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1. Deficiency of the minor spliceosome component U4atac snRNA secondarily results in ciliary defects in human and zebrafish

Author

Deepak Khatri, Audrey Putoux, Audric Cologne, Sophie Kaltenbach, Alicia Besson, Eloïse Bertiaux, Justine Guguin, Adèle Fendler, Marie A. Dupont, Clara Benoit-Pilven, Leila Qebibo, Samira Ahmed-Elie, Séverine Audebert-Bellanger, Pierre Blanc, Thomas Rambaud, Martin Castelle, Gaëlle Cornen, Sarah Grotto, Agnès Guët, Laurent Guibaud, Caroline Michot, Sylvie Odent, Lyse Ruaud, Elise Sacaze, Virginie Hamel, Rémy Bordonné, Anne-Louise Leutenegger, Patrick Edery, Lydie Burglen, Tania Attié-Bitach, Sylvie Mazoyer, Marion Delous, Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Genève = University of Geneva (UNIGE), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Hôpital Morvan [Brest], CH Morlaix, Maternité Port-Royal [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Hôpital Louis Mourier - AP-HP [Colombes], Université de Lyon, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Hôpital Robert Debré, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), This work was supported by CNRS, Inserm, Université de Montpellier, Université Paris 7 and Université Lyon 1 through recurrent funding, the Fondation Maladies Rares ('Small Animal Models and Rare Diseases' program, no. 20161207), the Agence Nationale de la Recherche (no. ANR-18CE12-0007-01), and the Fondation pour la recherche sur le Cerveau « Espoir en tête » (confocal microscope). E.B. was supported by an European Molecular Biology Organization long-term fellowship (ALTF-284-2019) and the Novartis Foundation for medical-biological Research (18B112)., and ANR-18-CE12-0007,U4ATAC-BRAIN,Rôle de l'épissage mineur dans le développement cérébral(2018)

Subjects
minor introns, [SDV.GEN]Life Sciences [q-bio]/Genetics, Multidisciplinary, MESH: Humans, MESH: Mutation, MESH: Fetal Growth Retardation, MESH: RNA, Small Nuclear, U4atac, splicing, genetic disease, MESH: Ciliopathies, MESH: Animals, MESH: Zebrafish, MESH: Female, MESH: Spliceosomes, primary cilium
Abstract

In the human genome, about 750 genes contain one intron excised by the minor spliceosome. This spliceosome comprises its own set of snRNAs, among which U4atac. Its noncoding gene, RNU4ATAC , has been found mutated in Taybi-Linder (TALS/microcephalic osteodysplastic primordial dwarfism type 1), Roifman (RFMN), and Lowry-Wood (LWS) syndromes. These rare developmental disorders, whose physiopathological mechanisms remain unsolved, associate ante- and post-natal growth retardation, microcephaly, skeletal dysplasia, intellectual disability, retinal dystrophy, and immunodeficiency. Here, we report bi-allelic RNU4ATAC mutations in five patients presenting with traits suggestive of the Joubert syndrome (JBTS), a well-characterized ciliopathy. These patients also present with traits typical of TALS/RFMN/LWS, thus widening the clinical spectrum of RNU4ATAC -associated disorders and indicating ciliary dysfunction as a mechanism downstream of minor splicing defects. Intriguingly, all five patients carry the n.16G>A mutation, in the Stem II domain, either at the homozygous or compound heterozygous state. A gene ontology term enrichment analysis on minor intron-containing genes reveals that the cilium assembly process is over-represented, with no less than 86 cilium-related genes containing at least one minor intron, among which there are 23 ciliopathy-related genes. The link between RNU4ATAC mutations and ciliopathy traits is supported by alterations of primary cilium function in TALS and JBTS-like patient fibroblasts, as well as by u4atac zebrafish model, which exhibits ciliopathy-related phenotypes and ciliary defects. These phenotypes could be rescued by WT but not by pathogenic variants-carrying human U4atac. Altogether, our data indicate that alteration of cilium biogenesis is part of the physiopathological mechanisms of TALS/RFMN/LWS, secondarily to defects of minor intron splicing.

