Daisy Rymen1, Martijn Lindhout2, Maria Spanou3, Farah Ashrafzadeh4, Ira Benkel5, Cornelia Betzler6,7, Christine Coubes8, Hans Hartmann9, Julie D Kaplan10,11, Diana Ballhausen12, Johannes Koch13, Jan Lotte6, Mohammad Hasan Mohammadi14, Marianne Rohrbach15, Argirios Dinopoulos3, Marieke Wermuth16, Daniel Willis17, Karin Brugger13, Ron A Wevers18, Eugen Boltshauser19, Jörgen Bierau2, Johannes A Mayr13, Saskia B Wortmann20,21. 1. Metabolic Center, University Hospitals Leuven, Leuven, Belgium. 2. Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands. 3. 3rd Paediatric Department, Attikon University Hospital, Athens, Greece. 4. Department of Pediatric Neurology, Mashhad University of Medical Sciences, Mashhad, Iran. 5. Klinik für Kinderneurologie und Kinderneurologisches Zentrum, EEG, Sana Kliniken Düsseldorf GmbH, Düsseldorf, Germany. 6. Clinic for Neuropediatrics and Neurological Rehabilitation, Epilepsy Center for Children and Adolescents, Schön Klinik Vogtareuth, Vogtareuth, Germany. 7. Institute for Transition, Rehabilitation and Palliation, Paracelsus Private Medical University of Salzburg, Salzburg, Austria. 8. Département de Génétique Médicale, Maladies Rares et Médecine Personnalisée, CHU, Montpellier, France. 9. Clinic for Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany. 10. Nemours A.I. DuPont Hospital for Children, Department of Pediatrics, Division of Medical Genetics, Wilmington, Delaware, DE, USA. 11. Department of Pediatrics, Division of Medical Genetics, University of Mississippi Medical Center, Jackson, MS, USA. 12. Pediatric unit for metabolic diseases, Woman-Mother-Child Department, University Hospital Lausanne, Lausanne, Switzerland. 13. University Children's Hospital, Paracelsus Medical University (PMU), Salzburg, Austria. 14. Department of Pediatrics, Zabol University of Medical Sciences, Zabol, Iran. 15. Division of Metabolism and Children's Research Centre, University Children's Hospital, 8032, Zürich, Switzerland. 16. Department of Pediatrics, Klinikum Links der Weser, Bremen, Germany. 17. Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA. 18. Department Laboratory Medicine, Translational Metabolic Laboratory, Radboudumc, Nijmegen, The Netherlands. 19. Department of Pediatric Neurology, Children's University Hospital, Zürich, Switzerland. 20. University Children's Hospital, Paracelsus Medical University (PMU), Salzburg, Austria. s.wortmann@salk.at. 21. Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Amalia Children's Hospital, Radboudumc, Nijmegen, The Netherlands. s.wortmann@salk.at.
Abstract
PURPOSE: Biallelic CAD variants underlie CAD deficiency (or early infantile epileptic encephalopathy-50, [EIEE-50]), an error of pyrimidine de novo biosynthesis amenable to treatment via the uridine salvage pathway. We further define the genotype and phenotype with a focus on treatment. METHODS: Retrospective case series of 20 patients. RESULTS: Our study confirms CAD deficiency as a progressive EIEE with recurrent status epilepticus, loss of skills, and dyserythropoietic anemia. We further refine the phenotype by reporting a movement disorder as a frequent feature, and add that milder courses with isolated developmental delay/intellectual disability can occur as well as onset with neonatal seizures. With no biomarker available, the diagnosis relies on genetic testing and functional validation in patient-derived fibroblasts. Underlying pathogenic variants are often rated as variants of unknown significance, which could lead to underrecognition of this treatable disorder. Supplementation with uridine, uridine monophosphate, or uridine triacetate in ten patients was safe and led to significant clinical improvement in most patients. CONCLUSION: We advise a trial with uridine (monophosphate) in all patients with developmental delay/intellectual disability, epilepsy, and anemia; all patients with status epilepticus; and all patients with neonatal seizures until (genetically) proven otherwise or proven unsuccessful after 6 months. CAD deficiency might represent a condition for genetic newborn screening.
PURPOSE: Biallelic CAD variants underlie CAD deficiency (or early infantile epileptic encephalopathy-50, [EIEE-50]), an error of pyrimidine de novo biosynthesis amenable to treatment via the uridine salvage pathway. We further define the genotype and phenotype with a focus on treatment. METHODS: Retrospective case series of 20 patients. RESULTS: Our study confirms CAD deficiency as a progressive EIEE with recurrent status epilepticus, loss of skills, and dyserythropoietic anemia. We further refine the phenotype by reporting a movement disorder as a frequent feature, and add that milder courses with isolated developmental delay/intellectual disability can occur as well as onset with neonatal seizures. With no biomarker available, the diagnosis relies on genetic testing and functional validation in patient-derived fibroblasts. Underlying pathogenic variants are often rated as variants of unknown significance, which could lead to underrecognition of this treatable disorder. Supplementation with uridine, uridine monophosphate, or uridine triacetate in ten patients was safe and led to significant clinical improvement in most patients. CONCLUSION: We advise a trial with uridine (monophosphate) in all patients with developmental delay/intellectual disability, epilepsy, and anemia; all patients with status epilepticus; and all patients with neonatal seizures until (genetically) proven otherwise or proven unsuccessful after 6 months. CAD deficiency might represent a condition for genetic newborn screening.
Entities:
Keywords:
EIEE; anemia; developmental delay; early infantile epileptic encephalopathy-50; epilepsy
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