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1. A partial form of inherited human USP18 deficiency underlies infection and inflammation

Author

Marta Martin-Fernandez, Sofija Buta, Tom Le Voyer, Zhi Li, Lasse Toftdal Dynesen, Françoise Vuillier, Lina Franklin, Fatima Ailal, Alice Muglia Amancio, Louise Malle, Conor Gruber, Ibtihal Benhsaien, Jennie Altman, Justin Taft, Caroline Deswarte, Manon Roynard, Alejandro Nieto-Patlan, Kunihiko Moriya, Jérémie Rosain, Nathalie Boddaert, Aziz Bousfiha, Yanick J. Crow, Dragana Jankovic, Alan Sher, Jean-Laurent Casanova, Sandra Pellegrini, Jacinta Bustamante, Dusan Bogunovic, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Signalisation des Cytokines - Cytokine Signaling, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre Hospitalo-universitaire Averroes [Casablanca], Université Hassan II [Casablanca] (UH2MC), National Institutes of Health [Bethesda] (NIH), Fundação Cristiano Varella [Muriaé/MG, Brasil] (FCV), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Radiologie et imagerie médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], School of Mathematics - University of Edinburgh, University of Edinburgh, Rockefeller University [New York], Howard Hughes Medical Institute [New York] (HHMI), Howard Hughes Medical Institute (HHMI)-New York University School of Medicine, NYU System (NYU)-NYU System (NYU)-Rockefeller University [New York]-Columbia University Irving Medical Center (CUIMC), This research was in part supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases of the National Institutes of Health, the National Institute of Allergy and Infectious Diseases (grant numbers R01AI127372, R01AI148963, R01AI151029, 5R01AI089970, and 5R37AI095983), the National Center for Research Resources and the National Center for Advancing Sciences of the National Institutes of Health (grant number 8UL1TR000043), The Rockefeller University, the St. Giles Foundation, The Yale Center for Mendelian Genomics funded by the National Human Genome Research Institute (UM1HG006504), INSERM, University of Paris, the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID) and the French National Research Agency (ANR) under the 'Investments for the future' program (grant number ANR-10-IAHU-01), and GENMSMD (ANR-16-CE17-0005-01 for J. Bustamante). T. LeVoyer is supported by the MD-PhD program of the Imagine Institute with the support of the Bettancourt-Schueller Foundation. Work in Institut Pasteur was supported by grants from Association de la Recherche sur le Cancer (ARC no. 20141201864) and Fondation pour la Recherche Médicale (grant DEQ. 2017033741) and by institutional funding from Institut Pasteur and INSERM. Z. Li was supported by Centre national de la recherche scientifique. L.T. Dynesen was supported by the EU Erasmus+ program. L. Franklin was supported by la Fondation de France (Prix Thérèse Lebrasseur to S. Pellegrini). L. Malle and C. Gruber were supported by National Institute of Child Health and Human Development-Interdisciplinary Training in Systems and Developmental Biology and Birth Defects T32HD075735., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-16-CE17-0005,GENMSMD,Dissection génétique de la Susceptibilité Mendélienne aux infections mycobactériennes chez l'homme(2016), Vuillier, Françoise, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, and Dissection génétique de la Susceptibilité Mendélienne aux infections mycobactériennes chez l'homme - - GENMSMD2016 - ANR-16-CE17-0005 - AAPG2016 - VALID

Subjects
MESH: Inflammation, MESH: Interleukin-12, MESH: Interleukin-23, Inflammation, MESH: Cytokines, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV]Life Sciences [q-bio], Immunology, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Ubiquitin Thiolesterase, Interleukin-12, Interleukin-23, [SDV] Life Sciences [q-bio], MESH: Ubiquitins, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cytokines, Humans, Immunology and Allergy, Ubiquitin Thiolesterase, Ubiquitins
Abstract

International audience; Human USP18 is an interferon (IFN)-stimulated gene product and a negative regulator of type I IFN (IFN-I) signaling. It also removes covalently linked ISG15 from proteins, in a process called deISGylation. In turn, ISG15 prevents USP18 from being degraded by the proteasome. Autosomal recessive complete USP18 deficiency is life-threatening in infancy owing to uncontrolled IFN-I–mediated autoinflammation. We report three Moroccan siblings with autoinflammation and mycobacterial disease who are homozygous for a new USP18 variant. We demonstrate that the mutant USP18 (p.I60N) is normally stabilized by ISG15 and efficient for deISGylation but interacts poorly with the receptor-anchoring STAT2 and is impaired in negative regulation of IFN-I signaling. We also show that IFN-γ–dependent induction of IL-12 and IL-23 is reduced owing to IFN-I–mediated impairment of myeloid cells to produce both cytokines. Thus, insufficient negative regulation of IFN-I signaling by USP18-I60N underlies a specific type I interferonopathy, which impairs IL-12 and IL-23 production by myeloid cells, thereby explaining predisposition to mycobacterial disease.

Published
2022

2. De novo mutation screening in childhood-onset cerebellar atrophy identifies gain-of-function mutations in the CACNA1G calcium channel gene

Author

Giulia Barcia, Laurence Hubert, Emily Fassi, Julien Thevenon, Laurence Faivre, Philippe Lory, Daniel Medina-Cano, Pierre Blanc, Nathalie Boddaert, Nami Altin, Karine Siquier-Pernet, Marlène Rio, Céline Vidal, Jean Chemin, Sylvain Hanein, Holly H. Zimmerman, Marwan Shinawi, Patrick Nitschke, Vincent Cantagrel, Cécile Fourage, Nadia Bahi-Buisson, Christine Bole-Feysot, Jeanne Amiel, Ali Ahmad, Arnold Munnich, Michael Nicouleau, Stanislas Lyonnet, Laurence Colleaux, Isabelle Desguerre, 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), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), Plateforme de génomique [SFR Necker], Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-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) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Necker - Enfants Malades [AP-HP], Plate Forme Paris Descartes de Bioinformatique (BIP-D), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de neurologie pédiatrique [CHU Necker], Neuroimagerie en psychiatrie (U1000), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Radiologie et imagerie médicale [CHU Necker], Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, ANR-16-CE12-0005,SCD-Mec,Mécanismes développementaux des anomalies structurelles cérébelleuses(2016), 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Sud - Paris 11 (UP11), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Male, 0301 basic medicine, Microcephaly, [SDV]Life Sciences [q-bio], Developmental Disabilities, medicine.disease_cause, Deep cerebellar nuclei, Cohort Studies, Calcium Channels, T-Type, Purkinje Cells, Epilepsy, 0302 clinical medicine, Cerebellum, Child, Exome sequencing, Mutation, Brain, Phenotype, Pedigree, Child, Preschool, Gain of Function Mutation, CACNA1G, Female, Cerebellar atrophy, medicine.symptom, voltage-gated calcium channel, Adult, medicine.medical_specialty, Adolescent, Cerebellar Ataxia, Biology, 03 medical and health sciences, cerebellar atrophy, Cerebellar Diseases, Intellectual Disability, Internal medicine, medicine, Humans, [SDV.GEN]Life Sciences [q-bio]/Genetics, Cerebellar ataxia, medicine.disease, de novo mutation, 030104 developmental biology, Endocrinology, Calcium, Calcium Channels, Neurology (clinical), Atrophy, Cav3.1, 030217 neurology & neurosurgery
Abstract

IF 10.848; International audience; Cerebellar atrophy is a key neuroradiological finding usually associated with cerebellar ataxia and cognitive development defect in children. Unlike the adult forms, early onset cerebellar atrophies are classically described as mostly autosomal recessive conditions and the exact contribution of de novo mutations to this phenotype has not been assessed. In contrast, recent studies pinpoint the high prevalence of pathogenic de novo mutations in other developmental disorders such as intellectual disability, autism spectrum disorders and epilepsy. Here, we investigated a cohort of 47 patients with early onset cerebellar atrophy and/or hypoplasia using a custom gene panel as well as whole exome sequencing. De novo mutations were identified in 35% of patients while 27% had mutations inherited in an autosomal recessive manner. Understanding if these de novo events act through a loss or a gain of function effect is critical for treatment considerations. To gain a better insight into the disease mechanisms causing these cerebellar defects, we focused on CACNA1G, a gene not yet associated with the early-onset form. This gene encodes the Cav3.1 subunit of T-type calcium channels highly expressed in Purkinje neurons and deep cerebellar nuclei. We identified four patients with de novo CACNA1G mutations. They all display severe motor and cognitive impairment, cerebellar atrophy as well as variable features such as facial dysmorphisms, digital anomalies, microcephaly and epilepsy. Three subjects share a recurrent c.2881G>A/p.Ala961Thr variant while the fourth patient has the c.4591A>G/p.Met1531Val variant. Both mutations drastically impaired channel inactivation properties with significantly slower kinetics (∼5 times) and negatively shifted potential for half-inactivation (>10 mV). In addition, these two mutations increase neuronal firing in a cerebellar nuclear neuron model and promote a larger window current fully inhibited by TTA-P2, a selective T-type channel blocker. This study highlights the prevalence of de novo mutations in early-onset cerebellar atrophy and demonstrates that A961T and M1531V are gain of function mutations. Moreover, it reveals that aberrant activity of Cav3.1 channels can markedly alter brain development and suggests that this condition could be amenable to treatment.

