Case report: Off-label use of low-dose perampanel in a 25-month-old girl with a pathogenic SYNGAP1 variant

Abstract

IntroductionPreclinical studies in a mouse model have shown that SYNGAP1 haploinsufficiency results in an epilepsy phenotype with excessive GluA2-AMPA insertion specifically on the soma of fast-spiking parvalbumin-positive interneurons associated with significant dysfunction of cortical gamma homeostasis that was rescued by perampanel (PER), an AMPA receptor blocker. In this single case, we aimed to investigate the presence of dysregulated cortical gamma in a toddler with a pathogenic SYNGAP1 variant and report on the effect of low-dose PER on electroencephalogram (EEG) and clinical profile.MethodsClinical data from physician's clinic notes; genetic testing reports; developmental scores from occupational therapy, physical therapy, speech and language therapy evaluations; and applied behavioral analysis reports were reviewed. Developmental assessments and EEG analysis were done pre- and post-PER.ResultsClinically, the patient showed improvements in the developmental profile and sleep quality post-PER. EEG spectral power analysis in our patient revealed a loss of gamma power modulation with behavioral-state transitions similar to what was observed in Syngap1+/− mice. Furthermore, the administration of low-dose PER rescued the dysfunctional cortical gamma homeostasis, similar to the preclinical study. However, as in the epileptic mice, PER did not curb epileptiform discharges or clinical seizures.ConclusionSimilar to the Syngap1+/− mice, cortical gamma homeostasis was dysregulated in the patient. This dysfunction was rescued by PER. These encouraging results necessitate further validation of gamma dysregulation as a potential translational EEG biomarker in SYNAP1-DEE. Low-dose PER can be explored as a therapeutic option through clinical trials.

Understanding the role of AMPA receptors in autism: insights from circuit and synapse dysfunction

“…Given that AMPA receptors are a key mediator of glutamatergic neurotransmission involved in many functions, the AMPAr antagonist, perampanel (originally approved as an anti-seizure medication), has been used in a wide variety non-epilepsy or epilepsy associated conditions, including in autism with associated epilepsy ( 146 ). Several studies have looked at the efficacy of perampanel in rare epilepsies, including epilepsy associated with SYNGAP1-DEE ( 147 – 149 ). One study focused on rare epilepsy, which often feature significant developmental phenotypes, and revealed high efficacy for perampanel ( 148 ).…”

“…One study focused on rare epilepsy, which often feature significant developmental phenotypes, and revealed high efficacy for perampanel ( 148 ). Two more-focused studies (one a small case series the other a case report) evaluated the impact of perampanel on behavior in autism with associated epilepsy ( 147 , 149 ). The case series revealed that 7 out of 17 patients showed improvement on autism behavioral assessments, including two out of five patients that did not show reductions in seizures ( 149 ).…”

“…The case series revealed that 7 out of 17 patients showed improvement on autism behavioral assessments, including two out of five patients that did not show reductions in seizures ( 149 ). The case report evaluated the response of cortical gamma frequencies to low dose perampanel treatment in a patient with SYNGAP1-DEE associated autism and epilepsy, a perspective based on a pre-clinical investigation ( 147 , 150 ). The group found that there was improvement in the EEG signatures of cortical dysfunction and improvement in behavior but failure in seizure improvement.…”

“…The group found that there was improvement in the EEG signatures of cortical dysfunction and improvement in behavior but failure in seizure improvement. Furthermore, as a case report, they were unable to evaluate whether the behavioral improvements were a result of perampanel or concomitant behavioral interventions ( 147 ). Nonetheless, the findings in these studies point to the exciting possibility that AMPAr antagonism may have some beneficial effects on behavior in some autism etiologies.…”