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1. CUX1-related neurodevelopmental disorder: Deep insights into phenotype-genotype spectrum and underlying pathology

Author

Henry Oppermann, Elia Marcos-Grañeda, Linnea Weiss, Christina Gurnett, Anne Marie Jelsig, Susanne Vineke, Bertrand Isidor, Sandra Mercier, Kari Magnussen, Pia Zacher, Mona Hashim, Alistair Pagnamenta, Simone Race, Siddharth Srivast, Zoë Frazier, Robert Maiwald, Matthias Pergande, Donatella Milani, Martina Rinelli, Jonathan Levy, Ilona Krey, Paolo Fontana, Fortunato Lonardo, Stephanie Riley, Jasmine Kretzer, Julia Rankin, Linda Reis, Elena Semina, Miriam Reuter, Stephen Scherer, Maria Iascone, Denisa Weis, Christina Fagerberg, Charlotte Brasch-Andersen, Lars Hansen, Alma Kuechler, Nathan Noble, Alice Gardham, Jessica Tenney, Geetanjali Rathore, Stefanie Beck-Woedl, Tobias Haack, Despina Pavlidou, Isis Atallah, Julia Vodopiutz, Andreas Janecke, Johannes Lemke, Rami Abou Jamra, Marta Nieto, Zeynep Tümer, and Konrad Platzer

Abstract

Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1+/− mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished cases). A Cux1+/− mouse model was used to analyze CUX1 expression in the brain and evaluate susceptibility to epilepsy. We describe 34 patients with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development, and intellectual disability. In Cux1+/− mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1+/− brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was also reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some patients, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. Furthermore, the balance of CUX1 isoform expression in the brain during development appears to be important for this favorable clinical course.

Published
2022
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3. PURA- Related Developmental and Epileptic Encephalopathy: Phenotypic and Genotypic Spectrum

Author

Dario Pruna, Theresa Grebe, Felippe Borlot, Michael J. Esser, Juan Pablo Appendino, Katherine L. Helbig, Elisa Ballardini, Casey Brew, Anne-Sophie Denommé-Pichon, Anne Ronan, Laurie A. Demmer, Usha Kini, Marta Somorai, Julie Vogt, Sébastien Moutton, Raffaella Faggioli, Julien Van-Gils, Davide Ognibene, Sara Olivotto, Sabine Grønborg, David Coman, David P. Bick, Guido Rubboli, Orrin Devinsky, Atiya S. Khan, Robyn Whitney, Christine Coubes, Caroline Nava, Karen Keough, SakkuBai R. Naidu, Lucio Giordano, Davide Colavito, Dominic Spadafore, Arnaud Isapof, Walla Al-Hertani, Antonio Vitobello, Andrea V. Andrade, Gaetano Cantalupo, Sandra Whalen, Boudewijn Gunning, Shanawaz Hussain, David Hunt, Nathan Noble, Bertrand Isidor, Beatriz Gamboni, Katrine M Johannesen, Julien Buratti, Stephanie Moortgat, Ida Cursio, Agnese Suppiej, Delphine Héron, Lía Mayorga, William Benko, Rahul Raman Singh, Cyril Mignot, Sotirios Keros, Aurore Garde, Nicola Foulds, Claudia A. L. Ruivenkamp, Elena Gardella, Barbara Scelsa, Fernanda Góes, Laurence Faivre, Richard J. Leventer, Ashley Collier, Farha Tokarz, Thomas Courtin, Klaas J. Wierenga, Xilma R. Ortiz-Gonzalez, Frédéric Tran-Mau-Them, Alejandra Mampel, Lynn Greenhalgh, Ashlea Franques, Amélie Piton, Felicia Varsalone, Marjolaine Willems, Alessandro Orsini, Diana Rodriguez, Clothilde Ormieres, Helen Stewart, Boris Keren, Austin Larson, Cathrine E. Gjerulfsen, Julie S. Cohen, Margot R.F. Reijnders, Mel Anderson, Shailesh Asakar, Rikke S. Møller, Alice Bonuccelli, Alexandra Afenjar, Claudio Graziano, Elaine Wirrell, Simona Damioli, Sangeetha Yoganathan, Devorah Segal, Ingo Helbig, Mindy H. Li, Rob P.W. Rouhl, Sarah Hicks, Allan Bayat, Holly Dubbs, Stefania Bigoni, Kelly Ratke, John Brandsema, Eva H. Brilstra, univOAK, Archive ouverte, The Danish Epilepsy Centre Filadelfia [Dianalund, Denmark], University of Southern Denmark (SDU), Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de référence Déficiences Intellectuelles de Causes Rares [CHU Pitié-Salpétrière], 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), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], 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), Mayo Clinic [Jacksonville], Département de pédiatrie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), 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, Hôpital d'Enfants [CHU Dijon], Hôpital du Bocage, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), 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, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Department of Pediatrics [Univ California San Diego] (UC San Diego), School of Medicine [Univ California San Diego] (UC San Diego), University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC)-University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC), and University of Colorado Anschutz [Aurora]

