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1.
Am J Hum Genet ; 111(9): 1994-2011, 2024 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-39168120

RESUMEN

Zinc and RING finger 3 (ZNRF3) is a negative-feedback regulator of Wnt/ß-catenin signaling, which plays an important role in human brain development. Although somatically frequently mutated in cancer, germline variants in ZNRF3 have not been established as causative for neurodevelopmental disorders (NDDs). We identified 12 individuals with ZNRF3 variants and various phenotypes via GeneMatcher/Decipher and evaluated genotype-phenotype correlation. We performed structural modeling and representative deleterious and control variants were assessed using in vitro transcriptional reporter assays with and without Wnt-ligand Wnt3a and/or Wnt-potentiator R-spondin (RSPO). Eight individuals harbored de novo missense variants and presented with NDD. We found missense variants associated with macrocephalic NDD to cluster in the RING ligase domain. Structural modeling predicted disruption of the ubiquitin ligase function likely compromising Wnt receptor turnover. Accordingly, the functional assays showed enhanced Wnt/ß-catenin signaling for these variants in a dominant negative manner. Contrarily, an individual with microcephalic NDD harbored a missense variant in the RSPO-binding domain predicted to disrupt binding affinity to RSPO and showed attenuated Wnt/ß-catenin signaling in the same assays. Additionally, four individuals harbored de novo truncating or de novo or inherited large in-frame deletion variants with non-NDD phenotypes, including heart, adrenal, or nephrotic problems. In contrast to NDD-associated missense variants, the effects on Wnt/ß-catenin signaling were comparable between the truncating variant and the empty vector and between benign variants and the wild type. In summary, we provide evidence for mirror brain size phenotypes caused by distinct pathomechanisms in Wnt/ß-catenin signaling through protein domain-specific deleterious ZNRF3 germline missense variants.


Asunto(s)
Encéfalo , Mutación de Línea Germinal , Trastornos del Neurodesarrollo , Fenotipo , Ubiquitina-Proteína Ligasas , Vía de Señalización Wnt , Humanos , Vía de Señalización Wnt/genética , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/patología , Femenino , Masculino , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Niño , Preescolar , beta Catenina/genética , beta Catenina/metabolismo , Adolescente , Mutación Missense , Estudios de Asociación Genética , Dominios Proteicos
2.
Am J Med Genet C Semin Med Genet ; : e32099, 2024 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-39016117

RESUMEN

COL4A1/2 variants are associated with highly variable multiorgan manifestations. Depicting the whole clinical spectrum of COL4A1/2-related manifestations is challenging, and there is no consensus on management and preventative strategies. Based on a systematic review of current evidence on COL4A1/2-related disease, we developed a clinical questionnaire that we administered to 43 individuals from 23 distinct families carrying pathogenic variants. In this cohort, we extended ophthalmological and cardiological examinations to asymptomatic individuals and those with only limited or mild, often nonspecific, clinical signs commonly occurring in the general population (i.e., oligosymptomatic). The most frequent clinical findings emerging from both the literature review and the questionnaire included stroke (203/685, 29.6%), seizures or epilepsy (199/685, 29.0%), intellectual disability or developmental delay (168/685, 24.5%), porencephaly/schizencephaly (168/685, 24.5%), motor impairment (162/685, 23.6%), cataract (124/685, 18.1%), hematuria (63/685, 9.2%), and retinal arterial tortuosity (58/685, 8.5%). In oligosymptomatic and asymptomatic carriers, ophthalmological investigations detected retinal vascular tortuosity (5/13, 38.5%), dysgenesis of the anterior segment (4/13, 30.8%), and cataract (2/13, 15.4%), while cardiological investigations were unremarkable except for mild ascending aortic ectasia in 1/8 (12.5%). Our multimodal approach confirms highly variable penetrance and expressivity in COL4A1/2-related conditions, even at the intrafamilial level with neurological involvement being the most frequent and severe finding in both children and adults. We propose a protocol for prevention and management based on individualized risk estimation and periodic multiorgan evaluations.

3.
Epilepsia ; 65(5): 1346-1359, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38420750

RESUMEN

OBJECTIVE: This study was undertaken to develop a standardized grading system based on expert consensus for evaluating the level of confidence in the localization of the epileptogenic zone (EZ) as reported in published studies, to harmonize and facilitate systematic reviews in the field of epilepsy surgery. METHODS: We conducted a Delphi study involving 22 experts from 18 countries, who were asked to rate their level of confidence in the localization of the EZ for various theoretical clinical scenarios, using different scales. Information provided in these scenarios included one or several of the following data: magnetic resonance imaging (MRI) findings, invasive electroencephalography summary, and postoperative seizure outcome. RESULTS: The first explorative phase showed an overall interrater agreement of .347, pointing to large heterogeneity among experts' assessments, with only 17% of the 42 proposed scenarios associated with a substantial level of agreement. A majority showed preferences for the simpler scale and single-item scenarios. The successive Delphi voting phases resulted in a majority consensus across experts, with more than two thirds of respondents agreeing on the rating of each of the tested single-item scenarios. High or very high levels of confidence were ascribed to patients with either an Engel class I or class IA postoperative seizure outcome, a well-delineated EZ according to all available invasive EEG (iEEG) data, or a well-delineated focal epileptogenic lesion on MRI. MRI signs of hippocampal sclerosis or atrophy were associated with a moderate level of confidence, whereas a low level was ascribed to other MRI findings, a poorly delineated EZ according to iEEG data, or an Engel class II-IV postoperative seizure outcome. SIGNIFICANCE: The proposed grading system, based on an expert consensus, provides a simple framework to rate the level of confidence in the EZ reported in published studies in a structured and harmonized way, offering an opportunity to facilitate and increase the quality of systematic reviews and guidelines in the field of epilepsy surgery.


