title: CAD mutations and uridine-responsive epileptic encephalopathy.
abstract: Unexplained global developmental delay and epilepsy in childhood pose a major socioeconomic burden. Progress in defining the molecular bases does not often translate into effective treatment. Notable exceptions include certain inborn errors of metabolism amenable to dietary intervention. CAD encodes a multifunctional enzyme involved in de novo pyrimidine biosynthesis. Alternatively, pyrimidines can be recycled from uridine. Exome sequencing in three families identified biallelic CAD mutations in four children with global developmental delay, epileptic encephalopathy, and anaemia with anisopoikilocytosis. Two died aged 4 and 5 years after a neurodegenerative disease course. Supplementation of the two surviving children with oral uridine led to immediate cessation of seizures in both. A 4-year-old female, previously in a minimally conscious state, began to communicate and walk with assistance after 9 weeks of treatment. A 3-year-old female likewise showed developmental progress. Blood smears normalized and anaemia resolved. We establish CAD as a gene confidently implicated in this neurometabolic disorder, characterized by co-occurrence of global developmental delay, dyserythropoietic anaemia and seizures. While the natural disease course can be lethal in early childhood, our findings support the efficacy of uridine supplementation, rendering CAD deficiency a treatable neurometabolic disorder and therefore a potential condition for future (genetic) newborn screening.
authors.affiliation: Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Koch
authors.affiliation: Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria j.koch@salk.at tobias.haack@med.uni-tuebingen.de.
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Mayr
authors.affiliation: Institute of Human Genetics, Technische Universität München, Munich, Germany.
authors.forename: Bader
authors.initials: B
authors.lastname: Alhaddad
authors.affiliation: Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Rauscher
authors.affiliation: Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Jörgen
authors.initials: J
authors.lastname: Bierau
authors.affiliation: Institute of Human Genetics, Technische Universität München, Munich, Germany.
authors.forename: Reka
authors.initials: R
authors.lastname: Kovacs-Nagy
authors.affiliation: Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboudumc Nijmegen, The Netherlands.|Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboudumc Nijmegen, The Netherlands.|Clinical Laboratory, Catharina Hospital Eindhoven, Eindhoven, The Netherlands.
authors.forename: Karlien L M
authors.initials: KL
authors.lastname: Coene
authors.affiliation: Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Bader
authors.affiliation: Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria.
authors.forename: Monika
authors.initials: M
authors.lastname: Holzhacker
authors.affiliation: Institute of Human Genetics, Technische Universität München, Munich, Germany.|Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.affiliation: Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboudumc Nijmegen, The Netherlands.
authors.forename: Hanka
authors.initials: H
authors.lastname: Venselaar
authors.affiliation: Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboudumc Nijmegen, The Netherlands.
authors.forename: Ron A
authors.initials: RA
authors.lastname: Wevers
authors.affiliation: Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Distelmaier
authors.affiliation: Department of Paediatric Epileptology, Mara Hospital, Bethel Epilepsy Center, Bielefeld, Germany.
authors.forename: Tilman
authors.initials: T
authors.lastname: Polster
authors.affiliation: Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria.|Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria.
authors.forename: Steffen
authors.initials: S
authors.lastname: Leiz
authors.affiliation: Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Betzler
authors.affiliation: Institute of Human Genetics, Technische Universität München, Munich, Germany.|Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.affiliation: Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sperl
authors.affiliation: Institute of Human Genetics, Technische Universität München, Munich, Germany.|Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.|Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria.|Institute of Human Genetics, Technische Universität München, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.affiliation: Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria.|Institute of Human Genetics, Technische Universität München, Munich, Germany.|Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Saskia B
authors.initials: SB
authors.lastname: Wortmann
authors.affiliation: Institute of Human Genetics, Technische Universität München, Munich, Germany j.koch@salk.at tobias.haack@med.uni-tuebingen.de.|Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.|Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Haack
mesh_terms: D000740:Anemia / Q000150:complications / Q000188:drug therapy / Q000235:genetics; D001221:Aspartate Carbamoyltransferase / Q000235:genetics*; D001921:Brain / Q000000981:diagnostic imaging; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing) / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D002658:Developmental Disabilities / Q000150:complications / Q000235:genetics; D004080:Dihydroorotase / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation / Q000235:genetics*; D013036:Spasms, Infantile / Q000150:complications / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics*; D014529:Uridine / Q000627:therapeutic use*
chemical_list: C033626:CAD trifunctional enzyme; D001221:Aspartate Carbamoyltransferase; D004080:Dihydroorotase; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing); D014529:Uridine
keywords: anaemia; anisopoikilocytosis; epilepsy; global developmental delay; uridine