Detection of brain somatic variation in epilepsy-associated developmental lesions

Epilepsy-associated developmental lesions, including malformations of cortical development and low-grade developmental tumors, represent a major cause of drug-resistant seizures requiring surgical intervention in children. Brain-restricted somatic mosaicism has been implicated in the genetic etiology of these lesions; however, many contributory genes remain unidentified. We enrolled 50 children undergoing epilepsy surgery into a translational research study. We performed exome and RNA-sequencing of resected brain tissue samples to identify somatic variation. We uncovered candidate disease-causing somatic variation affecting 28 patients (56%), as well as candidate germline variants affecting 4 patients (8%). We confirmed somatic findings using high-depth targeted DNA sequencing. In agreement with previous studies, we identified somatic variation affecting SLC35A2 and MTOR pathway genes in patients with focal cortical dysplasia. Somatic gains of chromosome 1q were detected in 30% (3 of 10) Type I FCD patients. Somatic variation of MAPK pathway genes (i.e., FGFR1, FGFR2, BRAF, KRAS) was associated with low-grade epilepsy-associated developmental tumors. Somatic structural variation accounted for over one-half of epilepsy-associated tumor diagnoses. Sampling across multiple anatomic regions revealed that somatic variant allele fractions vary widely within epileptogenic tissue. Finally, we identified putative disease-causing variants in genes (EEF2, NAV2, PTPN11) not yet associated with focal cortical dysplasia. These results further elucidate the genetic basis of structural brain abnormalities leading to focal epilepsy in children and point to new candidate disease genes.

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Somatic mutation involving diverse genes leads to a spectrum of focal cortical malformations

10.1101/2021.12.22.21267563 ◽

2021 ◽

Author(s):

Dulcie Lai ◽

Meethila Gade ◽

Edward Yang ◽

Hyun Yong Koh ◽

Nicole M. Walley ◽

...

Keyword(s):

Focal Cortical Dysplasia ◽

Hippocampal Sclerosis ◽

Cortical Development ◽

Copy Number Variants ◽

Cortical Dysplasia ◽

Disease Genes ◽

Type I ◽

Type Ii ◽

Loss Of Function ◽

Brain Malformations

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-AKT3-mTOR-signaling 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) classified using imaging and pathological findings. 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 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 very 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 FCD 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.

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Detection of epileptogenic focus using advanced dynamic statistical parametric mapping with magnetoencephalography in a patient with MRI-negative focal cortical dysplasia type IIB

Journal of Neurosurgery Pediatrics ◽

10.3171/2019.7.peds1948 ◽

2020 ◽

Vol 25 (1) ◽

pp. 78-82 ◽

Cited By ~ 1

Author(s):

Won Seok Chang ◽

Midori Nakajima ◽

Ayako Ochi ◽

Elysa Widjaja ◽

James T. Rutka ◽

...

Keyword(s):

Focal Epilepsy ◽

Histopathological Examination ◽

Focal Cortical Dysplasia ◽

Statistical Parametric Mapping ◽

Cortical Dysplasia ◽

Type I ◽

Head Turning ◽

Parametric Mapping ◽

The Right ◽

Video Eeg

Advanced dynamic statistical parametric mapping (AdSPM) with magnetoencephalography (MEG) was used to identify MRI-negative epileptogenic lesions in this report. A 15-year-old girl had MRI-negative and pharmacology-resistant focal-onset epilepsy. She experienced two types of seizures. Type I consisted of her arousal from sleep, staring, and a forced head-turning movement to the left, followed by secondary generalization. Type II began with an aura of dizziness followed by staring and postictal headache with fatigue. Scalp video-electroencephalography (EEG) captured two type I seizures originating from the right frontocentral region. MEG showed scattered dipoles over the right frontal region. AdSPM identified the spike source at the bottom of the right inferior frontal sulcus. Intracranial video-EEG captured one type I seizure, which originated from the depth electrode at the bottom of the sulcus and correlated with the AdSPM spike source. Accordingly, the patient underwent resection of the middle and inferior frontal gyri, including the AdSPM-identified spike source. Histopathological examination revealed that the patient had focal cortical dysplasia type IIB. To date, the patient has been seizure free for 2 years while receiving topiramate treatment. This is the first preliminary report to identify MRI-negative epilepsy using AdSPM. Further investigation of AdSPM would be valuable for cases of MRI-negative focal epilepsy.

