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7 results on '"Isabelle Desguerre"'

1. Differential Expression of Interferon-Alpha Protein Provides Clues to Tissue Specificity Across Type I Interferonopathies

Author

Alice Hadchouel, Odile Boespflug-Tanguy, Eric Jeziorski, Thomas Blauwblomme, Buthaina Al Adba, Alice Lepelley, Isabelle Desguerre, Gillian I. Rice, Edwin Carter, Véronique Hentgen, Christine Bodemer, Lorenzo Lodi, Sandrine Passemard, Yanick J. Crow, Marie Hully, Fanny Mochel, Camille Ducrocq, Magalie Barth, Jay Shetty, Brigitte Bader-Meunier, Isabelle Melki, Florence Renaldo, Vincent Bondet, Miguel Hie, Marie Pouletty, Russell C. Dale, Romain Lévy, Pierre Ellul, Simona Orcesi, Bénédicte Neven, Cécile Dumaine, Luis Seabra, Darragh Duffy, Fabienne Dulieu, Marie-Louise Frémond, Stéphane Blanche, Rainer Seidl, Maria José Martin-Niclos, Pierre Quartier, Laboratory of neurogenetics and neuroinflammation (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - 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), Azienda Ospedaliero Universitaria A. Meyer [Firenze, Italy], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP), University of Manchester [Manchester], University of Edinburgh, Sidra Medicine [Doha, Qatar], MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de neurochirurgie pédiatrique [CHU Necker], Service de dermatologie [CHU Necker], The University of Sydney, Service de neurologie pédiatrique [CHU Necker], Hôpitaux Pédiatriques de Nice Lenval (CHU-Lenval), Centre Hospitalier Universitaire de Nice (CHU Nice), Child and Adolescent Psychiatry Department [AP- HP Hôpital Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière] (I3), CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de Pneumologie Allergologie [CHU Necker], Centre Hospitalier de Versailles André Mignot (CHV), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département Pédiatrie [CHRU Montpellier], Pôle Femme Mère Enfant [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Fondazione 'Istituto Neurologico Nazionale C. Mondino', Università degli Studi di Pavia = University of Pavia (UNIPV), CHU Trousseau [APHP], Medizinische Universität Wien = Medical University of Vienna, Royal Hospital for Sick Children [Edinburgh], Y.J.C. acknowledges the European Research Council (GA309449 and 786142-E-T1IFNs) and a state subsidy managed by the National Research Agency (France) under the ‘Investments for the Future’ programme bearing the reference ANR-10-IAHU-01. The project was supported by MSDAVENIR (Devo-Decode Project). Y.J.C. and D.D. acknowledge the Agence Nationale de la Recherche (grant CE17001002)., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), European Project: 309449,EC:FP7:ERC,ERC-2012-StG_20111109,T1-IFN(2013), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut Pasteur [Paris], Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Centre National de Référence du Lupus Systémique, Syndrome des Anticorps Anti-phospholipides et Maladies Auto-immunes Systémiques Rares [CHU Pitié Salpêtrière], Service de Médecine Interne 2, maladies auto-immunes et systémiques [CHU Pitié-Salpêtrière], Institut E3M [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)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut E3M [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), UF Neurométabolique Bioclinique et Génétique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Pavia, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut E3M [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), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Adult, Male, 0301 basic medicine, medicine.medical_specialty, Adolescent, Immunology, Central nervous system, Alpha interferon, Aicardi-Goutières syndrome, cerebrospinal fluid, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Cerebrospinal fluid, Medical microbiology, Downregulation and upregulation, systemic lupus erythematosus, Interferon, Humans, Immunology and Allergy, Medicine, Child, Retrospective Studies, business.industry, Infant, Interferon-alpha, medicine.disease, 3. Good health, Hydrocephalus, Phenotype, 030104 developmental biology, medicine.anatomical_structure, Gene Expression Regulation, Organ Specificity, Case-Control Studies, Child, Preschool, Interferon Type I, Mutation, Aicardi–Goutières syndrome, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Disease Susceptibility, STING-associated vasculopathy with onset in infancy, business, 030215 immunology, medicine.drug
Abstract

