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Rapamycin prevents seizures after depletion of STRADA in a rare neurodevelopmental disorder. | LitMetric

AI Article Synopsis

  • PMSE is a rare disorder found in the Old Order Mennonite population, characterized by epilepsy, neurocognitive delays, and distinct brain abnormalities due to a specific genetic mutation in the LYK5/STRADA gene.
  • Research shows that inhibiting the mTORC1 pathway can correct issues caused by STRADA loss, both in lab tests with mouse cells and in samples from PMSE patients.
  • Treatment with rapamycin (sirolimus) in five PMSE patients led to fewer seizures and better language skills, suggesting mTORC1 inhibition could be a promising approach for PMSE and similar disorders.

Article 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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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3720125PMC
http://dx.doi.org/10.1126/scitranslmed.3005271DOI Listing

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