Asunto(s)
Consenso , Técnica Delphi , Electroencefalografía , Epilepsia , Imagen por Resonancia Magnética , Humanos , Imagen por Resonancia Magnética/normas , Epilepsia/cirugía , Epilepsia/diagnóstico por imagen , Epilepsia/diagnóstico
4.
Brain ; 146(8): 3404-3415, 2023 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-36852571

RESUMEN

Focal cortical dysplasia (FCD) type II is a highly epileptogenic developmental malformation and a common cause of surgically treated drug-resistant epilepsy. While clinical observations suggest frequent occurrence in the frontal lobe, mechanisms for such propensity remain unexplored. Here, we hypothesized that cortex-wide spatial associations of FCD distribution with cortical cytoarchitecture, gene expression and organizational axes may offer complementary insights into processes that predispose given cortical regions to harbour FCD. We mapped the cortex-wide MRI distribution of FCDs in 337 patients collected from 13 sites worldwide. We then determined its associations with (i) cytoarchitectural features using histological atlases by Von Economo and Koskinas and BigBrain; (ii) whole-brain gene expression and spatiotemporal dynamics from prenatal to adulthood stages using the Allen Human Brain Atlas and PsychENCODE BrainSpan; and (iii) macroscale developmental axes of cortical organization. FCD lesions were preferentially located in the prefrontal and fronto-limbic cortices typified by low neuron density, large soma and thick grey matter. Transcriptomic associations with FCD distribution uncovered a prenatal component related to neuroglial proliferation and differentiation, likely accounting for the dysplastic makeup, and a postnatal component related to synaptogenesis and circuit organization, possibly contributing to circuit-level hyperexcitability. FCD distribution showed a strong association with the anterior region of the antero-posterior axis derived from heritability analysis of interregional structural covariance of cortical thickness, but not with structural and functional hierarchical axes. Reliability of all results was confirmed through resampling techniques. Multimodal associations with cytoarchitecture, gene expression and axes of cortical organization indicate that prenatal neurogenesis and postnatal synaptogenesis may be key points of developmental vulnerability of the frontal lobe to FCD. Concordant with a causal role of atypical neuroglial proliferation and growth, our results indicate that FCD-vulnerable cortices display properties indicative of earlier termination of neurogenesis and initiation of cell growth. They also suggest a potential contribution of aberrant postnatal synaptogenesis and circuit development to FCD epileptogenicity.


Asunto(s)
Displasia Cortical Focal , Malformaciones del Desarrollo Cortical , Humanos , Reproducibilidad de los Resultados , Malformaciones del Desarrollo Cortical/diagnóstico por imagen , Malformaciones del Desarrollo Cortical/genética , Malformaciones del Desarrollo Cortical/patología , Encéfalo/patología , Imagen por Resonancia Magnética/métodos
5.
Brain ; 145(5): 1653-1667, 2022 06 03.
Artículo en Inglés | MEDLINE | ID: mdl-35416942

RESUMEN

Epilepsy presurgical investigation may include focal intracortical single-pulse electrical stimulations with depth electrodes, which induce cortico-cortical evoked potentials at distant sites because of white matter connectivity. Cortico-cortical evoked potentials provide a unique window on functional brain networks because they contain sufficient information to infer dynamical properties of large-scale brain connectivity, such as preferred directionality and propagation latencies. Here, we developed a biologically informed modelling approach to estimate the neural physiological parameters of brain functional networks from the cortico-cortical evoked potentials recorded in a large multicentric database. Specifically, we considered each cortico-cortical evoked potential as the output of a transient stimulus entering the stimulated region, which directly propagated to the recording region. Both regions were modelled as coupled neural mass models, the parameters of which were estimated from the first cortico-cortical evoked potential component, occurring before 80 ms, using dynamic causal modelling and Bayesian model inversion. This methodology was applied to the data of 780 patients with epilepsy from the F-TRACT database, providing a total of 34 354 bipolar stimulations and 774 445 cortico-cortical evoked potentials. The cortical mapping of the local excitatory and inhibitory synaptic time constants and of the axonal conduction delays between cortical regions was obtained at the population level using anatomy-based averaging procedures, based on the Lausanne2008 and the HCP-MMP1 parcellation schemes, containing 130 and 360 parcels, respectively. To rule out brain maturation effects, a separate analysis was performed for older (>15 years) and younger patients (<15 years). In the group of older subjects, we found that the cortico-cortical axonal conduction delays between parcels were globally short (median = 10.2 ms) and only 16% were larger than 20 ms. This was associated to a median velocity of 3.9 m/s. Although a general lengthening of these delays with the distance between the stimulating and recording contacts was observed across the cortex, some regions were less affected by this rule, such as the insula for which almost all efferent and afferent connections were faster than 10 ms. Synaptic time constants were found to be shorter in the sensorimotor, medial occipital and latero-temporal regions, than in other cortical areas. Finally, we found that axonal conduction delays were significantly larger in the group of subjects younger than 15 years, which corroborates that brain maturation increases the speed of brain dynamics. To our knowledge, this study is the first to provide a local estimation of axonal conduction delays and synaptic time constants across the whole human cortex in vivo, based on intracerebral electrophysiological recordings.