Published
2023
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2. Novel missense mutations in PTCHD1 alter its plasma membrane subcellular localization and cause intellectual disability and autism spectrum disorder

Author

Sylviane Marouillat, Marie-Laure Vuillaume, Thomas Smol, Rose-Anne Thépault, Lyse Ruaud, Sarah Grotto, Jamal Ghoumid, Nicolas Chatron, Annick Toutain, Marianne Till, Alain Verloes, Manon Dixneuf, Valérie Chune, Gaetan Lesca, Frédéric Laumonnier, Nathalie Couque, Bénédicte Gérard, Martine Raynaud, Judith Halewa, Dévina C. Ung, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL), Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Les Hôpitaux Universitaires de Strasbourg (HUS), Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364 (RADEME), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Robert Debré, Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, ANR-20-CE17-0006,ASDecode,Approches translationnelles pour la caractérisation de la voie PTCHD1 impliquée dans les troubles neurodéveloppementaux(2020), Laumonnier, Frédéric, Approches translationnelles pour la caractérisation de la voie PTCHD1 impliquée dans les troubles neurodéveloppementaux - - ASDecode2020 - ANR-20-CE17-0006 - AAPG2020 - VALID, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), and Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)

Subjects
Male, [SDV]Life Sciences [q-bio], Mutation, Missense, autism spectrum disorder, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, functional analyses, PTCHD1 (patched domain containing 1) gene, 03 medical and health sciences, Mice, in vitro cellular models, subcellular localization, Genetics, medicine, Missense mutation, Animals, Humans, Gene, Genetics (clinical), Research Articles, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Endoplasmic reticulum, 030305 genetics & heredity, Cell Membrane, Membrane Proteins, Subcellular localization, medicine.disease, In vitro, Transmembrane protein, Amino acid, [SDV] Life Sciences [q-bio], chemistry, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autism spectrum disorder, intellectual disability, missense variants, Research Article
Abstract

The X‐linked PTCHD1 gene, encoding a synaptic membrane protein, has been involved in neurodevelopmental disorders with the description of deleterious genomic microdeletions or truncating coding mutations. Missense variants were also identified, however, without any functional evidence supporting their pathogenicity level. We investigated 13 missense variants of PTCHD1, including eight previously described (c.152G>A,p.(Ser51Asn); c.217C>T,p.(Leu73Phe); c.517A>G,p.(Ile173Val); c.542A>C,p.(Lys181Thr); c.583G>A,p.(Val195Ile); c.1076A>G,p.(His359Arg); c.1409C>A,p.(Ala470Asp); c.1436A>G,p.(Glu479Gly)), and five novel ones (c.95C>T,p.(Pro32Leu); c.95C>G,p.(Pro32Arg); c.638A>G,p.(Tyr213Cys); c.898G>C,p.(Gly300Arg); c.928G>C,p.(Ala310Pro)) identified in male patients with intellectual disability (ID) and/or autism spectrum disorder (ASD). Interestingly, several of these variants involve amino acids localized in structural domains such as transmembrane segments. To evaluate their potentially deleterious impact on PTCHD1 protein function, we performed in vitro overexpression experiments of the wild‐type and mutated forms of PTCHD1‐GFP in HEK 293T and in Neuro‐2a cell lines as well as in mouse hippocampal primary neuronal cultures. We found that six variants impaired the expression level of the PTCHD1 protein, and were retained in the endoplasmic reticulum suggesting abnormal protein folding. Our functional analyses thus provided evidence of the pathogenic impact of missense variants in PTCHD1, which reinforces the involvement of the PTCHD1 gene in ID and in ASD., Thirteen missense variants in the PTCHD1 gene associated with X‐linked neurodevelopmental disorder were investigated to address their potentially deleterious impact. Their overexpression in various cell lines (HEK293T, Neuro‐2a) and in primary neuronal cultures revealed abnormal protein stability and impaired subcellular localization, thus providing further evidence for the significant impact of PTCHD1 genetic alterations in intellectual disability and in autism spectrum disorder.