International audience; Whilst upregulation of type I interferon (IFN) signaling is common across the type I interferonopathies (T1Is), central nervous system (CNS) involvement varies between these disorders, the basis of which remains unclear. We collected cerebrospinal fluid (CSF) and serum from patients with Aicardi-Goutières syndrome (AGS), STING-associated vasculopathy with onset in infancy (SAVI), presumed monogenic T1Is (pT1I), childhood systemic lupus erythematosus with neuropsychiatric features (nSLE), non-IFN-related autoinflammation (AI) and non-inflammatory hydrocephalus (as controls). We measured IFN-alpha protein using digital ELISA. Eighty-two and 63 measurements were recorded respectively in CSF and serum of 42 patients and 6 controls. In an intergroup comparison (taking one sample per individual), median CSF IFN-alpha levels were elevated in AGS, SAVI, pT1I, and nSLE compared to AI and controls, with levels highest in AGS compared to all other groups. In AGS, CSF IFN-alpha concentrations were higher than in paired serum samples. In contrast, serum IFN was consistently higher compared to CSF levels in SAVI, pT1I, and nSLE. Whilst IFN-alpha is present in the CSF and serum of all IFN-related diseases studied here, our data suggest the primary sites of IFN production in the monogenic T1I AGS and SAVI are, respectively, the CNS and the periphery. These results inform the diagnosis of, and future therapeutic approaches to, monogenic and multifactorial T1Is.

Published
2021

2. Transient magnetic resonance diffusion abnormalities in West syndrome: the radiological expression of non-convulsive status epilepticus?

Author

Vassili Valayannopoulos, Perrine Plouin, Nathalie Boddaert, Pascale Delonlay, Lucie Hertz-Pannier, Olivier Dulac, Isabelle Desguerre, Nadia Bahi-Buisson, and Ixtasu Marti

Subjects
Male, Pathology, medicine.medical_specialty, Basal Ganglia, Status Epilepticus, Cerebrospinal fluid, Thalamus, Developmental Neuroscience, Mesencephalon, medicine, Humans, medicine.diagnostic_test, business.industry, Brain, Infant, Magnetic resonance imaging, West Syndrome, medicine.disease, Magnetic Resonance Imaging, Hypsarrhythmia, Radiography, Cerebellar Nuclei, Inborn error of metabolism, Child, Preschool, Pediatrics, Perinatology and Child Health, Etiology, Female, Neurology (clinical), Brainstem, medicine.symptom, business, Spasms, Infantile, Follow-Up Studies, Diffusion MRI
Abstract

The purpose of this study was to report patients with pharmacoresistant West syndrome of unknown cause whose magnetic resonance imaging (MRI) with diffusion weighted imaging (DWI) showed a transient decrease of diffusion in subcortical structures. Of 20 patients investigated over a 2-year period, three males and three females constitute the present series. They had daily clusters of infantile spasms with hypsarrhythmia for 4 to 24 months before the first investigation. Four were severely hypotonic. All aetiological studies involving intermediary metabolism, peroxysomes, mitochondria, and neurotransmitters in cerebrospinal fluid were negative. Patients underwent DWI when first examined at the mean age of 13 months, and on follow-up examination 6 to 18 months later. Diffusion was decreased in the pallidi and posterior brainstem. It was also decreased for five patients in thalami and for three in dentate nuclei. Repeat MRI, performed when spasms were still present but hypsarrhythmia had ceased, did not show the same abnormalities. Because of recruitment bias, this series probably overestimates the true incidence of such DWI abnormalities. The eventuality of toxic lesions, including some inborn error of metabolism or drug toxicity, is considered unlikely although it could not be excluded. The contribution of the epileptic encephalopathy itself appears the most likely course.

