75 results on '"Malformations of Cortical Development, Group II"'
Search Results
2. Newborn Periventricular Nodular Heterotopia with Persistent Feeding Cyanosis and Apneic Spell: A Case Report
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Seok Jin Hong, Ji Eun Park, Young Bae Sohn, Yoong A Suh, Jang Hoon Lee, and Moon Sung Park
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periventricular nodular heterotopia ,malformations of cortical development, group ii ,apnea ,cyanosis ,ductus arteriosus, patent ,Pediatrics ,RJ1-570 - Abstract
Periventricular nodular heterotopia (PNH) is a neuronal migration disorder that occurs during early brain development. Patients with PNH may be asymptomatic and have normal intelligence; however, PNH is also known to cause various symptoms such as seizures, dyslexia, and cardiovascular anomalies. PNH is not commonly diagnosed during early infancy because of the lack of clinical manifestations during this period. We present the case of a female infant diagnosed with PNH based on brain magnetic resonance imaging, who had symptomatic patent ductus arteriosus that had to be ligated surgically and had prolonged feeding cyanosis with frequent apneic spells.
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- 2022
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3. Magnetic resonance imaging features of isolated periventricular heterotopia in pediatric epilepsy: a comparative study
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Benjamin James, Tittle, Mohit, Maheshwari, and Ahmad, Marashly
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Epilepsy ,Periventricular Nodular Heterotopia ,Humans ,Choristoma ,Child ,Magnetic Resonance Imaging ,Malformations of Cortical Development, Group II - Abstract
Periventricular nodular heterotopia is a neurodevelopmental disorder in which neurons fail to migrate to the cortical surface, forming discrete areas of grey matter adjacent to the lateral ventricles. Given that periventricular nodular heterotopia is seen as an incidental finding in patients without epilepsy, causality between periventricular nodular heterotopia and epilepsy cannot be assumed. Furthermore, the structural characteristics of periventricular nodular heterotopia in patients with epilepsy are poorly defined and can be misleading. In this article, we investigate whether structural radiological characteristics of heterotopia can predict epileptogenicity in pediatric patients.Pediatric patients with periventricular nodular heterotopia, but no other epilepsy-associated cortical abnormalities on magnetic resonance imaging, were identified and divided into two groups: with epilepsy and without epilepsy. Radiological characteristics of laterality, regionalization, largest dimension and number of nodules were compared between the two groups.Only periventricular nodular heterotopia spreading across several regions was associated with a statistically higher chance of epilepsy. Other features including laterality, individual region, number and largest dimension did not reliably predict epileptogenicity.Most radiological characteristics of periventricular nodular heterotopia are similar in patients with and without epilepsy. The involvement of multiple periventricular regions with heterotopia was the only feature that inferred a higher risk of epilepsy. Periventricular nodular heterotopia requires a comprehensive work-up and should be interpreted in the context of each individual patient and not assumed to be directly causative of epilepsy, nor unrelated to it. Therefore, further studies using additional structural and functional imaging modalities are needed to determine the radiological features of epileptogenic periventricular nodular heterotopia.
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- 2022
4. Inborn errors of metabolism leading to neuronal migration defects
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Hendrik Rosewich, Jutta Gärtner, Stephanie Grunewald, and Stina Schiller
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Lissencephaly ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Cortex (anatomy) ,Intellectual disability ,Genetics ,Polymicrogyria ,medicine ,Humans ,Genetics (clinical) ,030304 developmental biology ,Cerebral Cortex ,Neurons ,0303 health sciences ,Human brain ,medicine.disease ,Magnetic Resonance Imaging ,Prenatal development ,3. Good health ,medicine.anatomical_structure ,Schizencephaly ,Cerebral cortex ,Mutation ,Neuroscience ,Malformations of Cortical Development, Group II ,Metabolism, Inborn Errors ,030217 neurology & neurosurgery - Abstract
The development and organisation of the human brain start in the embryonic stage and is a highly complex orchestrated process. It depends on series of cellular mechanisms that are precisely regulated by multiple proteins, signalling pathways and non-protein-coding genes. A crucial process during cerebral cortex development is the migration of nascent neuronal cells to their appropriate positions and their associated differentiation into layer-specific neurons. Neuronal migration defects (NMD) comprise a heterogeneous group of neurodevelopmental disorders including monogenetic disorders and residual syndromes due to damaging factors during prenatal development like infections, maternal diabetes mellitus or phenylketonuria, trauma, and drug use. Multifactorial causes are also possible. Classification into lissencephaly, polymicrogyria, schizencephaly, and neuronal heterotopia is based on the visible morphologic cortex anomalies. Characteristic clinical features of NMDs are severe psychomotor developmental delay, severe intellectual disability, intractable epilepsy, and dysmorphisms. Neurometabolic disorders only form a small subgroup within the large group of NMDs. The prototypes are peroxisomal biogenesis disorders, peroxisomal ß-oxidation defects and congenital disorders of O-glycosylation. The rapid evolution of biotechnology has resulted in an ongoing identification of metabolic and non-metabolic disease genes for NMDs. Nevertheless, we are far away from understanding the specific role of cortical genes and metabolites on spatial and temporal regulation of human cortex development and associated malformations. This limited understanding of the pathogenesis hinders the attempt for therapeutic approaches. In this article, we provide an overview of the most important cortical malformations and potential underlying neurometabolic disorders.
- Published
- 2019
5. Neurodevelopmental malformations of the cerebellum and neocortex in the Shank3 and Cntnap2 mouse models of autism
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Yan Li, Raddy L. Ramos, Gonzalo H. Otazu, Katherine M. Keever, Adel Elnasher, Zachary L Lodato, and Ying Li
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Male ,CNTNAP2 ,Cerebellum ,Heterozygote ,Neocortex ,Nerve Tissue Proteins ,Biology ,Mice ,mental disorders ,Genetic model ,medicine ,Animals ,Humans ,Autistic Disorder ,Mice, Knockout ,General Neuroscience ,Microfilament Proteins ,Membrane Proteins ,medicine.disease ,Phenotype ,Mice, Inbred C57BL ,Disease Models, Animal ,Heterotopia (medicine) ,medicine.anatomical_structure ,nervous system ,Cerebellar vermis ,Autism ,Female ,Neuroscience ,Malformations of Cortical Development, Group II - Abstract
There are many mouse models of autism with broad use in neuroscience research. Genetic background can be a major contributor to the phenotype observed in any mouse model of disease, including genetic models of autism. C57BL/6 mice display spontaneous glio-neuronal heterotopia in the cerebellar vermis and neocortex which may also exist in mouse models of autism created on this background. In the present report, we document the presence of cerebellar and neocortical heterotopia in heterozygous and KO Shank3 and Cntnap2 mice which are due to the C57BL/6 genotype and discuss the role these malformations may play in research using these genetic models of autism.
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- 2021
6. Sevoflurane Postconditioning Ameliorates Neuronal Migration Disorder Through Reelin/Dab1 and Improves Long-term Cognition in Neonatal Rats After Hypoxic-Ischemic Injury
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Ping Zhao, Ziyi Wu, Hang Xue, Yahan Zhang, and Qiushi Gao
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Male ,Time Factors ,Nerve Tissue Proteins ,Hippocampal formation ,Toxicology ,Neuroprotection ,Rats, Sprague-Dawley ,Sevoflurane ,Cognition ,Cell Movement ,Medicine ,Animals ,Reelin ,Ischemic Postconditioning ,Adaptor Proteins, Signal Transducing ,Neurons ,biology ,business.industry ,General Neuroscience ,Dentate gyrus ,Autophagy ,medicine.disease ,DAB1 ,Rats ,Reelin Protein ,Neuronal migration disorder ,Neuroprotective Agents ,nervous system ,Animals, Newborn ,Hypoxia-Ischemia, Brain ,biology.protein ,Signal transduction ,business ,Neuroscience ,Malformations of Cortical Development, Group II ,Platelet Aggregation Inhibitors - Abstract
Sevoflurane postconditioning (SPC) has been widely reported to attenuate brain injury after hypoxia–ischemia encephalopathy (HIE) by inhibiting neural necrosis and autophagy. Moreover, recent reports revealed that sevoflurane facilitated hippocampal reconstruction via regulating migration. Yet, it remains unclear whether the promotion of neural migration by SPC repairs the hippocampal injury after HIE. Here, we hypothesize that SPC exerts a neuroprotective effect by ameliorating neuronal migration disorder after HIE and regulating Reelin expression. Furthermore, the downstream Reelin/Dab1 pathway may be involved. The classical Rice–Vannucci model of hypoxia–ischemia was performed on postnatal day 7 rat pups, which was followed by SPC at 1 minimum alveolar concentration (MAC 2.5%) for 30 min. Piceatannol, causing Reelin aggregation in vivo, was used to detect whether Reelin/Dab1 was involved in the neuroprotection effect of SPC. Hippocampal-dependent learning ability tests were conducted to assess the long-term effects on locomotor activity and spatial learning ability. Our findings suggest that hypoxia–ischemia injury inhibited neurons migrated outward from the basal zone of dentate gyrus, disrupted cytoarchitecture of the dentate gyrus (DG), and led to long-term cognition deficits. However, SPC could relieve the restricted hippocampal neurons and repair the hippocampal-dependent memory function damaged after HIE by attenuating the overactivation of the Reelin/Dab1 pathway. These results demonstrate that SPC plays a pivotal role in ameliorating neuronal migration disorder and maintaining normal cytoarchitecture of the DG via inhibiting overactivated Reelin expression. This process may involve overactivated Reelin/Dab1 signaling pathway and spatial learning ability by regulating the Reelin expression which may associate with its neuroprotection.
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- 2020
7. EML1-associated brain overgrowth syndrome with ribbon-like heterotopia
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Maarten H. Lequin, Nadia Bahi-Buisson, Gijs van Haaften, Sanne M C Savelberg, Richard J. Leventer, Simone Mandelstam, Renske Oegema, Grazia M.S. Mancini, Anne-Gaëlle Le Moing, David Francis, Fiona Francis, Angela Barnicoat, George McGillivray, Kshitij Mankad, University Medical Center [Utrecht], Murdoch Children's Research Institute (MCRI), University of Melbourne, CHU Amiens-Picardie, Université Sorbonne Paris Cité (USPC), Université Paris Descartes - Paris 5 (UPD5), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Great Ormond Street Hospital for Children [London] (GOSH), Institut du Fer à Moulin (IFM - Inserm U1270 - SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Sorbonne Université (SU), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and Clinical Genetics
- Subjects
0301 basic medicine ,Gray matter heterotopia ,Pathology ,medicine.medical_specialty ,gray matter heterotopia ,ribbon‐like heterotopia ,[SDV]Life Sciences [q-bio] ,Mutation, Missense ,030105 genetics & heredity ,03 medical and health sciences ,Lateral ventricles ,Genetics ,medicine ,Polymicrogyria ,megalencephaly ,Humans ,Megalencephaly ,polymicrogyria ,Genetics (clinical) ,Sequence Deletion ,ribbon-like heterotopia ,Research Reviews ,business.industry ,EML1 ,Research Review ,Brain ,medicine.disease ,3. Good health ,Hydrocephalus ,030104 developmental biology ,Heterotopia (medicine) ,Neuronal migration disorder ,Overgrowth syndrome ,business ,hydrocephalus ,Microtubule-Associated Proteins ,Malformations of Cortical Development, Group II ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
International audience; EML1 encodes the protein Echinoderm microtubule-associated protein-like 1 or EMAP-1 that binds to the microtubule complex. Mutations in this gene resulting in complex brain malformations have only recently been published with limited clinical descriptions. We provide further clinical and imaging details on three previously published families, and describe two novel unrelated individuals with a homozygous partial EML1 deletion and a homozygous missense variant c.760G>A, p.(Val254Met), respectively. From review of the clinical and imaging data of eight individuals from five families with biallelic EML1 variants, a very consistent imaging phenotype emerges. The clinical syndrome is characterized by mainly neurological features including severe developmental delay, drug-resistant seizures and visual impairment. On brain imaging there is megalencephaly with a characteristic ribbon-like subcortical heterotopia combined with partial or complete callosal agenesis and an overlying polymicrogyria-like cortical malformation. Several of its features can be recognized on prenatal imaging especially the abnormaly formed lateral ventricles, hydrocephalus (in half of the cases) and suspicion of a neuronal migration disorder. In conclusion, biallelic EML1 disease-causing variants cause a highly specific pattern of congenital brain malformations, severe developmental delay, seizures and visual impairment.
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- 2019
8. Pathologic Active mTOR Mutation in Brain Malformation with Intractable Epilepsy Leads to Cell-Autonomous Migration Delay
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Shin-ichi Horike, Kenji Sugai, Yuko Saito, Masayuki Itoh, Taisuke Otsuki, Yu-ichi Goto, Mikio Hoshino, Masayuki Sasaki, Tomoo Owa, Schuichi Koizumi, Akio Takahashi, Sae Hanai, Eiji Nakagawa, Naoki Ikegaya, Sayuri Sukigara, Takashi Saito, Noriko Sato, Takanobu Kaido, and Hongmei Dai
- Subjects
0301 basic medicine ,Drug Resistant Epilepsy ,Pathology ,medicine.medical_specialty ,Hemimegalencephaly ,Biology ,Transfection ,medicine.disease_cause ,Pathology and Forensic Medicine ,Mice ,03 medical and health sciences ,Tuberous sclerosis ,0302 clinical medicine ,Germline mutation ,Positron Emission Tomography Computed Tomography ,medicine ,Animals ,Humans ,Mutation frequency ,Cells, Cultured ,PI3K/AKT/mTOR pathway ,Mutation ,TOR Serine-Threonine Kinases ,Infant ,Electroencephalography ,Cell migration ,Cortical dysplasia ,medicine.disease ,Up-Regulation ,030104 developmental biology ,Female ,Malformations of Cortical Development, Group II ,030217 neurology & neurosurgery - Abstract
The activation of phosphatidylinositol 3-kinase–AKTs–mammalian target of rapamycin cell signaling pathway leads to cell overgrowth and abnormal migration and results in various types of cortical malformations, such as hemimegalencephaly (HME), focal cortical dysplasia, and tuberous sclerosis complex. However, the pathomechanism underlying abnormal cell migration remains unknown. With the use of fetal mouse brain, we performed causative gene analysis of the resected brain tissues from a patient with HME and investigated the pathogenesis. We obtained a novel somatic mutation of the MTOR gene, having approximately 11% and 7% mutation frequency in the resected brain tissues. Moreover, we revealed that the MTOR mutation resulted in hyperphosphorylation of its downstream molecules, S6 and 4E-binding protein 1, and delayed cell migration on the radial glial fiber and did not affect other cells. We suspect cell-autonomous migration arrest on the radial glial foot by the active MTOR mutation and offer potential explanations for why this may lead to cortical malformations such as HME.
