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Advanced Neurology mTOR inhibition in epilepsy

Table 3. (Continued)
Authors Study design Disease of primary n Age (y) a mTOR Durationa Seizure outcome Other findings
interest inhibitor
Moloney Open-labeled GATOR1-related 5 35 (15 – 49) Everolimus 12 m (7 – 31) Three achieved -
et al. 90 observational epilepsy (non-lesional) sz reduction
study • DEPDC5, n=4 by 74.3-86.1%
• NPRL3, n=1 (DEPDC5 LoF
variant).
One achieved
sz reduction by
43.9% (DEPDC5
missense variant).
One had no
improvement
(NPRL3).
Shiraishi Case report FCD II 1 2 Sirolimus 92 w Sz reduction by -
et al. 84 95%
Park et al. 86 Double- FCD II 22 13.5 (4 – 32) Everolimus 57 w - The optimal initial
blinded, dose of everolimus
crossover, was recommended for
randomized FCD-related seizures
clinical trial • 7 – 9 mg/m if
2
BSA 0.5 – 1 m 2
• 6 – 7 mg/m if BSA
2
was ≤1.5 m 2
Note: Age and duration were expressed in median (range) or mean±SD, unless indicated otherwise.
a
Abbreviations: BSA: Body surface area; FCD II: Focal cortical dysplasia; Phospho-S6: Ribosomal protein S6 phosphorylation; sz: Seizure;
LoF: Loss-of-function variants; TSC: Tuberous sclerosis complex; NS: Not clearly specified; d: Day (s); m: Month (s); w: Week (s); y: Year (s).

of 5 – 15 ng/mL. This dose was subsequently maintained 43.9% reduction in seizures, whereas no improvement was
throughout the remaining 8 weeks (maintenance period) observed in a patient with an NPRL3 variant. Myers and
90
88
87
of core phases. Thus far, 21 patients have completed the Scheffer postulated that DEPDC5 could be an exciting
core phases. Although the final results of the trial have yet potential therapeutic target, with DEPDC5 agonists likely
to be published, the findings will undoubtedly be valuable having anti-epileptogenic properties and potentially
for the future establishment of guidelines on the use of working synergistically with the ketogenic diet.
everolimus for patients with FCD.
6.2.4. Sturge-Weber syndrome (SWS)
6.2.3. GATOR1-related epilepsy or GATORopathy SWS is a congenital neurocutaneous disorder caused
GATOR1 is an important modulator in the mTOR by somatic activating mutations in the GNAQ gene.
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signaling network, responsible for inhibiting mTORC1 Somatic GNA11 variants can also result in distinctive
activity. Pathogenic variants in all three genes encoding features beyond the classical presentation of SWS, thereby
GATOR1 complex proteins, namely DEPDC5, NPRL2, and expanding the phenotypic spectrum of the syndrome.
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NPRL3, have been shown to cause both lesional and non- Both GNAQ and GNA11 encode alpha subunits of the G
q
lesional focal epilepsy. 88 protein, which are linked to G-protein-couped receptors.
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Kearney et al. reported two cases of non-lesional Pathogenic variants in these genes can lead to the
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DEPDC5-related refractory epilepsy that showed seizure dysregulation of several signaling pathways, including the
reduction of 33% and 85% after 6 months of everolimus phospholipase C pathway, the Hippo-YAP pathway, and
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treatment (Table 3). An open-label observational study by the MEK/ERK/mTOR pathway.
Moloney et al. (n=5) further suggested that everolimus Triana Junco et al. reported the use of sirolimus in
90
92
could be a potential precision therapy for GATOR1-related combination with aspirin in a 3-week-old infant with
epilepsy. In this study, three patients with DEPDC5 loss- bilateral SWS (Table 3). The patient remained seizure-
of-function variants achieved the best seizure reductions, free with normal neurodevelopment over a 23-month
ranging from 74.3 – 86.1%, with everolimus. Another follow-up period. A 2021 retrospective study involving
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92
patient with a DEPDC5 missense variant experienced a six patients with SWS and uncontrolled epilepsy observed
Volume 3 Issue 3 (2024) 14 doi: 10.36922/an.3568