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Neurobiology of Disease Jun 2023The mechanistic target of rapamycin (mTOR) signaling pathway is an essential regulator of numerous cellular activities such as metabolism, growth, proliferation, and... (Review)
Review
The mechanistic target of rapamycin (mTOR) signaling pathway is an essential regulator of numerous cellular activities such as metabolism, growth, proliferation, and survival. The mTOR cascade recently emerged as a critical player in the pathogenesis of focal epilepsies and cortical malformations. The 'mTORopathies' comprise a spectrum of cortical malformations that range from whole brain (megalencephaly) and hemispheric (hemimegalencephaly) abnormalities to focal abnormalities, such as focal cortical dysplasia type II (FCDII), which manifest with drug-resistant epilepsies. The spectrum of cortical dysplasia results from somatic brain mutations in the mTOR pathway activators AKT3, MTOR, PIK3CA, and RHEB and from germline and somatic mutations in mTOR pathway repressors, DEPDC5, NPRL2, NPRL3, TSC1 and TSC2. The mTORopathies are characterized by excessive mTOR pathway activation, leading to a broad range of structural and functional impairments. Here, we provide a comprehensive literature review of somatic mTOR-activating mutations linked to epilepsy and cortical malformations in 292 patients and discuss the perspectives of targeted therapeutics for personalized medicine.
Topics: Humans; Mosaicism; Mutation; Brain; Epilepsy; TOR Serine-Threonine Kinases; Malformations of Cortical Development; GTPase-Activating Proteins
PubMed: 37149062
DOI: 10.1016/j.nbd.2023.106144 -
Seminars in Neurology Jun 2015Focal cortical dysplasias are common malformations of cerebral cortical development and are highly associated with medically intractable epilepsy. They have been... (Review)
Review
Focal cortical dysplasias are common malformations of cerebral cortical development and are highly associated with medically intractable epilepsy. They have been classified into neuropathological subtypes (type Ia, Ib, IIa, IIb, and III) based on the severity of cytoarchitectural disruption--tangential or radial dispersion, or loss of laminar structure--and the presence of unique cells types such as cytomegalic neurons or balloon cells. Most focal cortical dysplasias can be identified on neuroimaging and many require resective epilepsy surgery to cure refractory seizures. The pathogenesis of focal cortical dysplasias remains to be defined, although there is recent evidence to suggest that focal cortical dysplasias arise from de novo somatic mutations occurring during brain development. Some focal cortical dysplasia subtypes show a link to the mammalian target of rapamycin signaling cascade; this has now extended to other cortical malformations, including hemimegalencephaly.
Topics: Animals; Drug Resistant Epilepsy; Humans; Malformations of Cortical Development; Neuroimaging; TOR Serine-Threonine Kinases; Tumor Suppressor Proteins
PubMed: 26060899
DOI: 10.1055/s-0035-1552617 -
Neurobiology of Disease Aug 2023Lesional epilepsy is a common and severe disease commonly associated with malformations of cortical development, including focal cortical dysplasia and... (Review)
Review
Lesional epilepsy is a common and severe disease commonly associated with malformations of cortical development, including focal cortical dysplasia and hemimegalencephaly. Recent advances in sequencing and variant calling technologies have identified several genetic causes, including both short/single nucleotide and structural somatic variation. In this review, we aim to provide a comprehensive overview of the methodological advancements in this field while highlighting the unresolved technological and computational challenges that persist, including ultra-low variant allele fractions in bulk tissue, low availability of paired control samples, spatial variability of mutational burden within the lesion, and the issue of false-positive calls and validation procedures. Information from genetic testing in focal epilepsy may be integrated into clinical care to inform histopathological diagnosis, postoperative prognosis, and candidate precision therapies.