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- 2017
9. Interneuron dysfunction in epilepsy: An experimental approach using immature brain insults to induce neuronal migration disorders
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Tomoyuki Takano and Chihiro Sawai
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0301 basic medicine ,Interneuron ,Biology ,Inhibitory postsynaptic potential ,Epileptogenesis ,03 medical and health sciences ,Epilepsy ,Glutamatergic ,0302 clinical medicine ,Interneurons ,Seizures ,medicine ,Animals ,musculoskeletal, neural, and ocular physiology ,Brain ,Neural Inhibition ,medicine.disease ,030104 developmental biology ,Neuronal migration disorder ,medicine.anatomical_structure ,nervous system ,Neurology ,Cerebral cortex ,GABAergic ,Female ,Neurology (clinical) ,Neuroscience ,030217 neurology & neurosurgery ,Malformations of Cortical Development, Group II - Abstract
The main elements of the microcircuits in the cerebral cortex are excitatory glutamatergic pyramidal cells and inhibitory γ-aminobutyric acid (GABA) interneurons. Hypofunction/degeneration of GABAergic interneurons has been hypothesized to be a key to the neural circuit dysfunction that underlies epileptogenesis and the development of recurrent spontaneous seizures. Using two experimental animal models of neuronal migration disorders, this review reports that the insults to the immature developing brain causes interneurons to fail to undergo normal processes such as production, migration, and organization. These results represent critical evidence that supports a link between interneuron dysfunction and epilepsy.
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- 2019
10. Epilepsy surgery in the first months of life: a large type IIb focal cortical dysplasia causing neonatal drug-resistant epilepsy
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Ingo, Borggraefe, Moritz, Tacke, Lucia, Gerstl, Steffen, Leiz, Roland, Coras, Ingmar, Blümcke, Armin, Giese, Birgit, Ertl-Wagner, Christian T, Thiel, Soheyl, Noachtar, and Aurelia, Peraud
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Drug Resistant Epilepsy ,Child, Preschool ,Humans ,Electroencephalography ,Female ,Magnetic Resonance Imaging ,Malformations of Cortical Development, Group II - Abstract
Focal cortical dysplasia is a common cause of medically refractory epilepsy in infancy and childhood. We report a neonate with seizures occurring within the first day of life. Continuous video-EEG monitoring led to detection of left motor seizures and a right frontal EEG seizure pattern. Brain MRI revealed a lesion within the right frontal lobe without contrast enhancement. The patient was referred for epilepsy surgery due to drug resistance to vitamin B6 and four antiepileptic drugs. Lesionectomy was performed at the age of two and a half months, and histopathological evaluation confirmed the diagnosis of focal cortical dysplasia type IIb (FCD IIb). The patient is free of unprovoked seizures without medication (Engel Class I) and is normally developed at 36 months after surgery. The case study demonstrates that FCD IIb may cause seizures within the first day of life and that epilepsy surgery can be successfully performed in medically intractable patients with a clearly identifiable seizure onset zone within the first three months of life. Although radical surgery such as hemispherectomy and multi-lobar resections are over-represented in early infancy, this case also illustrates a favourable outcome with a more limited resection in this age group.
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- 2019
11. Neuronal migration disorders: Focus on the cytoskeleton and epilepsy
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Melissa A. Stouffer, Jeffrey A. Golden, and Fiona Francis
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0301 basic medicine ,Neurodevelopment ,Hippocampus ,Biology ,Inhibitory postsynaptic potential ,Article ,Mouse model ,lcsh:RC321-571 ,03 medical and health sciences ,Epilepsy ,Laminar organization ,0302 clinical medicine ,Cell Movement ,medicine ,Humans ,Molecular and cellular mechanisms ,Axon ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Cytoskeleton ,Neurons ,Cortical malformation ,Neocortex ,Brain ,medicine.disease ,Human genetics ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,Neurology ,Cerebral cortex ,Neuroscience ,Malformations of Cortical Development, Group II ,030217 neurology & neurosurgery - Abstract
A wide spectrum of focal, regional, or diffuse structural brain abnormalities, collectively known as malformations of cortical development (MCDs), frequently manifest with intellectual disability (ID), epilepsy, and/or autistic spectrum disorder (ASD). As the acronym suggests, MCDs are perturbations of the normal architecture of the cerebral cortex and hippocampus. The pathogenesis of these disorders remains incompletely understood; however, one area that has provided important insights has been the study of neuronal migration. The amalgamation of human genetics and experimental studies in animal models has led to the recognition that common genetic causes of neurodevelopmental disorders, including many severe epilepsy syndromes, are due to mutations in genes regulating the migration of newly born post-mitotic neurons. Neuronal migration genes often, though not exclusively, code for proteins involved in the function of the cytoskeleton. Other cellular processes, such as cell division and axon/dendrite formation, which similarly depend on cytoskeletal functions, may also be affected. We focus here on how the susceptibility of the highly organized neocortex and hippocampus may be due to their laminar organization, which involves the tight regulation, both temporally and spatially, of gene expression, specialized progenitor cells, the migration of neurons over large distances and a birthdate-specific layering of neurons. Perturbations in neuronal migration result in abnormal lamination, neuronal differentiation defects, abnormal cellular morphology and circuit formation. Ultimately this results in disorganized excitatory and inhibitory activity leading to the symptoms observed in individuals with these disorders.
- Published
- 2016
12. Utility of fetal MRI for workup of fetal central nervous system anomalies in an Australian maternal-fetal medicine cohort
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Jeanette Taylor, Amanda Henry, Alec W. Welsh, S. Gopikrishna, and Kathryn Irwin
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Pediatrics ,medicine.medical_specialty ,Gestational Age ,Ultrasonography, Prenatal ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,Pregnancy ,medicine ,Humans ,Medical diagnosis ,Agenesis of the corpus callosum ,Retrospective Studies ,Fetus ,030219 obstetrics & reproductive medicine ,medicine.diagnostic_test ,business.industry ,Ultrasound ,Australia ,Infant, Newborn ,Brain ,Obstetrics and Gynecology ,Magnetic resonance imaging ,General Medicine ,Prognosis ,medicine.disease ,Magnetic Resonance Imaging ,Cohort ,Gestation ,Female ,Agenesis of Corpus Callosum ,business ,Intracranial Hemorrhages ,Abortion, Eugenic ,Malformations of Cortical Development, Group II ,Hydrocephalus ,Ventriculomegaly - Abstract
Objectives To evaluate how fetal MRI is influencing current clinical practice and outcomes for central nervous system (CNS) anomalies in the Australian maternal–fetal medicine (MFM) setting. Material and Methods Retrospective audit of cases January 2008–August 2013 referred for MFM ultrasound and MRI for suspected fetal CNS anomaly. Demographics, referral information, initial MFM diagnoses and investigations, MRI diagnoses, subsequent pregnancy management and perinatal outcome were examined. Results Fifty-seven women (41 singleton, 16 twin pregnancies) were seen at mean gestation of 23.7 ± 6.5 weeks. Major referral indications included ventriculomegaly (VM, 39%) and posterior fossa anomaly (PFA, 18%). MRI was performed at mean 27.2 ± 5.3 weeks. Diagnosis was altered from ultrasound in 31/57 cases (54%); 14 improving and 17 worsening prognosis. MRI findings worsening prognosis were more significant VM and PFA, agenesis of the corpus callosum, neuronal migration disorders and intraventricular haemorrhage. TOP or selective reduction occurred in 11 of 57 cases after full clinical workup (six where MRI worsened prognosis, five where MRI confirmed US poor prognosis). Mean gestation at birth was 37.2 ± 4.1 weeks for continuing pregnancies. There were nine cases of additional postnatal diagnoses, including four CNS anomalies. After neonatal workup, physical and/or developmental delay was anticipated for at least 14 of 43 (33%) infants. Conclusions MRI added significant diagnostic information in about half the cases referred for workup of suspected CNS anomaly. In six of 17 cases where MRI worsened prognosis, TOP was chosen. Both additional CNS and non-CNS anomalies were diagnosed postnatally in 20%, emphasising the uncertain prognosis for, and evolution of, suspected CNS anomaly in fetuses.
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- 2016
13. A deletion in Eml1 leads to bilateral subcortical heterotopia in the tish rat
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Stephen D. Turner, Suchitra Joshi, Pravin K Wagley, Denise K. Grosenbaugh, Alexander F. Koeppel, Howard P. Goodkin, Kevin S. Lee, Michael J. McConnell, and Mark Fitzgerald
- Subjects
Male ,0301 basic medicine ,Dysplasia ,Classical Lissencephalies and Subcortical Band Heterotopias ,Biology ,Electroencephalography ,Article ,lcsh:RC321-571 ,03 medical and health sciences ,Exon ,Epilepsy ,0302 clinical medicine ,Seizures ,medicine ,Animals ,Epilepsy surgery ,EEG ,Allele ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Cerebral Cortex ,medicine.diagnostic_test ,medicine.disease ,Rats ,Disease Models, Animal ,030104 developmental biology ,Heterotopia (medicine) ,Neurology ,Female ,Microtubule-Associated Proteins ,Neuroscience ,Malformations of Cortical Development, Group II ,030217 neurology & neurosurgery ,Dihybrid cross - Abstract
Children with malformations of cortical development (MCD) are at risk for epilepsy, developmental delays, behavioral disorders, and intellectual disabilities. For a subset of these children, antiseizure medications or epilepsy surgery may result in seizure freedom. However, there are limited options for treating or curing the other conditions, and epilepsy surgery is not an option in all cases of pharmacoresistant epilepsy. Understanding the genetic and neurobiological mechanisms underlying MCD is a necessary step in elucidating novel therapeutic targets. The tish (telencephalic internal structural heterotopia) rat is a unique model of MCD with spontaneous seizures, but the underlying genetic mutation(s) have remained unknown. DNA and RNA-sequencing revealed that a deletion encompassing a previously unannotated first exon markedly diminished Eml1 transcript and protein abundance in the tish brain. Developmental electrographic characterization of the tish rat revealed early-onset of spontaneous spike-wave discharge (SWD) bursts beginning at postnatal day (P) 17. A dihybrid cross demonstrated that the mutant Eml1 allele segregates with the observed dysplastic cortex and the early-onset SWD bursts in monogenic autosomal recessive frequencies. Our data link the development of the bilateral, heterotopic dysplastic cortex of the tish rat to a deletion in Eml1.
- Published
- 2020
14. Neuronal Migration Disorders
- Author
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Benjamin, Roberts
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Epilepsy ,Brain ,Humans ,Magnetic Resonance Imaging ,Malformations of Cortical Development, Group II - Abstract
Enhanced understanding of brain development has led to increased awareness of the links between disorders of neuronal migration and seizure disorders. A significant number of patients with intractable epilepsy have cortical malformations that originated during neuronal migration. Magnetic resonance imaging plays a primary role in the diagnosis and classification of neuronal migration disorders. These disorders include polymicrogyria, schizencephaly, lissencephaly, heterotopia, and focal cortical dysplasia. Imaging protocols continue to evolve to provide critical assessment of anatomic and physiologic traits of these disorders to better treat and prevent seizures.