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Angiocentric Glioma: A Clinicopathologic Review of 5 Tumors With Identification of Associated Cortical Dysplasia

Archives of Pathology & Laboratory Medicine ◽

10.5858/2010-0668-oar ◽

2011 ◽

Vol 135 (8) ◽

pp. 1037-1041 ◽

Cited By ~ 25

Author(s):

Trent Marburger ◽

Richard Prayson

Keyword(s):

Growth Pattern ◽

Focal Cortical Dysplasia ◽

Cortical Development ◽

Temporal Cortex ◽

Cortical Dysplasia ◽

Low Grade ◽

Type I ◽

Clinicopathologic Features ◽

Malformation Of Cortical Development ◽

Angiocentric Glioma

Context.—Angiocentric glioma is a rare, epilepsy-associated, low-grade neoplasm with a characteristic perivascular growth pattern. Objective.—To describe the clinicopathologic features of 5 angiocentric gliomas and to evaluate for coexistent malformation of cortical development/cortical dysplasia. Design.—Retrospective review of the clinicopathologic features of 5 angiocentric gliomas (3 males and 2 females; median age at surgery, 10 years; range, 3–19 years). Results.—Seizures were the most common presenting symptom (n = 4); 1 patient presented with headaches. Four of the tumors were located in the parieto-occipital, parietal, or temporal cortex and 1 case arose in the thalamus. All tumors consisted of an angiocentric growth pattern of bipolar spindle cells with mild pleomorphism. Three tumors also demonstrated a focal solid growth pattern. Evidence of adjacent malformation of cortical development/focal cortical dysplasia was observed in 4 of 4 cases with sufficient tissue for evaluation; all were Palmini et al type I lesions (type IA, n = 1; type IB, n = 3). All patients were alive at last known follow-up (17–131 months). Conclusions.—The thalamic location of 1 tumor represents an undescribed location for this typically superficial cortical tumor. A subset of angiocentric gliomas, similar to other low-grade chronic epilepsy-related tumors of childhood, are associated with coexistent malformation of cortical development, suggesting a developmental basis to their origin.

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

Molecular Brain ◽

10.1186/s13041-021-00832-4 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Arpna Srivastava ◽

Krishan Kumar ◽

Jyotirmoy Banerjee ◽

Manjari Tripathi ◽

Vivek Dubey ◽

...

Keyword(s):

Rna Sequencing ◽

Focal Cortical Dysplasia ◽

Phospholipid Metabolism ◽

Cortical Dysplasia ◽

Type Ii ◽

Tissue Samples ◽

Significant Enrichment ◽

Gene Expression Studies ◽

Oligodendrocyte Development ◽

High Throughput Gene Expression

AbstractFocal 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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The RASopathy Family: Consequences of Germline Activation of the RAS/MAPK Pathway

Endocrine Reviews ◽

10.1210/er.2017-00232 ◽

2018 ◽

Vol 39 (5) ◽

pp. 676-700 ◽

Cited By ~ 38

Author(s):

Mylène Tajan ◽

Romain Paccoud ◽

Sophie Branka ◽

Thomas Edouard ◽

Armelle Yart

Keyword(s):

