CAD mutations and uridine-responsive epileptic encephalopathy

Johannes Koch*, Johannes A. Mayr, Bader Alhaddad, Christian Rauscher, Jorgen Bierau, Reka Kovacs-Nagy, Karlien L. M. Coene, Ingrid Bader, Monika Holzhacker, Holger Prokisch, Hanka Venselaar, Ron A. Wevers, Felix Distelmaier, Tilman Polster, Steffen Leiz, Cornelia Betzler, Tim M. Strom, Wolfgang Sperl, Thomas Meitinger, Saskia B. WortmannTobias B. Haack

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

63 Citations (Web of Science)

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.

Original languageEnglish
Pages (from-to)279-286
Number of pages8
JournalBrain
Volume140
DOIs
Publication statusPublished - Feb 2017

Keywords

  • global developmental delay
  • epilepsy
  • anaemia
  • anisopoikilocytosis
  • uridine
  • OROTIC ACIDURIA
  • INBORN-ERRORS
  • METABOLISM

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