Uridine-responsive epileptic encephalopathy: precision treatment across the age spectrum

Objectives: Uridine-responsive epileptic encephalopathy or CAD deficiency is a disorder of de novo pyrimidine synthesis due to biallelic pathogenic variants in CAD, associated with developmental delay, movement disorder, epilepsy and dyserythropoietic anaemia. We describe two patients, who both showed a significant clinical response to uridine. Methods: Case note review Results: Patient 1, aged 10 months, presented with refractory status epilepticus at 3 weeks of age. MRI showed microcephaly, simplified gyral pattern and periventricular cysts. Trio whole exome sequencing (WGS) revealed compound heterozygous variants in CAD, with one novel variant and one previously reported. Treatment with uridine monophosphate (UMP) within 2 days of genetic diagnosis resulted in seizure cessation. Patient 2, aged 14 years, presented with learning difficulties, language impairment, focal epilepsy onset at 2.5 years (becoming pharmacoresistant over time), progressive cerebellar ataxia (from age 9 years) with loss of ambulant walking and dysarthria. Blood films revealed anisopoikilocytosis, serial neuroimaging revealed progressive cerebellar atrophy and a new pontine lesion associated with diffusion restriction at age 9 years. Trio WGS at 14 years of age revealed biallelic novel variants in CAD. After 3.5 months on UMP supplementation treatment, he became independently ambulant, seizure control improved significantly, and red cell distribution width normalised. Conclusion: CAD deficiency represents a treatable progressive neurological disorder. Requesting FBC / blood film in patients with drug resistant epilepsy associated with co-morbidities is key to diagnosis. Earlier genomic testing in infancy / early childhood epilepsy would permit earlier targeted treatment and improved outcome.
Keywords: Epilepsy, Neurogenetics, Neurometabolic, Development, metabolic