Published
2018

3. Integrating tractography in pelvic surgery: a proof of concept

Author

Sabine Sarnacki, Jean-Baptiste Marret, Cécile Muller, Laureline Berteloot, Alessandro Delmonte, David Grevent, Thomas Blanc, Quoc Peyrot, Isabelle Bloch, Nathalie Boddaert, Eva Mille, Alessio Virzi, Pietro Gori, Image, Modélisation, Analyse, GEométrie, Synthèse (IMAGES), Laboratoire Traitement et Communication de l'Information (LTCI), Institut Mines-Télécom [Paris] (IMT)-Télécom Paris-Institut Mines-Télécom [Paris] (IMT)-Télécom Paris, Département Images, Données, Signal (IDS), Télécom ParisTech, Institut Mines-Télécom [Paris] (IMT)-Télécom Paris, Service de radiologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Mathématiques de Marseille (I2M), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS), CHU Necker - Enfants Malades [AP-HP], Service de Radiologie et imagerie médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and HAL, TelecomParis

Subjects
medicine.medical_specialty, lcsh:Surgery, [INFO.INFO-IM] Computer Science [cs]/Medical Imaging, 03 medical and health sciences, 0302 clinical medicine, NF1 Tractography MRI Robotic pelvic surgery, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Medicine, Neurofibroma, Neurofibromatosis, ComputingMilieux_MISCELLANEOUS, Pelvic surgery, Dysesthesia, business.industry, lcsh:RJ1-570, lcsh:Pediatrics, lcsh:RD1-811, medicine.disease, Sacral plexus, body regions, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Peripheral nervous system, Pediatrics, Perinatology and Child Health, 030211 gastroenterology & hepatology, Surgery, Radiology, medicine.symptom, business, Tractography, Diffusion MRI
Abstract

Objective: To show the interest of tractography in pelvic surgery by a demonstrative case of neurofibroma resected by robotic assisted laparoscopy. Summary background data: Although diffusion tensor magnetic resonance imaging, along with tractography algorithms, is increasingly included in image guided neurosurgery methods, it is less frequently used for the peripheral nervous system such as the pelvic sacral plexus. We report one observation demonstrating the interest of such image data for pelvic surgery. Methods: A 12-years-old girl with neurofibromatosis presented with a growing left pelvic neurofibroma on repeated pelvic MRI with an increased SUV (2.83) on PET scan. A diffusion tensor pelvic MRI was performed before and after robotically assisted tumoral resection, and a tractography algorithm was applied on both images. Results: The pre-operative tractogram showed the nervous nature of the tumor in close contact with the left sacral plexus. Section of a nerve trunk encased in the neurofibroma was mandatory for the resection and well documented by the 3D enhanced vision provided by the robot. Post-operatively, the patient showed a slight paresthesia and dysesthesia of the left leg calf and of the plantar vault (left S2 territory), without any motor deficit. The post-operative tractogram showed a thinning of the left S2 sacral root and the disappearance of right aberrant nervous tracts. Conclusions: This clinical case validates the ability of pelvic tractography to deliver a proper imaging of the sacral nervous network and emphasizes the potential usefulness of this approach in pelvic surgery management, with perspectives of image-guided surgery. Keywords: NF1, Tractography, MRI, Robotic pelvic surgery

Published
2019

4. Imaging protocols for renal multiparametric MRI and MR urography: results of a consensus conference from the French Society of Genitourinary Imaging

Author

Isabelle Boulay, Marie-France Bellin, S. Brunelle, Ingrid Millet, Xavier Matillon, Jean Tourniaire, Nicolas Grenier, Olivier Rouvière, Laurence Rocher, Raphaële Renard-Penna, Thomas Sanzalone, Olivier Hélénon, Jean-François Lapray, David Eiss, Arnaud Lefevre, Jean-Michel Ménager, François Cornelis, Sébastien Ronze, Catherine Roy, N. Girouin, Marc André, Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Service de Radiologie [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département de radiologie [Institut Paoli Calmettes], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Nouvel Hôpital Civil de Strasbourg, Hôpital Européen [Fondation Ambroise Paré - Marseille], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Imagerie par Résonance Magnétique Médicale et Multi-Modalités (IR4M), Université Paris-Sud - Paris 11 (UP11)-Hôpital Bicêtre-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier Saint-Joseph [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Radiologie et imagerie médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Norimagerie Caluire, CHU Bordeaux [Bordeaux], Imagerie Médicale Créqui, Centre d'Imagerie Tourville, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre d'Imagerie des Gratte-Ciel, Hôpital Lapeyronie [Montpellier] (CHU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Imagerie médicale Val d'Ouest Charcot (IMVOC), Centre hospitalier de Valence, Clinique Rhône Durance, Service de Radiologie [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], CHU Tenon [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), Centre National de la Recherche Scientifique (CNRS)-Hôpital Bicêtre-Université Paris-Sud - Paris 11 (UP11), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)

Subjects
Male, Consensus Development Conferences as Topic, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, 030218 nuclear medicine & medical imaging, 0302 clinical medicine, Transitional cell carcinoma, MESH: Urinary Tract, Urinary Tract, Societies, Medical, Neuroradiology, Urinary bladder, medicine.diagnostic_test, Ultrasound, Interventional radiology, Urography, General Medicine, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, [SDV.IB]Life Sciences [q-bio]/Bioengineering, Female, Radiology, France, medicine.medical_specialty, Consensus, Urology, MESH: Societies, Medical, [SDV.CAN]Life Sciences [q-bio]/Cancer, Guidelines, 03 medical and health sciences, MESH: Urography, Magnetic resonance imaging, medicine, Humans, Radiology, Nuclear Medicine and imaging, MESH: Consensus, Multiparametric Magnetic Resonance Imaging, Hematuria, MESH: Multiparametric Magnetic Resonance Imaging, MESH: Humans, business.industry, MESH: Consensus Development Conferences as Topic, MESH: Urology, MESH: Male, MESH: France, Contrast medium, business, Kidney neoplasms, MESH: Female, Pyelogram
Abstract

To develop technical guidelines for magnetic resonance imaging aimed at characterising renal masses (multiparametric magnetic resonance imaging, mpMRI) and at imaging the bladder and upper urinary tract (magnetic resonance urography, MRU). The French Society of Genitourinary Imaging organised a Delphi consensus conference with a two-round Delphi survey followed by a face-to-face meeting. Two separate questionnaires were issued for renal mpMRI and for MRU. Consensus was strictly defined using a priori criteria. Forty-two expert uroradiologists completed both survey rounds with no attrition between the rounds. Fifty-six of 84 (67%) statements of the mpMRI questionnaire and 44/71 (62%) statements of the MRU questionnaire reached final consensus. For mpMRI, there was consensus that no injection of furosemide was needed and that the imaging protocol should include T2-weighted imaging, dual chemical shift imaging, diffusion-weighted imaging (use of multiple b-values; maximal b-value, 1000 s/mm2) and fat-saturated single-bolus multiphase (unenhanced, corticomedullary, nephrographic) contrast-enhanced imaging; late imaging (more than 10 min after injection) was judged optional. For MRU, the patients should void their bladder before the examination. The protocol must include T2-weighted imaging, anatomical fast T1/T2-weighted imaging, diffusion-weighted imaging (use of multiple b-values; maximal b-value, 1000 s/mm2) and fat-saturated single-bolus multiphase (unenhanced, corticomedullary, nephrographic, excretory) contrast-enhanced imaging. An intravenous injection of furosemide is mandatory before the injection of contrast medium. Heavily T2-weighted cholangiopancreatography-like imaging was judged optional. This expert-based consensus conference provides recommendations to standardise magnetic resonance imaging of kidneys, ureter and bladder. • Multiparametric magnetic resonance imaging (mpMRI) aims at characterising renal masses; magnetic resonance urography (MRU) aims at imaging the urinary bladder and the collecting systems. • For mpMRI, no injection of furosemide is needed. • For MRU, an intravenous injection of furosemide is mandatory before the injection of contrast medium; heavily T2-weighted cholangiopancreatography-like imaging is optional.

Published
2019

5. Successful Treatment of Saksenaea sp. Osteomyelitis by Conservative Surgery and Intradiaphyseal Incorporation of Amphotericin B Cement Beads

Author

Dea Garcia-Hermoso, Valérie Dumaine, Perrine Parize, Catherine Kauffmann-Lacroix, Olivier Lortholary, Sylvain Poirée, Anne-Claire Mamez, Fanny Lanternier, Vincent Jullien, Centre d'infectiologie Necker-Pasteur [CHU Necker], Institut Pasteur [Paris] (IP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Service d'orthopédie [CHU Cochin], Hôpital Cochin [AP-HP], Service de Radiologie et imagerie médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre hospitalier universitaire de Poitiers (CHU Poitiers), 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), CHU Necker - Enfants Malades [AP-HP], Institut Hospitalo-Universitaire Imagine, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), CHU Cochin [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut Pasteur [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), and Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]

Subjects
Male, medicine.medical_specialty, Combination therapy, medicine.medical_treatment, Amphotericin B/administration & dosage/therapeutic use, Saksenaea, 03 medical and health sciences, Pharmacotherapy, Diabetes Complications/microbiology, Osteomyelitis/drug therapy/microbiology/surgery, Amphotericin B, Mucormycosis/drug therapy/microbiology, medicine, Diabetes Mellitus, Humans, Pharmacology (medical), [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Pharmacology, 0303 health sciences, biology, 030306 microbiology, business.industry, Osteomyelitis, Mucormycosis, osteomyelitis, Middle Aged, medicine.disease, biology.organism_classification, amphotericin B, 3. Good health, Surgery, Infectious Diseases, Amputation, Debridement, Mucorales/drug effects, Mucorales, Liposomal amphotericin, Antifungal Agents/therapeutic use, antifungal agents, business, Drug Carriers/therapeutic use, medicine.drug
Abstract