Asunto(s)
Epilepsia , Potenciales Evocados , Teorema de Bayes , Encéfalo , Mapeo Encefálico/métodos , Estimulación Eléctrica/métodos , Potenciales Evocados/fisiología , Humanos
6.
Brain ; 145(8): 2687-2703, 2022 08 27.
Artículo en Inglés | MEDLINE | ID: mdl-35675510

RESUMEN

Vacuolar-type H+-ATPase (V-ATPase) is a multimeric complex present in a variety of cellular membranes that acts as an ATP-dependent proton pump and plays a key role in pH homeostasis and intracellular signalling pathways. In humans, 22 autosomal genes encode for a redundant set of subunits allowing the composition of diverse V-ATPase complexes with specific properties and expression. Sixteen subunits have been linked to human disease. Here we describe 26 patients harbouring 20 distinct pathogenic de novo missense ATP6V1A variants, mainly clustering within the ATP synthase α/ß family-nucleotide-binding domain. At a mean age of 7 years (extremes: 6 weeks, youngest deceased patient to 22 years, oldest patient) clinical pictures included early lethal encephalopathies with rapidly progressive massive brain atrophy, severe developmental epileptic encephalopathies and static intellectual disability with epilepsy. The first clinical manifestation was early hypotonia, in 70%; 81% developed epilepsy, manifested as developmental epileptic encephalopathies in 58% of the cohort and with infantile spasms in 62%; 63% of developmental epileptic encephalopathies failed to achieve any developmental, communicative or motor skills. Less severe outcomes were observed in 23% of patients who, at a mean age of 10 years and 6 months, exhibited moderate intellectual disability, with independent walking and variable epilepsy. None of the patients developed communicative language. Microcephaly (38%) and amelogenesis imperfecta/enamel dysplasia (42%) were additional clinical features. Brain MRI demonstrated hypomyelination and generalized atrophy in 68%. Atrophy was progressive in all eight individuals undergoing repeated MRIs. Fibroblasts of two patients with developmental epileptic encephalopathies showed decreased LAMP1 expression, Lysotracker staining and increased organelle pH, consistent with lysosomal impairment and loss of V-ATPase function. Fibroblasts of two patients with milder disease, exhibited a different phenotype with increased Lysotracker staining, decreased organelle pH and no significant modification in LAMP1 expression. Quantification of substrates for lysosomal enzymes in cellular extracts from four patients revealed discrete accumulation. Transmission electron microscopy of fibroblasts of four patients with variable severity and of induced pluripotent stem cell-derived neurons from two patients with developmental epileptic encephalopathies showed electron-dense inclusions, lipid droplets, osmiophilic material and lamellated membrane structures resembling phospholipids. Quantitative assessment in induced pluripotent stem cell-derived neurons identified significantly smaller lysosomes. ATP6V1A-related encephalopathy represents a new paradigm among lysosomal disorders. It results from a dysfunctional endo-lysosomal membrane protein causing altered pH homeostasis. Its pathophysiology implies intracellular accumulation of substrates whose composition remains unclear, and a combination of developmental brain abnormalities and neurodegenerative changes established during prenatal and early postanal development, whose severity is variably determined by specific pathogenic variants.


Asunto(s)
Encefalopatías , Epilepsia , Discapacidad Intelectual , Espasmos Infantiles , ATPasas de Translocación de Protón Vacuolares , Adenosina Trifosfato , Atrofia , Niño , Homeostasis , Humanos , Lactante , Lisosomas , Fenotipo
7.
Pract Neurol ; 23(4): 293-302, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-36823117

RESUMEN

Focal cortical dysplasia (FCD) is a malformation of cortical development characterised by disruption of cortical cytoarchitecture. Classification of FCDs subtypes has initially been based on correlation of the histopathology with relevant clinical, electroencephalographic and neuroimaging features. A recently proposed classification update recommends a multilayered, genotype-phenotype approach, integrating findings from histopathology, genetic analysis of resected tissue and presurgical MRI. FCDs are caused either by single somatic activating mutations in MTOR pathway genes or by double-hit inactivating mutations with a constitutional and a somatic loss-of-function mutation in repressors of the signalling pathway. Mild malformation with oligodendroglial hyperplasia in epilepsy is caused by somatic pathogenic SLC35A2 mutations. FCDs most often present with drug-resistant focal epilepsy or epileptic encephalopathy. Most patients respond to surgical treatment. The use of mechanistic target of rapamycin inhibitors may complement the surgical approach. Treatment approaches and outcomes have improved with advances in neuroimaging, neurophysiology and genetics, although predictors of treatment response have only been determined in part.