Topics: Humans; Brain; Mosaicism; Mutation; Epilepsy; Hemimegalencephaly; Malformations of Cortical Development
PubMed: 37343892
DOI: 10.1016/j.nbd.2023.106208 -
Neurology India 2015
PubMed: 26238918
DOI: 10.4103/0028-3886.162126 -
Molecular Syndromology Sep 2016Malformations of cortical development (MCD) represent a major cause of developmental disabilities, severe epilepsy, and reproductive disadvantage. Genes that have been... (Review)
Review
Malformations of cortical development (MCD) represent a major cause of developmental disabilities, severe epilepsy, and reproductive disadvantage. Genes that have been associated to MCD are mainly involved in cell proliferation and specification, neuronal migration, and late cortical organization. Lissencephaly-pachygyria-severe band heterotopia are diffuse neuronal migration disorders causing severe global neurological impairment. Abnormalities of the , , , , , , , , and genes have been associated with these malformations. More recent studies have also established a relationship between lissencephaly, with or without associated microcephaly, corpus callosum dysgenesis as well as cerebellar hypoplasia, and at times, a morphological pattern consistent with polymicrogyria with mutations of several genes , , , , , and , regulating the synthesis and function of microtubule and centrosome key components and hence defined as tubulinopathies. MCD only affecting subsets of neurons, such as mild subcortical band heterotopia and periventricular heterotopia, have been associated with abnormalities of the , , and genes and cause neurological and cognitive impairment that vary from severe to mild deficits. Polymicrogyria results from abnormal late cortical organization and is inconstantly associated with abnormal neuronal migration. Localized polymicrogyria has been associated with anatomo-specific deficits, including disorders of language and higher cognition. Polymicrogyria is genetically heterogeneous, and only in a small minority of patients, a definite genetic cause has been identified. Megalencephaly with normal cortex or polymicrogyria by MRI imaging, hemimegalencephaly and focal cortical dysplasia can all result from mutations in genes of the PI3K-AKT-mTOR pathway. Postzygotic mutations have been described for most MCD and can be limited to the dysplastic tissue in the less diffuse forms.
PubMed: 27781032
DOI: 10.1159/000448639 -
Brain : a Journal of Neurology Aug 2022Post-zygotically acquired genetic variants, or somatic variants, that arise during cortical development have emerged as important causes of focal epilepsies,...
Post-zygotically acquired genetic variants, or somatic variants, that arise during cortical development have emerged as important causes of focal epilepsies, particularly those due to malformations of cortical development. Pathogenic somatic variants have been identified in many genes within the PI3K-AKT-mTOR-signalling pathway in individuals with hemimegalencephaly and focal cortical dysplasia (type II), and more recently in SLC35A2 in individuals with focal cortical dysplasia (type I) or non-dysplastic epileptic cortex. Given the expanding role of somatic variants across different brain malformations, we sought to delineate the landscape of somatic variants in a large cohort of patients who underwent epilepsy surgery with hemimegalencephaly or focal cortical dysplasia. We evaluated samples from 123 children with hemimegalencephaly (n = 16), focal cortical dysplasia type I and related phenotypes (n = 48), focal cortical dysplasia type II (n = 44), or focal cortical dysplasia type III (n = 15). We performed high-depth exome sequencing in brain tissue-derived DNA from each case and identified somatic single nucleotide, indel and large copy number variants. In 75% of individuals with hemimegalencephaly and 29% with focal cortical dysplasia type II, we identified pathogenic variants in PI3K-AKT-mTOR pathway genes. Four of 48 cases with focal cortical dysplasia type I (8%) had a likely pathogenic variant in SLC35A2. While no other gene had multiple disease-causing somatic variants across the focal cortical dysplasia type I cohort, four individuals in this group had a single pathogenic or likely pathogenic somatic variant in CASK, KRAS, NF1 and NIPBL, genes previously associated with neurodevelopmental disorders. No rare pathogenic or likely pathogenic somatic variants in any neurological disease genes like those identified in the focal cortical dysplasia type I cohort were found in 63 neurologically normal controls (P = 0.017), suggesting a role for these novel variants. We also identified a somatic loss-of-function variant in the known epilepsy gene, PCDH19, present in a small number of alleles in the dysplastic tissue from a female patient with focal cortical dysplasia IIIa with hippocampal sclerosis. In contrast to focal cortical dysplasia type II, neither focal cortical dysplasia type I nor III had somatic variants in genes that converge on a unifying biological pathway, suggesting greater genetic heterogeneity compared to type II. Importantly, we demonstrate that focal cortical dysplasia types I, II and III are associated with somatic gene variants across a broad range of genes, many associated with epilepsy in clinical syndromes caused by germline variants, as well as including some not previously associated with radiographically evident cortical brain malformations.
