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NPRL3 loss alters neuronal morphology, mTOR localization, cortical lamination and seizure threshold.Brain : a Journal of Neurology Nov 2022Mutations in nitrogen permease regulator-like 3 (NPRL3), a component of the GATOR1 complex within the mTOR pathway, are associated with epilepsy and malformations of...
Mutations in nitrogen permease regulator-like 3 (NPRL3), a component of the GATOR1 complex within the mTOR pathway, are associated with epilepsy and malformations of cortical development. Little is known about the effects of NPRL3 loss on neuronal mTOR signalling and morphology, or cerebral cortical development and seizure susceptibility. We report the clinical phenotypic spectrum of a founder NPRL3 pedigree (c.349delG, p.Glu117LysFS; n = 133) among Old Order Mennonites dating to 1727. Next, as a strategy to define the role of NPRL3 in cortical development, CRISPR/Cas9 Nprl3 knockout in Neuro2a cells in vitro and in foetal mouse brain in vivo was used to assess the effects of Nprl3 knockout on mTOR activation, subcellular mTOR localization, nutrient signalling, cell morphology and aggregation, cerebral cortical cytoarchitecture and network integrity. The NPRL3 pedigree exhibited an epilepsy penetrance of 28% and heterogeneous clinical phenotypes with a range of epilepsy semiologies, i.e. focal or generalized onset, brain imaging abnormalities, i.e. polymicrogyria, focal cortical dysplasia or normal imaging, and EEG findings, e.g. focal, multi-focal or generalized spikes, focal or generalized slowing. Whole exome analysis comparing a seizure-free group (n = 37) to those with epilepsy (n = 24) to search for gene modifiers for epilepsy did not identify a unique genetic modifier that explained the variability in seizure penetrance in this cohort. Nprl3 knockout in vitro caused mTOR pathway hyperactivation, cell soma enlargement and the formation of cellular aggregates seen in time-lapse videos that were prevented with the mTOR inhibitors rapamycin or torin1. In Nprl3 knockout cells, mTOR remained localized on the lysosome in a constitutively active conformation, as evidenced by phosphorylation of ribosomal S6 and 4E-BP1 proteins, even under nutrient starvation (amino acid-free) conditions, demonstrating that Nprl3 loss decouples mTOR activation from neuronal metabolic state. To model human malformations of cortical development associated with NPRL3 variants, we created a focal Nprl3 knockout in foetal mouse cortex by in utero electroporation and found altered cortical lamination and white matter heterotopic neurons, effects which were prevented with rapamycin treatment. EEG recordings showed network hyperexcitability and reduced seizure threshold to pentylenetetrazol treatment. NPRL3 variants are linked to a highly variable clinical phenotype which we propose results from mTOR-dependent effects on cell structure, cortical development and network organization.
Topics: Animals; Humans; Mice; TOR Serine-Threonine Kinases; Malformations of Cortical Development; GTPase-Activating Proteins; Epilepsy; Neurons; Seizures; Sirolimus
PubMed: 35136953
DOI: 10.1093/brain/awac044 -
Annual Review of Pathology Jan 2019Malformations of cortical development encompass heterogeneous groups of structural brain anomalies associated with complex neurodevelopmental disorders and diverse... (Review)
Review
Malformations of cortical development encompass heterogeneous groups of structural brain anomalies associated with complex neurodevelopmental disorders and diverse genetic and nongenetic etiologies. Recent progress in understanding the genetic basis of brain malformations has been driven by extraordinary advances in DNA sequencing technologies. For example, somatic mosaic mutations that activate mammalian target of rapamycin signaling in cortical progenitor cells during development are now recognized as the cause of hemimegalencephaly and some types of focal cortical dysplasia. In addition, research on brain development has begun to reveal the cellular and molecular bases of cortical gyrification and axon pathway formation, providing better understanding of disorders involving these processes. New neuroimaging techniques with improved resolution have enhanced our ability to characterize subtle malformations, such as those associated with intellectual disability and autism. In this review, we broadly discuss cortical malformations and focus on several for which genetic etiologies have elucidated pathogenesis.
Topics: Cerebral Cortex; Hemimegalencephaly; Humans; Intellectual Disability; Lissencephaly; Malformations of Cortical Development; Microcephaly; Mutation; Neurodevelopmental Disorders; Neuroimaging; Polymicrogyria
PubMed: 30677308
DOI: 10.1146/annurev-pathmechdis-012418-012927 -
Acta Neuropathologica Communications Jul 2014Polymicrogyria (PMG) is a complex cortical malformation which has so far defied any mechanistic or genetic explanation. Adopting a broad definition of an abnormally... (Review)
Review
Polymicrogyria (PMG) is a complex cortical malformation which has so far defied any mechanistic or genetic explanation. Adopting a broad definition of an abnormally folded or festooned cerebral cortical neuronal ribbon, this review addresses the literature on PMG and the mechanisms of its development, as derived from the neuropathological study of many cases of human PMG, a large proportion in fetal life. This reveals the several processes which appear to be involved in the early stages of formation of polymicrogyric cortex. The most consistent feature of developing PMG is disruption of the brain surface with pial defects, over-migration of cells, thickening and reduplication of the pial collagen layers and increased leptomeningeal vascularity. Evidence from animal models is consistent with our observations and supports the notion that disturbance in the formation of the leptomeninges or loss of their normal signalling functions are potent contributors to cortical malformation. Other mechanisms which may lead to PMG include premature folding of the neuronal band, abnormal fusion of adjacent gyri and laminar necrosis of the developing cortex. The observation of PMG in association with other and better understood forms of brain malformation, such as cobblestone cortex, suggests mechanistic pathways for some forms of PMG. The role of altered physical properties of the thickened leptomeninges in exerting mechanical constraints on the developing cortex is also considered.