Published
2021
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3. The oculoauriculofrontonasal syndrome: Further clinical characterization and additional evidence suggesting a nontraditional mode of inheritance

Author

Stéphane Triau, Christel Thauvin-Robinet, Julien Thevenon, Guillaume Captier, David Geneviève, Audrey Putoux, Yannis Duffourd, Delphine Héron, Patrick Callier, Mirna Assoum, Laurence Faivre, Daphné Lehalle, Patrick Edery, Alice Goldenberg, Sarah Grotto, Bettina Bessières, Catherine Vincent-Delorme, Ange-Line Bruel, Hülya Kayserili, Christelle Cabrol, Nursel Elcioglu, Geneviève Baujat, Myriam Vezain, Alice Masurel, Massimiliano Rossi, Umut Altunoglu, Pierre Vabres, Pascale Saugier-Veber, Sandrine Marlin, 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), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Bourgogne Franche-Comté [COMUE] (UBFC), Departement of Genetics [University of Istanbul], Istanbul University, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Histologie Embryologie Cytogénétique [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), Département Chirurgie Pédiatrique [CHRU Montpellier], Pôle Femme Mère Enfant [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de foetopathologie (CHU d'Angers), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), CHU Lille, Service de Dermatologie (CHU de Dijon), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de chirurgie infantile [CHRU de Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de références des syndromes malformatifs et anomalies du développement [CHU Lyon], Hospices Civils de Lyon (HCL), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), CHU Pitié-Salpêtrière [APHP], Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Service de génétique clinique (CHU Lille), Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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], and 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)

Subjects
0301 basic medicine, Male, Inheritance Patterns, 030105 genetics & heredity, frontonasal dysplasia, whole exome sequencing, Craniofacial Abnormalities, 0302 clinical medicine, Polymicrogyria, Eye Abnormalities, Ear, External, 10. No inequality, Child, Genetics (clinical), Exome sequencing, whole genome sequencing, Thyroid agenesis, Hypoplasia, DNA-Binding Proteins, Phenotype, Child, Preschool, Female, Respiratory System Abnormalities, medicine.medical_specialty, Adolescent, Quantitative Trait Loci, Oculoauriculofrontonasal syndrome, 03 medical and health sciences, Exome Sequencing, Genetics, medicine, Humans, Genetic Predisposition to Disease, Frontonasal dysplasia, Genetic Association Studies, Whole genome sequencing, Homeodomain Proteins, business.industry, Facial cleft, Skull, Infant, Newborn, Facies, Infant, 030206 dentistry, medicine.disease, Dermatology, Spine, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Dysplasia, business, Tomography, Spiral Computed, Transcription Factors
Abstract

IF 2.264; International audience; The oculoauriculofrontonasal syndrome (OAFNS) is a rare disorder characterized by the association of frontonasal dysplasia (widely spaced eyes, facial cleft, and nose abnormalities) and oculo-auriculo-vertebral spectrum (OAVS)-associated features, such as preauricular ear tags, ear dysplasia, mandibular asymmetry, epibulbar dermoids, eyelid coloboma, and costovertebral anomalies. The etiology is unknown so far. This work aimed to identify molecular bases for the OAFNS. Among a cohort of 130 patients with frontonasal dysplasia, accurate phenotyping identified 18 individuals with OAFNS. We describe their clinical spectrum, including the report of new features (micro/anophtalmia, cataract, thyroid agenesis, polymicrogyria, olfactory bulb hypoplasia, and mandibular cleft), and emphasize the high frequency of nasal polyps in OAFNS (56%). We report the negative results of ALX1, ALX3, and ALX4 genes sequencing and next-generation sequencing strategy performed on blood-derived DNA from respectively, four and four individuals. Exome sequencing was performed in four individuals, genome sequencing in one patient with negative exome sequencing result. Based on the data from this series and the literature, diverse hypotheses can be raised regarding the etiology of OAFNS: mosaic mutation, epigenetic anomaly, oligogenism, or nongenetic cause. In conclusion, this series represents further clinical delineation work of the rare OAFNS, and paves the way toward the identification of the causing mechanism.

