Reversible Epileptic Encephalopathy upon Uridine Treatment in Patients with CAD Mutations

Objective: Unexplained developmental disability and epilepsy pose a major socioeconomic burden. Exome sequencing is revolutionizing diagnosis, however, does not often translate into effective treatment. Notable exceptions include certain inborn errors of metabolism amenable to dietary intervention. CAD codes a multifunctional enzyme in de novo pyrimidine biosynthesis. Alternatively, pyrimidines can be recycled from uridine.

Methods: In the context of a clinical exome sequencing study of 700 consecutive patients, 70 pediatric patients with global developmental delay and epilepsy were investigated.

Results: Exome sequencing in three families identified bi-allelic CAD mutations in four patients with developmental disability, epileptic encephalopathy, and anemia with anisopoikilocytosis. Supplementation of two affected children with oral uridine led to immediate cessation of seizures in both. A 4-year-old girl, previously in a minimally conscious state, began to communicate and walk with assistance after 9 weeks of treatment. A 3-year-old girl likewise showed developmental progress. Blood smears normalized, and anemia resolved. No side effects have been reported during follow-up of 12 and 10 months, respectively. Two untreated children died aged 4 and 5 years after a neurodegenerative disease.

Conclusion: We establish CAD as a gene confidently implicated in this neurometabolic disorder, characterized by co-occurrence of developmental disability, dyserythropoietic anemia 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 (genetic) newborn screening.