International audience; Osteoarticular mucormycosis cases are quite rare and challenging infections that are mostly due to direct inoculation during traumatic injury among immu-nocompetent patients. Classic management includes a combination of aggressive surgical debridement, which may lead to amputation, and long-term systemic lipo-somal amphotericin B therapy. This article describes the successful treatment of Sak-senaea sp. osteomyelitis in a patient with diabetes mellitus, using a combination of systemic antifungal therapy and conservative surgery with insertion of amphotericin-impregnated cement beads. KEYWORDS Mucorales, amphotericin B, antifungal agents, osteomyelitis M ucorales osteomyelitis still presents diagnostic and therapeutic challenges and is associated with high mortality rates despite a combined therapeutic strategy involving antifungal treatment and surgery (1). Members of the order Mucorales are present in soil and plant debris and could be responsible for osteoarticular mucormy-cosis as a consequence of contamination through disrupted cutaneous barriers after traumatic injury (2). Surgical management is classically aggressive and complicated, with poor functional outcomes or even amputation. We report the first successful conservative orthopedic treatment of Saksenaea sp. osteomyelitis in a patient with diabetes mellitus, using in situ amphotericin-impregnated cement beads in combination with systemic posaconazole therapy. A 63-year-old man was admitted for a painful and swollen right ankle. He had well-controlled diabetes mellitus, hypertension, and degenerative arthritis. He lived in France and had never travelled overseas. Seven years earlier, he had suffered ankle trauma due to a rockfall and developed a necrotic subcutaneous abscess and a diaphyseal periosteal reaction seen on X-ray films. He underwent surgical drainage of the abscess; the sample cultures remained sterile and the surgical wound outcome was marked by a purple painless cutaneous infiltration. Seven years after the first operation, the patient's ankle became painful again and a bone biopsy was performed, which revealed no microorganisms in cultures. Empirical broad-spectrum antibiotherapy was initiated, without efficacy. Lower leg pain, erythema, and edema worsened and a satellite, 4-cm, right inguinal area of lymphadenopathy appeared. The patient was afebrile and had moderate biological inflammatory syndrome (C-reactive protein level, 50 mg/liter). Magnetic resonance imaging (MRI) showed decreased signal intensity on Citation Parize P, Mamez A-C, Garcia-Hermoso D, Dumaine V, Poirée S, Kauffmann-Lacroix C, Jullien V, Lortholary O, Lanternier F. 2019. Successful treatment of Saksenaea sp. osteomyelitis by conservative surgery and intradiaphyseal incorporation of amphotericin B cement beads.

Published
2019

6. Type I interferon-mediated autoinflammation due to DNase II deficiency

Author

Flavio Faletra, Gabriele Stocco, Evelyn Hartmann, Chantal Brouzes, Flavia Guillem, Fabrice Porcheray, Florence Uettwiller, Carolina Uggenti, Diego Vozzi, Marion Rabant, Capucine Picard, Nicolas Cagnard, Elisa Piscianz, Olivier Hermine, Andrea Taddio, Sophie Candon, Gunther Hartmann, Leo A. H. Zeef, Pierre Quartier, Marie Alexandra Alyanakian, Brigitte Bader-Meunier, Benoit Beitz, Gillian I. Rice, Muriel Girard, Monique Fabre, Alberto Tommasini, Dominique Lasne, Marine Depp, Nathalie Boddaert, Mathieu P Rodero, Stefano Volpi, Marco Gattorno, Yanick J. Crow, Eva Bartok, Michael Dussiot, Michel Polak, Tiffany Pascreau, Roberta Caorsi, Erika Della Mina, Naoki Kitabayashi, Annalisa Marcuzzi, Vincent Bondet, Paolo Picco, Luis Seabra, Jacques Beltrand, Erica Valencic, Marie-Louise Frémond, Bénédicte Neven, Frédéric Rieux-Laucat, Darragh Duffy, Alessandra Tesser, Patrick Nitschke, Anna Monica Bianco, Marina Charbit, Annie Harroche, Serena Pastore, Winfried Barchet, Laboratory of neurogenetics and neuroinflammation (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Trieste, University of Bonn, Academic Unit of Medical Genetic, University of Manchester [Manchester], Microbiology Technology Institute, BIOASTER Microbiology Technology Institute [Lyon], Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Giannina Gaslini Institute, Istituto Giannina Gaslini, Genova, Immunologia Clinica e Sperimentale, Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Radiologie et imagerie médicale [CHU Necker], Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - Equipe Inserm U1163), Service de néphrologie pédiatrique [CHU Necker], Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Plate Forme Paris Descartes de Bioinformatique (BIP-D), Université Paris Descartes - Paris 5 (UPD5), Centre d'étude des Déficits Immunitaires, 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), Department of Life Sciences, Institute of Clinical Chemistry and Pharmacology, Center for Integrated Oncology, University Hospital of Bonn, Service d'Hématologie Adulte, IRCCS Burlo Garofolo, Inst Maternal & Child Hlth, Trieste, Italy, Y.J.C. acknowledges the European Research Council (GA 309449), and a state subsidymanaged by the National Research Agency (France) under the 'Investments for the Future'program bearing the reference ANR-10-IAHU-01. We thank ImmunoQure AGfor sharing of antibodies used to assess interferon alpha protein levels in the Simoa assay.M.-L.F. is supported by the Institut National de la Santé et de la Recherche Médicale(Grant number 000427993). A.T. and M.G. acknowledge the Italian Telethon (Grant no.GGP15241A). A.T. acknowledges the Institute for Maternal and Child Health-IRCCS'Burlo Garofolo' (RC 17/2014 funded by Italian Ministry of Health, art 12 and 12bis D.lgs 502/92), the 'Associazione Azzurra Malattie Rare'and the 'Beneficientia Stiftung in Vaduz'. We would like to thank Olivier pellet and Jerome Megret from theflow cytometry platform at SFR Necker (INSERM US24-CNRS UMS 3633) for their help withperipheral blood mononuclear cell subset isolation. We would like to thank the Geno-mics Platform, INSERM UMR1163 for whole-exome sequencing. E.B., G.H., and W.B.acknowledge DZIF funding and German Research Foundation (DFG) grants EXC1023:ImmunoSensation, CRCs 670 and 704, ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), European Project: 309449,EC:FP7:ERC,ERC-2012-StG_20111109,T1-IFN(2013), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-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-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), BIOASTER, 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), Università degli studi di Trieste = University of Trieste, Universität Bonn = University of Bonn, Institut Pasteur [Paris] (IP)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University Hospital Bonn, Vougny, Marie-Christine, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, Definition and characterization of type I interferonopathies - T1-IFN - - EC:FP7:ERC2013-03-01 - 2018-02-28 - 309449 - VALID, Rodero, Mathieu P., Tesser, Alessandra, Bartok, Eva, Rice, Gillian I., Della Mina, Erika, Depp, Marine, Beitz, Benoit, Bondet, Vincent, Cagnard, Nicola, Duffy, Darragh, Dussiot, Michael, Frã©mond, Marie-Louise, Gattorno, Marco, Guillem, Flavia, Kitabayashi, Naoki, Porcheray, Fabrice, Rieux-Laucat, Frederic, Seabra, Lui, Uggenti, Carolina, Volpi, Stefano, Zeef, Leo A. H., Alyanakian, Marie-Alexandra, Beltrand, Jacque, Bianco, Anna Monica, Boddaert, Nathalie, Brouzes, Chantal, Candon, Sophie, Caorsi, Roberta, Charbit, Marina, Fabre, Monique, Faletra, Flavio, Girard, Muriel, Harroche, Annie, Hartmann, Evelyn, Lasne, Dominique, Marcuzzi, Annalisa, Neven, Bã©nã©dicte, Nitschke, Patrick, Pascreau, Tiffany, Pastore, Serena, Picard, Capucine, Picco, Paolo, Piscianz, Elisa, Polak, Michel, Quartier, Pierre, Rabant, Marion, Stocco, Gabriele, Taddio, Andrea, Uettwiller, Florence, Valencic, Erica, Vozzi, Diego, Hartmann, Gunther, Barchet, Winfried, Hermine, Olivier, Bader-Meunier, Brigitte, Tommasini, Alberto, and Crow, Yanick J.

Subjects
Genetics and Molecular Biology (all), Male, 0301 basic medicine, Erythroblasts, [SDV]Life Sciences [q-bio], DNASE2, type I interferon, autoinflammation, exome sequencing, Up-Regulation/drug effects, General Physics and Astronomy, Erythroblasts/immunology, DNASE2, type I interferon, autoinflammation, exome sequencing, Biochemistry, LS3_11, 0302 clinical medicine, Interferon, Interferon-alpha/blood, Membranoproliferative glomerulonephritis, STAT1, Phosphorylation, lcsh:Science, Child, ComputingMilieux_MISCELLANEOUS, Deoxyribonucleases, Multidisciplinary, biology, RNA, Messenger/analysis, Chemistry (all), Endodeoxyribonucleases/deficiency, Up-Regulation, 3. Good health, STAT1 Transcription Factor, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, STAT1 Transcription Factor/metabolism, Antibody, Signal Transduction, medicine.drug, STAT3 Transcription Factor, [SDV.IMM] Life Sciences [q-bio]/Immunology, Adolescent, Science, Alpha interferon, Antiviral Agents/pharmacology, Hematopoiesis/immunology, Antiviral Agents, Article, General Biochemistry, Genetics and Molecular Biology, Deoxyribonucleases/deficiency, NO, Physics and Astronomy (all), 03 medical and health sciences, Downregulation and upregulation, medicine, Humans, RNA, Messenger, Signal Transduction/immunology, Endodeoxyribonucleases, Innate immune system, Sequence Analysis, RNA, Gene Expression Profiling, Hereditary Autoinflammatory Diseases, Interferon-alpha, General Chemistry, medicine.disease, Hematopoiesis, 030104 developmental biology, STAT3 Transcription Factor/metabolism, Hereditary Autoinflammatory Diseases/blood, Mutation, Immunology, biology.protein, Nucleic acid, lcsh:Q, Biochemistry, Genetics and Molecular Biology (all), 030215 immunology
Abstract

