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.

Tuberous sclerosis complex (TSC) is characterized by developmental malformations of the cerebral cortex known as tubers, comprised of cells that exhibit enhanced mammalian target of rapamycin (mTOR) signaling. To date, there are no reports of mTORC1 and mTORC2 activation in fetal tubers or in neural progenitor cells lacking Tsc2. We demonstrate mTORC1 activation by immunohistochemical detection of substrates phospho-p70S6K1 (T389) and phospho-S6 (S235/236), and mTORC2 activation by substrates phospho-PKCα (S657), phospho-Akt (Ser473), and phospho-SGK1 (S422) in fetal tubers. Then, we show that Tsc2 shRNA knockdown (KD) in mouse neural progenitor cells (mNPCs) in vitro results in enhanced mTORC1 (phospho-S6, phospho-4E-BP1) and mTORC2 (phospho-Akt and phospho-NDRG1) signaling, as well as a doubling of cell size that is rescued by rapamycin, an mTORC1 inhibitor. Tsc2 KD in vivo in the fetal mouse brain by in utero electroporation causes disorganized cortical lamination and increased cell volume that is prevented with rapamycin. We demonstrate for the first time that mTORC1 and mTORC2 signaling is activated in fetal tubers and in mNPCs following Tsc2 KD. These results suggest that inhibition of mTOR pathway signaling during embryogenesis could prevent abnormal brain development in TSC.

Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Objectives: To report outcomes of a cohort with displaced Femoral Neck Fractures (FNF) treated with a length/angle-stable construct augmented with an endosteal fibular allograft serving as a biologic dowel. Design: Prospective Setting: Level I Trauma Center Patients: The study group consists of twenty-seven patients with isolated FNF surgically treated by a single surgeon. Intervention: Open reduction of the femoral neck, fixed with a length-and angle stable-construct of two fully threated cannulated screws augmented with an endosteal fibular allograft serving as a biologic dowel. Main Outcome Measurements: Clinical and radiographic outcomes of the fixation construct and the viability of both the femoral head and the fibular allograft, host response to the allograft and osseous union was evaluated using a specialized sequence of contrast-enhanced MRI obtained at 3 and 12 months postoperatively. Results: This construct resulted in high union rates (89%; 24/27). Two patients suffered early catastrophic failure and one patient developed fracture non-union, all of wish underwent uneventful conversion to total hip arthroplasty. Three (11%) additional patients had removal of symptomatic implants. The clinical and radiographic outcomes were excellent. Twelve months MRIs revealed either partial or complete osseous incorporation of 86% the fibular allografts without signs of adverse reaction of the host to the allograft. Femoral head osteonecrosis segments were noted in 76% of patients on MRI, however radiographically there were no sign of osteonecrosis or segmental collapse. Conclusion: The fibular allograft reconstructs the comminuted femoral neck, and the osteointegration overtime increases the strength of the host-bone-graft interface. This added strength seems to provide the stability needed to better preserve the intra-operative reduction, obtain good outcomes and reduce the complications associated with FNF. Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. Design: Prospective.Setting: Level I Trauma Center. Patients:The study group consists of 27 patients with isolated FNF surgically treated by a single surgeon.Intervention: Open reduction of the femoral neck, fixed with a length-and angle-stable construct of 2 fully threaded cannulated screws augmented with an endosteal fibular allograft serving as a biologic dowel. Main Outcome Measurements:Clinical and radiographic outcomes of the fixation construct and the viability of both the femoral head and the fibular allograft, host response to the allograft and osseous union were evaluated using a specialized sequence of contrast-enhanced magnetic resonance imaging (MRI) obtained at 3 and 12 months postoperatively.Results: This construct resulted in high union rates (89%; 24 of 27).Two patients suffered early catastrophic failure and 1 patient developed fracture nonunion, all of wish underwent uneventful conversion to total hip arthroplasty. Three additional patients (11%) had removal of sy...