- Published
- 2018
15. Germline and somatic mutations in cortical malformations: Molecular defects in Argentinean patients with neuronal migration disorders
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Silvia Kochen, Nancy Medina, Sergio Alejandro Rodríguez-Quiroga, Dolores González-Morón, Damián Consalvo, Santiago Claverie, Marcelo A. Martí, Walter Silva, Cecilia Vazquez-Dusefante, Patricia Vega, Marcelo Andrés Kauffman, Marta Córdoba, and Sebastián Alexis Vishnopolska
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Male ,0301 basic medicine ,Heredity ,Molecular biology ,Gene Identification and Analysis ,lcsh:Medicine ,Germline ,Diagnostic Radiology ,Cohort Studies ,PAFAH1B1 ,Sequencing techniques ,0302 clinical medicine ,Medicine and Health Sciences ,FLNA ,DNA sequencing ,Copy-number variation ,lcsh:Science ,EPILEPSY ,Genetics ,education.field_of_study ,Multidisciplinary ,Radiology and Imaging ,Genomics ,Magnetic Resonance Imaging ,Genetic Mapping ,Phenotype ,Mutant Genotypes ,Female ,Transcriptome Analysis ,Research Article ,Next-Generation Sequencing ,DNA Copy Number Variations ,Genotype ,Imaging Techniques ,Population ,GENETIC ,Lissencephaly ,Biology ,Young Adult ,03 medical and health sciences ,Germline mutation ,Diagnostic Medicine ,medicine ,Humans ,education ,Mutation Detection ,Germ-Line Mutation ,Genetic heterogeneity ,lcsh:R ,Dideoxy DNA sequencing ,Biology and Life Sciences ,Computational Biology ,Human Genetics ,Genome Analysis ,medicine.disease ,Research and analysis methods ,Molecular biology techniques ,030104 developmental biology ,Mutation ,Somatic Mutation ,lcsh:Q ,Malformations of Cortical Development, Group II ,030217 neurology & neurosurgery - Abstract
Neuronal migration disorders are a clinically and genetically heterogeneous group of malformations of cortical development, frequently responsible for severe disability. Despite the increasing knowledge of the molecular mechanisms underlying this group of diseases, their genetic diagnosis remains unattainable in a high proportion of cases. Here, we present the results of 38 patients with lissencephaly, periventricular heterotopia and subcortical band heterotopia from Argentina. We performed Sanger and Next Generation Sequencing (NGS) of DCX, FLNA and ARX and searched for copy number variations by MLPA in PAFAH1B1, DCX, POMT1, and POMGNT1. Additionally, somatic mosaicism at 5% or higher was investigated by means of targeted high coverage NGS of DCX, ARX, and PAFAH1B1. Our approach had a diagnostic yield of 36%. Pathogenic or likely pathogenic variants were identified in 14 patients, including 10 germline (five novel) and 4 somatic mutations in FLNA, DCX, ARX and PAFAH1B1 genes. This study represents the largest series of patients comprehensively characterized in our population. Our findings reinforce the importance of somatic mutations in the pathophysiology and diagnosis of neuronal migration disorders and contribute to expand their phenotype-genotype correlations. Fil: González Morón, Dolores. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia ; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos ; Argentina Fil: Vishnopolska, Sebastián Alexis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina Fil: Consalvo, Damian. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos ; Argentina Fil: Medina, Nancy. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos ; Argentina Fil: Marti, Marcelo Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina Fil: Córdoba, Marta. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia ; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina Fil: Vazquez Dusefante, Cecilia. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos ; Argentina Fil: Claverie, Santiago. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos ; Argentina Fil: Rodríguez Quiroga, Sergio Alejandro. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos ; Argentina Fil: Vega, Patricia. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos ; Argentina Fil: Silva, Walter. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Hospital Italiano; Argentina Fil: Kochen, Sara Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos ; Argentina Fil: Kauffman, Marcelo Andres. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos ; Argentina. Universidad Austral; Argentina
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- 2017
16. Severe gyration and migration disorder in fetofetal transfusion syndrome: two case reports and a review of the literature on the neurological outcome of children with lesions on neuroimaging
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A. Bläser, Ina Sorge, Ulrich Thome, Rudolf Ascherl, Andreas Merkenschlager, Wieland Kiess, and Franz Wolfgang Hirsch
- Subjects
Adult ,Male ,medicine.medical_specialty ,Neuroimaging ,Fertilization in Vitro ,Nervous System Malformations ,Cerebral palsy ,03 medical and health sciences ,0302 clinical medicine ,Pregnancy ,medicine ,Polymicrogyria ,Humans ,030212 general & internal medicine ,030219 obstetrics & reproductive medicine ,medicine.diagnostic_test ,business.industry ,Cesarean Section ,Infant, Newborn ,Brain ,Magnetic resonance imaging ,General Medicine ,Fetofetal Transfusion ,medicine.disease ,Magnetic Resonance Imaging ,Surgery ,Frontal lobe ,Pediatrics, Perinatology and Child Health ,Female ,Neurology (clinical) ,Neurosurgery ,Nervous System Diseases ,business ,Malformations of Cortical Development, Group II ,Ventriculomegaly ,Follow-Up Studies - Abstract
Fetofetal transfusion syndrome is a dreaded cause of morbidity and mortality in monochorionic pregnancies. We present two pairs of twins one of which we have followed for more than 6 years. The donors suffer from cerebral palsy, orofacial, and motor problems, and both are significantly smaller than their recipient twins. Interestingly, cranial MRI revealed medial frontal lobe polymicrogyria, ventriculomegaly, and decreased thickness in both parietal lobes in both donors. We suggest this as a possible feature of fetofetal transfusion syndrome. A minireview of the literature on neuroimaging and neurodevelopmental outcome in fetofetal transfusion syndrome is presented. While the close resemblance of the imaging features of both cases is likely incidental further study of a connection between migration and gyration disorders and fetofetal transfusion syndrome is warranted.
- Published
- 2017
17. Clinical, imaging, and immunohistochemical characteristics of focal cortical dysplasia Type II extratemporal epilepsies in children: analyses of an institutional case series
- Author
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Friederike Knerlich-Lukoschus, Mary B. Connolly, Glenda Hendson, Christopher Dunham, and Paul Steinbok
- Subjects
0301 basic medicine ,Male ,Pathology ,medicine.medical_specialty ,Drug Resistant Epilepsy ,Intraoperative Neurophysiological Monitoring ,CD34 ,Neurosurgical Procedures ,White matter ,03 medical and health sciences ,Epilepsy ,0302 clinical medicine ,medicine ,Humans ,Prospective Studies ,Child ,Retrospective Studies ,Glial fibrillary acidic protein ,biology ,business.industry ,Brain ,Infant ,Histology ,General Medicine ,Cortical dysplasia ,medicine.disease ,Immunohistochemistry ,Magnetic Resonance Imaging ,030104 developmental biology ,medicine.anatomical_structure ,Child, Preschool ,biology.protein ,Female ,business ,030217 neurology & neurosurgery ,Immunostaining ,Malformations of Cortical Development, Group II ,Follow-Up Studies - Abstract
OBJECTIVE Focal cortical dysplasia (FCD) Type II is divided into 2 subgroups based on the absence (IIA) or presence (IIB) of balloon cells. In particular, extratemporal FCD Type IIA and IIB is not completely understood in terms of clinical, imaging, biological, and neuropathological differences. The aim of the authors was to analyze distinctions between these 2 formal entities and address clinical, MRI, and immunohistochemical features of extratemporal epilepsies in children. METHODS Cases formerly classified as Palmini FCD Type II nontemporal epilepsies were identified through the prospectively maintained epilepsy database at the British Columbia Children's Hospital in Vancouver, Canada. Clinical data, including age of seizure onset, age at surgery, seizure type(s) and frequency, affected brain region(s), intraoperative electrocorticographic findings, and outcome defined by Engel's classification were obtained for each patient. Preoperative and postoperative MRI results were reevaluated. H & E–stained tissue sections were reevaluated by using the 2011 International League Against Epilepsy classification system and additional immunostaining for standard cellular markers (neuronal nuclei, neurofilament, glial fibrillary acidic protein, CD68). Two additional established markers of pathology in epilepsy resection, namely, CD34 and α-B crystallin, were applied. RESULTS Seven nontemporal FCD Type IIA and 7 Type B cases were included. Patients with FCD Type IIA presented with an earlier age of epilepsy onset and slightly better Engel outcome. Radiology distinguished FCD Types IIA and IIB, in that Type IIB presented more frequently with characteristic cortical alterations. Nonphosphorylated neurofilament protein staining confirmed dysplastic cells in dyslaminated areas. The white-gray matter junction was focally blurred in patients with FCD Type IIB. α-B crystallin highlighted glial cells in the white matter and subpial layer with either of the 2 FCD Type II subtypes and balloon cells in patients with FCD Type IIB. α-B crystallin positivity proved to be a valuable tool for confirming the histological diagnosis of FCD Type IIB in specimens with rare balloon cells or difficult section orientation. Distinct nonendothelial cellular CD34 staining was found exclusively in tissue from patients with MRI-positive FCD Type IIB. CONCLUSIONS Extratemporal FCD Types IIA and IIB in the pediatric age group exhibited imaging and immunohistochemical characteristics; cellular immunoreactivity to CD34 emerged as an especially potential surrogate marker for lesional FCD Type IIB, providing additional evidence that FCD Types IIA and IIB might differ in their etiology and biology. Although the sample number in this study was small, the results further support the theory that postoperative outcome—defined by Engel's classification—is multifactorial and determined by not only histology but also the extent of the initial lesion, its location in eloquent areas, intraoperative electrocorticographic findings, and achieved resection grade.
- Published
- 2016
18. Embryonic disruption of the candidate dyslexia susceptibility gene homolog Kiaa0319-like results in neuronal migration disorders
- Author
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Gregory C. Johnson, Mary M.Y. Waye, K.A. Wright, Glenn D. Rosen, Maryann P. Platt, W.H. Tsang, A.J. Mehlhorn, R.T. Choi, M.W. Poon, S.Y. Yeung, Albert M. Galaburda, and William T. Adler
- Subjects
Neurogenesis ,Receptors, Cell Surface ,Biology ,Transfection ,Article ,Dyslexia ,Small hairpin RNA ,Neural Stem Cells ,medicine ,Animals ,Humans ,RNA, Small Interfering ,Cerebral Cortex ,Gene knockdown ,General Neuroscience ,Gene Expression Regulation, Developmental ,Nuclear Proteins ,medicine.disease ,Neural stem cell ,Rats ,Cell biology ,Corticogenesis ,Electroporation ,medicine.anatomical_structure ,Animals, Newborn ,Cerebral cortex ,Disease Susceptibility ,Rats, Transgenic ,Neuroscience ,Malformations of Cortical Development, Group II - Abstract
Developmental dyslexia, the most common childhood learning disorder, is highly heritable, and recent studies have identified KIAA0319-Like (KIAA0319L) as a candidate dyslexia susceptibility gene at the 1p36-34 (DYX8) locus. In this experiment, we investigated the anatomical effects of knocking down this gene during rat corticogenesis. Cortical progenitor cells were transfected using in utero electroporation on embryonic day (E) 15.5 with plasmids encoding either: (1) Kiaa0319l small hairpin RNA (shRNA), (2) an expression construct for human KIAA0319L, (3) Kiaa0319l shRNA+KIAA0319L expression construct (rescue), or (4) controls (scrambled Kiaa0319l shRNA or empty expression vector). Mothers were injected with 5-bromo-2-deoxyuridine (BrdU) at either E13.5, E15.5, or E17.5. Disruption of Kiaa0319l function (by knockdown, overexpression, or rescue) resulted in the formation of large nodular periventricular heterotopia in approximately 25% of the rats, which can be seen as early as postnatal day 1. Only a small subset of heterotopic neurons had been transfected, indicating non-cell autonomous effects of the transfection. Most heterotopic neurons were generated in mid- to late-gestation, and laminar markers suggest that they were destined for upper cortical laminae. Finally, we found that transfected neurons in the cerebral cortex were located in their expected laminae. These results indicate that KIAA0319L is the fourth of four candidate dyslexia susceptibility genes that is involved in neuronal migration, which supports the association of abnormal neuronal migration with developmental dyslexia.
- Published
- 2013
19. Agenesis of the corpus callosum and gray matter heterotopia in three patients with constitutional mismatch repair deficiency syndrome
- Author
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Mieke M. van Haelst, Rutger A.J. Nievelstein, Stephen P. Robertson, Milan Rimac, Danielle Bodmer, Michael T. Gabbett, Minna Nyström, Annekatrin Wernstedt, Johan Offerhaus, Birgit Krabichler, Johannes Zschocke, Martine Raphael, Katharina Wimmer, Minttu Kansikas, Wayne Nicholls, Ulrich Strasser, Annette F. Baas, Pediatric surgery, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), Pathology, and Other departments
- Subjects
Male ,Gray matter heterotopia ,Pediatrics ,Contractile Proteins ,0302 clinical medicine ,Pregnancy ,PMS2 ,Child ,Agenesis of the corpus callosum ,Genetics (clinical) ,Mismatch Repair Endonuclease PMS2 ,Adenosine Triphosphatases ,0303 health sciences ,education.field_of_study ,Microfilament Proteins ,Nuclear Proteins ,Syndrome ,Parotid Neoplasms ,3. Good health ,DNA-Binding Proteins ,Heterotopia (medicine) ,Child, Preschool ,030220 oncology & carcinogenesis ,Female ,Microsatellite Instability ,MutL Protein Homolog 1 ,medicine.medical_specialty ,Filamins ,Population ,Biology ,Article ,03 medical and health sciences ,Internal medicine ,Genetics ,medicine ,Humans ,education ,Adaptor Proteins, Signal Transducing ,030304 developmental biology ,constitutional mismatch repair deficiency syndrome ,agenesis of corpus callosum ,gray matter heterotopia ,biallelic germline mutation ,childhood cancer ,medicine.disease ,DNA Repair-Deficiency Disorders ,Pediatric cancer ,MSH6 ,DNA Repair Enzymes ,Endocrinology ,MSH2 ,Mutation ,Agenesis of Corpus Callosum ,Glioblastoma ,Malformations of Cortical Development, Group II - Abstract
Constitutional mismatch repair deficiency (CMMR-D) syndrome is a rare inherited childhood cancer predisposition caused by biallelic germline mutations in one of the four mismatch repair (MMR)-genes, MLH1, MSH2, MSH6 or PMS2. Owing to a wide tumor spectrum, the lack of specific clinical features and the overlap with other cancer predisposing syndromes, diagnosis of CMMR-D is often delayed in pediatric cancer patients. Here, we report of three new CMMR-D patients all of whom developed more than one malignancy. The common finding in these three patients is agenesis of the corpus callosum (ACC). Gray matter heterotopia is present in two patients. One of the 57 previously reported CMMR-D patients with brain tumors (therefore all likely had cerebral imaging) also had ACC. With the present report the prevalence of cerebral malformations is at least 4/60 (6.6%). This number is well above the population birth prevalence of 0.09-0.36 live births with these cerebral malformations, suggesting that ACC and heterotopia are features of CMMR-D. Therefore, the presence of cerebral malformations in pediatric cancer patients should alert to the possible diagnosis of CMMR-D. ACC and gray matter heterotopia are the first congenital malformations described to occur at higher frequency in CMMR-D patients than in the general population. Further systematic evaluations of CMMR-D patients are needed to identify possible other malformations associated with this syndrome. European Journal of Human Genetics (2013) 21, 55-61; doi: 10.1038/ejhg.2012.117; published online 13 June 2012
- Published
- 2013
20. Divergence and inheritance of neocortical heterotopia in inbred and genetically-engineered mice
- Author
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Raddy L. Ramos, Anthony W. Esposito, Valerie J. Bolivar, Jawad Ahsan, Alok Joshi, German Torres, Joshua A. Cuoco, Bruce J. Herron, and Alyssa R. Toia
- Subjects
0301 basic medicine ,C57BL/6 ,Consomic Strain ,Congenic ,Mice, Inbred Strains ,Mice, Transgenic ,Neocortex ,Penetrance ,Article ,03 medical and health sciences ,Epilepsy ,0302 clinical medicine ,Species Specificity ,medicine ,Inheritance Patterns ,Animals ,Allele ,Genetics ,biology ,General Neuroscience ,Homozygote ,medicine.disease ,biology.organism_classification ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,Heterotopia (medicine) ,Psychology ,Neuroscience ,030217 neurology & neurosurgery ,Malformations of Cortical Development, Group II - Abstract
Cortical function emerges from the intrinsic properties of neocortical neurons and their synaptic connections within and across lamina. Neurodevelopmental disorders affecting migration and lamination of the neocortex result in cognitive delay/disability and epilepsy. Molecular layer heterotopia (MLH), a dysplasia characterized by over-migration of neurons into layer I, are associated with cognitive deficits and neuronal hyperexcitability in humans and mice. The breadth of different inbred mouse strains that exhibit MLH and inheritance patterns of heterotopia remain unknown. A neuroanatomical survey of numerous different inbred mouse strains, 2 first filial generation (F1) hybrids, and one consomic strain (C57BL/6J-Chr 1A/J/NaJ) revealed MLH only in C57BL/6 mice and the consomic strain. Heterotopia were observed in numerous genetically-engineered mouse lines on a congenic C57BL/6 background. These data indicate that heterotopia formation is a weakly penetrant trait requiring homozygosity of one or more C57BL/6 alleles outside of chromosome 1. These data are relevant toward understanding neocortical development and disorders affecting neocortical lamination.
