相关发育性和癫痫性脑病：表型和基因型谱
Related Developmental and Epileptic Encephalopathy: Phenotypic and Genotypic Spectrum.
作者信息
Johannesen Katrine M, Gardella Elena, Gjerulfsen Cathrine E, Bayat Allan, Rouhl Rob P W, Reijnders Margot, Whalen Sandra, Keren Boris, Buratti Julien, Courtin Thomas, Wierenga Klaas J, Isidor Bertrand, Piton Amélie, Faivre Laurence, Garde Aurore, Moutton Sébastien, Tran-Mau-Them Frédéric, Denommé-Pichon Anne-Sophie, Coubes Christine, Larson Austin, Esser Michael J, Appendino Juan Pablo, Al-Hertani Walla, Gamboni Beatriz, Mampel Alejandra, Mayorga Lía, Orsini Alessandro, Bonuccelli Alice, Suppiej Agnese, Van-Gils Julien, Vogt Julie, Damioli Simona, Giordano Lucio, Moortgat Stephanie, Wirrell Elaine, Hicks Sarah, Kini Usha, Noble Nathan, Stewart Helen, Asakar Shailesh, Cohen Julie S, Naidu SakkuBai R, Collier Ashley, Brilstra Eva H, Li Mindy H, Brew Casey, Bigoni Stefania, Ognibene Davide, Ballardini Elisa, Ruivenkamp Claudia, Faggioli Raffaella, Afenjar Alexandra, Rodriguez Diana, Bick David, Segal Devorah, Coman David, Gunning Boudewijn, Devinsky Orrin, Demmer Laurie A, Grebe Theresa, Pruna Dario, Cursio Ida, Greenhalgh Lynn, Graziano Claudio, Singh Rahul Raman, Cantalupo Gaetano, Willems Marjolaine, Yoganathan Sangeetha, Góes Fernanda, Leventer Richard J, Colavito Davide, Olivotto Sara, Scelsa Barbara, Andrade Andrea V, Ratke Kelly, Tokarz Farha, Khan Atiya S, Ormieres Clothilde, Benko William, Keough Karen, Keros Sotirios, Hussain Shanawaz, Franques Ashlea, Varsalone Felicia, Grønborg Sabine, Mignot Cyril, Heron Delphine, Nava Caroline, Isapof Arnaud, Borlot Felippe, Whitney Robyn, Ronan Anne, Foulds Nicola, Somorai Marta, Brandsema John, Helbig Katherine L, Helbig Ingo, Ortiz-González Xilma R, Dubbs Holly, Vitobello Antonio, Anderson Mel, Spadafore Dominic, Hunt David, Møller Rikke S, Rubboli Guido
机构信息
Department of Epilepsy Genetics and Personalized Treatment (K.M.J., E.G., C.E.G., A.B., R.S.M., G.R.), The Danish Epilepsy Centre Filadelfia, member of ERN EpiCARE, Dianalund; Institute for Regional Health Research (K.M.J., E.G., A.B., R.S.M), University of Southern Denmark, Odense; Department of Neurology (R.P.W.R.), Maastricht University Medical Centre (MUMC+); Academic Centre for Epileptology Kempenhaeghe/MUMC+ (R.P.W.R.), Maastricht; School for Mental Health and Neuroscience (R.P.W.R.), Maastricht University; Department of Clinical Genetics (M.R.), Maastricht University Medical Center, the Netherlands; APHP, Sorbonne Université (S.W.), Hôpital Armand Trousseau, UF de Génétique Clinique, Centre de Référence Anomalies du Développement et Syndromes Malformatifs, Paris, France; Department of Genetics (B.K., J.B., T.C., C.N.), Pitié-Salpêtrière hospital, APHP, Sorbonne Université, Paris, France; Department of Clinical Genomics (K.J.W.), Mayo Clinic Florida, Jacksonville; Service de Génétique Médicale (B.I., A.P., A.-S.D.-P.), CHU de Nantes; Centre de Référence Anomalies du Développement et Syndromes Malformatifs (L.F., A.G., S.M.), FHU TRANSLAD, CHU Dijon; INSERM UMR1231 (L.F., A.G., S.M., F.T.M.-T., A.V.), GAD team, Université de Bourgogne-Franche Comté, Dijon; Unité Fonctionnelle dInnovation diagnostique des maladies rares (F.T.-M.-T., A.V.), Pôle de Biologie, FHU-TRANSLAD, CHU Dijon Bourgogne; Department of Medical Genetics (C.C., M.W.), Rare Diseases and Personalized Medicine, CHU Montpellier, France; Childrens Hospital Colorado (A.L.), Anschutz Medical Campus, Aurora, CO; Division of Clinical Neuroscience (M.J.E., J.P.A.), Department of Pediatrics, Alberta, Canada; Alberta Childrens Hospital (J.P.A., F.B.), Cumming School of Medicine, University of Calgary, Alberta, Canada; Department of Pediatrics (W.A.