Microbial nucleic acid recognition serves as the major stimulus to an antiviral response, implying a requirement to limit the misrepresentation of self nucleic acids as non-self and the induction of autoinflammation. By systematic screening using a panel of interferon-stimulated genes we identify two siblings and a singleton variably demonstrating severe neonatal anemia, membranoproliferative glomerulonephritis, liver fibrosis, deforming arthropathy and increased anti-DNA antibodies. In both families we identify biallelic mutations in DNASE2, associated with a loss of DNase II endonuclease activity. We record increased interferon alpha protein levels using digital ELISA, enhanced interferon signaling by RNA-Seq analysis and constitutive upregulation of phosphorylated STAT1 and STAT3 in patient lymphocytes and monocytes. A hematological disease transcriptomic signature and increased numbers of erythroblasts are recorded in patient peripheral blood, suggesting that interferon might have a particular effect on hematopoiesis. These data define a type I interferonopathy due to DNase II deficiency in humans., Nucleic acid sensing is important to ensure that an innate immune response is only mounted against microbial nucleic acid. Here, the authors identify loss-of-function mutations in the DNASE2 gene that cause type I interferon-mediated autoinflammation due to enhanced systemic interferon signaling.

Published
2017

7. Mutations in KEOPS-complex genes cause nephritic syndrome with primary microcephaly

Author

Sebastian A. Leidel, Sarah Vergult, Olivier Gribouval, Olivia Boyer, Annapurna Poduri, Fatih Ozaltin, Heon Yung Gee, Oraly Sanchez-Ferras, Ankana Daga, David A. Sweetser, Chyong Hsin Hsu, Carolin E. Sadowski, Nithiwat Vatanavicharn, Shirlee Shril, Bruno Collinet, Verena Matejas, Jeremy F.P. Ullmann, Jennifer A. Lawson, Weizhen Tan, David Chitayat, Peter Kannu, Emmanuelle Lemyre, Megan T. Cho, Gaëlle H. Martin, Amber Begtrup, Jui Hsing Chang, Matthias T.F. Wolf, Agnieszka Prytuła, Jennifer Hu, Peter C. Dedon, Sik Nin Wong, Gessica Truglio, Maxime Bouchard, Sandra D. Kienast, Tobias Hermle, Merlin Airik, Manish D. Sinha, Rebecca O. Littlejohn, Takashi Shiihara, Daniella Magen, Yu Yuan Ke, Kenza Soulami, Denny Schanze, Chitra Prasad, Dominique Liger, Svjetlana Lovric, Kazuyuki Nakamura, Jameela A. Kari, Wai Ming Lai, Wen Hui Tsai, Jeng Daw Tsai, Eugen Widmeier, Neveen A. Soliman, Tilman Jobst-Schwan, Shazia Ashraf, Amira Masri, Jia Rao, Jillian K. Warejko, Tamara Basta, Martin Zenker, Brendan Beeson, Corinne Antignac, Malcolm Bruce, Patrick E. Gipson, Mónica Furlano, Géraldine Mollet, Johanna Magdalena Schmidt, Jessica L. Waxler, Daniela A. Braun, Karin Scharmann, David Schapiro, Shrikant Mane, Shuan-Pei Lin, Marleen Praet, Patrick M. Gaffney, Werner L. Pabst, Charlotte A. Hoogstraten, Björn Menten, Nina De Rocker, Richard P. Lifton, Anne Claire Boschat, Klaas J. Wierenga, Chao Huei Chen, Cathy Kiraly-Borri, Nathalie Boddaert, Marie Claire Daugeron, Bert Callewaert, Gaik Siew Ch’ng, Sylvia Sanquer, Won-Il Choi, Udo Vester, Herman van Tilbeurgh, Rezan Topaloglu, David Viskochil, Elizabeth Roeder, Friedhelm Hildebrandt, I. Chiara Guerrera, Rhonda E. Schnur, Patrick Rump, Babak Behnam, Patrick Revy, Mastaneh Moghtaderi, Université Paris Descartes - Paris 5 (UPD5), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Sorbonne Paris Cité (USPC), Laboratoire des Maladies Rénales Héréditaires, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Département Microbiologie (Dpt Microbio), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Biologie Cellulaire des Archées (ARCHEE), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Service de néphrologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Division of Nephrology, Boston Children's Hospital, Institute of Human Genetics (University Hospital Magdeburg), University Hospital of the Otto von Guericke University of Magdeburg, Service de Radiologie et imagerie médicale [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), UPMC - UFR Sciences de la vie (UFR 927 ), Université Pierre et Marie Curie - Paris 6 (UPMC), Département Biochimie, Biophysique et Biologie Structurale (B3S), Fonction et Architecture des Assemblages Macromoléculaires (FAAM), Institut de biochimie et biophysique moléculaire et cellulaire (IBBMC), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Plateforme Protéomique Necker [SFR Necker] (PPN - 3P5), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-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) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-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) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de biochimie métabolique [CHU Necker], Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ghent University Hospital, Institut de génétique et microbiologie [Orsay] (IGM), Institute of Human Genetics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Max Planck Research Group for RNA Biology, Max Planck Institute for Molecular Biomedicine, Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, GeneDx [Gaithersburg, MD, USA], Université de Montréal (UdeM), CHU Sainte Justine [Montréal], University of Amman, Cabinet de Néphrologie pédiatrique [Casablanca, Maroc], Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Singapore-MIT Alliance for Research and Technology (SMART), Massachusetts Institute of Technology (MIT), Yale University [New Haven], Yale University School of Medicine, University of Toronto, Center for Medical Genetics [Ghent], Institute of Human Genetics, University Hospital Magdeburg, Service de Génétique Médicale [CHU Necker], Howard Hughes Medical Institute [Chevy Chase] (HHMI), Howard Hughes Medical Institute (HHMI), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Institut de Biologie Intégrative de la Cellule (I2BC), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), 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) (APHP)-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) (APHP), 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) (APHP), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University Hospital Erlangen, Université de Montréal [Montréal], Sapienza University [Rome], Singapore-MIT Alliance for Research and Technology (SMART) Centre, CREATE Tower, Singapore 138602, Singapore (SMART), Singapore-MIT Alliance for Research and Technology (SMART) Centre, Howard Hugues Medical Institute, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Yale School of Medicine [New Haven, Connecticut] (YSM), and Çocuk Sağlığı ve Hastalıkları

Subjects
Microcephaly, Nephrotic Syndrome, MICROBIO, FAAM, DNA Repair, cell migration, congenital nephrotic syndrome, Apoptosis, DNA damage response, Pediatrics, Galloway Mowat syndrome, Mice, gene silencing, Models, Cell Movement, GALLOWAY-MOWAT SYNDROME, molecular pathology, newborn, caspase 3, KEOPS complex, ARCHEE, microcephaly, Cytoskeleton, Genetics & Heredity, Mutation, Gene knockdown, clinical article, UNFOLDED PROTEIN RESPONSE, Intracellular Signaling Peptides and Proteins, Endoplasmic Reticulum Stress, transfer RNA, 3. Good health, Cell biology, TRANSFER-RNA MODIFICATION, Nephrosis, TPRKB protein, actin filament, phenotype, embryo, Article, loss of function mutation, in vivo study, 03 medical and health sciences, OSGEP protein, protein serine threonine kinase, Genetics, Humans, YEAST, human, mouse, autosomal recessive disorder, animal model, Molecular, MASS-SPECTROMETRY, DNA, zebrafish protein, medicine.disease, LAGE3 protein, Transfer, carrier protein, 030104 developmental biology, proteasome, cell proliferation, Multiprotein Complexes, Unfolded protein response, CRISPR-Cas Systems, Carrier Proteins, Models, Molecular, 0301 basic medicine, SECKEL-SYNDROME, Hernia, Protein Conformation, [SDV]Life Sciences [q-bio], Medizin, Post-Transcriptional, medicine.disease_cause, lethality, Gene Knockout Techniques, TP53RK protein, RNA, Transfer, multiprotein complex, gene mutation, RNA Processing, Post-Transcriptional, Zebrafish, Hiatal, child, biology, Podocytes, LAGE3 protein, human, apoptosis, Metalloendopeptidases, Protein-Serine-Threonine Kinases, unclassified drug, epidermal growth factor, female, O-sialoglycoprotein endopeptidase, endoplasmic reticulum stress, metalloproteinase, B3S, WDR73, RNA Processing, DNA repair, CRISPR-CAS9 system, animal experiment, Protein Serine-Threonine Kinases, GENOME MAINTENANCE, male, medicine, KINASE, Animals, signal peptide, controlled study, TPRKB protein, human, TP53RK protein, human, nonhuman, gene deletion, Telomere Homeostasis, Zebrafish Proteins, Actin cytoskeleton, biology.organism_classification, Molecular biology, actin related protein 2-3 complex, infant, Hernia, Hiatal, adolescent, RNA, homozygosity
Abstract

Galloway-Mowat syndrome (GAMOS) is a severe autosomal-recessive disease characterized by the combination of early-onset steroid-resistant nephrotic syndrome (SRNS) and microcephaly with brain anomalies. To date, mutations of WDR73 are the only known monogenic cause of GAMOS and in most affected individuals the molecular diagnosis remains elusive. We here identify recessive mutations of OSGEP, TP53RK, TPRKB, or LAGE3, encoding the 4 subunits of the KEOPS complex in 33 individuals of 30 families with GAMOS. CRISPR/Cas9 knockout in zebrafish and mice recapitulates the human phenotype of microcephaly and results in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibits cell proliferation, which human mutations fail to rescue, and knockdown of either gene activates DNA damage response signaling and induces apoptosis. OSGEP and TP53RK molecularly interact and co-localize with the actin-regulating ARP2/3 complex. Furthermore, knockdown of OSGEP and TP53RK induces defects of the actin cytoskeleton and reduces migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identify 4 novel monogenic causes of GAMOS, describe the first link between KEOPS function and human disease, and delineate potential pathogenic mechanisms.