Asunto(s)
Epilepsia Refractaria , Epilepsia , Displasia Cortical Focal , Malformaciones del Desarrollo Cortical , Humanos , Malformaciones del Desarrollo Cortical/diagnóstico por imagen , Malformaciones del Desarrollo Cortical/genética , Malformaciones del Desarrollo Cortical/terapia , Neurólogos , Epilepsia/patología , Mutación
8.
Ann Neurol ; 90(2): 274-284, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34185323

RESUMEN

OBJECTIVE: The MAST family of microtubule-associated serine-threonine kinases (STKs) have distinct expression patterns in the developing and mature human and mouse brain. To date, only MAST1 has been conclusively associated with neurological disease, with de novo variants in individuals with a neurodevelopmental disorder, including a mega corpus callosum. METHODS: Using exome sequencing, we identify MAST3 missense variants in individuals with epilepsy. We also assess the effect of these variants on the ability of MAST3 to phosphorylate the target gene product ARPP-16 in HEK293T cells. RESULTS: We identify de novo missense variants in the STK domain in 11 individuals, including 2 recurrent variants p.G510S (n = 5) and p.G515S (n = 3). All 11 individuals had developmental and epileptic encephalopathy, with 8 having normal development prior to seizure onset at <2 years of age. All patients developed multiple seizure types, 9 of 11 patients had seizures triggered by fever and 9 of 11 patients had drug-resistant seizures. In vitro analysis of HEK293T cells transfected with MAST3 cDNA carrying a subset of these patient-specific missense variants demonstrated variable but generally lower expression, with concomitant increased phosphorylation of the MAST3 target, ARPP-16, compared to wild-type. These findings suggest the patient-specific variants may confer MAST3 gain-of-function. Moreover, single-nuclei RNA sequencing and immunohistochemistry shows that MAST3 expression is restricted to excitatory neurons in the cortex late in prenatal development and postnatally. INTERPRETATION: In summary, we describe MAST3 as a novel epilepsy-associated gene with a potential gain-of-function pathogenic mechanism that may be primarily restricted to excitatory neurons in the cortex. ANN NEUROL 2021;90:274-284.


Asunto(s)
Epilepsia/diagnóstico por imagen , Epilepsia/genética , Variación Genética/genética , Proteínas Asociadas a Microtúbulos/genética , Proteínas Serina-Treonina Quinasas/genética , Adolescente , Adulto , Secuencia de Aminoácidos , Animales , Niño , Estudios de Cohortes , Epilepsia/metabolismo , Femenino , Estudios de Seguimiento , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas Asociadas a Microtúbulos/biosíntesis , Proteínas Serina-Treonina Quinasas/biosíntesis , Adulto Joven
9.
Epilepsia ; 63(4): 769-776, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35165888

RESUMEN

OBJECTIVE: Temporal plus epilepsy (TPE) represents a rare type of epilepsy characterized by a complex epileptogenic zone including the temporal lobe and the close neighboring structures. We investigated whether the complete resection of temporal plus epileptogenic zone as defined through stereoelectroencephalography (SEEG) might improve seizure outcome in 38 patients with TPE. METHODS: Inclusion criteria were as follows: epilepsy surgery performed between January 1990 and December 2001, SEEG defining a temporal plus epileptogenic zone, unilobar temporal operations ("temporal lobe epilepsy [TLE] surgery") or multilobar interventions including the temporal lobe ("TPE surgery"), magnetic resonance imaging either normal or showing signs of hippocampal sclerosis, and postoperative follow-up of at least 12 months. For each assessment of postoperative seizure outcome, at 1, 2, 5, and 10 years, we carried out descriptive analysis and classical tests of hypothesis, namely, Pearson χ2 test or Fisher exact test of independence on tables of frequency for each categorical variable of interest and Student t-test for each continuous variable of interest, when appropriate. RESULTS: Twenty-one patients underwent TPE surgery and 17 underwent TLE surgery with a follow-up of 12.4 ± 8.16 years. In the multivariate models, there was a significant effect of the time from surgery on Engel Class IA versus IB-IV outcome, with a steadily worsening trend from 5-year follow-up onward. TPE surgery was associated with better results than TLE surgery. SIGNIFICANCE: This study suggests that surgical outcome in patients with TPE can be improved by a tailored, multilobar resection and confirms that SEEG is mandatory when a TPE is suspected.