Noonan Syndrome ◽

Mapk Pathway ◽

Genetic Disorders ◽

Mapk Signaling ◽

Mendelian Inheritance ◽

Disease Genes ◽

Type I ◽

Future Directions ◽

Legius Syndrome ◽

Anagen Hair

Abstract Noonan syndrome [NS; Mendelian Inheritance in Men (MIM) #163950] and related syndromes [Noonan syndrome with multiple lentigines (formerly called LEOPARD syndrome; MIM #151100), Noonan-like syndrome with loose anagen hair (MIM #607721), Costello syndrome (MIM #218040), cardio-facio-cutaneous syndrome (MIM #115150), type I neurofibromatosis (MIM #162200), and Legius syndrome (MIM #611431)] are a group of related genetic disorders associated with distinctive facial features, cardiopathies, growth and skeletal abnormalities, developmental delay/mental retardation, and tumor predisposition. NS was clinically described more than 50 years ago, and disease genes have been identified throughout the last 3 decades, providing a molecular basis to better understand their physiopathology and identify targets for therapeutic strategies. Most of these genes encode proteins belonging to or regulating the so-called RAS/MAPK signaling pathway, so these syndromes have been gathered under the name RASopathies. In this review, we provide a clinical overview of RASopathies and an update on their genetics. We then focus on the functional and pathophysiological effects of RASopathy-causing mutations and discuss therapeutic perspectives and future directions.

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MRI of focal cortical dysplasia

Neuroradiology ◽

10.1007/s00234-021-02865-x ◽

2021 ◽

Author(s):

Horst Urbach ◽

Elias Kellner ◽

Nico Kremers ◽

Ingmar Blümcke ◽

Theo Demerath

Keyword(s):

Molecular Genetics ◽

Focal Cortical Dysplasia ◽

Cortical Development ◽

Cortical Dysplasia ◽

Added Value ◽

7 Tesla ◽

Type I ◽

Type Ii ◽

Malformations Of Cortical Development ◽

7 Tesla Mri

AbstractFocal cortical dysplasia (FCD) are histopathologically categorized in ILAE type I to III. Mild malformations of cortical development (mMCD) including those with oligodendroglial hyperplasia (MOGHE) are to be integrated into this classification yet. Only FCD type II have distinctive MRI and molecular genetics alterations so far. Subtle FCD including FCD type II located in the depth of a sulcus are often overlooked requiring the use of dedicated sequences (MP2RAGE, FLAWS, EDGE) and/or voxel (VBM)- or surface-based (SBM) postprocessing. The added value of 7 Tesla MRI has to be proven yet.

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Principles of Invasive EEG

Invasive Studies of the Human Epileptic Brain ◽

10.1093/med/9780198714668.003.0002 ◽

2018 ◽

pp. 19-25

Author(s):

Samden D. Lhatoo ◽

Nuria Lacuey ◽

Philippe Ryvlin

Keyword(s):

Temporal Lobe ◽

Epilepsy Surgery ◽

Focal Epilepsy ◽

Focal Cortical Dysplasia ◽

Cortical Dysplasia ◽

Palliative Surgery ◽

Mesial Temporal Sclerosis ◽

Choice Of Technique ◽

Inappropriate Choice

The growing requirement for invasive EEG in presurgical evaluation of intractable focal epilepsy has been driven largely by the increasing complexity of epilepsy surgery cases. Extratemporal surgeries now exceed anterior temporal lobe resections for mesial temporal sclerosis, and the proportion of patients undergoing invasive EEGs has significantly increased. Half of all patients undergoing stereotactic EEG (SEEG) evaluations are MRI-negative (usually with focal cortical dysplasia type 1 or 2) and a third are reoperations for failed resective or palliative surgery. Certain principles guide the decision to use invasive EEG and the choice of invasive EEG technique. SEEG has distinct advantages, as do subdural grid evaluations and intraoperative corticography. The consequences of loose hypotheses in the decision to invasively evaluate a patient, and of inappropriate choice of technique, include poor seizure outcomes after surgery, morbidity, and mortality. This chapter discusses the guiding principles for invasive studies of the human epileptic brain.

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Cortical Dyplasia: Complete Resection Correlates with Outcome…But, Complete Resection of What?

