scholarly journals DEPDC5 variant in focal cortical dysplasia: a case report and review of the literature

2021 ◽  
Vol 2021 (5) ◽  
Author(s):  
Joana Jesus-Ribeiro ◽  
Cristina Pereira ◽  
Conceição Robalo ◽  
Daniela J Pereira ◽  
Diana Duro ◽  
...  
Keyword(s):  
Focal Epilepsy ◽  
Focal Cortical Dysplasia ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Missense Variant ◽  
Cortical Dysplasia ◽  
Negative Regulator ◽  
Missense Variants ◽  
Borderline Intellectual Functioning ◽  
Unknown Significance

ABSTRACT Germline and 2-hit brain somatic variants in DEPDC5 gene, a negative regulator of the mammalian target of rapamycin (mTOR) pathway, are increasingly recognized in patients with focal cortical dysplasia (FCD). Next-generation targeted sequencing identified a heterozygous germline variant in DEPDC5 gene (c.3241A>C, p.Thr1081Pro), classified as of unknown significance, in a patient with clinical features compatible with DEPDC5 phenotype (FCD, focal epilepsy, attention-deficit/hyperactivity disorder and borderline intellectual functioning). This missense variant has previously been reported in two other epileptic patients. Although interpretation of missense variants remains a challenge, DEPDC5 variants in patients with FCD and epilepsy cannot be neglected. Null variants were the most frequently reported in FCD patients, but missense variants have been described as well. The recognition of DEPDC5 phenotype and the appropriate interpretation of the detected variants are essential, since it may have important treatment implications in the near future, namely the use of mTOR inhibitors.

scholarly journals Systematic analysis of PINK1 variants of unknown significance shows intact mitophagy function for most variants

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Kai Yu Ma ◽  
Michiel R. Fokkens ◽  
Teus van Laar ◽  
Dineke S. Verbeek
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Missense Variant ◽  
Population Based ◽  
Loss Of Function ◽  
Systematic Analysis ◽  
Missense Variants ◽  
Variants Of Unknown Significance ◽  
Disease Case ◽  
Unknown Significance

AbstractPathogenic variants in PINK1 cause early-onset Parkinson’s disease. Although many PINK1 variants have been reported, the clinical significance is uncertain for the majority of them. To gain insights into the consequences of PINK1 missense variants in a systematic manner, we selected 50 PINK1 missense variants from patient- and population-wide databases and systematically classified them using Sherloc, a comprehensive framework for variant interpretation based on ACMG-AMP guidelines. We then performed functional experiments, including mitophagy and Parkin recruitment assays, to assess the downstream consequences of PINK1 variants. Analysis of PINK1 missense variants based on Sherloc showed that the patient databases over-annotate variants as likely pathogenic. Furthermore, our study shows that pathogenic PINK1 variants are most often linked to a loss-of-function for mitophagy and Parkin recruitment, while this is not observed for variants of unknown significance. In addition to the Sherloc framework, the added layer of evidence of our functional tests suggests a reclassification of 9/50 missense variants. In conclusion, we suggest the assessment of multiple layers of evidence, including functional data on top of available clinical and population-based data, to support the clinical classification of a variant and show that the presence of a missense variant in PINK1 in a Parkinson’s disease case does not automatically imply pathogenicity.

Principles of Invasive EEG

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.

scholarly journals Seven tesla MRI improves detection of focal cortical dysplasia in patients with refractory focal epilepsy

2017 ◽  
Vol 2 (2) ◽  
pp. 162-171 ◽  
Author(s):  
Tim J. Veersema ◽  
Cyrille H. Ferrier ◽  
Pieter van Eijsden ◽  
Peter H. Gosselaar ◽  
Eleonora Aronica ◽  
...  
Keyword(s):  
Focal Epilepsy ◽  
Focal Cortical Dysplasia ◽  
Cortical Dysplasia

scholarly journals Particularities in differential diagnostics of epileptogenic brain malformations on the low-field MRI-device

2019 ◽  
Vol 13 (4) ◽  
pp. 23-39
Author(s):  
V. S. Khalilov ◽  
A. A. Kholin ◽  
B. R. Bakaeva ◽  
M. Yu. Bobylova ◽  
Kh. Sh. Gazdieva
Keyword(s):  
High Field ◽  
Focal Epilepsy ◽  
Focal Cortical Dysplasia ◽  
Cortical Dysplasia ◽  
Differential Diagnostics ◽  
High Field Mri ◽  
Low Field ◽  
Brain Malformations ◽  
Low Field Mri