Asunto(s)
Epilepsia del Lóbulo Temporal , Epilepsia , Electroencefalografía/métodos , Epilepsia del Lóbulo Temporal/diagnóstico por imagen , Epilepsia del Lóbulo Temporal/cirugía , Humanos , Estudios Retrospectivos , Convulsiones , Resultado del Tratamiento
10.
Epilepsia ; 63(1): 61-74, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34845719

RESUMEN

OBJECTIVE: Drug-resistant focal epilepsy is often caused by focal cortical dysplasias (FCDs). The distribution of these lesions across the cerebral cortex and the impact of lesion location on clinical presentation and surgical outcome are largely unknown. We created a neuroimaging cohort of patients with individually mapped FCDs to determine factors associated with lesion location and predictors of postsurgical outcome. METHODS: The MELD (Multi-centre Epilepsy Lesion Detection) project collated a retrospective cohort of 580 patients with epilepsy attributed to FCD from 20 epilepsy centers worldwide. Magnetic resonance imaging-based maps of individual FCDs with accompanying demographic, clinical, and surgical information were collected. We mapped the distribution of FCDs, examined for associations between clinical factors and lesion location, and developed a predictive model of postsurgical seizure freedom. RESULTS: FCDs were nonuniformly distributed, concentrating in the superior frontal sulcus, frontal pole, and temporal pole. Epilepsy onset was typically before the age of 10 years. Earlier epilepsy onset was associated with lesions in primary sensory areas, whereas later epilepsy onset was associated with lesions in association cortices. Lesions in temporal and occipital lobes tended to be larger than frontal lobe lesions. Seizure freedom rates varied with FCD location, from around 30% in visual, motor, and premotor areas to 75% in superior temporal and frontal gyri. The predictive model of postsurgical seizure freedom had a positive predictive value of 70% and negative predictive value of 61%. SIGNIFICANCE: FCD location is an important determinant of its size, the age at epilepsy onset, and the likelihood of seizure freedom postsurgery. Our atlas of lesion locations can be used to guide the radiological search for subtle lesions in individual patients. Our atlas of regional seizure freedom rates and associated predictive model can be used to estimate individual likelihoods of postsurgical seizure freedom. Data-driven atlases and predictive models are essential for evidence-based, precision medicine and risk counseling in epilepsy.


Asunto(s)
Epilepsia Refractaria , Epilepsia , Malformaciones del Desarrollo Cortical , Niño , Epilepsia Refractaria/complicaciones , Epilepsia Refractaria/diagnóstico por imagen , Epilepsia Refractaria/cirugía , Epilepsia/diagnóstico por imagen , Epilepsia/etiología , Epilepsia/cirugía , Libertad , Humanos , Imagen por Resonancia Magnética , Malformaciones del Desarrollo Cortical/complicaciones , Malformaciones del Desarrollo Cortical/diagnóstico por imagen , Malformaciones del Desarrollo Cortical/cirugía , Estudios Retrospectivos , Convulsiones/diagnóstico por imagen , Convulsiones/etiología , Convulsiones/cirugía , Resultado del Tratamiento
11.
Neurol Sci ; 43(7): 4453-4461, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-35312881

RESUMEN

The current study, conceived with the contribution of the Commission for Epilepsy Surgery of the Italian League Against Epilepsy (LICE) and the Epilepsy Study Group of the Italian Neurological Society (SIN), aimed to assess potential physician-related barriers to refer subjects for epilepsy surgery. All the members of SIN and LICE were invited by email to complete a 28-item online questionnaire. The survey items included: (1) individual and medical practice characteristics, (2) knowledge of current indications to select candidates for epilepsy surgery, (3) factors potentially affecting the attitude toward epilepsy surgery. Overall, 210 physicians completed the survey. More than half (63.3%) of the participants showed proper knowledge of the ILAE drug-resistance. Definition and almost two-thirds of them (71.9%) considered themselves adequately informed about indications, risks, and benefits of epilepsy surgery. Surgery was regarded as a valid option to be used as early as possible by 84.8% of the interviewees, and 71% of them estimated its complication rate to be low. However, more than half (63%) of the respondents reportedly referred patients for surgery only after the failure of 3-5 antiseizure medications. Overestimation of risks/complications of surgery and inadequate healthcare resources were identified as the main factor contrasting the patient referral for surgery by 43% and 40.5% of the participants, respectively. In conclusion, this survey confirms the existence of knowledge gap within both physicians and the healthcare system, as well as an educational need regarding epilepsy surgery. Further researches are warranted to define learning outcomes and optimize educational tools.


Asunto(s)
Epilepsia , Médicos , Epilepsia/tratamiento farmacológico , Epilepsia/cirugía , Conocimientos, Actitudes y Práctica en Salud , Humanos , Neurólogos , Encuestas y Cuestionarios
12.
Hum Mol Genet ; 28(22): 3755-3765, 2019 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-31411685