Topics: Cadherins; Cell Cycle Proteins; Epilepsy; Female; Hemimegalencephaly; Humans; Malformations of Cortical Development; Malformations of Cortical Development, Group I; Mutation; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Protocadherins; TOR Serine-Threonine Kinases
PubMed: 35441233
DOI: 10.1093/brain/awac117 -
Seizure Nov 2021To evaluate seizure and developmental outcomes in the short and long term in children with hemimegalencephaly (HMEG) after surgery.
OBJECTIVE
To evaluate seizure and developmental outcomes in the short and long term in children with hemimegalencephaly (HMEG) after surgery.
METHODS
This is a cohort study of 36 children who underwent surgery for HMEG were followed up for at least 1 year postoperatively. The Griffiths Mental Development Scales, Ages and Stages Questionnaire version 3, and Peabody Developmental Motor Scales were used to assess development.
RESULTS
The median postoperative follow-up duration was 2.7 (1.0-5.0) years, and median age at surgery was 1.9 years (5.8 months-5.9 years). At the last follow-up, 83% of children were seizure-free. the predicted probability of being seizure-free three years after surgery was 79%. The proportion of patients who were moderate to severe delay declined from 97% preoperatively to 76% at least 1 year after surgery. Catch-up, stabilization, and regression of developmental quotient (DQ) was observed in 41%, 35%, and 24% of children 3 months after surgery, respectively. The corresponding proportions during long-term follow-up were 40%, 33%, and 27%, respectively. Change of DQ shortly after surgery was negatively correlated with age at seizure onset and age at surgery. The long-term DQ was positively correlated with the preoperative DQ. Long-term change of DQ was positively correlated with change of DQ shortly after surgery.
CONCLUSIONS
Most of patients with HMEG could achieve seizure free after surgery. After surgery, the proportion of catch-up, stabilization, and regression in both short- and long-term DQ was approximately 40%, 35%, and 25%, respectively. The change of DQ shortly after surgery may be a predictor for long-term developmental change.
Topics: Child; Cohort Studies; Drug Resistant Epilepsy; Follow-Up Studies; Hemimegalencephaly; Humans; Pharmaceutical Preparations; Retrospective Studies; Seizures; Treatment Outcome
PubMed: 34416421
DOI: 10.1016/j.seizure.2021.08.006 -
Annual Review of Pathology Jan 2019Malformations of cortical development encompass heterogeneous groups of structural brain anomalies associated with complex neurodevelopmental disorders and diverse... (Review)
Review
Malformations of cortical development encompass heterogeneous groups of structural brain anomalies associated with complex neurodevelopmental disorders and diverse genetic and nongenetic etiologies. Recent progress in understanding the genetic basis of brain malformations has been driven by extraordinary advances in DNA sequencing technologies. For example, somatic mosaic mutations that activate mammalian target of rapamycin signaling in cortical progenitor cells during development are now recognized as the cause of hemimegalencephaly and some types of focal cortical dysplasia. In addition, research on brain development has begun to reveal the cellular and molecular bases of cortical gyrification and axon pathway formation, providing better understanding of disorders involving these processes. New neuroimaging techniques with improved resolution have enhanced our ability to characterize subtle malformations, such as those associated with intellectual disability and autism. In this review, we broadly discuss cortical malformations and focus on several for which genetic etiologies have elucidated pathogenesis.
Topics: Cerebral Cortex; Hemimegalencephaly; Humans; Intellectual Disability; Lissencephaly; Malformations of Cortical Development; Microcephaly; Mutation; Neurodevelopmental Disorders; Neuroimaging; Polymicrogyria
PubMed: 30677308
DOI: 10.1146/annurev-pathmechdis-012418-012927