Published
2017

8. Biallelic Mutations in LIPT2 Cause a Mitochondrial Lipoylation Defect Associated with Severe Neonatal Encephalopathy

Author

Audrey Boutron, Florence Habarou, Nathalie Boddaert, Tobias B. Haack, Johannes A. Mayr, Richard J. Rodenburg, G. Christoph Korenke, Chris Ottolenghi, Coraline Grisel, Holger Prokisch, Dominique Chretien, Christine Bole-Feysot, Stefan Kölker, Agnès Delahodde, Ivan Nemazanyy, Monika Eisermann, Thomas Meitinger, Nicolas Goudin, Agnès Rötig, Robert Barouki, Iris Marquardt, Marine Madrange, Patrick Nitschke, Pascale de Lonlay, Clément Pontoizeau, Yamina Hamel, Tim M. Strom, Elise Lebigot, Cécile Laroche, René G. Feichtinger, Bernadette Chadefaux-Vekemans, Kanetee Busiah, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Eurecom [Sophia Antipolis], ISA NMR Methods for Metabolism - Methodes RMN en métabolomique (2014-2018), Institut des Sciences Analytiques (ISA), Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Epilepsies de l'Enfant et Plasticité Cérébrale (U1129), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Dept Biochem, Universidade Federal de Pernambuco [Recife] (UFPE), Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Biochimie Métabolique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme de génomique [SFR Necker], Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Plate Forme Paris Descartes de Bioinformatique (BIP-D), Université Paris Descartes - Paris 5 (UPD5), Plateforme d'Imagerie Cellulaire [SFR Necker], Service de Radiologie et imagerie médicale [CHU Necker], Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Fonctions et dysfonctions de la mitochondrie (FDMITO), Département Biologie Cellulaire (BioCell), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Division of Inherited Metabolic Diseases, University Children's Hospital Heidelberg, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Helmholtz-Zentrum München (HZM), Institute of Human Genetics, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-German Research Center for Environmental Health-Helmholtz-Zentrum München (HZM), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de biochimie métabolique [CHU Necker], Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Service de Biochimie [CHU Bicêtre], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), NMR Methods for Metabolism - Methodes RMN en métabolomique, Centre National de la Recherche Scientifique (CNRS)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-École normale supérieure - Lyon (ENS Lyon), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], 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) (APHP)-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) (APHP), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, Technical University of Munich (TUM), Technische Universität München [München] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-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) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Helmholtz Zentrum München = German Research Center for Environmental Health, and Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz Zentrum München = German Research Center for Environmental Health

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], Dehydrogenase, chemistry.chemical_compound, 0302 clinical medicine, Amino Acids, Genetics (clinical), Cells, Cultured, Brain Diseases, Brain Mapping, Glycine cleavage system, Thioctic Acid, Brain, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Pyruvate dehydrogenase complex, encephalopathy, metabolic flux, Magnetic Resonance Imaging, 3. Good health, Mitochondria, Lipoic acid, Biochemistry, α-oxoglutarate dehydrogenase, Leucine, Protein Binding, medicine.medical_specialty, Lipoylation, Glycine, Biology, 03 medical and health sciences, Oxygen Consumption, pyruvate dehydrogenase, Internal medicine, Report, Genetics, medicine, LIPT2, Humans, hyperglycinemia, Infant, Newborn, Lipt2, Encephalopathy, Hyperglycinemia, Lipoic Acid, Metabolic Flux, Pyruvate Dehydrogenase, α-oxoglutarate Dehydrogenase, lipoic acid, 030104 developmental biology, Endocrinology, chemistry, Atrophy, Branched-chain alpha-keto acid dehydrogenase complex, Energy Metabolism, 030217 neurology & neurosurgery, Acyltransferases, Protein lipoylation
Abstract

Item does not contain fulltext Lipoate serves as a cofactor for the glycine cleavage system (GCS) and four 2-oxoacid dehydrogenases functioning in energy metabolism (alpha-oxoglutarate dehydrogenase [alpha-KGDHc] and pyruvate dehydrogenase [PDHc]), or amino acid metabolism (branched-chain oxoacid dehydrogenase, 2-oxoadipate dehydrogenase). Mitochondrial lipoate synthesis involves three enzymatic steps catalyzed sequentially by lipoyl(octanoyl) transferase 2 (LIPT2), lipoic acid synthetase (LIAS), and lipoyltransferase 1 (LIPT1). Mutations in LIAS have been associated with nonketotic hyperglycinemia-like early-onset convulsions and encephalopathy combined with a defect in mitochondrial energy metabolism. LIPT1 deficiency spares GCS deficiency and has been associated with a biochemical signature of combined 2-oxoacid dehydrogenase deficiency leading to early death or Leigh-like encephalopathy. We report on the identification of biallelic LIPT2 mutations in three affected individuals from two families with severe neonatal encephalopathy. Brain MRI showed major cortical atrophy with white matter abnormalities and cysts. Plasma glycine was mildly increased. Affected individuals' fibroblasts showed reduced oxygen consumption rates, PDHc, alpha-KGDHc activities, leucine catabolic flux, and decreased protein lipoylation. A normalization of lipoylation was observed after expression of wild-type LIPT2, arguing for LIPT2 requirement in intramitochondrial lipoate synthesis. Lipoic acid supplementation did not improve clinical condition nor activities of PDHc, alpha-KGDHc, or leucine metabolism in fibroblasts and was ineffective in yeast deleted for the orthologous LIP2.

Published
2017

9. Case report: an unexpected link between partial deletion of the SHANK3 gene and Heller’s dementia infantilis, a rare subtype of autism spectrum disorder

Author

Nadia Bahi-Buisson, Anne Philippe, Marlène Rio, Valérie Malan, Nathalie Boddaert, Jean-Paul Bonnefont, Laurence Robel, Yann Craus, Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Psychiatrie de l'enfant et de l'adolescent [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Service de neurologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Service de Radiologie et imagerie médicale [CHU Necker], Laboratoire de Cytogénétique, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -CHU Necker - Enfants Malades [AP-HP], Génétique moléculaire, Université Paris Descartes - Paris 5 ( UPD5 ) -CHU Necker - Enfants Malades [AP-HP], Santé mentale et santé publique ( SMSP - U1178 ), Université Paris-Sud - Paris 11 ( UP11 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Imagine - Institut des maladies génétiques (IMAGINE - U1163), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Santé mentale et santé publique (SMSP - U1178), Université Paris-Sud - Paris 11 (UP11)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and BMC, BMC

Subjects
Pediatrics, medicine.medical_specialty, Autism Spectrum Disorder, 22q13.3 deletion syndrome, Genetic counseling, Chromosomes, Human, Pair 22, [SDV]Life Sciences [q-bio], Autism, Case Report, Nerve Tissue Proteins, ASD, Intellectual Disability, Intellectual disability, medicine, Dementia, Humans, Child, SHANK3, Heller syndrome, [ SDV ] Life Sciences [q-bio], Childhood disintegrative disorder, medicine.disease, Regression, 3. Good health, Regression, Psychology, [SDV] Life Sciences [q-bio], Developmental disorder, Psychiatry and Mental health, Phenotype, Autism spectrum disorder, Female, Haploinsufficiency, Psychology, Gene Deletion, Childhood disintegrative disorder (CDD), Clinical psychology
Abstract

International audience; AbstractBackgroundDeletions and mutations involving the SHANK3 gene lead to a nonspecific clinical presentation with moderate to profound intellectual disability, severely delayed or absent speech, and autism spectrum disorders (ASD).Better knowledge of the clinical spectrum of SHANK3 haploinsufficiency is useful to facilitate clinical care monitoring and to guide molecular diagnosis, essential for genetic counselling.Case presentationHere, we report a detailed clinical description of a 10-year-old girl carrying a pathogenic interstitial 22q13.3 deletion encompassing only the first 17 exons of SHANK3.The clinical features displayed by the girl strongly suggested the diagnosis of dementia infantilis, described by Heller in 1908, also known as childhood disintegrative disorder.ConclusionOur present case confirms several observations according to which regression may be part of the clinical phenotype of SHANK3 haploinsufficiency. Therefore, we think it is crucial to look for mutations in the gene SHANK3 in patients diagnosed for childhood disintegrative disorder or any developmental disorder with a regressive pattern involving social and communicative skills as well as cognitive and instinctual functions, with onset around 3 years.