RESUMEN

Single germline or somatic activating mutations of mammalian target of rapamycin (mTOR) pathway genes are emerging as a major cause of type II focal cortical dysplasia (FCD), hemimegalencephaly (HME) and tuberous sclerosis complex (TSC). A double-hit mechanism, based on a primary germline mutation in one allele and a secondary somatic hit affecting the other allele of the same gene in a small number of cells, has been documented in some patients with TSC or FCD. In a patient with HME, severe intellectual disability, intractable seizures and hypochromic skin patches, we identified the ribosomal protein S6 (RPS6) p.R232H variant, present as somatic mosaicism at ~15.1% in dysplastic brain tissue and ~11% in blood, and the MTOR p.S2215F variant, detected as ~8.8% mosaicism in brain tissue, but not in blood. Overexpressing the two variants independently in animal models, we demonstrated that MTOR p.S2215F caused neuronal migration delay and cytomegaly, while RPS6 p.R232H prompted increased cell proliferation. Double mutants exhibited a more severe phenotype, with increased proliferation and migration defects at embryonic stage and, at postnatal stage, cytomegalic cells exhibiting eccentric nuclei and binucleation, which are typical features of balloon cells. These findings suggest a synergistic effect of the two variants. This study indicates that, in addition to single activating mutations and double-hit inactivating mutations in mTOR pathway genes, severe forms of cortical dysplasia can also result from activating mutations affecting different genes in this pathway. RPS6 is a potential novel disease-related gene.


Asunto(s)
Hemimegalencefalia/genética , Proteína S6 Ribosómica/genética , Serina-Treonina Quinasas TOR/genética , Animales , Encéfalo/metabolismo , Niño , Epilepsia Refractaria/genética , Epilepsia Refractaria/metabolismo , Epilepsia/genética , Femenino , Humanos , Malformaciones del Desarrollo Cortical/genética , Malformaciones del Desarrollo Cortical/metabolismo , Malformaciones del Desarrollo Cortical de Grupo I/genética , Ratones , Mosaicismo , Mutación , Neuronas/metabolismo , Proteína S6 Ribosómica/metabolismo , Serina-Treonina Quinasas TOR/metabolismo
13.
Epilepsia ; 62(1): 128-142, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33258120

RESUMEN

OBJECTIVE: To assess seizure and cognitive outcomes and their predictors in children (<16 years at surgery) and adults undergoing temporal lobe epilepsy (TLE) surgery in eight Italian centers. METHODS: This is a retrospective multicenter study. We performed a descriptive analysis and subsequently carried out multivariable mixed-effect models corrected for multiple comparisons. RESULTS: We analyzed data from 511 patients (114 children) and observed significant differences in several clinical features between adults and children. The possibility of achieving Engel class IA outcome and discontinuing antiepileptic drugs (AEDs) at last follow-up (FU) was significantly higher in children (P = .006 and < .0001). However, percentages of children and adults in Engel class I at last FU (mean ± SD, 45.9 ± 17 months in children; 45.9 ± 20.6 months in adults) did not differ significantly. We identified different predictors of seizure outcome in children vs adults and at short- vs long-term FU. The only variables consistently associated with class I outcome over time were postoperative electroencephalography (EEG) in adults (abnormal, improved,odds ratio [OR] = 0.414, P = .023, Q = 0.046 vs normal, at 2-year FU and abnormal, improved, OR = 0.301, P = .001, Q = 0.002 vs normal, at last FU) and the completeness of resection of temporal magnetic resonance (MR) abnormalities other than hippocampal sclerosis in children (OR = 7.93, P = .001, Q = 0.003, at 2-year FU and OR = 45.03, P < .0001, Q < 0.0001, at last FU). Cognitive outcome was best predicted by preoperative performances in either age group. SIGNIFICANCE: Clinical differences between adult and pediatric patients undergoing TLE surgery are reflected in differences in long-term outcomes and predictors of failures. Children are more likely to achieve sustained seizure freedom and withdraw AEDs after TLE surgery. Earlier referral should be encouraged as it can improve surgical outcome.


Asunto(s)
Cognición , Epilepsia del Lóbulo Temporal/cirugía , Procedimientos Neuroquirúrgicos , Adolescente , Adulto , Factores de Edad , Anticonvulsivantes/uso terapéutico , Niño , Preescolar , Intervención Médica Temprana , Electroencefalografía , Epilepsia del Lóbulo Temporal/tratamiento farmacológico , Epilepsia del Lóbulo Temporal/fisiopatología , Epilepsia del Lóbulo Temporal/psicología , Femenino , Hipocampo/patología , Humanos , Masculino , Malformaciones del Desarrollo Cortical/patología , Pruebas Neuropsicológicas , Complicaciones Posoperatorias/epidemiología , Pronóstico , Estudios Retrospectivos , Esclerosis , Adulto Joven
14.
Cereb Cortex ; 30(11): 6039-6050, 2020 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-32582916

RESUMEN

Protocadherin-19 (PCDH19) is a calcium dependent cell-adhesion molecule involved in neuronal circuit formation with prevalent expression in the limbic structures. PCDH19-gene mutations cause a developmental encephalopathy with prominent infantile onset focal seizures, variably associated with intellectual disability and autistic features. Diagnostic neuroimaging is usually unrevealing. We used quantitative MRI to investigate the cortex and white matter in a group of 20 PCDH19-mutated patients. By a statistical comparison between quantitative features in PCDH19 brains and in a group of age and sex matched controls, we found that patients exhibited bilateral reductions of local gyrification index (lGI) in limbic cortical areas, including the parahippocampal and entorhinal cortex and the fusiform and lingual gyri, and altered diffusivity features in the underlying white matter. In patients with an earlier onset of seizures, worse psychiatric manifestations and cognitive impairment, reductions of lGI and diffusivity abnormalities in the limbic areas were more pronounced. Developmental abnormalities involving the limbic structures likely represent a measurable anatomic counterpart of the reduced contribution of the PCDH19 protein to local cortical folding and white matter organization and are functionally reflected in the phenotypic features involving cognitive and communicative skills as well as local epileptogenesis.


