ArticleScience translational medicine2013
Rapamycin prevents seizures after depletion of STRADA in a rare neurodevelopmental disorder.
Article in Science translational medicine, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 68 papers, 1 of them a synthesis that pooled it.
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Who cites it
68 citing papers in PubMed, 1 synthesis or guideline pooled it, 115 citations in OpenAlex.
- Pathogenetic mechanisms of focal cortical dysplasia.Epilepsia · 2014Pooled it
- Neuron-derived extracellular vesicles to examine brain mTOR target engagement with sirolimus in patients with multiple system atrophy.Parkinsonism & related disorders · 2023Trial
- mTOR Inhibition with Sirolimus in Multiple System Atrophy: A Randomized, Double-Blind, Placebo-Controlled Futility Trial and 1-Year Biomarker Longitudinal Analysis.Movement disorders : official journal of the Movement Disorder Society · 2022Trial
- Trial
- The Clinical Spectrum and Neurodevelopmental Pathogenesis of KPTN-Related Disorder in a Mouse Model.Annals of neurology · 2026Article
- Delayed forebrain excitatory and inhibitory neurogenesis in STRADA-related megalencephaly via mTOR hyperactivity.Stem cell reports · 2026Article
- Deficiency ofZoological research · 2026Article
- Mechanistic Target of Rapamycin and Megalencephaly: Novel Research Strategies for Therapeutic Discovery.Epilepsy currents · 2026Article
- mTOR pathway diseases: challenges and opportunities from bench to bedside and the mTOR node.Orphanet journal of rare diseases · 2025Review
- Review
- Experimental and clinical tests of FDA-approved kinase inhibitors for the treatment of neurological disorders (update 2024).Exploration of drug science · 2025Article
- Rapamycin for longevity: the pros, the cons, and future perspectives.Frontiers in aging · 2025Review
- The molecular genetics of PI3K/PTEN/AKT/mTOR pathway in the malformations of cortical development.Genes & diseases · 2024Review
- Unexplained Causes of Glioma-Associated Epilepsies: A Review of Theories and an Area for Research.Cancers · 2023Review
- Models of KPTN-related disorder implicate mTOR signalling in cognitive and overgrowth phenotypes.Brain : a journal of neurology · 2023Article
- Seizure reduction in TSC2-mutant mouse model by an mTOR catalytic inhibitor.Annals of clinical and translational neurology · 2023Article
- Observation of a Possible Successful Treatment of DEPDC5-Related Epilepsy with mTOR Inhibitor.Neuropediatrics · 2023Article
- Advances in the mTOR signaling pathway and its inhibitor rapamycin in epilepsy.Brain and behavior · 2023Review
- In silico screening for clinical efficacy of antiseizure medications: Not all central nervous system drugs are alike.Epilepsia · 2023Article
- FDA-Approved Kinase Inhibitors in Preclinical and Clinical Trials for Neurological Disorders.Pharmaceuticals (Basel, Switzerland) · 2022Review
8 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
Abstract
A rare neurodevelopmental disorder in the Old Order Mennonite population called PMSE (polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome; also called Pretzel syndrome) is characterized by infantile-onset epilepsy, neurocognitive delay, craniofacial dysmorphism, and histopathological evidence of heterotopic neurons in subcortical white matter and subependymal regions. PMSE is caused by a homozygous deletion of exons 9 to 13 of the LYK5/STRADA gene, which encodes the pseudokinase STRADA, an upstream inhibitor of mammalian target of rapamycin complex 1 (mTORC1). We show that disrupted pathfinding in migrating mouse neural progenitor cells in vitro caused by STRADA depletion is prevented by mTORC1 inhibition with rapamycin or inhibition of its downstream effector p70 S6 kinase (p70S6K) with the drug PF-4708671 (p70S6Ki). We demonstrate that rapamycin can rescue aberrant cortical lamination and heterotopia associated with STRADA depletion in the mouse cerebral cortex. Constitutive mTORC1 signaling and a migration defect observed in fibroblasts from patients with PMSE were also prevented by mTORC1 inhibition. On the basis of these preclinical findings, we treated five PMSE patients with sirolimus (rapamycin) without complication and observed a reduction in seizure frequency and an improvement in receptive language. Our findings demonstrate a mechanistic link between STRADA loss and mTORC1 hyperactivity in PMSE, and suggest that mTORC1 inhibition may be a potential treatment for PMSE as well as other mTOR-associated neurodevelopmental disorders.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.