, Pierre Gourdy, Brigitte Delemer, Martine Auclair, Florence Tenenbaum, Camille Vatier, Tanya Stojkovic, Amélie Bonnefond, Marie Christine Verpont, Stephan Züchner, Pascale Cervera, Anne-Ségolène Cottereau, Sophie Christin-Maitre, Bruno Fève, Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Centre de Recherche en Nutrition Humaine Rhône-Alpes (CRNH-RA), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-CHU Saint-Etienne-Hospices Civils de Lyon (HCL)-CHU Grenoble, UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Pathologie de l'Adipocyte et des Cellules Hepatiques, CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), John P. Hussman Institute for Human Genomics, University of Miami Leonard M. Miller School of Medicine (UMMSM), Institut de recherche en biothérapie (IRB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Institut de biologie de Lille - UMS 3702 (IBL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Endocrinologie - Diabète - Nutrition [Reims], Université de Reims Champagne-Ardenne (URCA)-Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Reims (CHU Reims), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Institute of Cardiometabolism and Nutrition,Institut National de la Sante et de la Recherche MedicaleSorbonne UniversiteAFERO (Association Francaise d’Etude et de Recherche sur l’Obesite)
Subjects: Adult, Male, Leptin, 0301 basic medicine, medicine.medical_specialty, FGF21, Lipodystrophy, Endocrinology, Diabetes and Metabolism, Lipomatosis, Adipose tissue, GTP Phosphohydrolases, Mitochondrial Proteins, 03 medical and health sciences, 0302 clinical medicine, Insulin resistance, Internal medicine, Genetics, Mitofusin 2, Internal Medicine, medicine, Humans, RNA, Messenger, Lipoatrophy, ComputingMilieux_MISCELLANEOUS, Aged, Nutrition and Dietetics, Adiponectin, business.industry, Thermogenic markers, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, Mitochondria, Neuropathy, 3. Good health, 030104 developmental biology, Endocrinology, Adipose Tissue, Dyslipidemia, Positron-Emission Tomography, Lipomatosis, Multiple Symmetrical, Female, Cardiology and Cardiovascular Medicine, business, 030217 neurology & neurosurgery
Abstract: Background Multiple symmetric lipomatosis (MSL) is characterized by upper-body lipomatous masses frequently associated with metabolic and neurological signs. MFN2 pathogenic variants were recently implicated in a very rare autosomal recessive form of MSL. MFN2 encodes mitofusin-2, a mitochondrial fusion protein previously involved in Charcot-Marie-Tooth neuropathy. Objective To investigate the clinical, metabolic, tissular, and molecular characteristics of MFN2-associated MSL. Methods We sequenced MFN2 in 66 patients referred for altered fat distribution with one or several lipomas or lipoma-like regions and performed clinical and metabolic investigations in patients with positive genetic testing. Lipomatous tissues were studied in 3 patients. Results Six patients from 5 families carried a homozygous p.Arg707Trp pathogenic variant, representing the largest reported series of MFN2-associated MSL. Patients presented both lipomatous masses and a lipodystrophic syndrome (lipoatrophy, low leptinemia and adiponectinemia, hypertriglyceridemia, insulin resistance and/or diabetes). Charcot-Marie-Tooth neuropathy was of highly variable clinical severity. Lipomatous tissue mainly contained hyperplastic unilocular adipocytes, with few multilocular cells. It displayed numerous mitochondrial alterations (increased number and size, structural defects). As compared to control subcutaneous fat, mRNA and protein expression of leptin and adiponectin was strikingly decreased, whereas the CITED1 and fibroblast growth factor 21 (FGF21) thermogenic markers were strongly overexpressed. Consistently, serum FGF21 was markedly increased, and 18F-FDG-PET-scan revealed increased fat metabolic activity. Conclusion MFN2-related MSL is a novel mitochondrial lipodystrophic syndrome involving both lipomatous masses and lipoatrophy. Its complex neurological and metabolic phenotype justifies careful clinical evaluation and multidisciplinary care. Low leptinemia and adiponectinemia, high serum FGF21, and increased 18F-FDG body fat uptake may be disease markers.
Published: 2018
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48. Recurrent Fever Syndromes