Published
2018
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4. Type 0 Spinal Muscular Atrophy: Further Delineation of Prenatal and Postnatal Features in 16 Patients

Author

Anne-Marie Guerrot, Joelle Roume, Thierry Frebourg, Patricia Faure, Pascale Saugier-Veber, Sylvain Renolleau, Séverine Audebert-Bellanger, Gilles Morin, Isabelle Desguerre, Renaud Touraine, Ghislaine Plessis, Séverine Drunat, Marjolaine Willems, Sarah Grotto, Hubert Journel, Eric Verspyck, Brigitte Simon-Bouy, Jean-Marie Cuisset, Anne-Gaëlle Grebille, Stéphane Marret, Vincent Flurin, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Maladies Neuromusculaires de l'Enfant, Hôpital Roger Salengro [Lille], Team 4 'NeoVasc' - INSERM U1245, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Département de génétique médicale en pédiatrie [CHRU Brest], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service de neurologie pédiatrique [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), Génétique médicale [Centre Hospitalier de Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Institut d'histoire du temps présent (IHTP), Centre National de la Recherche Scientifique (CNRS), Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Neurobiologie des processus adaptatifs (NPA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), CHI Poissy-Saint-Germain, Centre Hospitalier de Versailles André Mignot (CHV), Service de Génétique Clinique Chromosomique et Moléculaire, CHU Saint-Etienne-Hôpital Nord - Saint-Etienne, Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Service de gynécologie et obstétrique [CHU Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Team 4 NeoVasc - Region Team ERI 28 INSERM (Neovasc), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)

Subjects
Heart Defects, Congenital, Male, 0301 basic medicine, Weakness, Pediatrics, medicine.medical_specialty, Genotype, [SDV]Life Sciences [q-bio], SMN1, Spinal Muscular Atrophies of Childhood, Ultrasonography, Prenatal, 03 medical and health sciences, Life Expectancy, 0302 clinical medicine, medicine, Humans, Increased nuchal translucency, ComputingMilieux_MISCELLANEOUS, Arthrogryposis, Respiratory Distress Syndrome, Newborn, Pregnancy, Reflex, Abnormal, business.industry, Homozygote, Infant, Newborn, Muscle weakness, Spinal muscular atrophy, medicine.disease, SMA, Survival of Motor Neuron 1 Protein, Cranial Nerve Diseases, Hypotonia, 3. Good health, Survival of Motor Neuron 2 Protein, 030104 developmental biology, Autonomic Nervous System Diseases, Neurology, Muscle Hypotonia, Female, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

Background Spinal muscular atrophy (SMA) is caused by homozygous inactivation of the SMN1 gene. The SMN2 copy number modulates the severity of SMA. The 0SMN1/1SMN2 genotype, the most severe genotype compatible with life, is expected to be associated with the most severe form of the disease, called type 0 SMA, defined by prenatal onset. Objective The aim of the study was to review clinical features and prenatal manifestations in this rare SMA subtype. Methods SMA patients with the 0SMN1/1SMN2 genotype were retrospectively collected using the UMD-SMN1 France database. Results Data from 16 patients were reviewed. These 16 patients displayed type 0 SMA. At birth, a vast majority had profound hypotonia, severe muscle weakness, severe respiratory distress, and cranial nerves involvement (inability to suck/swallow, facial muscles weakness). They showed characteristics of fetal akinesia deformation sequence and congenital heart defects. Recurrent episodes of bradycardia were observed. Death occurred within the first month. At prenatal stage, decreased fetal movements were frequently reported, mostly only by mothers, in late stages of pregnancy; increased nuchal translucency was reported in about half of the cases; congenital heart defects, abnormal amniotic fluid volume, or joint contractures were occasionally reported. Conclusion Despite a prenatal onset attested by severity at birth and signs of fetal akinesia deformation sequence, prenatal manifestations of type 0 SMA are not specific and not constant. As illustrated by the frequent association with congenital heart defects, type 0 SMA physiopathology is not restricted to motor neuron, highlighting that SMN function is critical for organogenesis.

Published
2016
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