Subjects
Pediatrics, medicine.medical_specialty, Socio-culturale, [SDV.GEN] Life Sciences [q-bio]/Genetics, Electroencephalography, Epilepsy, Developmental and Epileptic Encephalopathy, Intellectual disability, medicine, Genetics (clinical), feeding difficulties, [SDV.GEN]Life Sciences [q-bio]/Genetics, medicine.diagnostic_test, business.industry, fungi, medicine.disease, Hypotonia, Epileptic spasms, Neonatal hypotonia, neonatal hypotonia, Epilepsy syndromes, Cohort, epilepsy, Neurology (clinical), medicine.symptom, business
Abstract

Background and ObjectivesPurine-rich element-binding protein A (PURA) gene encodes Pur-α, a conserved protein essential for normal postnatal brain development. Recently, a PURA 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 PURA syndrome by collecting data, including EEG, from a large cohort of affected patients.MethodsData on unpublished and published cases were collected through the PURA Syndrome Foundation and the literature. Data on clinical, genetic, neuroimaging, and neurophysiologic features were obtained.ResultsA cohort of 142 patients was included. Characteristics of the PURA 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 PURA without any clear genotype-phenotype associations.DiscussionThe PURA 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.

Published
2021
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5. Agreement between questions about behavior function, the motivation assessment scale, functional assessment interview, and brief functional analysis of children’s challenging behaviors

Author

Maria G. Valdovinos, Nathan Noble, Elizabeth Schieber, and Ashley Fee

Subjects
media_common.quotation_subject, Clinical settings, General Medicine, Assessment scale, Psychology, Function (engineering), Functional analysis (psychology), media_common, Developmental psychology
Abstract

Indirect and direct assessments are widely used to measure the function of challenging behaviors of children in clinical settings. The current study involved comparing results from indirect assessments in identifying the functions of challenging behaviors of 24 children, i.e., Questions About Behavi

Published
2016
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6. Functional Analysis of Phenotypic Behaviors of a 5-Year-Old Male with Novel 4q21 Microdeletion

Author

Ashley Fee, Maria G. Valdovinos, and Nathan Noble

Subjects
medicine.medical_specialty, Neurology, Aggression, Neuropsychology, Microdeletion syndrome, medicine.disease, Intervention (counseling), Intellectual disability, medicine, Medical genetics, medicine.symptom, Psychiatry, Psychology, Functional analysis (psychology), Clinical psychology
Abstract

The 4q21 microdeletion syndrome is a relatively newer syndrome that has been recently characterized by mild to severe intellectual disability, growth delay, and behavioral problems. The literature reports that aggression and self-injurious behavior have been identified as elements of the 4q21 microdeletion behavioral phenotype (Bonnet et al. in Journal of Medical Genetics, 47, 377–384, 2010; Strehle et al. in American Journal of Medical Genetics Part A, 158A, 2139–2151, 2012; Tsang et al. in American Journal of Medical Genetics Part A, 158A, 2606–2609, 2012). In this case report, functional assessment of aggression and self-injurious behavior of a 5-year-old male with 4q21 microdeletion syndrome was completed to determine the function of behavior and evaluate the effectiveness of behavioral intervention. The assessment result informed treatment subsequently produced a decrease in the occurrence of problem behaviors. This is one of the first functional assessments completed on behaviors associated with 4q21 microdeletion. Furthermore, this study exemplifies the utility of functional assessments in assessing and treating behaviors in those with known genetic conditions.

Published
2015
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7. 2q24 deletions: further characterization of clinical findings and their relation to the SCN cluster

Author

Marcia C. Willing, Shivanand R. Patil, Manjunath Nimmakayalu, Val C. Sheffield, V. Kim Horton, Peter L. Nagy, Oleg A. Shchelochkov, Nathan Noble, Sara Copeland, and Thomas H. Wassink

Subjects
Male, Microcephaly, Biology, Bioinformatics, Sodium Channels, SCN3A, Gene cluster, Genetics, medicine, Humans, Abnormalities, Multiple, Copy-number variation, Child, Genetics (clinical), Genetic Association Studies, In Situ Hybridization, Fluorescence, Comparative Genomic Hybridization, Infant, Newborn, Facies, Infant, medicine.disease, Hypotonia, Child, Preschool, Chromosomes, Human, Pair 2, Multigene Family, Female, medicine.symptom, Chromosome Deletion, Haploinsufficiency, Developmental regression, Comparative genomic hybridization
Abstract

As the resolution of molecular cytogenetic methods continues to improve, it has become increasingly possible to refine genotype-phenotype correlations based upon gene involvement. We report three new patients with nonrecurrent deletions involving subbands of 2q24. These patients were referred for evaluation of developmental delay, but were found to have unique, nonoverlapping clinical features. Patient 1 presented with infantile seizures, microcephaly, and brain anomalies, along with facial dysmorphism, growth retardation, neuromuscular scoliosis, and later with developmental regression. Array comparative genomic hybridization (aCGH) detected an 8 Mb interstitial deletion encompassing the neuronal sodium channel (SCN) gene cluster. Patient 2 presented with growth retardation, congenital heart defect, and hypotonia. Patient 3 presented with developmental delay and behavioral problems. Patients 2 and 3 had no history of seizures, microcephaly, or brain anomalies and were found to have deletions of 2q24, ∼8 Mb and

Published
2011

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