Background.It has been suggested that the part of the cryptogenic epilepsies is a consequence of minor-foci disorders of cortical architectonics, the diagnosis of which is not always possible due to the unavailability of MR-scanners with high magnetic induction.Objective:determination of the best options of the low-field MRI-device for visualization of epileptogenic brain malformations in children with symptomatic focal forms of epilepsy.Materials and methods.Were analyzed MRI data of 24 children undergoing investigations regarding for difficult-to-treat or pharmacoresistant forms of focal epilepsy in the Department of Magnetic-Resonance Tomography, Central Children Clinical Hospital of FMB Agency  of Russia at 2015–2017. All the patients underwent brain MRI according to standard routine protocol. Simultaneously we review conclusions of epileptologist and the preliminary video-electroencefalographic monitoring data for determination of the optimal imaging protocol for every specific form of epilepsy. For imaging of the epileptogenic brain lesion the MRI study was conducted on open-ended device “Aperto” (Hitachi Ltd., Japan) of static magnetic field with the tension characteristics of 0.4 T. The thickness of the slices and the scan step was performed  at 3.0 and 3.5 mm (the maximum value of slice thickness and step due to the technical conditions of the used scanner without losing in signalto-noise ratio) with the use of special positioning of slices in the coronal and axial projections, T2, T1, STIR, FLAIR weighted images perpendicular and parallel to the long axis of the hippocampus.Results and conclusion.In 24 patients were revealed structural brain changes that have neuroradiological signs of brain malformations. In all the patients this changes were associated with difficult to treat and drug-resistant forms of focal epilepsy. The newly identified malformations were observed in 10 patients, and in 3 cases the changes detected after previous MRI (including high-field MRI-devices) whose results were false-negative. In 11 patients diffuse brain abnormalities had been revealed, including the combinations of several hypogenesis and dysplastic pathologies. In 13 patients were marked different types of hemispheric and regional disorders of cortical development including focal cortical dysplasia. Extensive unilateral and bilateral changes were clearly distinguishable on the routine MRI. The low-tension technique approximated to the epileptic scanning protocol in some cases allowed to assess the affected area and revealed the combination of different variants of pathological cortical organization. In 7 cases the preliminary diagnosis based on the results of previous MRI studies including high-field MRI-devices. In 2 of these patients this changes were minor-focal, not visualized according to the routine MRI protocol, and had the differentiation characteristics between focal cortical dysplasia IIb/dysembryoplastic neuroepithelial tumor/ganglioglioma types. Disappointing results of visualization of mesial-basal temporal lobe regions aimed to detect small-caliber intracortical formations were observed. These patients contained a separate group of 12 children for whom extensive investigation which includes high-field MRI scan protocol on epileptic program was recommended.

scholarly journals Detection of brain somatic variation in epilepsy-associated developmental lesions

2021 ◽  
Author(s):  
Tracy A Bedrosian ◽  
Katherine E Miller ◽  
Olivia E Grischow ◽  
Hyojung Yoon ◽  
Kathleen M Schieffer ◽  
...  
Keyword(s):  
Focal Epilepsy ◽  
Mapk Pathway ◽  
Focal Cortical Dysplasia ◽  
Somatic Mosaicism ◽  
Cortical Dysplasia ◽  
Disease Genes ◽  
Low Grade ◽  
Type I ◽  
Somatic Variation ◽  
Tissue Samples

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.

Focal cortical dysplasia links to sleep-related epilepsy in symptomatic focal epilepsy

2022 ◽  
Vol 127 ◽  
pp. 108507
Author(s):  
Yunling Wang ◽  
Chenmin He ◽  
Cong Chen ◽  
Zhongjin Wang ◽  
Wenjie Ming ◽  
...  
Keyword(s):  
Focal Epilepsy ◽  
Focal Cortical Dysplasia ◽  
Cortical Dysplasia

scholarly journals Familial focal epilepsy with focal cortical dysplasia due toDEPDC5mutations

2015 ◽  
Vol 77 (4) ◽  
pp. 675-683 ◽  
Author(s):  
Stéphanie Baulac ◽  
Saeko Ishida ◽  
Elise Marsan ◽  
Catherine Miquel ◽  
Arnaud Biraben ◽  
...  
Keyword(s):  
Focal Epilepsy ◽  
Focal Cortical Dysplasia ◽  
Cortical Dysplasia

scholarly journals Is Focal Cortical Dysplasia/Epilepsy Caused by Somatic MTOR Mutations Always a Unilateral Disorder?

