Abstracts

Rationale: Most epilepsies are diagnosed after onset of seizures. Screening newborns for monogenic epilepsies might allow early diagnosis and treatment, with the potential to improve outcomes and avoid prolonged diagnostic uncertainty. Because effective therapies are available for some genetic epilepsies, they may be excellent targets for screening, if an appropriate analyte can be identified. Our goal was to prioritize monogenic epilepsy disorders for newborn screening, based on expert opinion and literature review.  Methods: We interviewed a sample of pediatric neurologists and epileptologists. We asked which monogenic epilepsies they believed would be most appropriate for newborn screening, considering each epilepsy’s birth prevalence and the efficacy of available treatments. Next, we used their interview responses to design a survey that asked respondents to rank epilepsies according to their suitability for newborn screening. The survey was disseminated electronically to members of the pediatric epilepsy research consortium. Finally, we conducted a literature review on the top three epilepsies prioritized in the survey to determine how well they fit established criteria for newborn screening. These criteria were (1) the natural history of the disease is well understood,  (2) the disease is sufficiently prevalent that screening is worthwhile, (3) there is a latent or early symptomatic phase during which patients with the disease can be identified, and (4) there are treatments that improve long-term outcomes when given before onset of symptoms.   Results: We interviewed 17 pediatric neurologists who identified 16 specific epilepsy disorders. We received 25 responses to the survey from 86 contacted individuals (response rate 29%). Survey respondents prioritized pyridoxine dependent epilepsy (PDE), Glut1 deficiency syndrome (Glut1-DS), and tuberous sclerosis complex (TSC), as disorders most suitable for newborn screening. Based on our literature review, PDE best meets the established criteria for newborn screening. The natural history of PDE is well understood. Two analytes, α-aminoadipic semialdehyde and piperideine-6 carboxylate, are available to identify affected children during the latent phase of the disease, prior to onset of seizures. Lastly, there is evidence that early treatment of PDE with, triple therapy of pyridoxine, lysine restricted diet, and arginine, improves long-term outcomes. Glut1-DS and TSC were also prioritized highly by the respondents. The natural history of both of these diseases is well understood and both have a latent period during which early diagnosis and treatment may improve outcomes. Individuals with Glut1-DS improve with the ketogenic diet, and persons with TSC may benefit from use of mTOR inhibitors and vigabatrin. At the present time, analytes suitable for newborn screening are not available for either disease. The genetic loci for these conditions are well-known however, so genetic approaches to newborn screening may be beneficial.   Conclusions: Pyridoxine dependent epilepsy appears to meet established criteria for newborn screening. Glut1 deficiency syndrome and tuberous sclerosis are also candidates but fulfill fewer criteria. Effective newborn screening for monogenic epilepsies would provide an opportunity for implementation of disease modifying therapy that may lead to improved outcomes. Newborn screening for these epilepsies could also prevent unnecessary treatment with ineffective anticonvulsants and avoid prolonged diagnostic uncertainty. These findings may help prioritize future research into newborn screening methods to identify monogenic epilepsy disorders.  Funding: N/A.