Published
2008

3. Next-Generation Sequencing for Diagnosis and Tailored Therapy: A Case Report of Astrovirus-Associated Progressive Encephalitis

Author

Nizar Mahlaoui, Marie-Louise Frémond, Marine Dumarest, Capucine Picard, C. Hébert, Philippe Pérot, Guilhem Cros, Nicole Corre-Catelin, Isabelle Desguerre, Marc Eloit, Stéphane Blanche, Danielle Seilhean, Marc Lecuit, E. Muth, Bénédicte Neven, CHU Necker - Enfants Malades [AP-HP], Université Paris Descartes - Paris 5 (UPD5), Institut des Maladies Génétiques Imagine [Paris], Découverte de Pathogènes - Pathogen Discovery, Biologie des Infections - Biology of Infection, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), PathoQuest, Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Génétique Humaine des Maladies Infectieuses (Inserm U980), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), CHU Pitié-Salpêtrière [APHP], Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), Institut Pasteur [Paris], Service des Maladies infectieuses et tropicales [CHU Necker], Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP]-Institut des Maladies Génétiques Imagine [Paris], Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was funded by the French Government's Investissement d'Avenir program, Laboratoire d'Excellence 'Integrative Biology of Emerging Infectious Diseases' (Grant Number ANR-10-LABX-62-IBEID), and Institut National de la Santé et de la Recherche Médicale., We thank the platform Investigation Clinique et Accès aux Ressources Biologiques (Institut Pasteur, Paris) for help in the management of biological samples., ANR-10-LABX-62-IBEID,IBEID,Laboratoire d'Excellence 'Integrative Biology of Emerging Infectious Diseases'(2010), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Pasteur [Paris] (IP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Male, encephalitis, [SDV]Life Sciences [q-bio], Anti-Inflammatory Agents, X-linked agammaglobulinemia, law.invention, Epilepsy, astrovirus, Cerebrospinal fluid, MESH: Astroviridae Infections, law, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Astroviridae Infections, MESH: Sequence Analysis, RNA, Encephalitis, Viral, MESH: High-Throughput Nucleotide Sequencing, Polymerase chain reaction, medicine.diagnostic_test, biology, High-Throughput Nucleotide Sequencing, Genetic Diseases, X-Linked, General Medicine, 3. Good health, MESH: Encephalitis, Viral, Infectious Diseases, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, MESH: Epilepsy, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MESH: Genome, Viral, Encephalitis, MESH: Astroviridae, MESH: Antiviral Agents, Adolescent, Bruton, Genome, Viral, Antiviral Agents, DNA sequencing, Astrovirus, Cerebellar Diseases, medicine, MESH: Genetic Diseases, X-Linked, Humans, MESH: Agammaglobulinemia, MESH: Adolescent, MESH: Humans, Sequence Analysis, RNA, business.industry, Brain biopsy, MESH: Cerebellar Diseases, medicine.disease, biology.organism_classification, Virology, MESH: Male, agammaglobulinemia, MESH: Anti-Inflammatory Agents, Pediatrics, Perinatology and Child Health, Astroviridae, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; A boy with X-linked agammaglobulinemia experienced progressive global motor decline, cerebellar syndrome, and epilepsy. All standard polymerase chain reactions for neurotropic viruses were negative on cerebrospinal fluid and brain biopsy. Next-generation sequencing allowed fast identification of a new astrovirus strain (HAstV-VA1/HMO-C-PA), which led to tailor the patient's treatment, with encouraging clinical monitoring over 1 year.

Published
2015

4. Respiratory chain deficiency in a female with Aicardi-Goutières syndrome

Author

Agnès Rötig, Nadia Bahi-Buisson, Irina Giurgea, Lucie Hertz-Pannier, Arnold Munnich, Christine Barnerias, Pascale de Lonlay, Pierre Rustin, Nathalie Boddaert, and Isabelle Desguerre

