Mammalian target of rapamycin pathway mutations cause hemimegalencephaly and focal cortical dysplasia

D’Gama, Alissa M.; Geng, Ying; Couto, Javier; Martin, Beth; Boyle, Evan A.; LaCoursiere, Christopher M.; Hossain, Amer A.; Hatem, Nicole E.; Barry, Brenda J.; Kwiatkowski, David J.; Vinters, Harry V.; Barkovich, A. James; Shendure, Jay; Mathern, Gary W.; Walsh, Christopher A.; Poduri, Annapurna

doi:10.1002/ana.24357

Cited by 259 publications

(273 citation statements)

References 23 publications

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“…70 HME, which shares neuropathological features such as cytomegalic neurons and cortical dyslamination with FCDII, are also known to be associated with somatic mutations in PIK3CA, PIK3R2, AKT3, and MTOR, as well as germline mutations in PTEN and TSC2. 17,70 These genes encode wellknown regulators of the mTOR pathway, and their dysfunction can lead to aberrant activation of mTOR kinase. Together, these findings and the present results strongly suggest that hyperactivation of mTOR kinase by mutations in mTOR pathway genes underlies the molecular pathogenesis of FCD, which is the most common form of childhood intractable epilepsy and requires surgery as a treatment.…”

Section: Discussionmentioning

confidence: 99%

“…[17][18][19] Moreover, recent studies have reported that mosaic TSC1 or TSC2 mutations identified in blood and saliva can cause the milder clinical features of TSC. 20,21 Therefore, it is likely that somatic mutations in genes encoding these upstream regulators of mTOR kinase could be responsible for the development of FCDII in individuals who lack MTOR mutations.…”

Section: Introductionmentioning

confidence: 99%

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Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia

Lim

Gopalappa

Kim

et al. 2017

The American Journal of Human Genetics

174

159

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Focal cortical dysplasia (FCD) is a major cause of the sporadic form of intractable focal epilepsies that require surgical treatment. It has recently been reported that brain somatic mutations in MTOR account for 15%-25% of FCD type II (FCDII), characterized by cortical dyslamination and dysmorphic neurons. However, the genetic etiologies of FCDII-affected individuals who lack the MTOR mutation remain unclear. Here, we performed deep hybrid capture and amplicon sequencing (read depth of 1003-20,0123) of five important mTOR pathway genes-PIK3CA, PIK3R2, AKT3, TSC1, and TSC2-by using paired brain and saliva samples from 40 FCDII individuals negative for MTOR mutations. We found that 5 of 40 individuals (12.5%) had brain somatic mutations in TSC1 (c.64C>T [p.Arg22Trp] and c.610C>T [p.Arg204Cys]) and TSC2 (c.4639G>A [p.Val1547Ile]), and these results were reproducible on two different sequencing platforms. All identified mutations induced hyperactivation of the mTOR pathway by disrupting the formation or function of the TSC1-TSC2 complex. Furthermore, in utero CRISPR-Cas9-mediated genome editing of Tsc1 or Tsc2 induced the development of spontaneous behavioral seizures, as well as cytomegalic neurons and cortical dyslamination. These results show that brain somatic mutations in TSC1 and TSC2 cause FCD and that in utero application of the CRISPR-Cas9 system is useful for generating neurodevelopmental disease models of somatic mutations in the brain.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia

Lim

Gopalappa

Kim

et al. 2017

The American Journal of Human Genetics

174

159

View full text Add to dashboard Cite

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“…TSC is naturally a mutation of either TSC1 or TSC2 in 85%, whereas more than half of those cases show also mosaicism 43. Recent studies found somatic (mosaic) mutations affecting the mTOR signaling also in focal lesions of FCD II patients 4, 8, 21, 25, 32, 36. This is a very important aspect since as far as we know, in FCD, the mutations are localized and show profound variability in cellular expression.…”

Section: Discussionmentioning

confidence: 99%

Impaired oligodendroglial turnover is associated with myelin pathology in focal cortical dysplasia and tuberous sclerosis complex

