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Cited by 74Tuberous Sclerosis Complex ResearchEpilepsy research and treatmentPharmacological Effects and Toxicity Studies

Epileptogenesis in tuberous sclerosis complex-related developmental and epileptic encephalopathy

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Aronica, Eleonora, Specchio, Nicola, Luinenburg, Mark J, Curatolo, Paolo·2023·Brain
DOI 10.1093/brain/awad048PMC PMC10316778
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Abstract

Epileptogenesis in infants with tuberous sclerosis complex (TSC) is a gradual and dynamic process, leading to early onset and difficult-to-treat seizures. Several cellular, molecular and pathophysiologic mechanisms, including mammalian target of rapamycin (mTOR) dysregulation, GABAergic dysfunction and abnormal connectivity, may play a role in this epileptogenic process and may also contribute to the associated developmental encephalopathy. Disease-specific antiseizure medications or drugs targeting the mTOR pathway have proved to be effective in TSC-associated epilepsy. Pre-symptomatic administration of vigabatrin, a GABAergic drug, delays seizure onset and reduces the risk of a subsequent epileptic encephalopathy, such as infantile spasms syndrome or Lennox–Gastaut syndrome. Everolimus, a rapamycin-derived mTOR inhibitor, reduces seizure frequency, especially in younger patients. This evidence suggests that everolimus should be considered early in the course of epilepsy. Future trials are needed to optimize the use of everolimus and determine whether earlier correction of mTOR dysregulation can prevent progression to developmental and epileptic encephalopathies or mitigate their severity in infants with TSC. Clinical trials of several other potential antiseizure drugs (cannabidiol and ganaxolone) that target contributing mechanisms are also underway. This review provides an overview of the different biological mechanisms occurring in parallel and interacting throughout the life course, even beyond the epileptogenic process, in individuals with TSC. These complexities highlight the challenges faced in preventing and treating TSC-related developmental and epileptic encephalopathy.

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  • In syndromic forms, mutations in TSC1, TSC2, or PTEN lead to constitutive activation of mTOR signaling, driving aberrant cellular growth and structural brain anomalies.

    “In syndromic forms, mutations in genes such as TSC1, TSC2, or PTEN lead to constitutive activation of mTOR signaling, driving aberrant cellular growth and structural brain anomalies”

    From Biological hierarchy from genotype to phenotype in syndromic and non-syndromic autism spectrum disorder (2026) · cites this paper as Aronica et al., 2023

    Figure 1 in “Insights from human pathology and genetic models” states that loss-of-function mutations in TSC1 or TSC2 cause prenatal mTOR overactivation and describes mTORC1’s role in cell growth. The same section links mTORC1 activation to brain lesions, but says the mechanism of cortical tuber development remains debated. The passages found do not support extending this account to PTEN mutations. (LLM, conf=0.88)

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Authors
Aronica, E., Specchio, N., Luinenburg, M. J., & Curatolo, P.
Affiliations
  • Amsterdam Neuroscience (NL)
  • Bambino Gesù Children's Hospital (IT)
  • University of Rome Tor Vergata (IT)
Corresponding author
Specchio, Nicola
ORCID
Venue
Brain
Publisher
Oxford University Press (OUP)
Published
2023-02-20
Volume
146
Issue
7
Pages
2694-2710
ISSN
  • 0006-8950 (ISSN-L)
  • 1460-2156
DOI
10.1093/brain/awad048
PMC
PMC10316778
OpenAlex
W4321365533
Cited by
74
References
13
Citations by year
2026: 18 · 2025: 31 · 2024: 16 · 2023: 9
FWCI
2.64
Type
journal article
Language
en
Open access
Licence
Locations
  • Brain (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (submittedVersion, other-oa)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (submittedVersion, other-oa)
Funders
  • EpilepsieNL (2020-02)
  • ZonMw
Topics
  • Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
Keywords
tuberous sclerosis complex, developmental and epileptic encephalopathy, epileptogenesis, GABAergic dysfunction, brain connectivity, infantile spasms, Lennox-Gastaut syndrome, vigabatrin, everolimus, rapamycin, antiepileptic drugs, cannabidiol, ganaxolone
MeSH terms
Everolimus, Anticonvulsants, Epilepsy, Humans, Infant, Seizures, Tuberous Sclerosis, Sirolimus, TOR Serine-Threonine Kinases

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