-H.), Division of Genetics and Genomics, Boston Childrens Hospital and Harvard Medical School, MA; Instituto de Neurología Infanto Juvenil (B.G.), Neuroinfan; Instituto de Genetica-Hospital Universitario (A.M.), Universidad Nacional de Cuyo; Instituto de Histología y Embriología de Mendoza (IHEM) (L.M.), Universidad Nacional de Cuyo, Mendoza, Argentina; Azienda Ospedaliera Universitaria Pisana (A.O.); Neuropaediatric Section (A.B.), Pediatric Department, Santa Chiara University Hospital, Pisa; Department of Medical Sciences- Pediatric Section (A.S.), University of Ferrara, Italy; CHU Bordeaux (J.V.-G.), Bordeaux, France; West Midlands Regional Genetics Service (J.V.), Birmingham Women's and Children's Hospital, Birmingham, UK; Child Neuropsychiatric Division (S.D., L.G.), Spedali Civili, Brescia, Italy; Institut de Pathologie et de Génétique (IPG) (S.M.), Gosselies, Belgium; Divisions of Child and Adolescent Neurology and Epilepsy (E.W.), Department of Neurology, Mayo Clinic, Rochester, MN; Oxford Centre for Genomic Medicine (S.H., H.S.); Oxford University Hospitals NHS Trust (U.K.), United Kingdom; Blank Children's Developmental Center (N.N.), Unity Point Health, West Des Moines, IA; Sutter Medical Centre (S.A.), Sacramento, CA; Kennedy Krieger Institute (J.S.C.); Johns Hopkins University (S.R.N.), Baltimore, MD; Provincial Medical Genetics Program (A.C.), St. Johns Medical Center, NL, Canada; University Medical Center Utrecht (E.H.B.), Utrecht, the Netherlands; Rush University Medical Center (M.H.L., C.B.), Chicago, IL; Medical Genetic Unit (S.B., D.O.), Maternal and Child Department, Ferrara University Hospital; Medical Science Department (D.O.), Ferrara University; Neonatal Intensive Care Unit (E.B.), Pediatric Section, Department of Medical Sciences, Ferrara University, Italy; Department of Clinical Genetics (C.R.), LUMC, Leiden, the Netherlands; Pediatric Unit, Maternal and Child Department (R.F.), Ferrara University Hospital, Italy; APHP Trousseau (A.A., C.M., D.H.); Service de Neuropédiatrie (D.R., A.I.), Hopital Trousseau, Sorbonne Université, APHP.SU, Paris, France; HudsonAlpha Institute for Biotechnology (D.B.), Huntsville, AL; Department of Pediatrics (D.S., S.K.), Weill Cornell Medicine, New York; Queensland Children's Hospital (D.C.), Brisbane, QL, Australia; Department of Neurology (B.G.), Stichting Epilepsie Instellingen Nederland, Zwolle, the Netherlands; Department of Neurology (O.D.), NYU School of Medicine; Atrium Healths Levine Childrens Hospital (L.A.D.), Charlotte, NC; Phoenix Childrens Hospital (T.G.), the University of Arizona College of Medicine; Division of Child Neurology and Psychiatry (D.P.), Azienda Ospedaliero Universitaria; Neurology and Epileptology Unit (I.C.), Pediatric Department, Brotzu Hospital Trust, Cagliari, Italy; Liverpool Centre for Genomic Medicine (L.G., G.R.), Liverpool Womens NHS Foundation Trust, Liverpool, United Kingdom; U.O. Genetica Medica (C.G.), Policlinico S. Orsola-Malpighi, Bologna, Italy; Department of Children's neurosciences (R.R.S.), Guys and ST. Thomas' NHS foundation trust, London United Kingdom; Department of Child Neuropsychiatry (G.C.), University of Verona, Italy; Christian Medical College (S.Y.), Vellore, India; Neurology Pediatric Unit (F.G.), Pediatric Department, Fernandes Figueira Institute, Fiocruz, Brazil; Royal Childrens Hospital (F.J.L.), Melbourne, Australia; Research & Innovation S.r.l. (D.C.), Padova; Pediatric Neurology Unit (S.O., B.S., F.V.), V. Buzzi