Published
2015

10. Diagnostic contribution of positron emission tomography with [18F]fluorodeoxyglucose for invasive fungal infections

Author

Marie-Thérèse Rubio, A. Hot, Marc Lecuit, Sylvain Poirée, Marie-Elisabeth Bougnoux, M. Faraggi, Fanny Lanternier, Olivier Lortholary, Pierre Loulergue, C. Maunoury, Felipe Suarez, H. Coignard, Bertrand Dupont, Nizar Mahlaoui, Jean-Paul Viard, Centre d'infectiologie Necker-Pasteur [CHU Necker], Institut Pasteur [Paris] (IP)-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 des Maladies infectieuses et tropicales [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Université Paris Descartes - Paris 5 (UPD5), Médecine nucléaire [CHU HEGP], 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), Service de Radiologie et imagerie médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'immuno-hématologie pédiatrique [CHU Necker], Microorganismes et Barrières de l'Hôte (Equipe avenir), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Mycologie moléculaire, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-CHU Necker - Enfants Malades [AP-HP], Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]

Subjects
Male, [SDV]Life Sciences [q-bio], Aspergillosis, 030218 nuclear medicine & medical imaging, 0302 clinical medicine, MESH: Fluorodeoxyglucose F18, MESH: Child, Whole Body Imaging, Prospective Studies, Child, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, MESH: Aged, 0303 health sciences, MESH: Middle Aged, medicine.diagnostic_test, hepatosplenic candidiasis, General Medicine, Middle Aged, MESH: Positron-Emission Tomography, 3. Good health, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Infectious Diseases, Positron emission tomography, MESH: Young Adult, Female, Radiology, MESH: Radiopharmaceuticals, medicine.drug, Adult, Spondylodiscitis, Microbiology (medical), medicine.medical_specialty, Adolescent, Eumycetoma, Histoplasmosis, Young Adult, 03 medical and health sciences, MESH: Mycoses, MESH: Whole Body Imaging, Fluorodeoxyglucose F18, medicine, Humans, Aged, Fluorodeoxyglucose, MESH: Adolescent, MESH: Humans, 030306 microbiology, business.industry, MESH: Adult, medicine.disease, MESH: Prospective Studies, MESH: Male, Transplantation, [18F]FDG positron emission tomography, Mycoses, Positron-Emission Tomography, Radiopharmaceuticals, Zygomycosis, business, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Presented in part at the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy; 27–30 September 2006, San Francisco, CA, USA, Abstract M-1307; International audience; Optimal staging and evaluation of residual lesions of invasive fungal infections (IFIs) are major challenges in the immunocompromised host. Preliminary data have suggested that [ 18 F]fluorodeoxyglucose ([ 18 F]FDG) uptake may be observed in the course of active inva-sive fungal infections. The aim of this study was to assess the role of positron emission tomography with [ 18 F]FDG ([ 18 F]FDG-PET) in the diagnosis and staging of IFI. A prospective monocentric study evaluating [ 18 F]FDG-PET in 30 consecutive adults and children with European Organization for Research and Treatment of Cancer/Mycoses Study Group probable or proven IFI was performed. Twenty males and ten females (median age, 45 years (range 6-75 years)) were enrolled. Twenty-six were immunocompromised, as follows: haematological malignancy (18) with allogeneic stem cell transplantation (16/18), solid tumour (three), solid organ transplanta-tion (two), diabetes mellitus (two) and cystic fibrosis (one). IFIs were acute invasive aspergillosis (ten), chronic disseminated candidia-sis (ten), zygomycosis (two), black grains eumycetoma (two), pulmonary Histoplasma capsulatum var. capsulatum histoplasmosis (two), and Phomopsis sp. osteoarthritis, Scedosporium apiospermum and Candida krusei spondylodiscitis, and acute pulmonary coccidioidomyco-sis in one case each. An increased uptake of [ 18 F]FDG was observed in all areas previously identified by computed tomography and/ or magnetic resonance imaging to be involved by IFI. In 4/10 chronic disseminated candidiasis cases, [ 18 F]FDG-PET revealed small splenic abscesses that were unapparent on the corresponding computed tomography scan. [ 18 F]FDG uptake disappeared after 6 months of antifungal therapy in three patients with chronic disseminated candidiasis for whom the [ 18 F]FDG-PET was performed to assess the evolution of the disease. [ 18 F]FDG-PET could potentially be useful for the initial diagnosis and staging of IFI. Whether or not [ 18 F]FDG-PET might be useful for assessing the optimal duration of IFI therapy should now be assessed in a specific prospective study.

Published
2011
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11. Prospective pilot study of high-dose (10 mg/kg/day) liposomal amphotericin B (L-AMB) for the initial treatment of mucormycosis

Author

Benoit Guery, Pierre BUFFET, Stéphane Bretagne, Frédéric GRENOUILLET, Benjamin Wyplosz, Tristan Ferry, André Paugam, Yvon STERKERS, Sophie Cassaing, Philippe Moreau, Anne-Lise Bienvenu, Raoul Herbrecht, Anne Thiebaut-Bertrand, Mathilde Hunault, Cedric Arvieux, Jean-Pierre Gangneux, Boualem Sendid, Olivia Freynet, Pathogénie des infections systémiques (UMR_S 570), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Radiologie et imagerie médicale [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), Institut de génétique et microbiologie [Orsay] (IGM), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Mycologie moléculaire, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Service d’Oncologie et d’Hématologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France, Space Science Institute [Boulder] (SSI), Service greffe de moelle osseuse, Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'infectiologie Necker-Pasteur [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut Pasteur [Paris], This work was supported by a grant from Gilead Sciences, but the sponsor took no part in the scientific evaluation. L-AMB was kindly provided by Gilead Sciences., We thank Assistance Publique-Hôpitaux de Paris, promoter of the study. We thank URC Paris Descartes Necker (Beatrice Barbier) for the implementation, monitoring and data management of the study. We also thank Eric Dannaoui and Michel Huerre for their help in isolate collection and pathological slide reviews and Susan DeWolf for her helpful comments prior to submission. We thank Muriel Vray, Michel Tod, Vincent Jullien, Agnes Lefort and Caroline Charlier-Woerther for their participation in the safety committee., Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Institut Pasteur [Paris] (IP)-CHU Necker - Enfants Malades [AP-HP], Institut Pasteur [Paris]-CHU Necker - Enfants Malades [AP-HP], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Unité de recherche clinique / Centre d'investigation clinique [CHU Necker], Centre National de Référence des Mycoses invasives et antifongiques - Mycologie moléculaire (CNRMA), Hôpital de Hautepierre [Strasbourg], and AP-HP - Hôpital Bichat - Claude Bernard [Paris]

Subjects
Male, Antifungal Agents, [SDV]Life Sciences [q-bio], Pilot Projects, MESH: Mucormycosis/surgery, Gastroenterology, chemistry.chemical_compound, Amphotericin B, MESH: Child, Pharmacology (medical), Prospective Studies, Child, Prospective cohort study, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, MESH: Treatment Outcome, Response rate (survey), MESH: Aged, MESH: Middle Aged, Incidence (epidemiology), Middle Aged, MESH: Infant, 3. Good health, Treatment Outcome, Infectious Diseases, MESH: Young Adult, Child, Preschool, Female, medicine.drug, Adult, Microbiology (medical), medicine.medical_specialty, Adolescent, MESH: Amphotericin B/administration & dosage, MESH: Mucormycosis/drug therapy, Young Adult, Internal medicine, medicine, Humans, Mucormycosis, MESH: Debridement, Aged, MESH: Antifungal Agents/administration & dosage, Pharmacology, MESH: Adolescent, Creatinine, MESH: Humans, business.industry, MESH: Child, Preschool, Infant, MESH: Adult, medicine.disease, MESH: Pilot Projects, MESH: Male, MESH: Prospective Studies, Surgery, Clinical trial, Regimen, Debridement, chemistry, business, MESH: Female
Abstract

International audience; Background: Mucormycosis incidence is increasing and is associated with a high rate of mortality. Although lipid-based formulations of amphotericin B are the recommended first-line treatment, only one prospective trial in a limited number of patients has been performed to evaluate this regimen. Methods: Patients with proven or probable mucormycosis were included between June 2007 and March 2011. Patients were scheduled to receive 10 mg/kg/day liposomal amphotericin B (L-AMB) monotherapy for 1 month and surgery was performed when appropriate. The primary outcome was response rate at week 4 or at the end of treatment (EOT) if before week 4, evaluated by an independent committee. ClinicalTrials.gov Identifier: NCT00467883. Results: Forty patients were enrolled. Response was analysed in 33 patients at week 4. Most patients had a haem-atological malignancy as their primary underlying disease (53%). Seventy-one percent of patients underwent therapeutic surgery. The response rate at week 4 or at EOT was 36%, with 18% partial responses and 18% complete responses. The response rate at week 12 was 45%, with 13% partial responses and 32% complete responses. Overall mortality was 38% at week 12 and 53% at week 24. Serum creatinine doubled in 16 (40%) patients and returned to normal levels within 12 weeks in 10/16 (63%). Conclusions: High-dose LAMB for mucormycosis, in combination with surgery in 71% of cases, was associated with an overall response rate of 36% at week 4 and 45% at week 12 and creatinine level doubling in 40% of patients (transient in 63%). These results may serve as the basis for future clinical trials.