- Published
- 2016
21. Diffusion tensor imaging of subependymal heterotopia
- Author
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Gian Luca Romani, Massimo Caulo, C. Celentano, C. Briganti, Armando Tartaro, Riccardo Navarra, and B. Matarrelli
- Subjects
Adult ,Nerve Fibers, Myelinated ,White matter ,Nuclear magnetic resonance ,Pregnancy ,Fractional anisotropy ,medicine ,Subependymal zone ,Humans ,Epilepsy ,medicine.diagnostic_test ,Chemistry ,Radial diffusivity ,Infant, Newborn ,Magnetic resonance imaging ,medicine.disease ,Perinatal asphyxia ,Fetal Diseases ,Diffusion Tensor Imaging ,medicine.anatomical_structure ,Heterotopia (medicine) ,Neurology ,Female ,Neurology (clinical) ,Malformations of Cortical Development, Group II ,Diffusion MRI - Abstract
A magnetic resonance (MR) diffusion tensor imaging (DTI) study was performed in a newborn with bilateral subependymal heterotopia (SE). White matter fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD) were compared to values obtained in four newborns with moderate perinatal asphyxia and normal MRI findings. The reduction of FA and increase of AD and RD in the newborn with SE were the in vivo late expression of alterations in the intermediate zone, with an underlying arrest of neuronal migration.
- Published
- 2012
22. Van Maldergem syndrome: further characterisation and evidence for neuronal migration abnormalities and autosomal recessive inheritance
- Author
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Christine Hall, Paulien A Terhal, Lionel Van Maldergem, Ruth Newbury-Ecob, Petra J. G. Zwijnenburg, Louise C. Wilson, Philip Rich, Sahar Mansour, Marielle E M Swinkels, Stephen P. Robertson, Human genetics, and ICaR - Ischemia and repair
- Subjects
Joint Instability ,Male ,Pediatrics ,medicine.medical_specialty ,Foot Deformities, Congenital ,Karyotype ,Telecanthus ,Genes, Recessive ,Consanguinity ,Choanal atresia ,Article ,Craniofacial Abnormalities ,Diagnosis, Differential ,Camptodactyly ,Intellectual Disability ,Genetics ,medicine ,Humans ,Abnormalities, Multiple ,Child ,Genetics (clinical) ,business.industry ,Pachygyria ,Microtia ,Anatomy ,medicine.disease ,Blepharophimosis ,Pedigree ,Neonatal hypotonia ,Child, Preschool ,Female ,medicine.symptom ,business ,Hand Deformities, Congenital ,Malformations of Cortical Development, Group II - Abstract
We present six patients from five unrelated families with a condition originally described by Van Maldergem et al and provide follow-up studies of the original patient. The phenotype comprises a distinctive facial appearance that includes blepharophimosis, maxillary hypoplasia, telecanthus, microtia and atresia of the external auditory meatus, intellectual disability, digital contractures and skeletal anomalies together with subependymal and subcortical neuronal heterotopia. Affected patients typically have neonatal hypotonia, chronic feeding difficulties and respiratory problems. In our cohort, we have observed one instance of sibling recurrence and parental consanguinity in three of the families, indicating that autosomal recessive inheritance is likely.
- Published
- 2012
23. Neuronal migration disorders in microcephalic osteodysplastic primordial dwarfism type I/III
- Author
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Mitzi L. Murray, Gordana Juric-Sekhar, Ian A. Glass, Raj P. Kapur, Shawn E. Parnell, and Robert F. Hevner
- Subjects
Calbindins ,Microcephaly ,Dwarfism ,Lissencephaly ,Biology ,Osteochondrodysplasias ,Corpus callosum ,Article ,Pathology and Forensic Medicine ,Cellular and Molecular Neuroscience ,S100 Calcium Binding Protein G ,Neurofilament Proteins ,Glial Fibrillary Acidic Protein ,medicine ,Humans ,Genetic Testing ,Neurologic Examination ,Temporal cortex ,Fetal Growth Retardation ,Pachygyria ,Brain ,Infant ,Anatomy ,medicine.disease ,Radiography ,medicine.anatomical_structure ,Heterotopia (medicine) ,Cerebral cortex ,Calbindin 2 ,Female ,Neurology (clinical) ,Microtubule-Associated Proteins ,Malformations of Cortical Development, Group II - Abstract
Microcephalic osteodysplastic primordial dwarfism (MOPD) is a rare microlissencephaly syndrome, with at least two distinct phenotypic and genetic types. MOPD type II is caused by pericentrin mutations, while types I and III appear to represent a distinct entity (MOPD I/III) with variably penetrant phenotypes and unknown genetic basis. The neuropathology of MOPD I/III is little understood, especially in comparison to other forms of lissencephaly. Here, we report postmortem brain findings in an 11-month-old female infant with MOPD I/III. The cerebral cortex was diffusely pachygyric, with a right parietal porencephalic lesion. Histologically, the cortex was abnormally thick and disorganized. Distinct malformations were observed in different cerebral lobes, as characterized using layer-specific neuronal markers. Frontal cortex was severely disorganized and coated with extensive leptomeningeal glioneuronal heterotopia. Temporal cortex had a relatively normal 6-layered pattern, despite cortical thickening. Occipital cortex was variably affected. The corpus callosum was extremely hypoplastic. Brainstem and cerebellar malformations were also present, as well as old necrotic foci. Findings in this case suggest that the cortical malformation in MOPD I/III is distinct from other forms of pachygyria-lissencephaly.
- Published
- 2010
24. Fukutin-related protein is essential for mouse muscle, brain and eye development and mutation recapitulates the wide clinical spectrums of dystroglycanopathies
- Author
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Derek J. Blake, Helen E. Gruber, Jeffrey Rosenfeld, Elizabeth Keramaris-Vrantsis, Jignya Ashar, Natalia Zinchenko, James Norton, Qi L. Lu, Hart G.W. Lidov, Randy J. Thresher, and Yiumo Michael Chan
- Subjects
Glycosylation ,Blotting, Western ,Central nervous system ,Mutation, Missense ,Fluorescent Antibody Technique ,Gene Expression ,Eye ,Muscle Development ,medicine.disease_cause ,Polymerase Chain Reaction ,Mice ,chemistry.chemical_compound ,Transferases ,Genetics ,medicine ,Animals ,Missense mutation ,Gene Knock-In Techniques ,Pentosyltransferases ,Muscular dystrophy ,Dystroglycans ,Muscle, Skeletal ,Molecular Biology ,Genetics (clinical) ,Mice, Knockout ,Mutation ,Fukutin-related protein ,biology ,Brain ,Proteins ,General Medicine ,Muscular Dystrophy, Animal ,medicine.disease ,Phenotype ,Cell biology ,Blotting, Southern ,medicine.anatomical_structure ,chemistry ,Models, Animal ,biology.protein ,Eye development ,Protein Processing, Post-Translational ,Gene Deletion ,Malformations of Cortical Development, Group II - Abstract
Mutations in fukutin-related protein (FKRP) cause a common subset of muscular dystrophies characterized by aberrant glycosylation of alpha-dystroglycan (α-DG), collectively known as dystroglycanopathies. The clinical variations associated with FKRP mutations range from mild limb-girdle muscular dystrophy type 2I with predominantly muscle phenotypes to severe Walker-Warburg syndrome and muscle-eye-brain disease with striking structural brain and eye defects. In the present study, we have generated animal models and demonstrated that ablation of FKRP functions is embryonic lethal and that the homozygous-null embryos die before reaching E12.5. The homozygous knock-in mouse carrying the missense P448L mutation almost completely lacks functional glycosylation of α-DG in muscles and brain, validating the essential role of FKRP in the functional glycosylation of α-DG. However, the knock-in mouse survives and develops a wide range of structural abnormalities in the central nervous system, characteristics of neuronal migration defects. The brain and eye defects are highly reminiscent of the phenotypes seen in severe dystroglycanopathy patients. In addition, skeletal muscles develop progressive muscular dystrophy. Our results confirm that post-translational modifications of α-DG are essential for normal development of the brain and eyes. In addition, both the mutation itself and the levels of FKRP expression are equally critical for the survival of the animals. The exceptionally wide clinical spectrums recapitulated in the P448L mice also suggest the involvement of other factors in the disease progression. The mutant mouse represents a valuable model to further elucidate the functions of FKRP and develop therapies for FKRP-related muscular dystrophies.
- Published
- 2010
25. Neuronal migration disorders
- Author
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Renzo Guerrini and Elena Parrini
- Subjects
Pathology ,medicine.medical_specialty ,Lissencephaly ,Development ,Neuronal migration ,lcsh:RC321-571 ,Epilepsy ,Cell Movement ,medicine ,Polymicrogyria ,Humans ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Neurons ,Cortical malformation ,Genetic heterogeneity ,Cortical dysplasia ,Cerebral cortex ,medicine.disease ,Magnetic Resonance Imaging ,Reelin Protein ,Heterotopia (medicine) ,GPR56 ,medicine.anatomical_structure ,Neurology ,Mutation ,Psychology ,Neuroscience ,Malformations of Cortical Development, Group II ,MRI - Abstract
Lissencephaly-pachygyria-severe band heterotopia are diffuse neuronal migration disorders (NMDs) causing severe, global neurological impairment. Abnormalities of the LIS1, DCX, ARX, TUBA1A and RELN genes have been associated with these malformations. NMDs only affecting subsets of neurons, such as mild subcortical band heterotopia and periventricular heterotopia, cause neurological and cognitive impairment that vary from severe to mild deficits. They have been associated with abnormalities of the DCX, FLN1A, and ARFGEF2 genes. Polymicrogyria results from abnormal late cortical organization and is inconstantly associated with abnormal neuronal migration. Localized polymicrogyria has been associated with anatomo-specific deficits, including disorders of language and higher cognition. Polymicrogyria is genetically heterogeneous and only in a small minority of patients a definite genetic cause has been identified. Mutations of the GPR56 and SRPX2 genes have been related to isolated polymicrogyria. Focal migration abnormalities associated with abnormal cell types, such as focal cortical dysplasia, are highly epileptogenic and variably influence the functioning of the affected cortex. The functional consequences of abnormal neuronal migration are still poorly understood. Conservation of function in the malformed cortex, its atypical representation, and relocation outside the malformed area are all possible. Localization of function based on anatomic landmarks may not be reliable.
