Rapid diagnosis of KCNQ2 associated early infantile epileptic encephalopathy improved outcome

Dillon Y Chen., Shimul Chowdhury, Lauge Farnaes, Jennifer R. Friedman, Jose Honold, David P. Dimmock and Jeffrey J. Gold.  Rapid diagnosis of KCNQ2 associated early infantile epileptic encephalopathy improved outcome.  Pediatric Neurology, in press.

Early infantile epileptic encephalopathies (EIEEs) are a group of disorders with seizures presenting early in life. EIEE is associated with significant mortality and morbidity. Approximately 50 percent of the affected patients die in infancy and those who survive develop therapy-resistant epilepsy and significant developmental delays.  1 Structural brain lesions, metabolic disorders and genetic mutations, including KCNQ2, have been linked to EIEE.  Here, we report two neonates with EIEE due to KCNQ2 mutations, one with a novel mutation diagnosed through the rapid genomic sequencing program at Rady Children's Institute for Genomic Medicine (RCIGM) and one diagnosed classically, and demonstrate how rapid diagnosis positively impacted care...

Patient 1 and 2 presented shortly after birth for seizures. Initial evaluations were unrevealing. Video EEG was consistent with EIEE. In both patients, seizures were controlled by combination of phenobarbital, levetiracetam, topiramate and/or fosphenytoin. Fosphenytoin was tried for patient 1 but not continued due to difficulty achieving therapeutic levels. Their clinical course was complicated by the sedating effects of the AEDs, reemergence of seizure activity upon attempt to wean AED, and difficulty with oral feeding. For patient 1, a commercial genetic epilepsy panel was sent at Day of Life (DOL) 21, after other diagnostic workups did not reveal an etiology. The results returned seven weeks later, after the patient had been discharged on phenobarbital, levetiracetam and topiramate, and showed a heterozygous pathogenic missense mutation in the KCNQ2 gene (c.811C>T p.Ala294Val).  For patient 2, the establishment of RCIGM allowed for rapid sequencing not available to patient 1. By the RCIGM nomination process at the time, RCIGM enrolled neonates, with parental consent, at the Rady Children's Hospital who were thought by the treating team to have a condition potentially attributable to a genetic disorder. Thus, patient 2 and parents underwent RCIGM rapid whole genome sequencing at patient's DOL 2, and a de novo missense KCNQ2 variant (c.875T>C p.Leu292Pro) was reported at DOL 6. This missense variant had not been previously characterized but was deemed pathogenic based on the American College of Medical Genetics variant classification criteria.  Per the RCIGM protocol, a commercial epilepsy panel was also sent and confirmed the pathogenic variant. Carbamazepine was added given previous reports on sodium-channel-targeting AEDs and their improved efficacy on KCNQ2 associated EIEE.  6  Phenobarbital and topiramate were successfully weaned. Patient 2 was discharged on carbamazepine and levetiracetam at DOL 19. In contrast, patient 1 was discharged at DOL 60 due to difficulty balancing seizure control with sedation and feeding. Patient 2’s significantly shorter hospital stay resulted in an 11-fold less hospital-related cost (8.6% of patient 1). At the 9-month clinic visit, patient 2 was meeting developmental milestones and remained seizure-free with carbamazepine and levetiracetam therapy. Unfortunately, patient 1 relocated after discharge and no follow-up information was available.

EIEE is among the most severe epileptic syndromes. Clinical studies on patients with KCNQ2 -associated epileptic encephalopathy have demonstrated improved seizure control with AEDs that target sodium channels . Here, we report a new EIEE-related KCNQ2 variant. We demonstrate that a rapid genetic diagnosis of the KCNQ2 mutation allowed for a targeted medication regimen that rapidly controlled the seizures, shortened the hospital stay, improved prognosis, and improved health-care system efficiency.