Abstracts

Rationale:
Pathogenic variants in the SMC1A gene are known to cause disorders ranging from Cornelia de Lange syndrome to epilepsy. Fenfluramine (FFA), once coupled with phentermine in the infamous fen-phen duo for obesity treatment, faced a market withdrawal in the 1990s due to severe side effects. Recent insights, however, show FFA’s antiepileptic efficacy absent cardiac or pulmonary detriments. FFA is approved for seizure management in children aged two and above for Lennox-Gastaut and Dravet syndrome (Knupp etal, 2022). Our patient was less than two years old at the time of FFA initiation.




According to the serotonin and adenosine hypotheses of Sudden Unexpected Death in Epilepsy (SUDEP), serotonin and adenosine are two neurotransmitters that influence respiration during seizures. Adenosine aids in stopping seizures but depresses respiration. Medications that increase serotonin levels can reduce respiratory depression during or after seizures. Medications that elevate extracellular serotonin levels inhibit focal and generalized seizures and thus mitigate seizure-related respiratory depression. These mechanisms are what may underly the efficacy of FFA in reducing apneic seizures.




Methods:
This is a case study of a ten-month-old female with an SMC1A genetic mutation who presented with apneic and focal tonic seizures that began shortly after birth. Seizures persisted despite trials of medications including phenobarbital, levetiracetam, lacosamide, clobazam, brivaracetam, topiramate, and fluoxetine. Before starting the medication, an echocardiogram was performed. She was titrated from 0.1 mg/kg BID for seven days, to 0.2 mg/kg BID for seven days, and finally to 0.35 mg/kg BID.









A detailed chart review of parent-reported seizure frequency in office visits, phone calls, emergency room visits, and hospital admissions from birth until May 2024 was performed. The change in seizure frequency and hospital admissions due to refractory seizures are illustrated in the two attached images.




Results: FFA therapy led to a dramatic over 95% reduction in seizure frequency over five months, offering a promising seizure control in this patient. This patient went from experiencing seizures every one to two days that last up to twelve minutes, to three months seizure-free. Afterwards, refractory seizures were often triggered by illness while her baseline seizure frequency remained significantly reduced.

Conclusions: This case study reaffirms FFA’s potential as a seizure treatment in pediatric neurology, particularly for patients with SMC1A mutations with apneic seizure, and underlines the imperative for further investigative efforts in this subgroup. Furthermore, the drastic reduction in apneic seizure frequency in this patient emphasized FFA's specific potential in preventing long-term hypoxic brain injury.

Funding: N/A