- Published
- 2010
26. Molecular genetics of attention-deficit/hyperactivity disorder: an overview
- Author
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David Coghill, Susann Scherag, Katja Becker, Barbara Franke, Tobias Banaschewski, Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health [Mannheim], Medical Faculty [Mannheim]-Medical Faculty [Mannheim], Philipps Universität Marburg, Department of Child and Adolescent Psychiatry, Universität Duisburg-Essen [Essen], Department of Human Genetics, Radboud University Medical Center [Nijmegen], Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], Division of Medical Sciences, Centre for Neuroscience (Psychiatry and Behaviour), and University of Dundee
- Subjects
Candidate gene ,Medizin ,Genome-wide association study ,Review ,Candidate gene studies ,0302 clinical medicine ,ddc:150 ,Developmental and Educational Psychology ,Psychology ,GWAS ,Aetiology ,Child ,Neurotransmitter Agents ,0303 health sciences ,biology ,Psychological Disorders, Mental Health Treatment and Prevention ,General Medicine ,3. Good health ,Psychiatry and Mental health ,Phenotype ,Norepinephrine transporter ,psychische Störungen, Behandlung und Prävention ,Autism spectrum disorder ,Functional Neurogenomics [DCN 2] ,Cell Division ,Genetic Markers ,medicine.medical_specialty ,Adolescent ,Serotonergic ,Genomic disorders and inherited multi-system disorders [IGMD 3] ,03 medical and health sciences ,Molecular genetics ,mental disorders ,Genetics ,medicine ,ADHD ,Humans ,Attention deficit hyperactivity disorder ,Genetic Predisposition to Disease ,Pediatrics, Perinatology, and Child Health ,030304 developmental biology ,medicine.disease ,Review article ,Psychologie ,Pediatrics, Perinatology and Child Health ,biology.protein ,Neuroscience ,Malformations of Cortical Development, Group II ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
Contains fulltext : 89108.pdf (Publisher’s version ) (Closed access) As heritability is high in attention-deficit/hyperactivity disorder (ADHD), genetic factors must play a significant role in the development and course of this disorder. In recent years a large number of studies on different candidate genes for ADHD have been published, most have focused on genes involved in the dopaminergic neurotransmission system, such as DRD4, DRD5, DAT1/SLC6A3, DBH, DDC. Genes associated with the noradrenergic (such as NET1/SLC6A2, ADRA2A, ADRA2C) and serotonergic systems (such as 5-HTT/SLC6A4, HTR1B, HTR2A, TPH2) have also received considerable interest. Additional candidate genes related to neurotransmission and neuronal plasticity that have been studied less intensively include SNAP25, CHRNA4, NMDA, BDNF, NGF, NTF3, NTF4/5, GDNF. This review article provides an overview of these candidate gene studies, and summarizes findings from recently published genome-wide association studies (GWAS). GWAS is a relatively new tool that enables the identification of new ADHD genes in a hypothesis-free manner. Although these latter studies could be improved and need to be replicated they are starting to implicate processes like neuronal migration and cell adhesion and cell division as potentially important in the aetiology of ADHD and have suggested several new directions for future ADHD genetics studies. 01 maart 2010
- Published
- 2010
27. Case Report
- Author
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Jules C. Beal
- Subjects
Male ,medicine.medical_specialty ,Locus (genetics) ,Gene mutation ,Epilepsy ,Seizures ,Chromosome Duplication ,Gene duplication ,Humans ,Medicine ,Autistic Disorder ,Psychiatry ,Genetic testing ,Chromosomes, Human, Pair 15 ,medicine.diagnostic_test ,business.industry ,medicine.disease ,Neuronal migration disorder ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Autism ,Neurology (clinical) ,business ,Neurocognitive ,Neuroscience ,Malformations of Cortical Development, Group II - Abstract
Neuronal migration disorders are a group of disorders that cause structural brain abnormalities and varying degrees of neurocognitive impairment, resulting from abnormal neuronal migration during brain development. There are several mutations that have been associated with these disorders. Here the case of a 4-year-old autistic boy is presented, who was found to have evidence of a neuronal migration disorder on magnetic resonance imaging (MRI) during a workup for seizures. Genetic testing did not reveal any of the gene mutations known to be associated with neuronal migration disorders but did reveal a microduplication at chromosome 15q13.3, a locus that has been previously associated with autism, cognitive impairment, and seizures. Although the concurrent presence of the genetic and structural abnormalities does not necessarily imply causality, the simultaneous independent occurrence of both conditions is certainly unusual. It is possible that there may be an association between this duplication syndrome and aberrant neuronal migration.
- Published
- 2013
28. Ethanol inhibition of aspartyl-asparaginyl-β-hydroxylase in fetal alcohol spectrum disorder: Potential link to the impairments in central nervous system neuronal migration
- Author
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Jade J. Carter, Elizabeth Silbermann, Rolf I. Carlson, Jack R. Wands, Ming Tong, Lisa Longato, and Suzanne M. de la Monte
- Subjects
Central Nervous System ,medicine.medical_specialty ,Cerebellum ,Health (social science) ,medicine.medical_treatment ,Motility ,Toxicology ,Biochemistry ,Article ,Mixed Function Oxygenases ,Glycogen Synthase Kinase 3 ,Behavioral Neuroscience ,Pregnancy ,GSK-3 ,Internal medicine ,medicine ,Animals ,Rats, Long-Evans ,GSK3B ,Cells, Cultured ,Caspase ,Neurons ,Glycogen Synthase Kinase 3 beta ,Ethanol ,biology ,Insulin ,Neurotoxicity ,General Medicine ,medicine.disease ,Rats ,Endocrinology ,medicine.anatomical_structure ,Neurology ,Fetal Alcohol Spectrum Disorders ,Caspases ,biology.protein ,Female ,Signal transduction ,Malformations of Cortical Development, Group II - Abstract
Fetal alcohol spectrum disorder (FASD) is caused by prenatal exposure to alcohol and associated with hypoplasia and impaired neuronal migration in the cerebellum. Neuronal survival and motility are stimulated by insulin and insulin-like growth factor (IGF), whose signaling pathways are major targets of ethanol neurotoxicity. To better understand the mechanisms of ethanol-impaired neuronal migration during development, we examined the effects of chronic gestational exposure to ethanol on aspartyl (asparaginyl)-beta-hydroxylase (AAH) expression, because AAH is regulated by insulin/IGF and mediates neuronal motility. Pregnant Long-Evans rats were pair-fed isocaloric liquid diets containing 0, 8, 18, 26, or 37% ethanol by caloric content from gestation day 6 through delivery. Cerebella harvested from postnatal day 1 pups were used to examine AAH expression in tissue, and neuronal motility in Boyden chamber assays. We also used cerebellar neuron cultures to examine the effects of ethanol on insulin/IGF-stimulated AAH expression, and assess the role of GSK-3beta-mediated phosphorylation on AAH protein levels. Chronic gestational exposure to ethanol caused dose-dependent impairments in neuronal migration and corresponding reductions in AAH protein expression in developing cerebella. In addition, prenatal ethanol exposure inhibited insulin and IGF-I-stimulated directional motility in isolated cerebellar granule neurons. Ethanol-treated neuronal cultures (50mMx96h) also had reduced levels of AAH protein. Mechanistically, we showed that AAH protein could be phosphorylated on Ser residues by GSK-3beta, and that chemical inhibition of GSK-3beta and/or global Caspases increases AAH protein in both control- and ethanol-exposed cells. Ethanol-impaired neuronal migration in FASD is associated with reduced AAH expression. Because ethanol increases the activities of both GSK-3beta and Caspases, the inhibitory effect of ethanol on neuronal migration could be mediated by increased GSK-3beta phosphorylation and Caspase degradation of AAH protein.
- Published
- 2009
29. Loss of Tsc2 in radial glia models the brain pathology of tuberous sclerosis complex in the mouse
- Author
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R. Michelle Reith, James McKenna, Henry Cheng-ju Wu, Ulrike Mietzsch, Michael J. Gambello, and Sharon W. Way
- Subjects
Pathology ,Hippocampal formation ,Hippocampus ,Mice ,Tuberous sclerosis ,0302 clinical medicine ,Cell Movement ,Tuberous Sclerosis ,Megalencephaly ,Myelin Sheath ,Genetics (clinical) ,Neurons ,0303 health sciences ,Glial fibrillary acidic protein ,Stem Cells ,TOR Serine-Threonine Kinases ,Brain ,Articles ,General Medicine ,Oligodendroglia ,medicine.anatomical_structure ,Cerebral cortex ,Neuroglia ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Central nervous system ,Neuropathology ,Mechanistic Target of Rapamycin Complex 1 ,Biology ,03 medical and health sciences ,Glial Fibrillary Acidic Protein ,Tuberous Sclerosis Complex 2 Protein ,Genetics ,medicine ,Animals ,Humans ,Progenitor cell ,Molecular Biology ,Cell Proliferation ,030304 developmental biology ,Integrases ,Tumor Suppressor Proteins ,Proteins ,medicine.disease ,nervous system diseases ,Disease Models, Animal ,Animals, Newborn ,Multiprotein Complexes ,biology.protein ,Malformations of Cortical Development, Group II ,030217 neurology & neurosurgery ,Transcription Factors - Abstract
Tuberous sclerosis complex (TSC) is an autosomal dominant, tumor predisposition disorder characterized by significant neurodevelopmental brain lesions, such as tubers and subependymal nodules. The neuropathology of TSC is often associated with seizures and intellectual disability. To learn about the developmental perturbations that lead to these brain lesions, we created a mouse model that selectively deletes the Tsc2 gene from radial glial progenitor cells in the developing cerebral cortex and hippocampus. These Tsc2 mutant mice were severely runted, developed post-natal megalencephaly and died between 3 and 4 weeks of age. Analysis of brain pathology demonstrated cortical and hippocampal lamination defects, hippocampal heterotopias, enlarged dysplastic neurons and glia, abnormal myelination and an astrocytosis. These histologic abnormalities were accompanied by activation of the mTORC1 pathway as assessed by increased phosphorylated S6 in brain lysates and tissue sections. Developmental analysis demonstrated that loss of Tsc2 increased the subventricular Tbr2-positive basal cell progenitor pool at the expense of early born Tbr1-positive post-mitotic neurons. These results establish the novel concept that loss of function of Tsc2 in radial glial progenitors is one initiating event in the development of TSC brain lesions as well as underscore the importance of Tsc2 in the regulation of neural progenitor pools. Given the similarities between the mouse and the human TSC lesions, this model will be useful in further understanding TSC brain pathophysiology, testing potential therapies and identifying other genetic pathways that are altered in TSC.
- Published
- 2009
30. The relevance of human fetal subplate zone for developmental neuropathology of neuronal migration disorders and cortical dysplasia
- Author
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Ivica Kostović, Mario Vukšić, Miloš Judaš, and Goran Sedmak
- Subjects
Pharmacology ,Cerebral Cortex ,Neurons ,Compartment (ship) ,Synaptogenesis ,Neuropathology ,Biology ,Cortical dysplasia ,medicine.disease ,Malformations of Cortical Development ,Psychiatry and Mental health ,medicine.anatomical_structure ,Cerebral cortex ,Cell Movement ,Physiology (medical) ,Subplate ,Human fetal ,cortical dysplasia ,disorders of neuronal migration ,human fetal connectome ,radial migration ,tangential migration ,Connectome ,medicine ,Humans ,Pharmacology (medical) ,Neuroscience ,Review Articles ,Malformations of Cortical Development, Group II - Abstract
The human fetal cerebral cortex develops through a series of partially overlapping histogenetic events which occur in transient cellular compartments, such as the subplate zone. The subplate serves as waiting compartment for cortical afferent fibers, the major site of early synaptogenesis and neuronal differentiation and the hub of the transient fetal cortical circuitry. Thus, the subplate has an important but hitherto neglected role in the human fetal cortical connectome. The subplate is also an important compartment for radial and tangential migration of future cortical neurons. We review the diversity of subplate neuronal phenotypes and their involvement in cortical circuitry and discuss the complexity of late neuronal migration through the subplate as well as its potential relevance for pathogenesis of migration disorders and cortical dysplasia. While migratory neurons may become misplaced within the subplate, they can easily survive by being involved in early subplate circuitry ; this can enhance their subsequent survival even if they have immature or abnormal physiological activity and misrouted connections and thus survive into adulthood. Thus, better understanding of subplate developmental history and various subsets of its neurons may help to elucidate certain types of neuronal disorders, including those accompanied by epilepsy.
- Published
- 2015
31. Somatic Mutations in the MTOR gene cause focal cortical dysplasia type IIb
- Author
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Mitsuko, Nakashima, Hirotomo, Saitsu, Nobuyuki, Takei, Jun, Tohyama, Mitsuhiro, Kato, Hiroki, Kitaura, Masaaki, Shiina, Hiroshi, Shirozu, Hiroshi, Masuda, Keisuke, Watanabe, Chihiro, Ohba, Yoshinori, Tsurusaki, Noriko, Miyake, Yingjun, Zheng, Tatsuhiro, Sato, Hirohide, Takebayashi, Kazuhiro, Ogata, Shigeki, Kameyama, Akiyoshi, Kakita, and Naomichi, Matsumoto
- Subjects
Adult ,Male ,Malformations of Cortical Development ,HEK293 Cells ,Adolescent ,TOR Serine-Threonine Kinases ,Mutation ,Brain ,Humans ,Female ,Child ,Malformations of Cortical Development, Group II - Abstract
Focal cortical dysplasia (FCD) type IIb is a cortical malformation characterized by cortical architectural abnormalities, dysmorphic neurons, and balloon cells. It has been suggested that FCDs are caused by somatic mutations in cells in the developing brain. Here, we explore the possible involvement of somatic mutations in FCD type IIb.We collected a total of 24 blood-brain paired samples with FCD, including 13 individuals with FCD type IIb, 5 with type IIa, and 6 with type I. We performed whole-exome sequencing using paired samples from 9 of the FCD type IIb subjects. Somatic MTOR mutations were identified and further investigated using all 24 paired samples by deep sequencing of the entire gene's coding region. Somatic MTOR mutations were confirmed by droplet digital polymerase chain reaction. The effect of MTOR mutations on mammalian target of rapamycin (mTOR) kinase signaling was evaluated by immunohistochemistry and Western blotting analyses of brain samples and by in vitro transfection experiments.We identified four lesion-specific somatic MTOR mutations in 6 of 13 (46%) individuals with FCD type IIb showing mutant allele rates of 1.11% to 9.31%. Functional analyses showed that phosphorylation of ribosomal protein S6 in FCD type IIb brain tissues with MTOR mutations was clearly elevated, compared to control samples. Transfection of any of the four MTOR mutants into HEK293T cells led to elevated phosphorylation of 4EBP, the direct target of mTOR kinase.We found low-prevalence somatic mutations in MTOR in FCD type IIb, indicating that activating somatic mutations in MTOR cause FCD type IIb.