Subjects
Pathology, medicine.medical_specialty, Chromatography, Gas, Mitochondrial Diseases, Lymphocytosis, Encephalopathy, Ketone Bodies, Basal Ganglia, White matter, Cerebrospinal fluid, Developmental Neuroscience, Seizures, Pyruvic Acid, Basal ganglia, Humans, Medicine, Lactic Acid, Muscle, Skeletal, business.industry, Dementia, Vascular, Calcinosis, Interferon-alpha, Skeletal muscle, Syndrome, medicine.disease, Magnetic Resonance Imaging, Mitochondrial respiratory chain, medicine.anatomical_structure, Pediatrics, Perinatology and Child Health, Aicardi–Goutières syndrome, Female, Neurology (clinical), Psychomotor Disorders, medicine.symptom, business
Abstract

Aicardi-Goutières syndrome (AGS) is an early-onset progressive encephalopathy characterized by calcifications of the basal ganglia, white matter abnormalities, chronic cerebrospinal fluid (CSF) lymphocytosis, and/or a raised level of CSF interferon (INF)-alpha. We report a female with mitochondrial respiratory chain deficiency fulfilling the criteria of AGS. Disease onset was in the first year of age with seizures and psychomotor regression. To date, at 4 years of age, she presents a severe encephalopathy, increased INF-alpha in the CSF, and calcifications of basal ganglia on computerized tomography. Cerebral magnetic resonance imaging showed bilateral and symmetric hypersignal of the posterior white matter. A complex I deficiency of the mitochondrial respiratory chain was found in skeletal muscle, which was associated with a complex IV deficiency in cultured skin fibroblasts. The question of whether this oxidative phosphorylation deficiency is primary or secondary in AGS is open to debate. We suggest giving consideration to systematic evaluation of the mitochondrial respiratory chain in skeletal muscle and skin fibroblasts of other AGS patients.

Published
2006

5. Enterovirus 71 Meningoencephalitis During Chemotherapy in a Child With Metastatic Osteosarcoma

Author

Marie-Christine Escande, Daniel Orbach, Isabelle Desguerre, Isabelle Fromantin, Pierre Frange, Eva Safar, Nathalie Franck, and Jean Michon

Subjects
Male, medicine.medical_specialty, medicine.medical_treatment, Immunoglobulins, Bone Neoplasms, medicine.disease_cause, Gastroenterology, Cerebrospinal fluid, Meningoencephalitis, Internal medicine, Enterovirus Infections, medicine, Enterovirus 71, Humans, Child, Enterovirus, Osteosarcoma, Chemotherapy, Lung, biology, business.industry, Hematology, Aplasia, medicine.disease, biology.organism_classification, Virology, Treatment Outcome, medicine.anatomical_structure, Oncology, Pediatrics, Perinatology and Child Health, business
Abstract

Enterovirus meningoencephalitis is rare but can be severe. Very few cases of these infections have been reported in pediatric oncology. We report the case of a 10-year-old boy with tibial osteosarcoma and lung metastases who developed enterovirus 71 meningoencephalitis during aplasia. Clinical features comprised fever, hypotension, vesicular rash, generalized seizures, and altered consciousness. Diagnosis was confirmed by polymerase chain reaction on samples of cerebrospinal fluid and skin vesicles. The patient received treatment with intravenous immunoglobulins with an excellent outcome with no cutaneous or neurologic sequelae. Immunoglobulin therapy could be considered in cases of invasive enteroviral infection with such severity in pediatric oncology.

Published
2007

6. Clinical, cellular, and neuropathological consequences of AP1S2 mutations: further delineation of a recognizable X-linked mental retardation syndrome