Epilepsy Currents ◽

10.1111/j.1535-7511.2009.01306.x ◽

2009 ◽

Vol 9 (4) ◽

pp. 100-102 ◽

Cited By ~ 2

Author(s):

Theodore H. Schwartz

Keyword(s):

Fdg Pet ◽

Pediatric Patients ◽

Focal Cortical Dysplasia ◽

Cortical Dysplasia ◽

Seizure Outcome ◽

Type I ◽

Type Ii ◽

Presurgical Evaluation ◽

Mri Scans

Incomplete Resection of Focal Cortical Dysplasia Is the Main Predictor of Poor Postsurgical Outcome. Krsek P, Maton B, Jayakar P, Dean P, Korman B, Rey G, Dunoyer C, Pacheco-Jacome E, Morrison G, Ragheb J, Vinters HV, Resnick T, Duchowny M. Neurology 2009;72(3):217–223. BACKGROUND: Focal cortical dysplasia (FCD) is recognized as the major cause of focal intractable epilepsy in childhood. Various factors influencing postsurgical seizure outcome in pediatric patients with FCD have been reported. OBJECTIVE: To analyze different variables in relation to seizure outcome in order to identify prognostic factors for selection of pediatric patients with FCD for epilepsy surgery. METHODS: A cohort of 149 patients with histologically confirmed mild malformations of cortical development or FCD with at least 2 years of postoperative follow-up was retrospectively studied; 113 subjects had at least 5 years of postoperative follow-up. Twenty-eight clinical, EEG, MRI, neuropsychological, surgical, and histopathologic parameters were evaluated. RESULTS: The only significant predictor of surgical success was completeness of surgical resection, defined as complete removal of the structural MRI lesion (if present) and the cortical region exhibiting prominent ictal and interictal abnormalities on intracranial EEG. Unfavorable surgical outcomes are mostly caused by overlap of dysplastic and eloquent cortical regions. There were nonsignificant trends toward better outcomes in patients with normal intelligence, after hemispherectomy and with FCD type II. Other factors such as age at seizure onset, duration of epilepsy, seizure frequency, associated pathologies including hippocampal sclerosis, extent of EEG and MRI abnormalities, as well as extent and localization of resections did not influence outcome. Twenty-five percent of patients changed Engel's class of seizure outcome after the second postoperative year. CONCLUSIONS: The ability to define and fully excise the entire region of dysplastic cortex is the most powerful variable influencing outcome in pediatric patients with focal cortical dysplasia. FDG-PET/MRI Coregistration Improves Detection of Cortical Dysplasia in Patients with Epilepsy. Salamon N, Kung J, Shaw SJ, Koo J, Koh S, Wu JY, Lerner JT, Sankar R, Shields WD, Engel J Jr, Fried I, Miyata H, Yong WH, Vinters HV, Mathern GW. Neurology 2008;71(20):1594–1601. OBJECTIVE: Patients with cortical dysplasia (CD) are difficult to treat because the MRI abnormality may be undetectable. This study determined whether fluorodeoxyglucose (FDG)-PET/MRI coregistration enhanced the recognition of CD in epilepsy surgery patients. METHODS: Patients from 2004–2007 in whom FDG-PET/MRI coregistration was a component of the presurgical evaluation were compared with patients from 2000–2003 without this technique. For the 2004–2007 cohort, neuroimaging and clinical variables were compared between patients with mild Palmini type I and severe Palmini type II CD. RESULTS: Compared with the 2000–2003 cohort, from 2004–2007 more CD patients were detected, most had type I CD, and fewer cases required intracranial electrodes. From 2004–2007, 85% of type I CD cases had normal non–University of California, Los Angeles (UCLA) MRI scans. UCLA MRI identified CD in 78% of patients, and 37% of type I CD cases had normal UCLA scans. EEG and neuroimaging findings were concordant in 52% of type I CD patients, compared with 89% of type II CD patients. FDG-PET scans were positive in 71% of CD cases, and type I CD patients had less hypometabolism compared with type II CD patients. Postoperative seizure freedom occurred in 82% of patients, without differences between type I and type II CD cases. CONCLUSIONS: Incorporating fluorodeoxyglucose-PET/MRI coregistration into the multimodality presurgical evaluation enhanced the noninvasive identification and successful surgical treatment of patients with cortical dysplasia (CD), especially for the 33% of patients with nonconcordant findings and those with normal MRI scans from mild type I CD.

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