2020 ◽  
Vol 7 (1) ◽  
pp. e540
Author(s):  
Renzo Guerrini ◽  
Mara Cavallin ◽  
Tommaso Pippucci ◽  
Anna Rosati ◽  
Francesca Bisulli ◽  
...  
Keyword(s):  
Focal Cortical Dysplasia ◽  
Mammalian Target Of Rapamycin ◽  
Complete Removal ◽  
Cortical Dysplasia ◽  
Contralateral Hemisphere ◽  
Wide Margin ◽  
Intractable Seizures ◽  
The Brain ◽  
Time Of Origin ◽  
Brain Study

ObjectiveTo alert about the wide margin of unpredictability that distribution of somatic MTOR mosaicism may have in the brain and the risk for independent epileptogenesis arising from the seemingly healthy contralateral hemisphere after complete removal of epileptogenic focal cortical dysplasia (FCD).MethodsClinical, EEG, MRI, histopathology, and molecular genetics in 2 patients (1 and 2) treated with focal resections and subsequent complete hemispherectomy for epileptogenic FCD due to somatic MTOR mutations. Autoptic brain study of bilateral asymmetric hemispheric dysplasia and identification of alternative allele fraction (AAF) rates for AKT1 (patient 3).ResultsThe strongly hyperactivating p.Ser2215Phe (patient 1) and p.Leu1460Pro (patient 2) MTOR mutations were at low-level AAF in the dysplastic tissue. After repeated resections and eventual complete hemispherectomy, both patients manifested intractable seizures arising from the contralateral, seemingly healthy hemisphere. In patient 3, the p.Glu17Lys AKT1 mutation exhibited random distribution and AAF rates in different tissues with double levels in the more severely dysplastic cerebral hemisphere.ConclusionsOur understanding of the distribution of somatic mutations in the brain in relation to the type of malformation and its hypothesized time of origin may be faulty. Large studies may reveal that the risk of a first surgery being disappointing might be related more to the specific somatic mammalian target of rapamycin mutation identified than to completeness of resection and that the advantages of repeated resections after a first unsuccessful operation should be weighed against the risk of the contralateral hemisphere becoming in turn epileptogenic.

scholarly journals Problems of diagnosing focal cortical dysplasia

2021 ◽  
Vol 13 (1) ◽  
pp. 33-43
Author(s):  
K. D. Yakovleva ◽  
E. A. Kantemirova ◽  
D. V. Dmitrenko
Keyword(s):  
Clinical Case ◽  
Focal Epilepsy ◽  
Focal Cortical Dysplasia ◽  
Epileptiform Activity ◽  
Epileptic Seizures ◽  
Cortical Dysplasia ◽  
Differential Diagnostics ◽  
Pharmacoresistant Epilepsy ◽  
Structural Epilepsy ◽  
Generalized Epilepsy

Focal cortical dysplasia (FCD) is one of the most common causes in developing pharmacoresistant epilepsy. We present the clinical case of the patient with generalized seizures. Routine electroencephalography (EEG) data registered diffuse epileptiform activity that allowed to diagnose genetic  eneralized epilepsy and pharmacoresistant course of seizures.After performing magnetic resonance imaging using the epileptological program and video-EEG-monitoring, the diagnosis was revised: structural focal epilepsy with seizures with  focal onset with oroalimentary, gesture automatisms in the right hand, bilateral tonic-clonic, uncompensated by levetiracetam monotherapy (1500 mg/day). Background disease: congenital  malformation of the brain: FCD in the basal parts of the left temporal lobe. Lacosamide was added to the therapy in the drug dose 300 mg/day, and the frequency of epileptic seizures decreased. Differential diagnosis between genetic generalized  epilepsy and structural epilepsy with FCD usually poses no  obstacles. However, in some cases, structural epilepsy occurs  under the “mask” of generalized epilepsy. Hence, this clinical  case demonstrates the importance of diagnostic measures in the  differential diagnostics of various forms of epilepsy to determine  further tactics of patient management. 

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