The mTOR signalling cascade: paving new roads to cure neurological disease

Nature Reviews Neurology, Journal Year: 2016, Volume and Issue: 12(7), P. 379 - 392

Published: June 24, 2016

Language: Английский

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Dissecting the genetic basis of focal cortical dysplasia: a large cohort study

Acta Neuropathologica, Journal Year: 2019, Volume and Issue: 138(6), P. 885 - 900

Published: Aug. 23, 2019

Genetic malformations of cortical development (MCDs), such as mild MCDs (mMCD), focal dysplasia (FCD), and hemimegalencephaly (HME), are major causes severe pediatric refractory epilepsies subjected to neurosurgery. FCD2 characterized by neuropathological hallmarks that include enlarged dysmorphic neurons (DNs) balloon cells (BCs). Here, we provide a comprehensive assessment the contribution germline somatic variants in large cohort surgical MCD cases. We enrolled monocentric study 80 children with drug-resistant epilepsy postsurgical diagnosis mMCD, FCD1, FCD2, or HME. performed targeted gene sequencing ( ≥ 2000X read depth) on matched blood–brain samples search for low-allele frequency mTOR pathway FCD genes. were able elucidate 29% mMCD/FCD1 patients 63% FCD2/HME patients. Somatic loss-of-function N-glycosylation pathway-associated SLC35A2 found gain-of-function MTOR its activators (AKT3, PIK3CA, RHEB), well germline, two-hit repressors (DEPDC5, TSC1, TSC2) exclusively show panel-negative cases display strong pS6-immunostaining, stressing all mTORopathies. Analysis microdissected demonstrated DNs BCs carry pathogenic variants. further observed correlation between density pathological variant-detection likelihood. Single-cell microdissection followed enriched pools unveiled second-hit loss-of-heterozygosity DEPDC5 case. In conclusion, this indicates two distinct genetic entities: while mosaic mTORopathies, not caused mTOR-pathway-hyperactivating variants, ~ 30% related glycosylation defects. framework efficient testing FCD/HME, linking neuropathology findings emphasizing usefulness molecular evaluation epileptic neurosurgical population.

Language: Английский

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Somatic Mutations Activating the mTOR Pathway in Dorsal Telencephalic Progenitors Cause a Continuum of Cortical Dysplasias

Cell Reports, Journal Year: 2017, Volume and Issue: 21(13), P. 3754 - 3766

Published: Dec. 1, 2017

Focal cortical dysplasia (FCD) and hemimegalencephaly (HME) are epileptogenic neurodevelopmental malformations caused by mutations in mTOR pathway genes. Deep sequencing of these genes FCD/HME brain tissue identified an etiology 27 66 cases (41%). Radiographically indistinguishable lesions somatic activating AKT3, MTOR, PIK3CA germline loss-of-function DEPDC5, NPRL2, TSC1/2, including TSC2 isolated HME demonstrating a "two-hit" model. Mutations the same gene cause disease continuum from FCD to bilateral overgrowth, reflecting progenitor cell developmental time when mutation occurred. Single-cell demonstrated activation neurons all lesions. Conditional Pik3ca mouse cortex showed that excitatory glia, but not interneurons, is sufficient for abnormal overgrowth. These data suggest dorsal telencephalic progenitors, some specifically neuron lineage, causes dysplasia.

Language: Английский

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The ASD Living Biology: from cell proliferation to clinical phenotype

Molecular Psychiatry, Journal Year: 2018, Volume and Issue: 24(1), P. 88 - 107

Published: June 19, 2018

Abstract Autism spectrum disorder (ASD) has captured the attention of scientists, clinicians and lay public because its uncertain origins striking unexplained clinical heterogeneity. Here we review genetic, genomic, cellular, postmortem, animal model, cell model evidence that shows ASD begins in womb. This leads to a new theory is multistage, progressive brain development, spanning nearly all prenatal life. can begin as early 1st 2nd trimester with disruption proliferation differentiation. It continues neural migration, laminar disorganization, altered neuron maturation neurite outgrowth, synaptogenesis reduced network functioning. Among most commonly reported high-confidence ( hcASD ) genes, 94% express during life affect these fetal processes neocortex, amygdala, hippocampus, striatum cerebellum. A majority genes are pleiotropic, proliferation/differentiation and/or synapse development. Proliferation subsequent stages also be disrupted by maternal immune activation trimester. Commonly implicated pathways, PI3K/AKT RAS/ERK, pleiotropic multiple from through functional In different individuals, variation how when pathways dysregulated, will lead different, even opposing effects, producing well later Thus, pathogenesis not set at one point time does reside process, but rather cascade pathogenic vast toddlers. Despite this knowledge biology womb, current research methods have provided individualized information: What early-age molecular cellular differences underlie each individual child? Without such knowledge, rapid advances biological-based diagnostic, prognostic, precision medicine treatments cannot occur. Missing, therefore, what call Living Biology. conceptual paradigm shift towards focus on abnormal underlying within living individual. The concept emphasizes specific need for foundational child’s development beginnings stages. Biology seeks linking genetic vitro molecular, measurements vivo post-natal presentation progression child. We first study, which confirms multistage nature provides fetal-stage explanation overgrowth. Within-child novel coin here advocates integration information generate group-level explanations, clinically useful prognoses, approaches truly beneficial infant toddler ASD.

