Abstracts

Rationale: Whole exome sequencing (WES) can be a powerful diagnostic tool when more targeted testing strategies have resulted in negative or inconclusive results. Here we report a sib-pair affected by a severe epileptic encephalopathy whose epilepsy was managed unsuccessfully for many years without knowledge of an underlying genetic etiology. Through WES, it was determined that the underlying cause of the phenotype in these children is a recently identified metabolic disorder that includes epilepsy as a primary feature. Methods: The affected siblings have strikingly similar presentations including intractable epilepsy, intellectual disability, and developmental regression. The family pedigree can be seen in fig. A. The siblings had negative metabolic testing, and prior genetic testing (epilepsy gene panel and chromosomal microarray) was non-diagnostic. The affected boy is 13 years old and was reported to have met all developmental milestones prior to onset of generalized tonic-clonic seizures at 2 years of age. He began having atonic seizures at 3 years of age which were controlled with the ketogenic diet. Due to subsequent febrile status epilepticus he was put into a pharmacologically induced coma for five months, associated with a total loss of acquired skills. He also underwent focal resection for attempted epilepsy treatment. MRI shows global atrophy of the cortex and cerebellum. The affected girl is 5 years old with generalized tonic-clonic seizure onset at 3 ½ years of age. Prior to seizure onset her motor milestones were slightly delayed and she had regression of acquired skills after seizure onset. MRI was normal initially but then showed progressive cerebellar atrophy. Results: WES identified compound heterozygous variants in the CAD gene in both siblings. A recent publication by Koch et al. reported patients with variants in CAD who had a clinical presentation similar to the siblings we report on here. This publication reported that the patients responded favorably to uridine supplementation, including seizure freedom, marked improvement in cognition and progress in acquisition of motor milestones. It is hypothesized that uridine supplementation bypasses CAD in the pyrimidine biosynthesis pathway (Fig B.) Conclusions: This case highlights the effectiveness of WES when genetic testing has been non-diagnostic. Our patients were treated unsuccessfully for an extended period of time in an attempt to bring their seizures under control, including intracranial surgery for the affected male. While this strategy was appropriate at the time, had the genetic diagnosis been possible earlier, alternative strategies might have been pursued. Through WES, a diagnosis was made for patients whose phenotype until that point was of unknown etiology, and precision treatment can now be pursued. Our sibling pair will begin uridine supplementation, as a result of this finding.  In addition, our group is creating zebrafish models to study the effect of loss of function of CAD. Funding: N/A