Expanding the clinical and genetic spectrum of CAD deficiency: an epileptic encephalopathy treatable with uridine supplementation

Daisy Rymen, Martijn Lindhout, Maria Spanou, Farah Ashrafzadeh, Ira Benkel, Cornelia Betzler, Christine Coubes, Hans Hartmann, Julie D. Kaplan, Diana Ballhausen, Johannes Koch, Jan Lotte, Mohammad Hasan Mohammadi, Marianne Rohrbach, Argirios Dinopoulos, Marieke Wermuth, Daniel Willis, Karin Brugger, Ron A. Wevers, Eugen BoltshauserJorgen Bierau, Johannes A. Mayr, Saskia B. Wortmann*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

12 Citations (Web of Science)


Purpose BiallelicCADvariants 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.

Original languageEnglish
Pages (from-to)1589-1597
Number of pages9
JournalGenetics in Medicine
Issue number10
Publication statusPublished - Oct 2020


  • anemia
  • epilepsy
  • developmental delay
  • early infantile epileptic encephalopathy-50
  • EIEE

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