Language: Английский

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Phosphatidylinositol 3-Kinase, Growth Disorders, and Cancer

New England Journal of Medicine, Journal Year: 2018, Volume and Issue: 379(21), P. 2052 - 2062

Published: Nov. 21, 2018

Phosphatidylinositol 3-kinase (PI3K) is involved in multiple cell processes, including insulin signaling, growth, immunity, and brain development. It activated a wide variety of cancers being targeted as treatment, with notable success lymphoma.

Language: Английский

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Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA

The American Journal of Human Genetics, Journal Year: 2015, Volume and Issue: 98(1), P. 58 - 74

Published: Dec. 31, 2015

Language: Английский

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Association ofMTORMutations With Developmental Brain Disorders, Including Megalencephaly, Focal Cortical Dysplasia, and Pigmentary Mosaicism

JAMA Neurology, Journal Year: 2016, Volume and Issue: 73(7), P. 836 - 836

Published: May 9, 2016

Focal cortical dysplasia (FCD), hemimegalencephaly, and megalencephaly constitute a spectrum of malformations development with shared neuropathologic features. These disorders are associated significant childhood morbidity mortality.To identify the underlying molecular cause FCD, diffuse megalencephaly.Patients or (mean age, 11.7 years; range, 2-32 years) were recruited from Pediatric Hospital A. Meyer, University Hong Kong, Seattle Children's Research Institute June 2012 to 2014. Whole-exome sequencing (WES) was performed on 8 children FCD hemimegalencephaly using standard-depth (50-60X) in peripheral samples (blood, saliva, skin) affected child their parents deep (150-180X) brain tissue. Targeted WES used screen 93 molecularly unexplained focal overgrowth. Histopathologic functional assays phosphatidylinositol 3-kinase-AKT (serine/threonine kinase)-mammalian target rapamycin (mTOR) pathway activity resected tissue cultured neurons validate mutations.Whole-exome targeted identified variants this developmental disorders.Low-level mosaic mutations MTOR 4 type 2a alternative allele fractions ranging 0.012 0.086. Intermediate-level mutation (p.Thr1977Ile) also 3 unrelated pigmentary mosaicism skin. Finally, constitutional de novo (p.Glu1799Lys) intellectual disability. Molecular analysis 2 FCD2a whom multiple available revealed gradient an epicenter most epileptogenic area. When expressed neurons, all here drive constitutive activation mTOR complex 1 enlarged neuronal size.In study, overgrowth phenotypes extending megalencephaly, distinguished by different levels mosaicism. may be sufficient cellular hypertrophy provide demonstration pattern substantiate link between

Language: Английский

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Definitions and classification of malformations of cortical development: practical guidelines

Brain, Journal Year: 2020, Volume and Issue: 143(10), P. 2874 - 2894

Published: May 11, 2020

Malformations of cortical development are a group rare disorders commonly manifesting with developmental delay, cerebral palsy or seizures. The neurological outcome is extremely variable depending on the type, extent and severity malformation involved genetic pathways brain development. Neuroimaging plays an essential role in diagnosis these malformations, but several issues regarding malformations definitions classification remain unclear. purpose this consensus statement to provide standardized terminology for neuroradiological pattern interpretation. A committee international experts paediatric neuroradiology prepared systematic literature reviews formulated neuroimaging recommendations collaboration geneticists, neurologists pathologists during meetings context European Network Neuro-MIG initiative Brain (https://www.neuro-mig.org/). features practical provided aid both expert non-expert radiologists who may encounter patients their practice, aim improving imaging interpretation worldwide.

Language: Английский

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Somatic mosaicism and neurodevelopmental disease

Nature Neuroscience, Journal Year: 2018, Volume and Issue: 21(11), P. 1504 - 1514

Published: Oct. 15, 2018

Language: Английский

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The ILAE consensus classification of focal cortical dysplasia: An update proposed by an ad hoc task force of the ILAE diagnostic methods commission

Epilepsia, Journal Year: 2022, Volume and Issue: 63(8), P. 1899 - 1919

Published: June 15, 2022

Abstract Ongoing challenges in diagnosing focal cortical dysplasia (FCD) mandate continuous research and consensus agreement to improve disease definition classification. An International League Against Epilepsy (ILAE) Task Force (TF) reviewed the FCD classification of 2011 identify existing gaps provide a timely update. The following methodology was applied achieve this goal: survey published literature indexed with ((Focal Cortical Dysplasia) AND (epilepsy)) between 01/01/2012 06/30/2021 ( n = 1349) PubMed identified knowledge gained since 2012 new developments field. online consulted ILAE community about current use scheme 367 people answering. TF performed an iterative clinico‐pathological genetic study objectively measure diagnostic gap blood/brain samples from 22 patients suspicious for submitted epilepsy surgery. confirmed molecular‐genetic characterizations involving mechanistic Target Of Rapamycin (mTOR) pathway type II (FCDII), SLC35A2 mild malformations development (mMCDs) oligodendroglial hyperplasia (MOGHE). electro‐clinical‐imaging phenotypes surgical outcomes were better defined validated FCDII. Little information acquired on clinical, histopathological, or characteristics I (FCDI) III (FCDIII). mMCDs, FCDI, characterization as fields improvement updated Our importance immunohistochemical staining, neuroimaging, tests yield. proposes include MOGHE, “no definite histopathology” categories histopathological can be further augmented by advanced neuroimaging studies comprehensively diagnose subtypes; these different levels should then integrated into multi‐layered scheme. This update may help foster multidisciplinary efforts toward understanding novel targeted treatment options.

Language: Английский

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