- Published
- 2014
32. Basic mechanisms of epileptogenesis in pediatric cortical dysplasia
- Author
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Carlos Cepeda, Michael S. Levine, Sara Abdijadid, and Gary W. Mathern
- Subjects
Pathology ,medicine.medical_specialty ,Dysmorphic neurons ,Biology ,Epileptogenesis ,gamma-Aminobutyric acid ,Article ,Balloon cells ,Epilepsy ,Neurodevelopmental disorder ,Physiology (medical) ,medicine ,Animals ,Humans ,Pharmacology (medical) ,Pharmacology & Pharmacy ,PI3K/AKT/mTOR pathway ,gamma-Aminobutyric Acid ,Pharmacology ,Neurons ,Sirolimus ,Cortical dysplasia ,Neurosciences ,Brain ,Pharmacology and Pharmaceutical Sciences ,medicine.disease ,Malformations of Cortical Development ,Psychiatry and Mental health ,Electrophysiology ,mTOR pathway ,Group II ,Signal transduction ,Neuroscience ,Malformations of Cortical Development, Group II ,medicine.drug ,Signal Transduction - Abstract
© 2014 John Wiley & Sons Ltd. Cortical dysplasia (CD) is a neurodevelopmental disorder due to aberrant cell proliferation and differentiation. Advances in neuroimaging have proven effective in early identification of the more severe lesions and timely surgical removal to treat epilepsy. However, the exact mechanisms of epileptogenesis are not well understood. This review examines possible mechanisms based on anatomical and electrophysiological studies. CD can be classified as CD type I consisting of architectural abnormalities, CD type II with the presence of dysmorphic cytomegalic neurons and balloon cells, and CD type III which occurs in association with other pathologies. Use of freshly resected brain tissue has allowed a better understanding of basic mechanisms of epileptogenesis and has delineated the role of abnormal cells and synaptic activity. In CD type II, it was demonstrated that balloon cells do not initiate epileptic activity, whereas dysmorphic cytomegalic and immature neurons play an important role in generation and propagation of epileptic discharges. An unexpected finding in pediatric CD was that GABA synaptic activity is not reduced, and in fact, it may facilitate the occurrence of epileptic activity. This could be because neuronal circuits display morphological and functional signs of dysmaturity. In consequence, drugs that increase GABA function may prove ineffective in pediatric CD. In contrast, drugs that counteract depolarizing actions of GABA or drugs that inhibit the mammalian target of rapamycin (mTOR) pathway could be more effective.
- Published
- 2014
33. Dynamic changes of interictal post-spike slow waves toward seizure onset in focal cortical dysplasia type II
- Author
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Ayako Ochi, Yosuke Sato, Tohru Okanishi, Ryan Anderson, Sam M. Doesburg, Simeon M. Wong, Hiroshi Otsubo, and Dragos A. Nita
- Subjects
Male ,medicine.medical_specialty ,Adolescent ,Action Potentials ,Seizure onset zone ,Seizure onset ,stomatognathic system ,Seizures ,Physiology (medical) ,Internal medicine ,Medicine ,Humans ,In patient ,Ictal ,Child ,Retrospective Studies ,business.industry ,Electroencephalography ,Cortical dysplasia ,medicine.disease ,Brain Waves ,eye diseases ,Sensory Systems ,Epileptic activity ,stomatognathic diseases ,Neurology ,Child, Preschool ,Cardiology ,Female ,Neurology (clinical) ,business ,Neuroscience ,Malformations of Cortical Development, Group II - Abstract
Objective A post-spike slow wave (PSS) as part of a spike and slow wave is presumably related to inhibition of epileptic activity. In this study, we evaluated dynamic changes of PSS power toward seizure onset in patients with focal cortical dysplasia (FCD) type II. Methods We collected data from 10 pediatric patients with FCD type II, who underwent invasive monitoring with subdural grids. The PSS were averaged based on spike-triggering in 30 s epochs during both interictal and preictal periods. We quantitatively measured and compared PSS power and distribution between interictal and preictal periods, both within and outside the seizure onset zone (SOZ). Results PSS power was significantly higher in all areas during preictal period compared with interictal period. During preictal period, PSS power within SOZ was significantly higher than outside SOZ. From interictal to preictal period, the number of electrodes with high power PSS significantly increased within SOZ and decreased outside SOZ. Conclusions Toward seizure onset, PSS power increased in all areas, predominantly within SOZ, and became confined into SOZ in a subset of FCD type II patients. Significance Preictal PSS power increase and confinement into SOZ accompany transition to seizures.
- Published
- 2014
34. Cellular and axonal constituents of neocortical molecular layer heterotopia
- Author
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William J. Brunken, Nga Yan Siu, Raddy L. Ramos, Lisa A. Gabel, Blair J. Hoplight, Kathleen T. Yee, and Sarah E. Van Dine
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Immunocytochemistry ,Neocortex ,Biology ,Inhibitory postsynaptic potential ,Mice ,Developmental Neuroscience ,medicine ,Polymicrogyria ,Animals ,Mice, Knockout ,Neurons ,Cobblestone Lissencephaly ,medicine.disease ,Immunohistochemistry ,Axons ,Mice, Inbred C57BL ,Disease Models, Animal ,medicine.anatomical_structure ,Heterotopia (medicine) ,nervous system ,Neurology ,Excitatory postsynaptic potential ,Neuroglia ,Neuroscience ,Malformations of Cortical Development, Group II - Abstract
Human neocortical molecular layer heterotopia consist of aggregations of hundreds of neurons and glia in the molecular layer (layer I) and are indicative of neuronal migration defect. Despite having been associated with dyslexia, epilepsy, cobblestone lissencephaly, polymicrogyria, and Fukuyama muscular dystrophy, a complete understanding of the cellular and axonal constituents of molecular layer heterotopia is lacking. Using a mouse model, we identify diverse excitatory and inhibitory neurons as well as glia in heterotopia based on molecular profiles. Using immunocytochemistry, we identify diverse afferents in heterotopia from subcortical neuromodulatory centers. Finally, we document intracortical projections to/from heterotopia. These data are relevant toward understanding how heterotopia affect brain function in diverse neurodevelopmental disorders.
- Published
- 2014
35. Heat shock factor 2 is a stress-responsive mediator of neuronal migration defects in models of fetal alcohol syndrome
- Author
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Federico Miozzo, Rachid El Fatimy, Illiasse Massaoudi, Ryma Abane, Kazue Hashimoto-Torii, Pasko Rakic, Liliana Paslaru, Aurélie de Thonel, Délara Sabéran-Djoneidi, Valérie Mezger, Anne Le Mouël, Elisabeth Christians, Leslie Schwendimann, Pierre Gressens, Centre épigénétique et destin cellulaire ( EDC ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris Diderot - Paris 7 ( UPD7 ), ED 387 iViv, Université Pierre et Marie Curie - Paris 6 ( UPMC ), Neuroprotection du Cerveau en Développement ( PROTECT ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Département de Médecine Générale, Physiologie de la Nutrition et Toxicologie (NUTox) (U866, Lipides et nutrition, équipe 7) ( NUTox ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ) -Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Fundeni Hospital, Yale University School of Medicine, Yale School of Medicine, Laboratoire de Biologie du Développement de Villefranche sur mer ( LBDV ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ), Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7), Université Pierre et Marie Curie - Paris 6 (UPMC), Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiologie de la Nutrition et Toxicologie (NUTox) (U866, Lipides et nutrition, équipe 7) (NUTox), Lipides - Nutrition - Cancer (U866) (LNC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire de Biologie du Développement de Villefranche sur mer (LBDV), Observatoire océanologique de Villefranche-sur-mer (OOVM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Centre épigénétique et destin cellulaire (EDC), Yale School of Medicine [New Haven, Connecticut] (YSM), HAL UPMC, Gestionnaire, and Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)
- Subjects
[SDV]Life Sciences [q-bio] ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Mice ,0302 clinical medicine ,radial neuronal migration ,Heat Shock Transcription Factors ,HSF1 ,[SDV.BDD]Life Sciences [q-bio]/Development Biology ,Research Articles ,Heat-Shock Proteins ,ComputingMilieux_MISCELLANEOUS ,Regulation of gene expression ,Cerebral Cortex ,Mice, Knockout ,0303 health sciences ,[SDV.BDD.EO] Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis ,Cell biology ,heat shock factors ,DNA-Binding Proteins ,[SDV.TOX] Life Sciences [q-bio]/Toxicology ,medicine.anatomical_structure ,Cerebral cortex ,Fetal Alcohol Spectrum Disorders ,[SDV.TOX]Life Sciences [q-bio]/Toxicology ,[ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Molecular Medicine ,transcription ,Protein Binding ,Doublecortin Protein ,Fetal alcohol syndrome ,Biology ,03 medical and health sciences ,Mediator ,Stress, Physiological ,Heat shock protein ,[SDV.BDD] Life Sciences [q-bio]/Development Biology ,medicine ,Animals ,[ SDV.BDD ] Life Sciences [q-bio]/Development Biology ,microtubule‐associated proteins ,Transcription factor ,030304 developmental biology ,microtubule-associated proteins ,[SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,medicine.disease ,Heat shock factor ,Disease Models, Animal ,[SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis ,Gene Expression Regulation ,Immunology ,fetal alcohol syndrome ,030217 neurology & neurosurgery ,Malformations of Cortical Development, Group II ,Transcription Factors ,Neuroscience - Abstract
Fetal alcohol spectrum disorder (FASD) is a frequent cause of mental retardation. However, the molecular mechanisms underlying brain development defects induced by maternal alcohol consumption during pregnancy are unclear. We used normal and Hsf2-deficient mice and cell systems to uncover a pivotal role for heat shock factor 2 (HSF2) in radial neuronal migration defects in the cortex, a hallmark of fetal alcohol exposure. Upon fetal alcohol exposure, HSF2 is essential for the triggering of HSF1 activation, which is accompanied by distinctive post-translational modifications, and HSF2 steers the formation of atypical alcohol-specific HSF1–HSF2 heterocomplexes. This perturbs the in vivo binding of HSF2 to heat shock elements (HSEs) in genes that control neuronal migration in normal conditions, such as p35 or the MAPs (microtubule-associated proteins, such as Dclk1 and Dcx), and alters their expression. In the absence of HSF2, migration defects as well as alterations in gene expression are reduced. Thus, HSF2, as a sensor for alcohol stress in the fetal brain, acts as a mediator of the neuronal migration defects associated with FASD. Subject Categories Development & Differentiation; Neuroscience
- Published
- 2014
36. Periventricular heterotopia in 6q terminal deletion syndrome: role of the C6orf70 gene
- Author
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Alistair T. Pagnamenta, George McGillivray, Jill Clayton-Smith, Stephen P. Robertson, Emilie Pallesi-Pocachard, William B. Dobyns, Samuel F. Berkovic, Francesca Novara, Valerio Conti, Davide Mei, Aurelie Carabalona, Jenny C. Taylor, Stefano Lise, Usha Kini, Carlos Cardoso, David A. Keays, Ingrid E. Scheffer, Orsetta Zuffardi, Richard J. Leventer, Emmanuelle Buhler, Françoise Watrin, François Michel, Alfonso Represa, Renzo Guerrini, Elena Parrini, and Pasquale Striano
- Subjects
Adult ,Male ,Pathology ,medicine.medical_specialty ,Adolescent ,Developmental Disabilities ,Haploinsufficiency ,Biology ,Cohort Studies ,03 medical and health sciences ,Colpocephaly ,Lateral ventricles ,0302 clinical medicine ,Periventricular Nodular Heterotopia ,Polymicrogyria ,medicine ,FLNA ,Missense mutation ,Animals ,Humans ,Abnormalities, Multiple ,Exome ,Rats, Wistar ,Child ,Exome sequencing ,030304 developmental biology ,0303 health sciences ,Epilepsy ,Brain ,Infant ,Syndrome ,medicine.disease ,6q terminal deletion syndrome ,Magnetic Resonance Imaging ,Rats ,nervous system ,Mutation ,Chromosomes, Human, Pair 6 ,Female ,Neurology (clinical) ,Chromosome Deletion ,030217 neurology & neurosurgery ,Malformations of Cortical Development, Group II - Abstract
Periventricular nodular heterotopia is caused by defective neuronal migration that results in heterotopic neuronal nodules lining the lateral ventricles. Mutations in filamin A (FLNA) or ADP-ribosylation factor guanine nucleotide-exchange factor 2 (ARFGEF2) cause periventricular nodular heterotopia, but most patients with this malformation do not have a known aetiology. Using comparative genomic hybridization, we identified 12 patients with developmental brain abnormalities, variably combining periventricular nodular heterotopia, corpus callosum dysgenesis, colpocephaly, cerebellar hypoplasia and polymicrogyria, harbouring a common 1.2 Mb minimal critical deletion in 6q27. These anatomic features were mainly associated with epilepsy, ataxia and cognitive impairment. Using whole exome sequencing in 14 patients with isolated periventricular nodular heterotopia but no copy number variants, we identified one patient with periventricular nodular heterotopia, developmental delay and epilepsy and a de novo missense mutation in the chromosome 6 open reading frame 70 (C6orf70) gene, mapping in the minimal critical deleted region. Using immunohistochemistry and western blots, we demonstrated that in human cell lines, C6orf70 shows primarily a cytoplasmic vesicular puncta-like distribution and that the mutation affects its stability and subcellular distribution. We also performed in utero silencing of C6orf70 and of Phf10 and Dll1, the two additional genes mapping in the 6q27 minimal critical deleted region that are expressed in human and rodent brain. Silencing of C6orf70 in the developing rat neocortex produced periventricular nodular heterotopia that was rescued by concomitant expression of wild-type human C6orf70 protein. Silencing of the contiguous Phf10 or Dll1 genes only produced slightly delayed migration but not periventricular nodular heterotopia. The complex brain phenotype observed in the 6q terminal deletion syndrome likely results from the combined haploinsufficiency of contiguous genes mapping to a small 1.2 Mb region. Our data suggest that, of the genes within this minimal critical region, C6orf70 plays a major role in the control of neuronal migration and its haploinsufficiency or mutation causes periventricular nodular heterotopia.
