Newborn babies are at risk to have seizures. Common causes of neonatal seizures include perinatal hypoxia-ischemia, stroke, intracranial bleeding, CNS infection, and some metabolic disorders that can be diagnosed by blood or brain fluid (CSF) tests done in the hospital.1,2 In about 5-10 percent of babies with seizures, the seizures are the first sign of specific genetic changes that cause milder or more severe forms of epilepsy.3 These genetic epilepsies include benign familial neonatal seizures (BFNE, which is caused by variants in KCNQ2, and more rarely KCNQ3) and early infantile epileptic encephalopathy (EIEE). EIEE can result from pathogenic changes in many different genes, but when seizure onset is within the first days and weeks of life, the more common causes include KCNQ2 and SCN2A, genes encoding potassium and sodium channels, respectively.3-5
Some evidence suggests that babies with genetic epilepsy may benefit from specialized treatments that are already available. For example, recent studies suggest that sodium channel blockers may be helpful for seizure control in patients with loss-of-function variants in KCNQ2 and KCNQ3, and in gain-of-function variants in SCN2A and SCN8A.5,6 Moreover, newer treatments are being developed that hold promise but remain untested. However, in many centers it remains difficult to obtain hospital and/or insurance authorization for genetic testing of inpatient neonates.7 This can lead to delay in diagnosis. ERGENT is designed to test whether existing criteria can be used to prospectively identify babies with very high risk of genetic epilepsy early (within days of seizure onset). If successful, ERGENT could help make early testing more available, and support feasibility of future interventional trials.
Patients with neonatal-onset seizures become eligible for ERGENT after a standard-of-care diagnostic work-up for more common metabolic, non-genetic, and/or structural causes of neonatal seizures has been performed and been negative. This required work-up includes blood studies, brain MRI, and EEG, and often may include lumbar puncture. Eligibility requires either (1) an electrographic (EEG proven) seizure or a clearly abnormal interictal EEG background. However, patients with histories typical of Benign Familial Neonatal Seizures (autosomal dominant inheritance pattern, normal or near normal interictal EEG and neurological exam) are eligible. The neonate’s neurological exam, when not seizing, may be normal or abnormal. Seizure onset must occur by 14 days post term birth, and application must be made online within 30 days of seizure onset.
If a patient is enrolled, the treating doctor will be given a study code allowing an Invitae Epilepsy Gene Panel to be performed without charge to the patient or hospital. Blood from enrolled babies and their parents will be drawn as part of routine care using hospital materials or a free Invitae kit (for parents, saliva is accepted) and sent to the lab. Invitae will analyze the samples via its usual clinical test workflow in its CLIA-certified laboratory. Within 10-21 (average 14) calendar days, Invitae will return a full clinical genetics testing report to the ordering doctor.
For enrollment, ERGENT requires that your patient’s parent sign an informed consent form and medical records release form. This will allow ERGENT researchers to access your patient’s hospital records. We will review your patient’s condition and treatment, in order to identify factors that may help improve future diagnosis and treatment of neonatal-onset genetic epilepsy. All the information we save will be held securely. Anything identifying your patient’s family specifically (such as name, location, contact info) will not be included in what we save. The family’s identity will never be revealed to others unless they request us to. Treating physicians provide their own contact information to enable enrollment and reporting.
Yes, we welcome this. As in other studies conducted by our team,8-10 and as required by many of the journals where work in our field is published, we follow the guidelines of the ICMJE . ERGENT referring providers who are interested, please let us know.
Three foundations formed by parents of children affected by early onset genetic epilepsy are collaborating to provide the money for this study (see sponsor page for details). The funders want to shorten the time families often wait before obtaining a specific genetic diagnosis, and encourage future development of new targeted treatments. Invitae is providing reduced cost testing and results reporting to ERGENT as a collaboration with the research team and family groups.
You can apply and free text your questions in the application. We will contact you promptly. Alternatively, you can email us directly at firstname.lastname@example.org. We will reply and arrange a time to speak by phone.
- Glass HC, Shellhaas RA, Wusthoff CJ, et al. Contemporary Profile of Seizures in Neonates: A Prospective Cohort Study. J Pediatr 2016;174:98-103 e101.
- Mizrahi EM, Kellaway P Characterization and classification of neonatal seizures. Neurology 1987; 37:1837-1844.
- Shellhaas RA, Wusthoff CJ, Tsuchida TN, et al. Profile of neonatal epilepsies: Characteristics of a prospective US cohort. Neurology 2017;89:893-899.
- Olson HE, Kelly M, LaCoursiere CM, et al. Genetics and genotype-phenotype correlations in early onset epileptic encephalopathy with burst suppression. Ann Neurol 2017;81:419-429.
- Wolff M, Johannesen KM, Hedrich UBS, et al. Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders. Brain 2017;140:1316-1336.
- Pisano T, Numis AL, Heavin SB, et al. Early and effective treatment of KCNQ2 encephalopathy. Epilepsia 2015;56:685-691.
- Berg AT, Coryell J, Saneto RP, et al. Early-Life Epilepsies and the Emerging Role of Genetic Testing. JAMA Pediatr 2017;171:863-871.
- Millichap JJ, Park KL, Tsuchida T, et al. KCNQ2 encephalopathy: Features, mutational hot spots, and ezogabine treatment of 11 patients. Neurol Genet 2016;2:e96.
- Mulkey SB, Ben-Zeev B, Nicolai J, et al. Neonatal nonepileptic myoclonus is a prominent clinical feature of KCNQ2 gain-of-function variants R201C and R201H. Epilepsia 2017;58:436-445.
- Millichap JJ, Miceli F, De Maria M, et al. Infantile spasms and encephalopathy without preceding neonatal seizures caused by KCNQ2 R198Q, a gain-of-function variant. Epilepsia 2017;58:e10-e15.
Applications for Study Now Available
The online application is brief (2-5 minutes). An acceptance decision is returned quickly, typically within 1-2 hours, always within 8-16 hours. See inclusion criteria.
ERGENT has been reviewed and approved by the interdisciplinary human subjects research committee (IRB) at Baylor College of Medicine.