Published
2015

12. IFT81, encoding an IFT-B core protein, as a very rare cause of a ciliopathy phenotype

Author

Josseline Kaplan, Tania Attié-Bitach, Meriem Garfa-Traore, Michael Taschner, Esben Lorentzen, Catherine Caillaud, Markus Schueler, Hanan M. Fathy, Xavier Gérard, Valérie Cormier-Daire, Heon Yung Gee, Nathalie Boddaert, Richard P. Lifton, Jonathan D. Porath, Jennifer A. Lawson, Jan Halbritter, Daniela A. Braun, Sophie Saunier, Friedhelm Hildebrandt, Philippe Bastin, Sophie Thomas, Edgar A. Otto, Jean-Michel Rozet, Isabelle Perrault, Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Division of Nephrology, Boston Children's Hospital, University Clinic, Leipzig, Pediatric Nephrology Unit, University of Alexandria, Service de Radiologie et imagerie médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Max Planck Institute for Biochemistry, Max-Planck-Institut, Yale School of Medicine, University of Michigan [Ann Arbor], Biologie Cellulaire des Trypanosomes, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), CHU Necker - Enfants Malades [AP-HP], Howard Hughes Medical Institute [Chevy Chase] ( HHMI ), Howard Hugues Medical Institute, This work was further supported by grants from the following funding agencies: the National Institutes of Health (NIH) to FH (DK068308), the ‘Agence Nationale de la Recherche’ (ANR) to SS and TA (20100BLAN112202, ANR-10-IAHY-01), the ‘Fondation pour la Recherche Médicale’ to SS (DEQ20130326532), the ‘Institut National de la Santé et de la Recherche Médicale’ (INSERM), the ‘Imagine Institute’, the ‘Association Retina France’ and PHRC GENPHENACL to JMR and JK. FH is an Investigator of the Howard Hughes Medical Institute (HHMI) and a Warren E Grupe Professor. The authors declare that they have no competing financial interests., ANR : IAHY, ANR-10-IAHY-01, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Alexandria University [Alexandrie], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Max-Planck-Institut für Biochemie = Max Planck Institute of Biochemistry (MPIB), Max-Planck-Gesellschaft, Yale School of Medicine [New Haven, Connecticut] (YSM), University of Michigan System, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Howard Hughes Medical Institute [Chevy Chase] (HHMI), Howard Hughes Medical Institute (HHMI), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), Lassailly-Bondaz, Anne, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Max Planck Institute of Biochemistry (MPIB), Yale University School of Medicine, and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
Candidate gene, Muscle Proteins, Biology, medicine.disease_cause, Eye, Kidney, Ciliopathies, Intraflagellar transport, Nephronophthisis, [ SDV.MP ] Life Sciences [q-bio]/Microbiology and Parasitology, GLI2, medicine, Genetics, Humans, Molecular genetics, Cilia, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, Genetics (clinical), Mutation, Renal Medicine, Cilium, New Loci, Sequence Analysis, DNA, medicine.disease, Ciliopathy, Ophthalmology, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, sense organs
Abstract

International audience; Background Bidirectional intraflagellar transport (IFT) consists of two major protein complexes, IFT-A and IFT-B. In contrast to the IFT-B complex, all components of IFT-A have recently been linked to human ciliopathies when defective. We therefore hypothesised that mutations in additional IFT-B encoding genes can be found in patients with multisystemic ciliopathies. Methods We screened 1628 individuals with renoocular ciliopathies by targeted next-generation sequencing of ciliary candidate genes, including all IFT-B encoding genes. Results Consequently, we identified a homozygous mutation in IFT81 affecting an obligatory donor splice site in an individual with nephronophthisis and polydactyly. Further, we detected a loss-of-stop mutation with extension of the deduced protein by 10 amino acids in an individual with neuronal ceroid lipofuscinosis-1. This proband presented with retinal dystrophy and brain lesions including cerebellar atrophy, a phenotype to which the IFT81 variant might contribute. Cultured fibroblasts of this latter affected individual showed a significant decrease in ciliated cell abundance compared with controls and increased expression of the transcription factor GLI2 suggesting deranged sonic hedgehog signalling. Conclusions This work describes identification of mutations of IFT81 in individuals with symptoms consistent with the clinical spectrum of ciliopathies. It might represent the rare case of a core IFT-B complex protein found associated with human disease. Our data further suggest that defects in the IFT-B core are an exceedingly rare finding, probably due to its indispensable role for ciliary assembly in development.

Published
2015

13. Last Generation Triazoles for Imported Eumycetoma in Eleven Consecutive Adults

Author

Cédric Arvieux, Marie-Elisabeth Bougnoux, Karima Amazzough, Samuel Pineau, Yoann Crabol, Valérie Zeller, Stéphane Barete, Marc Lecuit, Olivier Lortholary, C. Maunoury, Fanny Lanternier, Sylvain Poirée, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Radiologie et imagerie médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité de Parasitologie-Mycologie, Service de Microbiologie [Hôpital Necker-Enfants-Malades, Paris], Assistance Publique - Hôpitaux de Paris, Médecine nucléaire [CHU HEGP], 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), Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Médecine interne [Diaconesses Croix Saint-Simon], Groupe Hospitalier Diaconesses Croix Saint-Simon, Service des maladies infectieuses et réanimation médicale [Rennes] = Infectious Disease and Intensive Care [Rennes], CHU Pontchaillou [Rennes], Service de maladies infectieuses et tropicales [Nantes], Université de Nantes (UN)-Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Biologie des Infections - Biology of Infection, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Centre d'infectiologie Necker-Pasteur [CHU Necker], Institut Pasteur [Paris] (IP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de Référence Mycologie et Antifongiques-Mycologie Moléculaire (CNRMA), Institut Pasteur [Paris] (IP), HAL UPMC, Gestionnaire, Service de dermatologie et allergologie [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Unité de Parasitologie-Mycologie, Service de Microbiologie, Hôpital Necker-Enfants-Malades, Médecine nucléaire [CHU Pompidou], Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Service de Dermatologie [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Tenon [APHP], Maladies infectieuses et réanimation médicale [CHU Rennes], Université de Nantes ( UN ) -Hôtel-Dieu-Centre hospitalier universitaire de Nantes ( CHU Nantes ), Biologie des Infections, Institut Pasteur [Paris]-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre National de Référence Mycologie et Antifongiques-Mycologie Moléculaire ( CNRMA ), Institut Pasteur [Paris], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service des maladies infectieuses et réanimation médicale [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut Pasteur [Paris], Imagine - Institut des maladies génétiques (IHU), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - AP-HP Hôpital Necker - Enfants Malades [Paris], Centre d’Infectiologie Necker Pasteur, Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Necker - Enfants Malades - Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) - CHU Tenon [APHP], Service des maladies infectieuses et réanimation médicale, Université de Rennes 1 (UR1) - Hôpital Pontchaillou, Université de Nantes (UN) - Hôtel-Dieu - CHU Nantes, Institut Pasteur [Paris] - Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de Référence des Mycoses invasives et antifongiques-Mycologie moléculaire (CNRMA), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Male, Posaconazole, Pathology, Antifungal Agents, beta-Glucans, Madurella, 0302 clinical medicine, Fusarium, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Exophiala, Medicine and Health Sciences, Child, Skin, 0303 health sciences, medicine.diagnostic_test, biology, lcsh:Public aspects of medicine, Fungal Diseases, Magnetic Resonance Imaging, 3. Good health, [SDV] Life Sciences [q-bio], [ SDV.MHEP.MI ] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Treatment Outcome, Infectious Diseases, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Proteoglycans, Radiology, medicine.drug, Research Article, Adult, medicine.medical_specialty, lcsh:Arctic medicine. Tropical medicine, [SDV.SP.MED] Life Sciences [q-bio]/Pharmaceutical sciences/Medication, Adolescent, lcsh:RC955-962, 030231 tropical medicine, Eumycetoma, 03 medical and health sciences, Young Adult, [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication, Fluorodeoxyglucose F18, medicine, Subcutaneous Mycoses, Humans, Retrospective Studies, Fluorodeoxyglucose, Voriconazole, 030306 microbiology, business.industry, Soft Tissue Infections, [ SDV.SP.MED ] Life Sciences [q-bio]/Pharmaceutical sciences/Medication, Madurella mycetomatis, Public Health, Environmental and Occupational Health, Magnetic resonance imaging, Exophiala jeanselmei, lcsh:RA1-1270, Triazoles, medicine.disease, biology.organism_classification, Mycetoma, Positron-Emission Tomography, business
Abstract

Background Optimal management of eumycetoma, a severely debilitating chronic progressive fungal infection of skin, disseminating to bone and viscera, remains challenging. Especially, optimal antifungal treatment and duration are ill defined. Methodology/Principal Findings We conducted a monocentric retrospective study of 11 imported cases of eumycetoma treated by voriconazole or posaconazole for at least 6 months. Response to treatment was assessed through evolution of clinical and magnetic resonance imaging (MRI). (1→3) ß-D-glucan (BG) and positron emission tomography using [18F] fluorodeoxyglucose (PET/CT) results were also assessed. Identified species were Fusarium solani complex (n = 3); Madurella mycetomatis, (n = 3), and Exophiala jeanselmei, (n = 1). Moreover, two coelomycetes and one phaeohyphomycetes strains without species identification were retrieved. Serum BG and PET/CT were abnormal in 7/8 and 6/6 patients tested, respectively. Patients received last generation azoles for a mean duration of 25.9±18 months. Complete response (major clinical and MRI improvement) was observed in 5/11 patients, partial response (minor MRI improvement or stable MRI findings) in 5 and failure (MRI evidence of disease progression) in one, with a 73±39 [6–132] months mean follow-up. Relapse occurred in 2 patients after treatment discontinuation. Optimal outcome was associated with fungal species, initiation of last generation triazole therapy (, Author Summary Eumycetoma is a severe chronic progressive fungal infection of skin and ultimately bone or viscera that affect mainly people with low economic status. Optimal treatment of this condition relies on medical and often surgical therapy and remains challenging because of lack of gold standard therapy and high rate of relapse after treatment discontinuation. In this retrospective study we assessed whether modern triazoles (voriconazole and posaconazole) suited to eumycetoma treatment and if tailored treatment duration, based on serial evaluation of a serum biomarker of fungal infection (Serum (1→3) ß-D-Glucan, (BD)), magnetic resonance imaging (MRI) or positron emission tomography using [18F] fluorodeoxyglucose (PET/CT) would be useful. We found that modern triazoles were efficient treatments of eumycetoma, allowing complete or partial response in 10/11 of patients, without significant side effects. Moreover, patients with treatment discontinuation based on normalization of BD, MRI or PET/CT seemed to have better long-term outcome than those with clinical cure but still abnormal BD or imaging results.

