Genomic and Epigenetic Advances in Focal Cortical Dysplasia Types I and II: A Scoping Review

Jesus‐Ribeiro, Joana; Pires, Luís Miguel; Melo, João Daniel; Ribeiro, Ilda Patrícia; Rebelo, Olinda; Sales, Francisco; Freire, Antônio Fernando Menezes; Melo, Joana Barbosa

doi:10.3389/fnins.2020.580357

Cited by 28 publications

(28 citation statements)

References 59 publications

(302 reference statements)

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“…CTGF/CCN2 negatively regulates myelination through the mTOR pathway [ 50 ]. Mutations in mTOR pathway genes were reported in FCD [ 51 , 52 ]. Our previous study also demonstrated differential epigenetic regulation of the mTOR pathway in FCD [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic profiling of high- and low-spiking regions reveals novel epileptogenic mechanisms in focal cortical dysplasia type II patients

et al. 2021

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Focal cortical dysplasia (FCD) is a malformation of the cerebral cortex with poorly-defined epileptogenic zones (EZs), and poor surgical outcome in FCD is associated with inaccurate localization of the EZ. Hence, identifying novel epileptogenic markers to aid in the localization of EZ in patients with FCD is very much needed. High-throughput gene expression studies of FCD samples have the potential to uncover molecular changes underlying the epileptogenic process and identify novel markers for delineating the EZ. For this purpose, we, for the first time performed RNA sequencing of surgically resected paired tissue samples obtained from electrocorticographically graded high (MAX) and low spiking (MIN) regions of FCD type II patients and autopsy controls. We identified significant changes in the MAX samples of the FCD type II patients when compared to non-epileptic controls, but not in the case of MIN samples. We found significant enrichment for myelination, oligodendrocyte development and differentiation, neuronal and axon ensheathment, phospholipid metabolism, cell adhesion and cytoskeleton, semaphorins, and ion channels in the MAX region. Through the integration of both MAX vs non-epileptic control and MAX vs MIN RNA sequencing (RNA Seq) data, PLP1, PLLP, UGT8, KLK6, SOX10, MOG, MAG, MOBP, ANLN, ERMN, SPP1, CLDN11, TNC, GPR37, SLC12A2, ABCA2, ABCA8, ASPA, P2RX7, CERS2, MAP4K4, TF, CTGF, Semaphorins, Opalin, FGFs, CALB2, and TNC were identified as potential key regulators of multiple pathways related to FCD type II pathology. We have identified novel epileptogenic marker elements that may contribute to epileptogenicity in patients with FCD and could be possible markers for the localization of EZ.

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Section: Discussionmentioning

confidence: 99%

Transcriptomic profiling of high- and low-spiking regions reveals novel epileptogenic mechanisms in focal cortical dysplasia type II patients

et al. 2021

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“…As recently reported by us and other groups, we confirmed a trend of association between FCD with MTOR hotspot mutations, as well as HMEG/DMEG and PIK3CA mutations. 9,10 In fact, among the FCD patients that were positive for a hotspot mutation, the two common MTOR variants were present in five cases (four cases positive for p.S2215F and one positive for p.S2215Y). In contrast, of our HMEG/DMEG cohort, 5 cases had the PIK3CA p.E545K variant, and one had p.E542K.…”

Section: Discussionmentioning

confidence: 98%

“…A custom ddPCR-based panel was designed using probes targeting six common mutations in three PI3K-AKT-MTOR pathway genes, namely PIK3CA (p.E542K, p.E545K, p.H1047R), AKT3 (p.E17K), and MTOR (p.S2215Y, p.S2215F). We selected these specific variants as they are the most common variants seen in FCD-HMEG phenotypes, 10,19,20 as well as the most common mutations in these genes in somatic tissues in cancer (COSMIC, Catalogue of Somatic Mutations in Cancer). ddPCR probes were purchased as validated assays from Bio-Rad (see Supplementary Table 1 for list of probes used).…”

Section: Droplet Digital Polymerase Chain Reaction (Ddpcr) Testingmentioning

confidence: 99%

“…To address these challenges, we designed an ultra-deep targeted sequencing panel using droplet digital polymerase chain reaction (ddPCR) that includes six of the most common PI3K-AKT-MTOR mutations identified in this spectrum. 9,10 Droplet digital PCR (ddPCR) is an allele-specific detection method where the PCR reaction is partitioned into ~20,000 separate emulsion droplets. This method has been optimized to quantify extremely low-frequency single nucleotide variants and copy number abnormalities (down to 0.01% variant allele fraction; VAF).…”

Section: Introductionmentioning

confidence: 99%

“…[12][13][14][15] The PI3K-AKT-MTOR-related developmental brain disorders, including most notably FCD and HMEG, have a narrow mutational spectrum, with a few "hotspot" mutations or variants representing a sizable portion of molecularly-solved cases. 4,6,9,10 Therefore, we tested these common mutations as a first tier molecular method to complement the neuroimaging and neuropathology diagnosis, in a large cohort of affected individuals to efficiently identify mutations and studying the relationship between levels of mosaicism and key neuroimaging and neuropathological features.…”

Section: Introductionmentioning

confidence: 99%

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Analysis of common PI3K-AKT-MTOR mutations in pediatric surgical epilepsy by droplet digital PCR reveals novel clinical and molecular insights