et al. 2017

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Conventional antiepileptic drugs suppress the excessive firing of neurons during seizures. In drug‐resistant patients, treatment failure indicates an alternative important epileptogenic trigger. Two epilepsy‐associated pathologies show myelin deficiencies in seizure‐related brain regions: Focal Cortical Dysplasia IIB (FCD) and cortical tubers in Tuberous Sclerosis Complex (TSC). Studies uncovering white matter‐pathology mechanisms are therefore urgently needed to gain more insight into epileptogenesis, the propensity to maintain seizures, and their associated comorbidities such as cognitive defects. We analyzed epilepsy surgery specimens of FCD IIB (n = 22), TSC (n = 8), and other malformations of cortical development MCD (n = 12), and compared them to autopsy and biopsy cases (n = 15). The entire lesional pathology was assessed using digital immunohistochemistry, immunofluorescence and western blotting for oligodendroglial lineage, myelin and mTOR markers, and findings were correlated to clinical parameters. White matter pathology with depleted myelin and oligodendroglia were found in 50% of FCD IIB and 62% of TSC cases. Other MCDs had either a normal content or even showed reactive oligodendrolial hyperplasia. Furthermore, myelin deficiency was associated with increased mTOR expression and the lower amount of oligodendroglia was linked with their precursor cells (PDGFRa). The relative duration of epilepsy (normalized to age) also correlated positively to mTOR activation and negatively to myelination. Decreased content of oligodendroglia and missing precursor cells indicated insufficient oligodendroglial development, probably mediated by mTOR, which may ultimately lead to severe myelin loss. In terms of disease management, an early and targeted treatment could restore normal myelin development and, therefore, alter seizure threshold and improve cognitive outcome.

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“…29 mTORC1 activation is not exclusive to epilepsy associated with TSC. Genes responsible for regulation of mTORC1 have been identified in epileptic patients with isolated focal cortical dysplasia IIb, 30,31 hemimegencephaly, 32 and syndromic epilepsies caused by DEPDEC5, 32,33 PTEN, 34 and STRADA. 35 Loss of mTORC1 regulation has been identified in animal models of acquired epilepsies, including temporal lobe epilepsy and posttraumatic epilepsy, which are responsive to sirolimus treatment.…”

Section: Classification Of Evidence This Interventional Study Providesmentioning

confidence: 99%

Long-term treatment of epilepsy with everolimus in tuberous sclerosis

et al. 2016

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Objective: To evaluate the long-term benefit and safety of everolimus for the treatment of medically refractory epilepsy in patients with tuberous sclerosis complex (TSC).Methods: Everolimus was titrated over 4 weeks and continued an additional 8 weeks in a prospective, open-label, phase I/II clinical trial design. Participants demonstrating initial benefit continued treatment until study completion (48 months). The primary endpoint was percentage of patients with a $50% reduction in seizure frequency compared to baseline. Secondary endpoints assessed absolute seizure frequency, adverse events (AEs), behavior, and quality of life.Results: Of the 20 participants who completed the initial study phase, 18 continued extended treatment. Fourteen of 18 (78%) participants completed the study, all but 1 of whom reported $50% reduction in seizure frequency at 48 months. All participants reported at least 1 AE, the vast majority (94%) of which were graded mild or moderate severity. Improvements in behavior and quality of life were also observed, but failed to achieve statistical significance at 48 months.Conclusions: Improved seizure control was maintained for 4 years in the majority of patients with TSC with medically refractory epilepsy treated with everolimus. Long-term treatment with everolimus is safe and well-tolerated in this population. Everolimus may be a therapeutic option for refractory epilepsy in TSC. More than 80% of individuals with tuberous sclerosis complex (TSC) develop epilepsy, usually within the first year of life.1 Epilepsy in an estimated third of these individuals is refractory to conventional anticonvulsant medications, 2 heightening the urgency for development of effective treatments. TSC1 and TSC2, the causative genes for TSC, regulate the protein kinase mammalian target of rapamycin complex 1 (mTORC1). Pharmacologic inhibitors of mTORC1 are now approved to treat multiple clinical aspects of TSC, including subependymal giant cell astrocytomas (SEGA), 3,4 renal angiomyolipomas, 5 and pulmonary lymphangioleiomyomatosis. 6 mTORC1 inhibitors also have been reported to be effective for treatment of topical angiofibromas and cardiac rhabdomyomas in TSC. 7,8 Preclinical studies in TSC mouse models demonstrate that mTORC1 inhibitors effectively prevent seizures.9,10 TSC patients in early (open-label) clinical trials to treat SEGA with everolimus reported reduced frequency of daily seizures and increased rates of seizure freedom, 4,[11][12][13] but seizure benefit could not be demonstrated in more recent (placebo-controlled, randomized) From the Departments of Pediatrics and Neurology

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Mammalian target of rapamycin pathway mutations cause hemimegalencephaly and focal cortical dysplasia

Cited by 259 publications

References 23 publications

Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia

Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia

Impaired oligodendroglial turnover is associated with myelin pathology in focal cortical dysplasia and tuberous sclerosis complex

Long-term treatment of epilepsy with everolimus in tuberous sclerosis

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