Journal article
Expanding the clinical and genetic spectrum of CAD deficiency: an epileptic encephalopathy treatable with uridine supplementation.
- Rymen D Metabolic Center, University Hospitals Leuven, Leuven, Belgium.
- Lindhout M Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands.
- Spanou M 3rd Paediatric Department, Attikon University Hospital, Athens, Greece.
- Ashrafzadeh F Department of Pediatric Neurology, Mashhad University of Medical Sciences, Mashhad, Iran.
- Benkel I Klinik für Kinderneurologie und Kinderneurologisches Zentrum, EEG, Sana Kliniken Düsseldorf GmbH, Düsseldorf, Germany.
- Betzler C Clinic for Neuropediatrics and Neurological Rehabilitation, Epilepsy Center for Children and Adolescents, Schön Klinik Vogtareuth, Vogtareuth, Germany.
- Coubes C Département de Génétique Médicale, Maladies Rares et Médecine Personnalisée, CHU, Montpellier, France.
- Hartmann H Clinic for Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.
- Kaplan JD Nemours A.I. DuPont Hospital for Children, Department of Pediatrics, Division of Medical Genetics, Wilmington, Delaware, DE, USA.
- Ballhausen D Pediatric unit for metabolic diseases, Woman-Mother-Child Department, University Hospital Lausanne, Lausanne, Switzerland.
- Koch J University Children's Hospital, Paracelsus Medical University (PMU), Salzburg, Austria.
- Lotte J Clinic for Neuropediatrics and Neurological Rehabilitation, Epilepsy Center for Children and Adolescents, Schön Klinik Vogtareuth, Vogtareuth, Germany.
- Mohammadi MH Department of Pediatrics, Zabol University of Medical Sciences, Zabol, Iran.
- Rohrbach M Division of Metabolism and Children's Research Centre, University Children's Hospital, 8032, Zürich, Switzerland.
- Dinopoulos A 3rd Paediatric Department, Attikon University Hospital, Athens, Greece.
- Wermuth M Department of Pediatrics, Klinikum Links der Weser, Bremen, Germany.
- Willis D Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.
- Brugger K University Children's Hospital, Paracelsus Medical University (PMU), Salzburg, Austria.
- Wevers RA Department Laboratory Medicine, Translational Metabolic Laboratory, Radboudumc, Nijmegen, The Netherlands.
- Boltshauser E Department of Pediatric Neurology, Children's University Hospital, Zürich, Switzerland.
- Bierau J Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands.
- Mayr JA University Children's Hospital, Paracelsus Medical University (PMU), Salzburg, Austria.
- Wortmann SB University Children's Hospital, Paracelsus Medical University (PMU), Salzburg, Austria. s.wortmann@salk.at.
- 2020-08-22
Published in:
- Genetics in medicine : official journal of the American College of Medical Genetics. - 2020
English
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.
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.
- Language
-
- English
- Open access status
- closed
- Identifiers
-
- DOI 10.1038/s41436-020-0933-z
- PMID 32820246
- Persistent URL
- https://sonar.ch/global/documents/145791
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