Author: Isabelle Jéru
Subjects: Mevalonate kinase deficiency, Innate immune system, medicine.diagnostic_test, business.industry, Familial Mediterranean fever, medicine.disease, Systemic inflammation, Pathophysiology, Pharyngitis, Immunology, medicine, Tumor necrosis factor alpha, medicine.symptom, business, Genetic testing
Abstract: Recurrent fever syndromes (RFS) are autoinflammatory disorders characterized by self-limited recurrent episodes of fever and systemic inflammation, associated with inflammatory manifestations. Five clinical entities can be considered as the prototypical RFS: familial Mediterranean fever (FMF), tumour necrosis factor (TNF), receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), cryopyrin-associated periodic syndromes (CAPS), and periodic fever, aphthosis, pharyngitis, and adenitis (PFAPA). Genetic testing plays a key role in establishing their diagnosis. In addition, recent development of next-generation sequencing technologies has led to the rapid identification of a number of additional genes responsible for very rare RFS. Since RFS affect multiple organs with potentially severe complications, management of patients is complex and warrants a multidisciplinary approach. The main therapeutic options encompass nonspecific anti-inflammatory approaches, such as corticosteroids and non-steroidal anti-inflammatory drugs, as well as biological agents. The study of the pathophysiology of RFS led to the discovery of multiple receptors of the innate immune system recognizing pathogens and endogenous danger signals. Although a number of pathogenic processes have been demonstrated as underlying these disorders, dysregulation of the interleukin-1β (IL-1β) signalling pathway was found to play a key role in most RFS. This catalysed major advances in the development of targeted biologic therapies, particularly IL-1 blocking treatments. Nevertheless, some patients will require more tailored therapeutic approaches.
Published: 2018
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49. Brief Report: Involvement ofTNFRSF11AMolecular Defects in Autoinflammatory Disorders

Author: Serge Amselem, Shayan Sheykholeslami, Sandra Chantot-Bastaraud, Gaëlle Le Borgne, Véronique Hentgen, Philippe Duquesnoy, Isabelle Jéru, Sonia Karabina, Emmanuelle Cochet, Bruno Copin, Mathieu Mahevas, Florence Dastot-Le Moal, Laurence Faivre, Jean-Claude Lecron, Valérie Malan, and Maria Teresa Mitjavila-Garcia
Subjects: Mutation, Innate immune system, Point mutation, Immunology, Biology, medicine.disease_cause, Frameshift mutation, Proinflammatory cytokine, Rheumatology, Genotype, Gene duplication, medicine, Immunology and Allergy, Copy-number variation
Abstract: Objective Autoinflammatory disorders are caused by a primary dysfunction of the innate immune system. Among these disorders are hereditary recurrent fevers, which are characterized by recurrent episodes of fever and inflammatory manifestations affecting multiple tissues. Hereditary recurrent fevers often lack objective diagnostic criteria, thereby hampering the identification of disease-causing genes. This study was undertaken to identify a gene responsible for hereditary recurrent fevers. Methods Copy number variations and point mutations were sought by array-comparative genomic hybridization and polymerase chain reaction sequencing, respectively. Serum cytokine levels were measured using Luminex technology. The effect of TNFRSF11A molecular defects on NF-κB signaling in cells expressing wild-type and mutated forms of the receptor was evaluated by luciferase assay. Results A patient with multiple congenital anomalies and hereditary recurrent fever was found to carry a de novo heterozygous complex chromosomal rearrangement encompassing a duplication of TNFRSF11A, a gene known to regulate fever in rodents. We also identified a heterozygous frameshift mutation (p.Met416Cysfs*110) in TNFRSF11A in a mother and daughter with isolated hereditary recurrent fever. This mutation was associated with increased secretion of several inflammatory cytokines (tumor necrosis factor α [TNFα], interleukin-18 [IL-18], IL-1 receptor antagonist, interferon-γ) and altered the biologic effects of the receptor on NF-κB signaling. The disease in the patients described herein exhibits striking clinical similarities to TNF receptor–associated periodic syndrome, another hereditary recurrent fever involving a gene of the same family (TNFRSF1A). Conclusion The involvement of TNFRSF11A in hereditary recurrent fever highlights the key role of this receptor in innate immunity. The present results also suggest that TNFRSF11A screening could serve as a new diagnostic test for autoinflammatory disorders.
Published: 2014
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50. On-demand treatment with anakinra: a treatment option for selected TRAPS patients: Fig. 1

Author: Véronique Hentgen, Véronique Despert, Claire Grimwood, and Isabelle Jéru
Subjects: medicine.medical_specialty, Anakinra, On demand treatment, Rheumatology, business.industry, medicine, Treatment options, Pharmacology (medical), Intensive care medicine, business, medicine.drug
Published: 2015
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