Asunto(s)
Sistema Límbico/fisiopatología , Protocadherinas/genética , Espasmos Infantiles/genética , Espasmos Infantiles/fisiopatología , Adolescente , Adulto , Mapeo Encefálico/métodos , Niño , Preescolar , Femenino , Humanos , Lactante , Imagen por Resonancia Magnética/métodos , Masculino , Mutación , Sustancia Blanca/fisiopatología , Adulto Joven
15.
Neurol Sci ; 42(6): 2249-2260, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33797619

RESUMEN

In 2009, the Commission for Epilepsy Surgery of the Italian League Against Epilepsy (LICE) conducted an overview about the techniques used for the pre-surgical evaluation and the surgical treatment of epilepsies. The recognition that, in selected cases, surgery can be considered the first-line approach, suggested that the experience gained by the main Italian referral centers should be pooled in order to provide a handy source of reference. In light of the progress made over these past years, some parts of that first report have accordingly been updated. The present revision aims to harmonize the general principles regulating the patient selection and the pre-surgical work-up, as well as to expand the use of epilepsy surgery, that still represents an underutilized resource, regrettably. The objective of this contribution is drawing up a methodological framework within which to integrate the experiences of each group in this complex and dynamic sector of the neurosciences.


Asunto(s)
Epilepsia , Neurociencias , Epilepsia/cirugía , Humanos , Procedimientos Neuroquirúrgicos , Selección de Paciente , Derivación y Consulta
16.
Ann Diagn Pathol ; 54: 151774, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-34182416

RESUMEN

Dysembryoplastic neuroepithelial tumors (DNT) is a benign (World Health Organisation, WHO, grade I) glioneuronal tumor and it represent one of the most frequent neoplasm in patient affected by seizures. The epileptic neuronal activity can be determined by abnormal synchronization, excessive glutamate excitation and\or inadequate GABA inhibition. Increasing evidence suggests that the astrocytes might be involved in this process even if neurons play a relevant role. In particular astrocytes promote the clearance of glutamate, a potent excitatory neurotransmitter of the central nervous system. Indeed, elevated concentrations of extracellular glutamate may determine iper-excitability and seizures as well as other neurological disorders. So, astrocytes, converting glutamate into glutamine via the enzyme glutamine synthetase (GS), could play a protective anti-seizures role. In the present study, we analyzed the immunohistochemical expression of GS in 20 DNTs specimens documenting a constant immunoistochemical expression of GS in astrocytes of the lesional tissue and of the cerebral cortex.


Asunto(s)
Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Glutamato-Amoníaco Ligasa/metabolismo , Neoplasias Neuroepiteliales/metabolismo , Adolescente , Astrocitos/metabolismo , Astrocitos/patología , Neoplasias Encefálicas/patología , Niño , Preescolar , Femenino , Glioma/patología , Humanos , Inmunohistoquímica/métodos , Masculino , Neoplasias Neuroepiteliales/patología , Neuronas/patología , Adulto Joven
17.
Epilepsia ; 61(2): 216-227, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31876960

RESUMEN

OBJECTIVE: To profile European trends in pediatric epilepsy surgery (<16 years of age) between 2008 and 2015. METHODS: We collected information on volumes and types of surgery, pathology, and seizure outcome from 20 recognized epilepsy surgery reference centers in 10 European countries. RESULTS: We analyzed retrospective aggregate data on 1859 operations. The proportion of surgeries significantly increased over time (P < .0001). Engel class I outcome was achieved in 69.3% of children, with no significant improvement between 2008 and 2015. The proportion of histopathological findings consistent with glial scars significantly increased between the ages of 7 and 16 years (P for trend = .0033), whereas that of the remaining pathologies did not vary across ages. A significant increase in unilobar extratemporal surgeries (P for trend = .0047) and a significant decrease in unilobar temporal surgeries (P for trend = .0030) were observed between 2008 and 2015. Conversely, the proportion of multilobar surgeries and unrevealing magnetic resonance imaging cases remained unchanged. Invasive investigations significantly increased, especially stereo-electroencephalography. We found different trends comparing centers starting their activity in the 1990s to those whose programs were developed in the past decade. Multivariate analysis revealed a significant variability of the proportion of the different pathologies and surgical approaches across countries, centers, and age groups between 2008 and 2015. SIGNIFICANCE: Between 2008 and 2015, we observed a significant increase in the volume of pediatric epilepsy surgeries, stability in the proportion of Engel class I outcomes, and a modest increment in complexity of the procedures.


