GABA Biomarkers in Dravet Syndrome

Epileptic seizures may result from too much excitation or too little inhibition in the area in which abnormal discharges start. Excitation and inhibition of neurons are mediated by g-aminobutyric acid (GABA) neurotransmitter among others. Several lines of evidence indicate an abnormal pathophysiological mechanism of GABA in children with Dravet Syndrome (DS). Other studies show that measures of the beta and gamma brain activity with non-invasive electrophysiological techniques correlate with the levels of GABA in the human brain. Here, we propose to assess these measures in children with SCN1A+DS and neurodeveloping healthy controls aiming to develop noninvasive biomarkers for the monitoring of the levels of GABA in their brain. Such a biomarker would be useful for understanding the pathophysiological GABA mechanism in children with DS and potentially guide the development of future GABAergic modulation treatments.

Inclusion criteria

• Authorized representative (parent/caregiver) must be willing and able to give informed consent for the participant's participation in the study. Participants capable of providing informed assent must be willing to provide their assent.
• Participant and their parent/caregiver are willing and able (in the PI's opinion) to comply with all study requirements.
• Participant is male or female aged between 0 months and 18 years of age, inclusive, at the time of consent.
• Participant has a confirmed pathogenic or likely pathogenic SCN1A mutation, as demonstrated by genetic testing.
• Participant had normal development prior to onset of first seizure as defined by the Centers for Disease Control and Prevention (CDC 2019).
• Participant had an onset of seizures, defined as first focal clonic/hemiclonic, generalized/focal, generalized tonic-clonic/clonic, atonic, prolonged seizure, or status epilepticus between age 3 and 5 months, inclusive.
• Participant should have an evaluation by a pediatric neurologist with a diagnosis of DS.

Exclusion criteria

• Participant has a copy number variant of SCN1A, including SCN1A microdeletion, affecting other genes.
• Participant has an SCN1A mutation present on both alleles.
• Participant has a known pathogenic or clinically suspected mutation in a seizure-associated gene besides SCN1A.
• Participant has a confirmed mutation in a gene besides SCN1A, that is known to increase the severity of the seizure phenotype.
• Participant has a known gain-of-function mutation, as defined by functional studies, including p.Thr226Met.
• Participant has a history of notable developmental deficit that was evident prior to seizure onset, by physician report.
• Participant has a known central nervous system structural abnormality as found on magnetic resonance imaging or computed tomography scan of brain which, in the opinion of the Principal Investigator (PI), is not consistent with the clinical phenotype of DS. Note: Prior scans may be used, and no new scan is required to confirm normal imaging.
• Metal implants.
• Baclofen pump.
• Inability or unwillingness of patient or parent/legally authorized representative to give written informed consent (and/or assent as appropriate).