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Pathogenetic mechanisms of focal cortical dysplasia.

ABSTRACT: Focal cortical dysplasias (FCDs) constitute a prevalent cause of intractable epilepsy in children, and is one of the leading conditions requiring epilepsy surgery. Despite recent advances in the cellular and molecular biology of these conditions, the pathogenetic mechanisms of FCDs remain largely unknown. The purpose if this work is to review the molecular underpinnings of FCDs and to highlight potential therapeutic targets. A systematic review of the literature regarding the histologic, molecular, and electrophysiologic aspects of FCDs was conducted. Disruption of the mammalian target of rapamycin (mTOR) signaling comprises a common pathway underlying the structural and electrical disturbances of some FCDs. Other mechanisms such as viral infections, prematurity, head trauma, and brain tumors are also posited. mTOR inhibitors (i.e., rapamycin) have shown positive results on seizure management in animal models and in a small cohort of patients with FCD. Encouraging progress has been achieved on the molecular and electrophysiologic basis of constitutive cells in the dysplastic tissue. Despite the promising results of mTOR inhibitors, large-scale randomized trials are in need to evaluate their efficacy and side effects, along with additional mechanistic studies for the development of novel, molecular-based diagnostic and therapeutic approaches.

SUBMITTER: Marin-Valencia I

PROVIDER: S-EPMC4107035 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Pathogenetic mechanisms of focal cortical dysplasia.

Marin-Valencia Isaac I Guerrini Renzo R Gleeson Joseph G JG

Epilepsia 20140523 7

Focal cortical dysplasias (FCDs) constitute a prevalent cause of intractable epilepsy in children, and is one of the leading conditions requiring epilepsy surgery. Despite recent advances in the cellular and molecular biology of these conditions, the pathogenetic mechanisms of FCDs remain largely unknown. The purpose if this work is to review the molecular underpinnings of FCDs and to highlight potential therapeutic targets. A systematic review of the literature regarding the histologic, molecul ...[more]

PMID: 24861491

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Project description:BackgroundTuberous sclerosis complex (TSC) and some focal cortical dysplasias (FCDs) are associated with dysfunctional mTOR signaling, resulting in increased cell growth and ribosomal S6 protein phosphorylation (phospho-S6). mTOR inhibitors can reduce TSC tumor growth and seizure frequency, and preclinical FCD studies indicate seizure suppression. This pilot study evaluated safety of mTOR inhibitor everolimus in treatment resistant (failure of >2 anti-seizure medications) TSC and FCD patients undergoing surgical resection and to assess mTOR signaling and molecular pathways.Methods and findingsWe evaluated everolimus in 14 treatment resistant epilepsy patients undergoing surgical resection (4.5 mg/m2 daily for 7 days; n = 4 Active, mean age 18.3 years, range 4-26; n = 10, Control, mean age 13.1, range 3-45). Everolimus was well tolerated. Mean plasma everolimus in Active participants were in target range (12.4 ng/ml). Brain phospho-S6 was similar in Active and Control participants with a lower trend in Active participants, with Ser235/236 1.19-fold (p = 0.67) and Ser240/244 1.15-fold lower (p = 0.66). Histologically, Ser235/236 was 1.56-fold (p = 0.37) and Ser240/244 was 5.55-fold lower (p = 0.22). Brain proteomics identified 11 proteins at <15% false discovery rate associated with coagulation system (p = 1.45x10-9) and acute phase response (p = 1.23x10-6) activation. A weighted gene correlation network analysis (WGCNA) of brain proteomics and phospho-S6 identified 5 significant modules. Higher phospho-S6 correlated negatively with cellular respiration and synaptic transmission and positively with organophosphate metabolic process, nuclear mRNA catabolic process, and neuron ensheathment. Brain metabolomics identified 14 increased features in Active participants, including N-acetylaspartylglutamic acid. Plasma proteomics and cytokine analyses revealed no differences.ConclusionsShort-term everolimus before epilepsy surgery in TSC and FCD resulted in no adverse events and trending lower mTOR signaling (phospho-S6). Future studies should evaluate implications of our findings, including coagulation system activation and everolimus efficacy in FCD, in larger studies with long-term treatment to better understand molecular and clinical effects.Clinical trials registrationClinicalTrials.gov NCT02451696.

