Abstract Details

Title The Ketogenic Diet in DEPDC5-related Epilepsies: Clinical and Preclinical Observations

Topic Epilepsy/Clinical Neurophysiology (EEG)

Presentation(s) P2 - Poster Session 2 (11:45 AM-12:45 PM)

Poster/Presentation
Number 1-002

Objective

Disruption of DEPDC5 gene function has been linked to drug-resistant epilepsy in both, human and animal models. DEPDC5 is a negative regulator of nutrient signaling through mTOR. The ketogenic diet (KD) is a commonly prescribed therapy for drug-resistant epilepsy. The utility of KD for therapeutic treatment of DEPDC5-related epilepsies remains unknown.

Background DEP domain-containing protein 5 (DEPDC5) pathogenic loss-of-function variants in humans are the most common genetic cause of familial focal epilepsy. Previous studies suggest caloric restriction reduces seizures through DEPDC5 signaling mechanisms. Depdc5-knockout mouse models experience seizures and increased neuronal mTOR activity unresponsive to amino acid withdrawal. KD has been shown to reduce mTOR and seizure activity across several rodent models. It is unclear if KD would reduce seizures in preclinical models of or patients with DEPDC5-related epilepsy.

Design/Methods We used mice with functionally homozygous loss of Dedpc5 in the brain. Depdc5 knockout mice and littermate control mice were randomly assigned at wean (postnatal day 21) to start KD or a control diet with weekly weights and monthly blood ketones and glucose levels. A cohort of DEPDC5-related epilepsy patients were identified from the epilepsy genetics clinic. Clinical demographics and outcomes to dietary therapies for epilepsy were collected.

Results KD Depdc5 knockout mice (n=13) had greater ketone levels at 4 weeks than KD littermate controls (n=22) (p=0.008). Depdc5 knockout mice on KD either rapidly lost weight within one week of diet assignment (n=5/26, χ 2 = 8.966; p=0.0297) or severe dermatitis, requiring sacrifice (n=17/26). Eighteen DEPDC5-related epilepsy patients were identified of which 17% (n=3/18) tried the KD. KD was ineffective in all three cases, due to excessive acidosis at initiation (n=2/3) or no impact on seizures (n=1/3).

Conclusions In our limited study of KD in a retrospective clinical and preclinical context of DEPDC5-related epilepsies, KD had little impact on seizures and unanticipated adverse effects.

Authors/Disclosures
Nishtha Gupta, MD PRESENTER	Dr. Gupta has nothing to disclose.
Yini Liang	No disclosure on file
Karenna Groff	No disclosure on file
Christopher J. Yuskaitis, MD, PhD (Takeda Pharacueticals)	Dr. Yuskaitis has nothing to disclose.

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