- Published
- 2013
37. Sudden death in a patient with mosaic ring X Turner syndrome and a neuronal migration disorder
- Author
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Cheryl Longman, Nasser Al-Hilaly, Richard E. Johnson, Rosslyn Rankin, James MacKenzie, Patricia Atkinson, and Meriel McEntagart
- Subjects
Pathology ,medicine.medical_specialty ,Turner Syndrome ,Ring (chemistry) ,Hippocampus ,Sudden death ,Pathology and Forensic Medicine ,Death, Sudden ,Turner syndrome ,Humans ,Medicine ,Ring Chromosomes ,Genetics (clinical) ,Chromosomes, Human, X ,Mosaicism ,business.industry ,Infant ,General Medicine ,medicine.disease ,Neuronal migration disorder ,Karyotyping ,Pediatrics, Perinatology and Child Health ,Female ,Anatomy ,business ,Malformations of Cortical Development, Group II - Published
- 2008
38. Type II Cortical Dysplasia in Dominant Frontal Lobe Presenting as Gelastic Epilepsy
- Author
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Rana R. Said, Drew Michael Thodeson, Michael M. Dowling, Divyanshu Dubey, Susan Arnold, and Deepa Sirsi
- Subjects
Male ,Tomography, Emission-Computed, Single-Photon ,business.industry ,Electroencephalography ,Anatomy ,Cortical dysplasia ,medicine.disease ,Magnetic Resonance Imaging ,Frontal Lobe ,Diagnosis, Differential ,Developmental Neuroscience ,Neurology ,Frontal lobe ,Gelastic seizure ,Pediatrics, Perinatology and Child Health ,medicine ,Humans ,Epilepsies, Partial ,Neurology (clinical) ,medicine.symptom ,Child ,business ,Malformations of Cortical Development, Group II - Published
- 2015
39. A Behavioral Evaluation of Sex Differences in a Mouse Model of Severe Neuronal Migration Disorder
- Author
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Amanda R. Rendall, Dongnhu T. Truong, Ashley Bonet, Roslyn Holly Fitch, and Glenn D. Rosen
- Subjects
Male ,lcsh:Medicine ,Morris water navigation task ,Mice, Transgenic ,Biology ,Nervous System Malformations ,Severity of Illness Index ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Sex Factors ,Feedback, Sensory ,Intellectual disability ,medicine ,Animals ,lcsh:Science ,Maze Learning ,Social Behavior ,030304 developmental biology ,0303 health sciences ,Multidisciplinary ,Behavior, Animal ,lcsh:R ,Dyslexia ,Wild type ,medicine.disease ,Phenotype ,Disease Models, Animal ,Neuronal migration disorder ,Autism ,lcsh:Q ,Female ,Abnormality ,Neuroscience ,030217 neurology & neurosurgery ,Malformations of Cortical Development, Group II ,Research Article - Abstract
Disruption of neuronal migration in humans is associated with a wide range of behavioral and cognitive outcomes including severe intellectual disability, language impairment, and social dysfunction. Furthermore, malformations of cortical development have been observed in a number of neurodevelopmental disorders (e.g. autism and dyslexia), where boys are much more commonly diagnosed than girls (estimates around 4 to 1). The use of rodent models provides an excellent means to examine how sex may modulate behavioral outcomes in the presence of comparable abnormal neuroanatomical presentations. Initially characterized by Rosen et al. 2012, the BXD29- Tlr4(lps-2J) /J mouse mutant exhibits a highly penetrant neuroanatomical phenotype that consists of bilateral midline subcortical nodular heterotopia with partial callosal agenesis. In the current study, we confirm our initial findings of a severe impairment in rapid auditory processing in affected male mice. We also report that BXD29- Tlr4(lps-2J) /J (mutant) female mice show no sparing of rapid auditory processing, and in fact show deficits similar to mutant males. Interestingly, female BXD29- Tlr4(lps-2J) /J mice do display superiority in Morris water maze performance as compared to wild type females, an affect not seen in mutant males. Finally, we report new evidence that BXD29- Tlr4(lps-2J) /J mice, in general, show evidence of hyper-social behaviors. In closing, the use of the BXD29- Tlr4(lps-2J) /J strain of mice - with its strong behavioral and neuroanatomical phenotype - may be highly useful in characterizing sex independent versus dependent mechanisms that interact with neural reorganization, as well as clinically relevant abnormal behavior resulting from aberrant neuronal migration.
- Published
- 2013
40. Rufinamide for the treatment of refractory epilepsy secondary to neuronal migration disorders
- Author
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Pasquale Parisi, Romina Moavero, Domenica Battaglia, Alberto Verrotti, Dario Pruna, Giangennaro Coppola, Paolo Curatolo, Raffaella Cusmai, Sara Matricardi, Federico Vigevano, Alberto Spalice, Giancarlo Di Gennaro, and Alfredo D'Aniello
- Subjects
Male ,Pediatrics ,Rufinamide refractory epilepsy ,Refractory seizures ,Rufinamide ,Neuronal migration disorders ,Epilepsy ,Partial epilepsy ,Germany ,Prospective Studies ,Child ,Adolescent ,Adult ,Anticonvulsants ,Child, Preschool ,Female ,Humans ,Italy ,Malformations of Cortical Development, Group II ,Treatment Outcome ,Triazoles ,Young Adult ,Neurology ,Neurology (clinical) ,education.field_of_study ,Settore MED/39 - Neuropsichiatria Infantile ,Malformations of Cortical Development ,Settore MED/26 - NEUROLOGIA ,Tolerability ,Group II ,Anesthesia ,Vomiting ,medicine.symptom ,medicine.drug ,medicine.medical_specialty ,Side effect ,Population ,Irritability ,medicine ,refractory seizures ,rufinamide ,neuronal migration disorders ,partial epilepsy ,Adverse effect ,education ,Preschool ,business.industry ,medicine.disease ,business - Abstract
Summary Objective To evaluate the efficacy and tolerability of add-on rufinamide in children with refractory epilepsy symptomatic of neuronal migration disorders. Materials and methods We recruited 69 patients in a prospective, open-label, add-on treatment study from six Italian and one German centers for pediatric and adolescent epilepsy care according to the following criteria: age 3 or above; focal or generalized seizures refractory to at least three previous antiepileptic drugs (AEDs), alone or in combination, secondary to neuronal migration disorders; two or more seizures per month in the last 6 months; use of another AED, but no more than three, at baseline. Informed consent from parents and/or caregivers was obtained at the time of enrollment. Results We enrolled 69 patients with a mean age of 15 years (range 3–43). Forty-three patients (62%) had a 50–99% seizure reduction, and two (3%) became seizure-free. Seizure frequency was unchanged in 18 (26%) and worsened in 6 (8.7%). Twenty-nine patients (42%) reported adverse side effects, whilst taking rufinamide. Irritability was the most common side effect (11 patients), followed by decreased appetite (10), mood shift (6), vomiting (5), drowsiness (4), and decreased attention (2). Blood levels of concomitant anticonvulsive drugs were transiently abnormal in 5 patients. Conclusion In our population of severely refractory epilepsy due to neuronal migration disorders, rufinamide appeared to be effective and generally well tolerated.
- Published
- 2013
41. Cytoskeleton in action: lissencephaly, a neuronal migration disorder
- Author
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Hyang Mi, Moon and Anthony, Wynshaw-Boris
- Subjects
Cerebral Cortex ,Neurons ,Doublecortin Protein ,Nervous System Malformations ,Article ,Mice ,Reelin Protein ,nervous system ,Cell Movement ,Animals ,Humans ,Lissencephaly ,Microtubule-Associated Proteins ,Cytoskeleton ,Malformations of Cortical Development, Group II - Abstract
During neocortical development, the extensive migratory movements of neurons from their place of birth to their final location are essential for the coordinated wiring of synaptic circuits and proper neurological function. Failure or delay in neuronal migration causes severe abnormalities in cortical layering, which consequently results in human lissencephaly ('smooth brain'), a neuronal migration disorder. The brains of lissencephaly patients have less-convoluted gyri in the cerebral cortex with impaired cortical lamination of neurons. Since microtubule (MT) and actin-associated proteins play important functions in regulating the dynamics of MT and actin cytoskeletons during neuronal migration, genetic mutations or deletions of crucial genes involved in cytoskeletal processes lead to lissencephaly in human and neuronal migration defects in mouse. During neuronal migration, MT organization and transport are controlled by platelet-activating factor acetylhydrolase isoform 1b regulatory subunit 1 (PAFAH1B1, formerly known as LIS1, Lissencephaly-1), doublecortin (DCX), YWHAE, and tubulin. Actin stress fibers are modulated by PAFAH1B1 (LIS1), DCX, RELN, and VLDLR (very low-density lipoprotein receptor)/LRP8 (low-density lipoprotein-related receptor 8, formerly known as APOER2). There are several important levels of crosstalk between these two cytoskeletal systems to establish accurate cortical patterning in development. The recent understanding of the protein networks that govern neuronal migration by regulating cytoskeletal dynamics, from human and mouse genetics as well as molecular and cellular analyses, provides new insights on neuronal migration disorders and may help us devise novel therapeutic strategies for such brain malformations.
- Published
- 2013
42. Molecular layer heterotopia of the cerebellar vermis in mutant and transgenic mouse models on a C57BL/6 background
- Author
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German Torres, Elizabeth George, Blair J. Hoplight, Raddy L. Ramos, Joerg R. Leheste, Sarah E. Van Dine, Eric K. Richfield, and Dhruv B. Patel
- Subjects
C57BL/6 ,Genetically modified mouse ,Male ,Pathology ,medicine.medical_specialty ,Cerebellar dysplasia ,Mutant ,Mice, Transgenic ,Green fluorescent protein ,Mice ,Cerebellum ,medicine ,Animals ,biology ,General Neuroscience ,Cerebellar function ,medicine.disease ,biology.organism_classification ,Mice, Mutant Strains ,Mice, Inbred C57BL ,Heterotopia (medicine) ,nervous system ,Cerebellar vermis ,Female ,Neuroscience ,Malformations of Cortical Development, Group II - Abstract
C57BL/6 mice exhibit spontaneous cerebellar malformations consisting of heterotopic neurons and glia in the molecular layer of the vermis (Tanaka and Marunouchi, 2005; Mangaru et al., 2013). Malformations are only found between folia VIII and IX and are indicative of deficits of neuronal migration during cerebellar development. In the present report we test the prediction that mutant and transgenic mouse models on a C57BL/6 background will also exhibit these same cerebellar malformations. Consistent with our hypothesis, we found that 2 spontaneous mutant models of Parkinson's disease on a C57BL/6 background had cerebellar malformations. In addition, we found that numerous transgenic mouse lines on a full or partial C57BL/6 background including eGFP-, YFP- and Cre-transgenic mice also exhibited heterotopia. These data suggest that histological analyses be performed in studies of cerebellar function or development when using C57BL/6 or other mice on this background in order for correct interpretation of research results.
- Published
- 2013
43. Knockdown of the candidate dyslexia susceptibility gene homolog dyx1c1 in rodents: effects on auditory processing, visual attention, and cortical and thalamic anatomy
- Author
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Caitlin E, Szalkowski, Anne B, Booker, Dongnhu T, Truong, Steven W, Threlkeld, Glenn D, Rosen, and Roslyn H, Fitch
- Subjects
Cerebral Cortex ,Male ,Geniculate Bodies ,Hippocampus ,Article ,Rats ,Gene Knockdown Techniques ,Auditory Perception ,Visual Perception ,Animals ,Attention ,Female ,RNA Interference ,Agenesis of Corpus Callosum ,Rats, Wistar ,Carrier Proteins ,Maze Learning ,Malformations of Cortical Development, Group II - Abstract
The current study investigated the behavioral and neuroanatomical effects of embryonic knockdown of the candidate dyslexia susceptibility gene (CDSG) homolog Dyx1c1 through RNA interference in rats. Specifically, we examined long-term effects on visual attention abilities in males, in addition to assessing rapid and complex auditory processing abilities in male and, for the first time, female rats. Results replicated prior evidence of complex acoustic processing deficits in Dyx1c1 male rats, and revealed new evidence of comparable deficits in Dyx1c1 female rats. Moreover, we found new evidence that knocking down Dyx1c1 produced orthogonal impairments in visual attention in the male sub-group. Stereological analyses of male brains from prior RNA interference studies revealed that, despite consistent visible evidence of disruptions in neuronal migration (i.e., heterotopia), knockdown of Dyx1c1 did not significantly alter cortical volume, hippocampal volume, or midsagittal area of the corpus callosum (measured in a separate cohort of like-treated Dyx1c1 male rats). Dyx1c1 transfection did however lead to significant changes in medial geniculate nucleus (MGN) anatomy, with a significant shift to smaller MGN neurons in Dyx1c1 transfected animals. Combined results provide important information about the impact of Dyx1c1 on behavioral functions that parallel domains known to be affected in language impaired populations, as well as information about widespread changes to the brain following early disruption of this candidate dyslexia susceptibility gene.
- Published
- 2012
44. Expanding the spectrum of TUBA1A-related cortical dysgenesis to Polymicrogyria
- Author
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Franck J. Fourniol, Marine Line Jacquemont, Karine Poirier, Fiona Francis, Jamel Chelly, Isabelle Souville, Nathalie Boddaert, Jean Marie Lepage, Nadia Bahi-Buisson, Stéphanie Valence, Yoann Saillour, Cherif Beldjord, and Isabelle Desguerre
- Subjects
Male ,Cerebellar dysplasia ,Molecular Sequence Data ,Mutation, Missense ,Lissencephaly ,Biology ,medicine.disease_cause ,Article ,Tubulin ,Genetics ,Polymicrogyria ,medicine ,Missense mutation ,Humans ,Amino Acid Sequence ,Child ,Genetics (clinical) ,Mutation ,Pachygyria ,Infant ,medicine.disease ,Pedigree ,Protein Structure, Tertiary ,Malformations of Cortical Development ,Dysplasia ,Child, Preschool ,Mutation testing ,Female ,Malformations of Cortical Development, Group II - Abstract
De novo mutations in the TUBA1A gene are responsible for a wide spectrum of neuronal migration disorders, ranging from lissencephaly to perisylvian pachygyria. Recently, one family with polymicrogyria (PMG) and mutation in TUBA1A was reported. Hence, the purpose of our study was to determine the frequency of TUBA1A mutations in patients with PMG and better define clinical and imaging characteristics for TUBA1A-related PMG. We collected 95 sporadic patients with non-syndromic bilateral PMG, including 54 with perisylvian PMG and 30 PMG with additional brain abnormalities. Mutation analysis of the TUBA1A gene was performed by sequencing of PCR fragments corresponding to TUBA1A-coding sequences. Three de novo missense TUBA1A mutations were identified in three unrelated patients with PMG representing 3.1% of PMG and 10% of PMGs with complex cerebral malformations. These patients had bilateral perisylvian asymmetrical PMG with dysmorphic basal ganglia cerebellar vermian dysplasia and pontine hypoplasia. These mutations (p.Tyr161His; p.Val235Leu; p.Arg390Cys) appear distributed throughout the primary structure of the alpha-tubulin polypeptide, but their localization within the tertiary structure suggests that PMG-related mutations are likely to impact microtubule dynamics, stability and/or local interactions with partner proteins. These findings broaden the phenotypic spectrum associated with TUBA1A mutations to PMG and further emphasize that additional brain abnormalities, that is, dysmorphic basal ganglia, hypoplastic pons and cerebellar dysplasia are key features for the diagnosis of TUBA1A-related PMG.
