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Koch, J.* ; Mayr, J.A.* ; Alhaddad, B.* ; Rauscher, C.* ; Bierau, J.* ; Kovács-Nagy, R.* ; Coene, K.L.M.* ; Bader, I.* ; Holzhacker, M.* ; Prokisch, H. ; Venselaar, H.* ; Wevers, R.A.* ; Distelmaier, F.* ; Polster, T.* ; Leiz, S.* ; Betzler, C.* ; Strom, T.M. ; Sperl, W.* ; Meitinger, T. ; Wortmann, S.B. ; Haack, T.B.

CAD mutations and uridine-responsive epileptic encephalopathy.

Brain 140, 279-286 (2016)
Publ. Version/Full Text Research data DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords anaemia; anisopoikilocytosis; epilepsy; global developmental delay; uridine; Orotic Aciduria; Inborn-errors; Metabolism
ISSN (print) / ISBN 0006-8950
e-ISSN 1460-2156
Journal Brain: A Journal of Neurology
Quellenangaben Volume: 140, Issue: 2, Pages: 279-286 Article Number: , Supplement: ,
Publisher Oxford University Press
Publishing Place Oxford
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)