Author

Francis Brunelle, Arnold Munnich, Nathalie Boddaert, Anne Philippe, Guntram Borck, Laurence Robel, Alexandre Benmerah, Férechté Encha-Razavi, Anahi Molla-Herman, Laurence Colleaux, Isabelle Desguerre, Universität Ulm - Ulm University [Ulm, Allemagne], 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), 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 Cytogénétique et Embryologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de Mathématiques Jean Leray (LMJL), Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN), Troubles du comportement alimentaire de l'adolescent (UMR_S 669), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11), Service de Neuropédiatrie, Service de radiologie pédiatrique [CHU Necker], Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), 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)-CHU Necker - Enfants Malades [AP-HP], Université de Nantes - Faculté des Sciences et des Techniques, and Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Adaptor Protein Complex sigma Subunits, Protein subunit, Biology, medicine.disease_cause, mental retardation, 03 medical and health sciences, cerebral calcifications, 0302 clinical medicine, elevated CSF protein levels, clathrin, Genetics, medicine, Humans, Family, Gene, Genetics (clinical), AP1S2, Cerebrospinal Fluid, 030304 developmental biology, Brain Chemistry, 0303 health sciences, Mutation, AP-1, Phenotype, Hypotonia, Pedigree, Transport protein, Protein Subunits, Protein Transport, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Speech delay, Mental Retardation, X-Linked, Female, adaptor protein complex 1, medicine.symptom, 030217 neurology & neurosurgery
Abstract

International audience; Communicated by Andreas Gal Mutations in the AP1S2 gene, encoding the r1B subunit of the clathrin-associated adaptor protein complex (AP)-1, have been recently identified in five X-linked mental retardation (XLMR) families, including the original family with Fried syndrome. Studying four patients in two unrelated families in which AP1S2 nonsense and splice-site mutations segregated, we found that affected individuals presented, in addition to previously described features, with elevated protein levels in cerebrospinal fluid (CSF). Moreover, computed tomography scans demonstrated that the basal ganglia calcifications associated with AP1S2 mutations appeared during childhood and might be progressive. Based on these observations, we propose that AP1S2 mutations are responsible for a clinically recognizable XLMR and autism syndrome associating hypotonia, delayed walking, speech delay, aggressive behavior, brain calcifications, and elevated CSF protein levels. Using the AP-2 complex, in which the r subunit is encoded by one single gene, as a model system, we demonstrated that r subunits are essential for the stability of human AP complexes. By contrast, no major alteration of the stability, subcellular localization, and function of the AP-1 complex was observed in fibroblasts derived from a patient carrying an AP1S2 mutation. Similarly, neither macro-nor microscopic defects were observed in the brain of an affected fetus. Altogether, these data suggest that the absence of an AP-1 defect in peripheral tissues is due to functional redundancy among AP-1 r subunits (r1A, r1B, and r1C) and that the phenotype observed in our patients results from a subtle and brain-specific defect of the AP-1-dependent intracellular protein traffic. Hum Mutat 29(7), 966-974, 2008. r r 2008 Wiley-Liss, Inc.

Published
2008

7. Respiratory chain deficiency in a female with Aicardi-Goutières syndrome.

Author

Christine Barnérias, Irina Giurgea, Lucie Hertz-Pannier, Nadia Bahi-Buisson, Nathalie Boddaert, Pierre Rustin, Agnés Rotig, Isabelle Desguerre, Arnold Munnich, and Pascale de Lonlay

Subjects
BASAL ganglia, CEREBROSPINAL fluid, INTERFERONS, MUSCULOSKELETAL system diseases, FIBROBLASTS
Abstract

Aicardi-Goutières syndrome (AGS) is an early-onset progressive encephalopathy characterized by calcifications of the basal ganglia, white matter abnormalities, chronic cerebrospinal fluid (CSF) lymphocytosis, and/or a raised level of CSF interferon (INF)-α. We report a female with mitochondrial respiratory chain deficiency fulfilling the criteria of AGS. Disease onset was in the first year of age with seizures and psychomotor regression. To date, at 4 years of age, she presents a severe encephalopathy, increased INF-α in the CSF, and calcifications of basal ganglia on computerized tomography. Cerebral magnetic resonance imaging showed bilateral and symmetric hypersignal of the posterior white matter. A complex I deficiency of the mitochondrial respiratory chain was found in skeletal muscle, which was associated with a complex IV deficiency in cultured skin fibroblasts. The question of whether this oxidative phosphorylation deficiency is primary or secondary in AGS is open to debate. We suggest giving consideration to systematic evaluation of the mitochondrial respiratory chain in skeletal muscle and skin fibroblasts of other AGS patients. [ABSTRACT FROM AUTHOR]

Published
2006

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