Asunto(s)
Epilepsia/cirugía , Neurocirugia/tendencias , Procedimientos Neuroquirúrgicos/tendencias , Adolescente , Factores de Edad , Niño , Preescolar , Electroencefalografía , Epilepsia/epidemiología , Epilepsia/patología , Europa (Continente)/epidemiología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Neurocirugia/estadística & datos numéricos , Procedimientos Neuroquirúrgicos/estadística & datos numéricos , Estudios Retrospectivos , Convulsiones/epidemiología , Lóbulo Temporal/diagnóstico por imagen , Lóbulo Temporal/cirugía , Resultado del Tratamiento
19.
Epilepsy Behav ; 93: 22-28, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30780077

RESUMEN

OBJECTIVE: The objective of the study was to evaluate clinical characteristics and outcome of hemispherotomy in children and adolescents with hemispheric refractory epilepsy in an Italian cohort of patients. METHODS: We retrospectively evaluated the clinical course and outcome of 92 patients with refractory epilepsy who underwent hemispherotomy in three Italian epilepsy centers between 2006 and 2016. Three different approaches for hemispherotomy were used: parasagittal, modified parasagittal, and lateral. RESULTS: Mean age at epilepsy onset was 1.8 ±â€¯2.51 years, and mean duration of epilepsy prior to surgery was 7.4 ±â€¯5.6 years. Mean age at surgery was 9.2 ±â€¯8.0 years. After a mean follow-up of 2.81 ±â€¯2.4 years, 66 of 90 patients (two lost from follow-up, 73.3%) were seizure-free (Engel class I). The etiology of epilepsy was related to acquired lesions (encephalomalacia or gliosis) in 44 patients (47.8%), congenital malformations (cortical dysplasia, hemimegalencephaly, other cortical malformations) in 38 (41.3%), and progressive conditions (Rasmussen or Sturge-Weber syndrome) in 10 patients (10.9%). Regarding seizure outcome, we could not identify statistically significant differences between vertical and lateral approaches (p = 0.154). Seizure outcome was not statistically different in patients with congenital vs acquired or progressive etiologies (p = 0.43). Acute postoperative seizures (APOS) correlated with poor outcome (p < 0.05). On multivariate analysis, presurgical focal to bilateral tonic-clonic seizures (Odds Ratio (OR) = 3.63, 95% Confidence Interval (CI): 1.86-15.20, p = 0.048) independently predicted seizure recurrence. Twenty-one patients (22.8%) exhibited postoperative complications, with no unexpected and persistent neurological deficit. More than 50% of the patients completely tapered drugs. SIGNIFICANCE: Our data confirm hemispherotomy to be a safe and effective procedure in patients with drug resistant epilepsies due to hemispheric lesions. Presurgical focal to bilateral tonic-clonic seizures are the strongest predictor of seizure recurrence after surgery, independently from the type of hemispherotomy.


Asunto(s)
Epilepsia Refractaria/cirugía , Hemisferectomía , Adolescente , Adulto , Niño , Preescolar , Epilepsia Refractaria/diagnóstico , Epilepsia Refractaria/etiología , Femenino , Estudios de Seguimiento , Humanos , Lactante , Italia , Masculino , Complicaciones Posoperatorias/epidemiología , Recurrencia , Estudios Retrospectivos , Resultado del Tratamiento , Adulto Joven
20.
Cereb Cortex ; 28(3): 1076-1086, 2018 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-28334078

RESUMEN

Polymicrogyria is a malformation of cortical folding and layering underlying different cognitive and neurological manifestations. The polymicrogyric cortex has heterogeneous morphofunctional patterns, qualitatively described at magnetic resonance imaging (MRI) by variable severity gradients and functional activations. We investigated the link between abnormal cortical folding and cortical function in order to improve surgical planning for patients with polymicrogyria and intractable epilepsy. We performed structural and functional MRI on 14 patients with perisylvian polymicrogyria and adopted surface-based methods to detect alterations of cortical thickness (CT) and local gyrification index (LGI) compared with normal cortex (30 age-matched subjects). We quantitatively assessed the grade of anatomic disruption of the polymicrogyric cortex and defined its relationship with decreased cortical function. We observed a good matching between visual analysis and morphometric measurements. CT maps revealed sparse clusters of thickening, while LGI maps disclosed circumscribed regions of maximal alteration with a uniformly decreasing centrifugal gradient. In polymicrogyric areas in which gyral and sulcal patterns were preserved, functional activation maintained the expected location, but was reduced in extent. Morphofunctional correlations, evaluated along cortico-cortical paths between maximum morphologic alterations and significant activations, identified an interindividual threshold for LGI (z-value = -1.09) beyond which functional activations were no longer identifiable.


Asunto(s)
Mapeo Encefálico , Polimicrogiria/diagnóstico por imagen , Polimicrogiria/fisiopatología , Estudios de Casos y Controles , Femenino , Lateralidad Funcional , Humanos , Procesamiento de Imagen Asistido por Computador , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Oxígeno/sangre
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