Project description:Focal cortical dysplasias are a common subtype of malformation of cortical development, which frequently presents with a spectrum of cognitive and behavioural abnormalities as well as pharmacoresistant epilepsy. Focal cortical dysplasia type II is typically caused by somatic mutations resulting in mammalian target of rapamycin (mTOR) hyperactivity, and is the commonest pathology found in children undergoing epilepsy surgery. However, surgical resection does not always result in seizure freedom, and is often precluded by proximity to eloquent brain regions. Gene therapy is a promising potential alternative treatment and may be appropriate in cases that represent an unacceptable surgical risk. Here, we evaluated a gene therapy based on overexpression of the Kv1.1 potassium channel in a mouse model of frontal lobe focal cortical dysplasia. An engineered potassium channel (EKC) transgene was placed under control of a human promoter that biases expression towards principal neurons (CAMK2A) and packaged in an adeno-associated viral vector (AAV9). We used an established focal cortical dysplasia model generated by in utero electroporation of frontal lobe neural progenitors with a constitutively active human Ras homolog enriched in brain (RHEB) plasmid, an activator of mTOR complex 1. We characterized the model by quantifying electrocorticographic and behavioural abnormalities, both in mice developing spontaneous generalized seizures and in mice only exhibiting interictal discharges. Injection of AAV9-CAMK2A-EKC in the dysplastic region resulted in a robust decrease (∼64%) in the frequency of seizures. Despite the robust anti-epileptic effect of the treatment, there was neither an improvement nor a worsening of performance in behavioural tests sensitive to frontal lobe function. AAV9-CAMK2A-EKC had no effect on interictal discharges or behaviour in mice without generalized seizures. AAV9-CAMK2A-EKC gene therapy is a promising therapy with translational potential to treat the epileptic phenotype of mTOR-related malformations of cortical development. Cognitive and behavioural co-morbidities may, however, resist an intervention aimed at reducing circuit excitability.

Project description:Neuroimaging studies have consistently shown distributed brain anomalies in epilepsy syndromes associated with a focal structural lesion, particularly mesiotemporal sclerosis. Conversely, a system-level approach to focal cortical dysplasia has been rarely considered, likely due to methodological difficulties in addressing variable location and topography. Given the known heterogeneity in focal cortical dysplasia histopathology, we hypothesized that lesional connectivity consists of subtypes with distinct structural signatures. Furthermore, in light of mounting evidence for focal anomalies impacting whole-brain systems, we postulated that patterns of focal cortical dysplasia connectivity may exert differential downstream effects on global network topology. We studied a cohort of patients with histologically verified focal cortical dysplasia type II (n = 27), and age- and sex-matched healthy controls (n = 34). We subdivided each lesion into similarly sized parcels and computed their connectivity to large-scale canonical functional networks (or communities). We then dichotomized connectivity profiles of lesional parcels into those belonging to the same functional community as the focal cortical dysplasia (intra-community) and those adhering to other communities (inter-community). Applying hierarchical clustering to community-reconfigured connectome profiles identified three lesional classes with distinct patterns of functional connectivity: decreased intra- and inter-community connectivity, a selective decrease in intra-community connectivity, and increased intra- as well as inter-community connectivity. Hypo-connectivity classes were mainly composed of focal cortical dysplasia type IIB, while the hyperconnected lesions were type IIA. With respect to whole-brain networks, patients with hypoconnected focal cortical dysplasia and marked structural damage showed only mild imbalances, while those with hyperconnected subtle lesions had more pronounced topological alterations. Correcting for interictal epileptic discharges did not impact connectivity patterns. Multivariate structural equation analysis provided a mechanistic model of such complex, diverging interactions, whereby the focal cortical dysplasia structural makeup shapes its functional connectivity, which in turn modulates whole-brain network topology.

Project description:ObjectiveThe advent of next-generation sequencing (NGS) enabled the detection of low-level brain somatic variants in postsurgical tissue of focal cortical dysplasia (FCD). The genetic background of FCD Type I remains elusive, while the mammalian target of rapamycin (mTOR) pathway seems to have a relevant role in the pathogenesis of FCD Type II. Our goal was to uncover information on the molecular basis of FCD, performing whole genome sequencing (WGS) in postsurgical tissue to detect candidate brain-specific somatic variants, and evaluate their clinical significance.DesignWGS was performed using paired peripheral venous blood and postsurgical pathological brain deoxyribonucleic acid (DNA) samples. Libraries were prepared using the Roche KAPA HyperPrep polymerase chain reaction (PCR) free library preparation kit. Paired-end 150bp reads were generated on the Illumina NovaSeq platform. The FASTQ files were processed using the nf-core sarek pipeline (version 3.0) to call somatic variants, which were then annotated with ANNOVAR. A screening strategy was applied to obtain relevant variants.ResultsTwo female patients with drug-resistant epilepsy due to FCD who underwent surgical treatment were included. Regarding neuropathological diagnosis, one patient had FCD Type Ia and the other had FCD Type IIa. Five somatic nonsynonymous single nucleotide variants (SNVs) were detected using WGS, three in FCD Ia tissue (WDR24 p.Trp259Gly; MICAL1 p.Lys1036Arg; and KATNB1 p.Leu566Ile) and two in FCD IIa tissue (MATN4 p.Phe91Val and ANKRD6 p.His386Gln). All variants were predicted to be potentially pathogenic by at least two different tools. However, they were classified as variants of uncertain significance (VUS) according to the American College of Medical Genetics and Genomics (ACMG) criteria.ConclusionBrain-specific somatic missense variants were identified by NGS in new candidate genes (WDR24, MICAL1, KATNB1, MATN4, and ANKRD6) using postsurgical FCD tissue, which may contribute to further understanding of the genetic background of FCD. All the reported genes were previously related to epilepsy and/or malformations of central nervous system (CNS) and cortical development. However, the pathogenicity assessment of these variants and, consequently, their impact on clinical practice still poses an important challenge.

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Pathogenetic mechanisms of focal cortical dysplasia.

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Pathogenetic mechanisms of focal cortical dysplasia.

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