Topics: Cerebral Cortex; Female; Fetus; Humans; Male; Polymicrogyria
PubMed: 25047116
DOI: 10.1186/s40478-014-0080-3 -
Journal of Medical Genetics May 2005Polymicrogyria is a relatively common malformation of cortical development, characterised by multiple small gyri with abnormal cortical lamination. The different forms... (Review)
Review
Polymicrogyria is a relatively common malformation of cortical development, characterised by multiple small gyri with abnormal cortical lamination. The different forms of polymicrogyria encompass a wide range of clinical, aetiological, and histological findings. Advances in imaging have improved the diagnosis and classification of the condition. The molecular basis of polymicrogyria is beginning to be elucidated with the identification of a gene, GPR56, for bilateral frontoparietal polymicrogyria. Functional studies of the GPR56 gene product will yield insights not only into the causes of polymicrogyria but also into the mechanisms of normal cortical development and the regional patterning of the cerebral cortex. Based on imaging studies, several other region specific patterns of polymicrogyria have been identified, and there is increasing evidence that these may also have a significant genetic component to their aetiology. This paper reviews current knowledge of the different polymicrogyria syndromes, with discussion of clinical and imaging features, patterns of inheritance, currently mapped loci, candidate genes, chromosomal abnormalities, and implications for genetic counselling.
Topics: Cerebral Cortex; Chromosome Aberrations; Genetic Counseling; Humans; Intellectual Disability; Magnetic Resonance Imaging; Nervous System Malformations; Syndrome
PubMed: 15863665
DOI: 10.1136/jmg.2004.023952 -
Epilepsia Feb 2010
Topics: Brain; Brain Mapping; Cognition Disorders; Down-Regulation; Electroencephalography; Epilepsy; Frontal Lobe; Functional Laterality; Genotype; Humans; Magnetic Resonance Imaging; Malformations of Cortical Development; Parietal Lobe; Phenotype; Point Mutation; Receptors, G-Protein-Coupled; Receptors, GABA-A
PubMed: 20331704
DOI: 10.1111/j.1528-1167.2009.02434.x -
The Neuroradiology Journal Aug 2018Pallister-Killian syndrome (PKS) is a rare chromosomal duplication disorder caused by additional copies of the short arm of chromosome 12 (12p). Clinically PKS is... (Review)
Review
Pallister-Killian syndrome (PKS) is a rare chromosomal duplication disorder caused by additional copies of the short arm of chromosome 12 (12p). Clinically PKS is characterized by craniofacial dysmorphism with neonatal frontotemporal alopecia, hypertelorism, and low-set ears as well as kyphoscoliosis, severe intellectual disability, epilepsy, and abnormal muscle tone. Comprehensive high-resolution brain MR findings of PKS in childhood have not been previously illustrated in the medical literature. We present detailed neuroimaging findings from a child with PKS and thoroughly review previously reported structural brain abnormalities in this patient population. MRI abnormalities common to PKS include cerebral volume loss, malformations of cortical development, corpus callosum dysgenesis, white matter disease, and craniofacial malformations. In our patient, new findings of perisylvian with occipital polymicrogyria, vermian dysplasia, brachium pontis signal abnormality, dural anomalies, and unilateral atlas assimilation were noted. Micrencephaly and cortical dysplasia provide a likely explanation for severe intellectual disability and epilepsy in this patient population.
Topics: Abnormalities, Multiple; Adolescent; Brain; Chromosome Disorders; Chromosomes, Human, Pair 12; Humans; Male; Neuroimaging
PubMed: 29260614
DOI: 10.1177/1971400917744798 -
AJNR. American Journal of Neuroradiology Nov 2022Zhu-Tokita-Takenouchi-Kim syndrome is a severe multisystem malformation disorder characterized by developmental delay and a diverse array of congenital abnormalities....
BACKGROUND AND PURPOSE
Zhu-Tokita-Takenouchi-Kim syndrome is a severe multisystem malformation disorder characterized by developmental delay and a diverse array of congenital abnormalities. However, these currently identified phenotypic components provide limited guidance in diagnostic situations, due to both the nonspecificity and variability of these features. Here we report a case series of 7 individuals with a molecular diagnosis of Zhu-Tokita-Takenouchi-Kim syndrome, 5 ascertained by their presentation with the neuronal migration disorder, periventricular nodular heterotopia.