Childrens Hospital, Milan, Italy; Department of Paediatrics (A.V.A.), London Health Science Centre/Schulich School of Medicine and Dentisty, University of Western Ontario, London, ON, Canada; Ambry Genetics (K.R.), Aliso Viejo, CA; Advocate Lutheran General Hospital (F.T.), Park Ridge, IL; PPG Pediatric Neurology (A.S.K.), Parkview Health, Fort Wayne, IN; Department of Medical Genetics (C.O.), AP-HP, Necker-Enfants Malades Hospital, Paris, France; Department of Neurology (W.B.), UC Davis, Sacramento, CA; Department of Pediatrics (K.K.), Texas A&M University Medical School, Austin; Leeds General Infirmary (S.H,), United Kingdom; Thompson River Pediatrics (A.F.), Johnstown, CO; Department of Neuropediatrics (S.G.), University Hospital Copenhagen, Denmark; Division of Neurology (F.B., R.W.), Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada; Hunter Genetics Unit, Waratah, Australia (A.R.); Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, United Kingdom (N.F., D.H.); KBO-Kinderzentrum München, Munich, Germany (M.S.); Division of Neurology, Epilepsy Neurogenetics Initiative, Childrens Hospital of Philadelphia (J.B., K.L.H., I.H., X.R.O-G, H.D.); Perelman School of Medicine, Philadelphia, PA (J.B.); PURA Syndrome Foundation, Greensborough, Australia (I.H., M.A., D.S.); PURA Syndrome Foundation, Kansas City, MO (I.H., D.S.).
出版信息
Neurol Genet. 2021 Nov 15;7(6):e613. doi: 10.1212/NXG.0000000000000613. eCollection 2021 Dec.
BACKGROUND AND OBJECTIVES
Purine-rich element-binding protein A () gene encodes Pur-α, a conserved protein essential for normal postnatal brain development. Recently, a syndrome characterized by intellectual disability, hypotonia, epilepsy, and dysmorphic features was suggested. The aim of this study was to define and expand the phenotypic spectrum of syndrome by collecting data, including EEG, from a large cohort of affected patients.
METHODS
Data on unpublished and published cases were collected through the Syndrome Foundation and the literature. Data on clinical, genetic, neuroimaging, and neurophysiologic features were obtained.
RESULTS
A cohort of 142 patients was included. Characteristics of the syndrome included neonatal hypotonia, feeding difficulties, and respiratory distress. Sixty percent of the patients developed epilepsy with myoclonic, generalized tonic-clonic, focal seizures, and/or epileptic spasms. EEG showed generalized, multifocal, or focal epileptic abnormalities. Lennox-Gastaut was the most common epilepsy syndrome. Drug refractoriness was common: 33.3% achieved seizure freedom. We found 97 pathogenic variants in without any clear genotype-phenotype associations.
DISCUSSION
The syndrome presents with a developmental and epileptic encephalopathy with characteristics recognizable from neonatal age, which should prompt genetic screening. Sixty percent have drug-resistant epilepsy with focal or generalized seizures. We collected more than 90 pathogenic variants without observing overt genotype-phenotype associations.
背景与目的
富含嘌呤元件结合蛋白A（PurA）基因编码Pur-α，这是一种对出生后脑正常发育至关重要的保守蛋白。最近，有人提出了一种以智力障碍、肌张力减退、癫痫和畸形特征为特点的综合征。本研究的目的是通过收集大量受影响患者的数据（包括脑电图数据）来定义和扩展PurA综合征的表型谱。
方法
通过PurA综合征基金会和文献收集未发表及已发表病例的数据。获取临床、遗传、神经影像学和神经生理学特征的数据。
结果
纳入了142例患者的队列。PurA综合征的特征包括新生儿肌张力减退、喂养困难和呼吸窘迫。60%的患者出现癫痫，发作类型包括肌阵挛、全身强直阵挛、局灶性发作和/或癫痫痉挛。脑电图显示广泛性、多灶性或局灶性癫痫异常。Lennox-Gastaut综合征是最常见的癫痫综合征。药物难治性很常见：33.3%的患者实现了无癫痫发作。我们在PurA中发现了97个致病变异，未发现任何明确的基因型-表型关联。
讨论
PurA综合征表现为一种发育性和癫痫性脑病，其特征从新生儿期即可识别，这应促使进行基因筛查。60%的患者患有耐药性癫痫，发作类型为局灶性或全身性发作。我们收集了90多个致病变异，未观察到明显的基因型-表型关联。
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