Pirozzi¹,

Berkseth²,

Shear³

et al. 2021

Preprint

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Focal malformations of cortical development (FMCD) including focal cortical dysplasia (FCD), hemimegalencephaly (HMEG) and megalencephaly (MEG), constitute a spectrum of neurodevelopmental disorders associated with brain overgrowth, cellular and architectural dysplasia, intractable epilepsy, autism, and intellectual disability. Importantly, FCD is the most common cause of intractable pediatric focal epilepsy. Gain and loss of function mutations in the PI3K-AKT-MTOR pathway have been identified in this spectrum, with variable levels of mosaicism and tissue distribution. In this study, we aimed to assess droplet digital Polymerase Chain Reaction (ddPCR) as a first-tier molecular diagnostic method, as well as define genotype-phenotype relationships among the most common PI3K-AKT-MTOR pathway mutations in FMCD. A total of 144 specimens, including 113 brain samples, were collected from 58 individuals with intractable focal epilepsy phenotypes including FCD, MEG, HMEG and other types of developmental cortical lesions. We designed an ultra-deep and highly sensitive molecular diagnostic panel using ddPCR for six of the most common mutations in three PI3K-AKT-MTOR pathway genes, namely PIK3CA (p.E542K, p.E545K, p.H1047R), AKT3 (p.E17K) and MTOR (p.S2215F, p.S2215Y). We quantified the level of mosaicism across all samples and correlated genotypes with key phenotype, neuroimaging and neuropathological data. Pathogenic variants were identified in 17 individuals, with an overall molecular solve rate of 29.31%. Variant allele fractions (VAF) ranged from 0.1% to 22.67% across all positive samples. Our data shows that MTOR mutations are mostly associated with FCD, whereas PIK3CA mutations are more frequent in the HMEG-DMEG spectrum. The presence of one of these common PI3K-AKT-MTOR-mutations correlated with earlier onset of seizures. However, levels of mosaicism did not correlate with the severity of the cortical malformation by neuroimaging or neuropathological examination. Interestingly, we could not identify the six most common pathogenic variants in other types of cortical lesions (e.g., polymicrogyria or mesial temporal sclerosis) suggesting that PI3K-AKT-MTOR mutations are specifically causal in the FCD-HMEG-MEG spectrum. Finally, our data suggest that ultra-deep targeted molecular analysis for the most common PI3K-AKT-MTOR mutations via ddPCR is an effective molecular diagnostic approach for FMCD phenotypes with a good diagnostic yield when paired with neuroimaging and neuropathology evaluations. The high sensitivity and low DNA input requirements suggests that ddPCR is an effective molecular diagnostic tool for disorders caused by somatic mutations with a narrow mutational spectrum, including specific subtypes of pediatric epilepsy surgical phenotypes such as FCD and HMEG.

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Networks Underlie Temporal Onset of Dysplasia‐Related Epilepsy: A MELD Study

You

Krishnamurthy

et al. 2022

Annals of Neurology

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Objective The purpose of this study was to evaluate if focal cortical dysplasia (FCD) co‐localization to cortical functional networks is associated with the temporal distribution of epilepsy onset in FCD. Methods International (20 center), retrospective cohort from the Multi‐Centre Epilepsy Lesion Detection (MELD) project. Patients included if >3 years old, had 3D pre‐operative T1 magnetic resonance imaging (MRI; 1.5 or 3 T) with radiologic or histopathologic FCD after surgery. Images processed using the MELD protocol, masked with 3D regions‐of‐interest (ROI), and co‐registered to fsaverage_sym (symmetric template). FCDs were then co‐localized to 1 of 7 distributed functional cortical networks. Negative binomial regression evaluated effect of FCD size, network, histology, and sulcal depth on age of epilepsy onset. From this model, predictive age of epilepsy onset was calculated for each network. Results Three hundred eighty‐eight patients had median age seizure onset 5 years (interquartile range [IQR] = 3–11 years), median age at pre‐operative scan 18 years (IQR = 11–28 years). FCDs co‐localized to the following networks: limbic (90), default mode (87), somatomotor (65), front parietal control (52), ventral attention (32), dorsal attention (31), and visual (31). Larger lesions were associated with younger age of onset (p = 0.01); age of epilepsy onset was associated with dominant network (p = 0.04) but not sulcal depth or histology. Sensorimotor networks had youngest onset; the limbic network had oldest age of onset (p values <0.05). Interpretation FCD co‐localization to distributed functional cortical networks is associated with age of epilepsy onset: sensory neural networks (somatomotor and visual) with earlier onset, and limbic latest onset. These variations may reflect developmental differences in synaptic/white matter maturation or network activation and may provide a biological basis for age‐dependent epilepsy onset expression. ANN NEUROL 2022;92:503–511

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Genomic and Epigenetic Advances in Focal Cortical Dysplasia Types I and II: A Scoping Review

Cited by 28 publications

References 59 publications

Transcriptomic profiling of high- and low-spiking regions reveals novel epileptogenic mechanisms in focal cortical dysplasia type II patients

Transcriptomic profiling of high- and low-spiking regions reveals novel epileptogenic mechanisms in focal cortical dysplasia type II patients

Analysis of common PI3K-AKT-MTOR mutations in pediatric surgical epilepsy by droplet digital PCR reveals novel clinical and molecular insights

Networks Underlie Temporal Onset of Dysplasia‐Related Epilepsy: A MELD Study

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