CAD mutations and uridine-responsive epileptic encephalopathy

Brain. 2017 Feb;140(2):279-286. doi: 10.1093/brain/aww300.

Johannes Koch ¹, Johannes A Mayr ², Bader Alhaddad ³, Christian Rauscher ¹, Jörgen Bierau ⁴, Reka Kovacs-Nagy ³, Karlien L M Coene ⁵ ⁶ ⁷, Ingrid Bader ¹, Monika Holzhacker ¹, Holger Prokisch ³ ⁸, Hanka Venselaar ⁶, Ron A Wevers ⁵, Felix Distelmaier ⁹, Tilman Polster ¹⁰, Steffen Leiz ¹ ¹, Cornelia Betzler ¹, Tim M Strom ³ ⁸, Wolfgang Sperl ¹, Thomas Meitinger ³ ⁸ ¹ ³, Saskia B Wortmann ¹ ³ ⁸, Tobias B Haack ¹¹ ⁸ ⁴

Affiliations

1 Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria.
2 Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria j.koch@salk.at tobias.haack@med.uni-tuebingen.de.
3 Institute of Human Genetics, Technische Universität München, Munich, Germany.
4 Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands.
5 Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboudumc Nijmegen, The Netherlands.
6 Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboudumc Nijmegen, The Netherlands.
7 Clinical Laboratory, Catharina Hospital Eindhoven, Eindhoven, The Netherlands.
8 Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
9 Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
10 Department of Paediatric Epileptology, Mara Hospital, Bethel Epilepsy Center, Bielefeld, Germany.
11 Institute of Human Genetics, Technische Universität München, Munich, Germany j.koch@salk.at tobias.haack@med.uni-tuebingen.de.

PMID: 28007989 DOI: 10.1093/brain/aww300

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.

Keywords

anaemia; anisopoikilocytosis; epilepsy; global developmental delay; uridine.

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