MATERIALS AND METHODS
Individuals with a molecular diagnosis of Zhu-Tokita-Takenouchi-Kim syndrome were recruited from 2 sources, a high-throughput sequencing study of individuals with periventricular nodular heterotopia or from clinical diagnostic sequencing studies. We analyzed available brain MR images of recruited individuals to characterize periventricular nodular heterotopia distribution and to identify the presence of any additional brain abnormalities.
RESULTS
Pathogenic variants in , causative of Zhu-Tokita-Takenouchi-Kim syndrome, were identified in 7 individuals. Brain MR images from these individuals were re-analyzed. A characteristic set of imaging anomalies in addition to periventricular nodular heterotopia was identified, including the elongation of the pituitary stalk, cerebellar enlargement with an abnormally shaped posterior fossa, rounding of the caudate nuclei, hippocampal malformations, and cortical anomalies including polymicrogyria or dysgyria.
CONCLUSIONS
The recurrent neuroradiologic changes identified here represent an opportunity to guide diagnostic formulation of Zhu-Tokita-Takenouchi-Kim syndrome on the basis of brain MR imaging evaluation.
Topics: Humans; Periventricular Nodular Heterotopia; Brain; Magnetic Resonance Imaging; Brain Diseases; Intellectual Disability
PubMed: 36229163
DOI: 10.3174/ajnr.A7663 -
Frontiers in Cellular Neuroscience 2015Neurodevelopment is a complex, dynamic process that involves a precisely orchestrated sequence of genetic, environmental, biochemical, and physical events. Developmental... (Review)
Review
Neurodevelopment is a complex, dynamic process that involves a precisely orchestrated sequence of genetic, environmental, biochemical, and physical events. Developmental biology and genetics have shaped our understanding of the molecular and cellular mechanisms during neurodevelopment. Recent studies suggest that physical forces play a central role in translating these cellular mechanisms into the complex surface morphology of the human brain. However, the precise impact of neuronal differentiation, migration, and connection on the physical forces during cortical folding remains unknown. Here we review the cellular mechanisms of neurodevelopment with a view toward surface morphogenesis, pattern selection, and evolution of shape. We revisit cortical folding as the instability problem of constrained differential growth in a multi-layered system. To identify the contributing factors of differential growth, we map out the timeline of neurodevelopment in humans and highlight the cellular events associated with extreme radial and tangential expansion. We demonstrate how computational modeling of differential growth can bridge the scales-from phenomena on the cellular level toward form and function on the organ level-to make quantitative, personalized predictions. Physics-based models can quantify cortical stresses, identify critical folding conditions, rationalize pattern selection, and predict gyral wavelengths and gyrification indices. We illustrate that physical forces can explain cortical malformations as emergent properties of developmental disorders. Combining biology and physics holds promise to advance our understanding of human brain development and enable early diagnostics of cortical malformations with the ultimate goal to improve treatment of neurodevelopmental disorders including epilepsy, autism spectrum disorders, and schizophrenia.
PubMed: 26217183
DOI: 10.3389/fncel.2015.00257 -
Seizure Apr 2020Designed from the 60s to the 80s for adults, and despite the development of many new techniques, invasive explorations still have indications in children with focal... (Review)
Review
Designed from the 60s to the 80s for adults, and despite the development of many new techniques, invasive explorations still have indications in children with focal drug-resistant epilepsy. The main types are stereoelectroencephalography (SEEG) and subdural explorations (SDE). They provide precise information on the localization of the epileptogenic zone (EZ), its relationships with eloquent cortex, and the feasibility of performing a tailored surgical resection. Thermocoagulations, which are a diagnostic and therapeutic tool, can be performed using SEEG electrodes. Both techniques are feasible in children, with an age limitation for SEEG (which requires a bone thickness above 2 mm). The complication rate is higher with SDE. Opposed for a long time and never compared in a systematic study, they should presently be considered complementary. The indications cannot be directly inferred from those for adults, as there are pediatric particularities in the seizures' semiology, functional areas, imaging and urgent situations. We successively discuss the choice in individual cases of SEEG or SDE respectively, the specific problematic in infancy and early childhood, the schema in SEEG for cryptogenic epilepsies (in particular insular), the particularities of polymicrogyria and deeply located lesions, and finally, SEEG designed for thermocoagulations. Future improvements should include more accurate implantation schemas thanks to advanced non-invasive explorations and possibilities to perform SEEG in infants.
Topics: Adolescent; Child; Child, Preschool; Drug Resistant Epilepsy; Electrocoagulation; Electrocorticography; Epilepsies, Partial; Humans; Stereotaxic Techniques
PubMed: 30503504
DOI: 10.1016/j.seizure.2018.11.008