Published
2014

14. Recurrent Streptococcus pyogenes genital infection in a woman: test and treat the partner!

Author

Florence Brossier, Sylvie Epelboin, Loïc Epelboin, Emilienne Verkaeren, Eric Caumes, Nathalie Boddaert, Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Dpt gynécologie [CHU Bichat], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Radiologie et imagerie médicale [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Service de Bactériologie et d'Hygiène Hospitalière [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), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Infectious and tropical diseases [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Service de Bactériologie-Hygiène Hospitalière [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Gynécologie - Obstétrique [CHU Bichat], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Microbiology (medical), medicine.medical_specialty, Streptococcus pyogenes, medicine.disease_cause, lcsh:Infectious and parasitic diseases, Recurrence, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Streptococcal Infections, medicine, Humans, lcsh:RC109-216, Sex organ, Antibiotic prophylaxis, Vaginitis, business.industry, Streptococcus, General Medicine, Middle Aged, Amoxicillin, Vulvovaginitis, medicine.disease, Asymptomatic diseases, Dermatology, 3. Good health, Surgery, [ SDV.MHEP.MI ] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Sexual Partners, Infectious Diseases, Bacteraemia, Female, Endometritis, business, Asymptomatic carrier, medicine.drug
Abstract

International audience; Group A Streptococcus (GAS) is a well-known cause of vulvovaginitis in prepubescent girls, but it is rarely described in adult women. We describe the case of a 64-year-old woman who presented with endometritis revealed by GAS bacteraemia, followed by recurrent vulvovaginitis due to a wild-type strain of GAS. She relapsed twice despite amoxicillin treatment. Her husband was found to be an asymptomatic carrier after GAS was identified in nasal and rectal swabs. She was cured after eradication of carriage in both herself and her husband with amoxicillin and rifampin. When recurrent Streptococcus pyogenes genital infections occur, test and treat the partner.

Published
2014

15. Kystes atypiques et tumeurs kystiques du rein : considérations anatomopathologiques, radiologiques et chirurgicales. Conclusions du forum AFU 2007. [Atypical cysts and cystic tumours of the kidney: Histological, radiological and surgical considerations. Conclusions of the AFU 2007 forum.]

Author

Long, Jean-Alexandre, Neuzillet, Yann, Corréas, Jean-Michel, de Fromont, Marc, Lang, Hervé, Méjean, Arnaud, Poissonnier, Laura, Patard, Jean-Jacques, Escudier, Bernard, Davin, Jean-Louis, Ccafu, Sous-Comité Rein, Service d'urologie, CHU Grenoble-Hôpital Michallon, Service d'urologie et de transplantation rénale, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM), Service de Radiologie et imagerie médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département de pathologie, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Service d'urologie [Rennes] = Urology [Rennes], Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Département d'immunothérapie, Institut Gustave Roussy (IGR), CHU La Milétrie, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille ( APHM ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -CHU Necker - Enfants Malades [AP-HP], Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140-Centre National de la Recherche Scientifique ( CNRS ), Institut Gustave Roussy ( IGR ), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), and De Villemeur, Hervé

Subjects
[ SDV.MHEP.UN ] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer
Abstract

International audience; Malignant tumours may have a cystic appearance. They are dominated by multilocular cystic renal cell carcinoma, usually low-grade, which rarely metastasize. The Bosniak classification distinguishes non suspicious lesions (type I and II) from suspicious lesions (type III and IV) requiring resection and lesions requiring follow-up (type IIF). The main feature suggestive of malignancy is the enhancement of the septa and the walls of the cyst. Renal cysts classified as IIF require surveillance by contrast-enhanced imaging (CT, MRI or ultrasound). The treatment of cystic tumours is based on surgery. Partial nephrectomy is recommended in this type of tumour regardless of the size. Laparoscopy is a validated technique in experienced hands. Aspiration is not very effective for the treatment of benign cysts, but may be useful for diagnosis. Surgical resection of the roof of the cyst is the most effective technique.

Published
2009

16. Prise en charge du cancer du rein en 2007 : actualités et recommandations [Kidney cancer management in 2007: news and recommendations]

Author

Cornu, Jean-Nicolas, Rouprêt, Morgan, Lang, Hervé, Long, Jean-Alexandre, Neuzillet, Yann, Patard, Jean-Jacques, Piéchaud, Thierry, Corréas, Jean-Michel, de Fromont, Marc, Escudier, Bernard, Méjean, Arnaud, Service d'urologie et transplantation rénales [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Service d'urologie, CHU Strasbourg, CHU Grenoble-Hôpital Michallon, Service d'urologie et de transplantation rénale, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille ( APHM ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Clinique Saint Augustin, Service de Radiologie et imagerie médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Département de pathologie, Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Département d'immunothérapie, Institut Gustave Roussy ( IGR ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -CHU Necker - Enfants Malades [AP-HP], Service d'urologie et transplantation rénales [CHU Pitié-Salpêtrière], 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), Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM), Service d'urologie [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Institut Gustave Roussy (IGR), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'urologie [Rennes] = Urology [Rennes], Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Service d'Urologie [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), and De Villemeur, Hervé

Subjects
[ SDV.MHEP.UN ] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer
Abstract

International audience; In case of a single renal cell carcinoma strictly located in the kidney, the radical nephrectomy remains the treatment of choice. However, it has been estimated that nearly 30 to 40 % of renal cell carcinoma are about to recur after primitive surgery. In certain cases, conservative surgery can be discussed as an alternative to radical treatment, especially in case of exophytic renal tumour or less than 4 cm in diameter. New ablative techniques (radiofrequency and cryoablation) have shown promising results but the follow-up is still very limited. French national recommendation regarding kidney cancer have been updated in 2007 and following the development of clinical trials using antiangiogenic agents. Regarding the use of antiangiogenic agents, several points have to be taken into account: existence of renal cell carcinoma, presence of metastasis, number of metastasis, location and risk factor prognosis determination.

Published
2008

17. Retention of Plasmodium falciparum ring-infected erythrocytes in the slow, open microcirculation of the human spleen

Author

Sophie Kernéis, Mickael Lesurtel, Jean-Marc Tréluyer, Peter H. David, Valentine Brousse, Pierre Buffet, Déborah Hirt, Anne Couvelard, Guillaume Deplaine, Huot Khun, Geneviève Milon, Nicolas Goasguen, Catherine Ottone, Odile Mercereau-Puijalon, Alain Sauvanet, Sébastien Mulé, Jean-Michel Correas, Thierry Jo Molina, Innocent Safeukui, Inès Vigan-Womas, Immunologie moléculaire des parasites, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Service de Radiologie et imagerie médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Saint-Vincent de Paul, Hôpital Beaujon [AP-HP], Institut Pasteur [Paris] (IP), Hôpital Hôtel-Dieu [Paris], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), This work was supported by the Institut Pasteur Transverse Research Programs (Paris, France, PTR no. 85), by the 'Fonds dédié Combattre les maladies parasitaires,' Sanofi Aventis-Ministère de L'Enseignement Supérieur et de la Recherche Institut Pasteur, the latter also supporting a postdoctoral fellowship (I.S.), and by a grant from Fondation pour la Recherche Medicale (Paris, France, V.B.). Research of the IMP Unit at Institut Pasteur is partly supported by the BioMalPar European Network of Excellence supported by a European grant (LSHP-CT-2004-503578) from the Priority 1 'Life Sciences, Genomics and Biotechnology for Health' in the 6th Framework Program (Paris, France). Research in the Immunophysiology and Intracellular Parasitism unit is partly supported by Agence Nationale de Recherche sur le SIDA (Paris, France)., and European Project: 503578,FP6-LIFESCIHEALTH,BIOMALPAR(2004)

Subjects
Erythrocytes, MESH: Spleen, Immunology, Population, Plasmodium falciparum, Spleen, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, In Vitro Techniques, Biochemistry, Microcirculation, Pathogenesis, Andrology, MESH: Microcirculation, medicine, Animals, Humans, MESH: Animals, education, MESH: Plasmodium falciparum, MESH: In Vitro Techniques, education.field_of_study, MESH: Humans, MESH: Erythrocytes, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, Hematology, MESH: Blood Flow Velocity, biology.organism_classification, Perfusion, medicine.anatomical_structure, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Cerebral Malaria, Regional Blood Flow, Circulatory system, Red pulp, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Regional Blood Flow, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Perfusion, Blood Flow Velocity
Abstract

The current paradigm in Plasmodium falciparum malaria pathogenesis states that young, ring-infected erythrocytes (rings) circulate in peripheral blood and that mature stages are sequestered in the vasculature, avoiding clearance by the spleen. Through ex vivo perfusion of human spleens, we examined the interaction of this unique blood-filtering organ with P falciparum–infected erythrocytes. As predicted, mature stages were retained. However, more than 50% of rings were also retained and accumulated upstream from endothelial sinus wall slits of the open, slow red pulp microcirculation. Ten percent of rings were retained at each spleen passage, a rate matching the proportion of blood flowing through the slow circulatory compartment established in parallel using spleen contrast-enhanced ultrasonography in healthy volunteers. Rings displayed a mildly but significantly reduced elongation index, consistent with a retention process, due to their altered mechanical properties. This raises the new paradigm of a heterogeneous ring population, the less deformable subset being retained in the spleen, thereby reducing the parasite biomass that will sequester in vital organs, influencing the risk of severe complications, such as cerebral malaria or severe anemia. Cryptic ring retention uncovers a new role for the spleen in the control of parasite density, opening novel intervention opportunities.

Published
2008

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