- Published
- 2012
45. Neonatal hypoxia and seizures
- Author
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Maria Gillam-Krakauer and Brian S. Carter
- Subjects
medicine.medical_specialty ,Pediatrics ,Central nervous system ,Encephalopathy ,Electroencephalography ,Infections ,Diagnosis, Differential ,Seizures ,medicine ,Humans ,Neonatology ,Neonatal seizure ,Hypoxia, Brain ,medicine.diagnostic_test ,business.industry ,Infant, Newborn ,Hypoxia (medical) ,Hypothermia ,medicine.disease ,medicine.anatomical_structure ,Cerebral blood flow ,Anesthesia ,Pediatrics, Perinatology and Child Health ,Hypoxia-Ischemia, Brain ,Anticonvulsants ,medicine.symptom ,business ,Intracranial Hemorrhages ,Malformations of Cortical Development, Group II - Abstract
1. Maria Gillam-Krakauer, MD* 2. Brian S. Carter, MD† 1. *Assistant Professor of Pediatrics, Division of Neonatology, Vanderbilt University Medical Center, Nashville, TN. 2. †Professor of Pediatrics, Section of Neonatology, Children's Mercy Hospital, Kansas City, MO. * Abbreviations: AED: : antiepileptic drug AMPA: : α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid ATP: : adenosine triphosphate CSF: : cerebrospinal fluid HIE: : hypoxic-ischemic encephalopathy MOCO: : molybdenum cofactor NMDA: : N -methyl-d-aspartic acid With 1 to 3 in 1,000 term neonates experiencing seizures, pediatricians need to know how to determine the seizure cause and manage appropriately, using brain imaging and treatments such as therapeutic hypothermia, xenon, and other pharmacologic therapies, in order to minimize long-term sequelae and leverage the infant brain's tremendous capacity for repair in the first 2 years after birth. After completing this article, readers should be able to: 1. Understand the pathophysiology of neonatal seizures. 2. Know the many disorders associated with seizures in the newborn. 3. Be aware of the characteristics of different neonatal seizure syndromes. 4. Know how to evaluate a newborn who is having seizures. 5. Be aware of the treatments for neonatal seizures. 6. Understand the characteristics and management of hypoxic-ischemic encephalopathy. Seizures occur during the newborn period at an incidence of ∼1 to 3 per 1,000 infants born at term. (1)(2)(3) Numerous systemic and neurologic conditions can manifest as seizures. Cerebral hypoxia-ischemia, defined as partial lack of oxygen resulting in reduction of blood flow to the brain, is the most frequent cause of seizures in the newborn period. It is important to determine the cause of neonatal seizures and institute the appropriate therapy to minimize the long-term sequelae of both the underlying condition and the seizure. Seizures are paroxysmal alterations in neurologic function caused by excessive synchronous depolarization of neurons within the central nervous system. Regardless of the underlying pathology manifesting as a seizure, all seizures are due to a shift in cell energy. This shift can result from failure of the adenosine triphosphate (ATP)–dependent sodium-potassium (Na+-K+) pump, an imbalance of inhibitory and excitatory neurotransmitters, and both excessive …
- Published
- 2012
46. Extra-cell cycle regulatory functions of cyclin-dependent kinases (CDK) and CDK inhibitor proteins contribute to brain development and neurological disorders
- Author
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Yoichi Kosodo, Mima Shikanai, and Takeshi Kawauchi
- Subjects
Cerebral Cortex ,Interkinetic nuclear migration ,biology ,Neurogenesis ,Cyclin A ,Cell Cycle ,Cell Biology ,Review ,Cell cycle ,Neural stem cell ,Cyclin-Dependent Kinases ,Cell biology ,nervous system ,Neural Stem Cells ,Cyclin-dependent kinase ,Genetics ,biology.protein ,Animals ,Humans ,Progenitor cell ,Malformations of Cortical Development, Group II ,Cyclin-dependent kinase inhibitor protein ,Cyclin-Dependent Kinase Inhibitor Proteins - Abstract
In developing brains, neural progenitors exhibit cell cycle-dependent nuclear movement within the ventricular zone [interkinetic nuclear migration (INM)] and actively proliferate to produce daughter progenitors and/or neurons, whereas newly generated neurons exit from the cell cycle and begin pial surface-directed migration and maturation. Dysregulation of the balance between the proliferation and the cell cycle exit in neural progenitors is one of the major causes of microcephaly (small brain). Recent studies indicate that cell cycle machinery influences not only the proliferation but also INM in neural progenitors. Furthermore, several cell cycle-related proteins, including p27(kip1) , p57(kip2) , Cdk5, and Rb, regulate the migration of neurons in the postmitotic state, suggesting that the growth arrest confers dual functions on cell cycle regulators. Consistently, several types of microcephaly occur in conjunction with neuronal migration disorders, such as periventricular heterotopia and lissencephaly. However, cell cycle re-entry by disturbance of growth arrest in mature neurons is thought to trigger neuronal cell death in Alzheimer's disease. In this review, we introduce the cell cycle protein-mediated regulation of two types of nuclear movement, INM and neuronal migration, during cerebral cortical development, and discuss the roles of growth arrest in cortical development and neurological disorders.
- Published
- 2012
47. Neuronal migration defect of the developing cerebellar vermis in substrains of C57BL/6 mice: cytoarchitecture and prevalence of molecular layer heterotopia
- Author
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Matthew Sherman, Lisa A. Gabel, Elsaid Salem, Eric K. Richfield, Zareema Mangaru, Ankur Bhambri, Sarah E. Van Dine, Raddy L. Ramos, and Joshua C. Brumberg
- Subjects
Neurons ,Cerebellum ,Cerebellar dysplasia ,Biology ,Inhibitory postsynaptic potential ,medicine.disease ,Mice, Inbred C57BL ,Mice ,medicine.anatomical_structure ,Heterotopia (medicine) ,nervous system ,Developmental Neuroscience ,Neurology ,Cytoarchitecture ,medicine ,Cerebellar vermis ,Prevalence ,GABAergic ,Animals ,Motor learning ,Neuroscience ,Neuroglia ,Malformations of Cortical Development, Group II - Abstract
Abnormal development of the cerebellum is often associated with disorders of movement, postural control, and motor learning. Rodent models are widely used to study normal and abnormal cerebellar development and have revealed the roles of many important genetic and environmental factors. In the present report we describe the prevalence and cytoarchitecture of molecular-layer heterotopia, a malformation of neuronal migration, in the cerebellar vermis of C57BL/6 mice and closely-related strains. In particular, we found a diverse number of cell-types affected by these malformations including Purkinje cells, granule cells, inhibitory interneurons (GABAergic and glycinergic), and glia. Heterotopia were not observed in a sample of wild-derived mice, outbred mice, or inbred mice not closely related to C57BL/6 mice. These data are relevant to the use of C57BL/6 mice as models in the study of brain and behavior relationships and provide greater understanding of human cerebellar dysplasia.
- Published
- 2012
48. Array-based characterization of an interstitial de-novo deletion of chromosome 4q in a patient with a neuronal migration defect and hypocalcemia plus a literature review
- Author
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Guiomar Perez-Nanclares Leal, Marta Moreno-García, Francisco Javier Fernández-Martínez, J. Pozo, and Jaime Cruz-Rojo
- Subjects
Neuronal migration ,Pathology and Forensic Medicine ,Cerebellum ,Medicine ,Humans ,Salivary Proteins and Peptides ,Genetics (clinical) ,Ultrasonography ,Genetics ,Comparative Genomic Hybridization ,Epilepsy ,Hypocalcemia ,business.industry ,Genome, Human ,Infant, Newborn ,Mucins ,Chromosome ,Chromosome Mapping ,Infant ,General Medicine ,Pediatrics, Perinatology and Child Health ,Female ,Anatomy ,Chromosome Deletion ,Chromosomes, Human, Pair 4 ,business ,Malformations of Cortical Development, Group II - Published
- 2012
49. Loss of Microtubule-to-Actin Linkage Disrupts Cortical Development
- Author
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Yuanyi Feng and Ashley S. Pawlisz
- Subjects
Utrophin ,Duchenne muscular dystrophy ,Cell Cycle Proteins ,Biochemistry ,Basement Membrane ,Dystrophin ,Mice ,0302 clinical medicine ,Molecular Cell Biology ,Biology (General) ,Dystroglycans ,Mice, Knockout ,Cerebral Cortex ,0303 health sciences ,biology ,General Neuroscience ,Neural stem cell ,Cell biology ,Phenotype ,Synopsis ,General Agricultural and Biological Sciences ,Lissencephaly ,Microtubule-Associated Proteins ,Research Article ,QH301-705.5 ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Glycoprotein complex ,medicine ,Dystroglycan ,Genetics ,Animals ,Humans ,Biology ,030304 developmental biology ,General Immunology and Microbiology ,Cell Membrane ,medicine.disease ,Disease Models, Animal ,nervous system ,1-Alkyl-2-acetylglycerophosphocholine Esterase ,biology.protein ,Pikachurin ,sense organs ,030217 neurology & neurosurgery ,Malformations of Cortical Development, Group II ,Developmental Biology ,Neuroscience - Abstract
Lis1-Nde1 integrates cerebral cortical neurogenesis with neuronal migration by stabilizing the basal-lateral surface of radial glial cells., Radial glial cells (RGCs) are distinctive neural stem cells with an extraordinary slender bipolar morphology and dual functions as precursors and migration scaffolds for cortical neurons. Here we show a novel mechanism by which the Lis1-Nde1 complex maintains RGC functions through stabilizing the dystrophin/dystroglycan glycoprotein complex (DGC). A direct interaction between Nde1 and utrophin/dystrophin allows for the assembly of a multi-protein complex that links the cytoskeleton to the extracellular matrix of RGCs to stabilize their lateral membrane, cell-cell adhesion, and radial morphology. Lis1-Nde1 mutations destabilized the DGC and resulted in deformed, disjointed RGCs and disrupted basal lamina. Besides impaired RGC self-renewal and neuronal migration arrests, Lis1-Nde1 deficiencies also led to neuronal over-migration. Additional to phenotypic resemblances of Lis1-Nde1 with DGC, strong synergistic interactions were found between Nde1 and dystroglycan in RGCs. As functional insufficiencies of LIS1, NDE1, and dystroglycan all cause lissencephaly syndromes, our data demonstrated that a three-dimensional regulation of RGC's cytoarchitecture by the Lis1-Nde1-DGC complex determines the number and spatial organization of cortical neurons as well as the size and shape of the cerebral cortex., Author Summary The processes of neurogenesis and neuronal migration within the developing cerebral cortex must be tightly orchestrated to enable ordered generation and transportation of neurons to designated cortical layers. The mechanism by which these two processes are integrated remains elusive. Radial glial cells, the major neural stem cells in the developing brain, serve both as progenitors and migration scaffolds for cortical neurons as they migrate. The cortical developmental disease lissencephaly (smooth brain) is a result of defects in neurogenesis and neuronal migration, and is associated with the protein LIS1 and its binding partner NDE1. In this study, we show that several key players in human cerebral cortical development, including LIS1, NDE1, dystrophin, and dystroglycan, form a molecular complex to regulate cortical neurogenesis and neuronal migration in a mouse model. This multi-protein complex is active on the basal-lateral surface of radial glial cells, which is known to provide guidance to migrating neurons. When we depleted NDE1 in mice, dystrophin and dystroglycan were lost from the membrane and radial glial cells were deformed, indicating the importance of the multi-protein complex for proper cell morphology. This effect on morphology resulted in a loss of normal migration and cortical phenotypes similar to lissencephaly. Our findings suggest that genes that regulate the structure and function of the basal-lateral membrane of radial glial cells may integrate the dual functions of these cells and determine the size, shape, and function of the cerebral cortex.
- Published
- 2011
50. Sudden unexpected death in epilepsy: a retrospective analysis of 24 adult cases
- Author
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Michael S. Pollanen and Sarathchandra Kodikara
- Subjects
Adult ,Male ,Pediatrics ,medicine.medical_specialty ,Poison control ,Autopsy ,Context (language use) ,Pathology and Forensic Medicine ,Medication Adherence ,Epilepsy ,Death, Sudden ,Young Adult ,Age Distribution ,Risk Factors ,Medicine ,Humans ,Young adult ,Forensic Pathology ,Collapse (medical) ,Aged ,Retrospective Studies ,business.industry ,Brain ,Retrospective cohort study ,General Medicine ,Middle Aged ,medicine.disease ,Brain Injuries ,Etiology ,Anticonvulsants ,Female ,Medical emergency ,medicine.symptom ,business ,Lissencephaly ,Malformations of Cortical Development, Group II - Abstract
Sudden unexpected death in epilepsy is a common form of seizure-related death but is poorly appreciated by the medical profession. A number of risk factors have been identified in this context including male gender, young adult age group (20–40 years), poor compliance with antiepileptic drugs, polytherapy, and presence of neuropathological lesions. In addition it has been noted that most of the victims sustained an unwitnessed collapse at home. In this paper, we describe a retrospective review of 24 adult cases of sudden unexpected death in epilepsy. The study recognizes two risk factors; poor compliance with anti-epileptic monotherapy and an age between 20 and 29 years. All the victims were found dead at home and only one had a witnessed collapse. Our study shows a variety of neuropathological findings as the etiology. The completeness of the autopsy findings for all the cases is a strength compared to some of the other studies.
- Published
- 2011
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