RESUMO
The development of interventions to prevent congenital Zika syndrome (CZS) has been limited by the lack of an established nonhuman primate model. Here we show that infection of female rhesus monkeys early in pregnancy with Zika virus (ZIKV) recapitulates many features of CZS in humans. We infected 9 pregnant monkeys with ZIKV, 6 early in pregnancy (weeks 6-7 of gestation) and 3 later in pregnancy (weeks 12-14 of gestation), and compared findings with uninfected controls. 100% (6 of 6) of monkeys infected early in pregnancy exhibited prolonged maternal viremia and fetal neuropathology, including fetal loss, smaller brain size, and histopathologic brain lesions, including microcalcifications, hemorrhage, necrosis, vasculitis, gliosis, and apoptosis of neuroprogenitor cells. High-resolution MRI demonstrated concordant lesions indicative of deep gray matter injury. We also observed spinal, ocular, and neuromuscular pathology. Our data show that vascular compromise and neuroprogenitor cell dysfunction are hallmarks of CZS pathogenesis, suggesting novel strategies to prevent and to treat this disease.
Assuntos
Feto/virologia , Neurônios/patologia , Infecção por Zika virus/patologia , Zika virus/patogenicidade , Animais , Animais Recém-Nascidos , Apoptose , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Calcinose/patologia , Calcinose/veterinária , Feminino , Idade Gestacional , Macaca mulatta , Imageamento por Ressonância Magnética , Necrose , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/virologia , Neurônios/virologia , Gravidez , Índice de Gravidade de Doença , Vasculite/patologia , Vasculite/veterinária , Infecção por Zika virus/veterinária , Infecção por Zika virus/virologiaRESUMO
After infection, many factors coordinate the population expansion and differentiation of CD8+ effector and memory T cells. Using data of unparalleled breadth from the Immunological Genome Project, we analyzed the CD8+ T cell transcriptome throughout infection to establish gene-expression signatures and identify putative transcriptional regulators. Notably, we found that the expression of key gene signatures can be used to predict the memory-precursor potential of CD8+ effector cells. Long-lived memory CD8+ cells ultimately expressed a small subset of genes shared by natural killer T and γδ T cells. Although distinct inflammatory milieu and T cell precursor frequencies influenced the differentiation of CD8+ effector and memory populations, core transcriptional signatures were regulated similarly, whether polyclonal or transgenic, and whether responding to bacterial or viral model pathogens. Our results provide insights into the transcriptional regulation that influence memory formation and CD8+ T cell immunity.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Memória Imunológica/genética , Memória Imunológica/imunologia , Infecções/genética , Infecções/imunologia , Transcrição Gênica , Animais , Linfócitos T CD8-Positivos/citologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Análise por Conglomerados , Biologia Computacional/métodos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Masculino , Camundongos , Receptores de Antígenos de Linfócitos T/genéticaRESUMO
Cytolytic activity by CD8(+) cytotoxic T lymphocytes (CTLs) is a powerful strategy for the elimination of intracellular pathogens and tumor cells. The destructive capacity of CTLs is progressively dampened during chronic infection, yet the environmental cues and molecular pathways that influence immunological 'exhaustion' remain unclear. Here we found that CTL immunity was regulated by the central transcriptional response to hypoxia, which is controlled in part by hypoxia-inducible factors (HIFs) and the von Hippel-Lindau tumor suppressor VHL. Loss of VHL, the main negative regulator of HIFs, led to lethal CTL-mediated immunopathology during chronic infection, and VHL-deficient CTLs displayed enhanced control of persistent viral infection and neoplastic growth. We found that HIFs and oxygen influenced the expression of pivotal transcription, effector and costimulatory-inhibitory molecules of CTLs, which was relevant to strategies that promote the clearance of viruses and tumors.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/imunologia , Melanoma Experimental/imunologia , Neoplasias Cutâneas/imunologia , Linfócitos T Citotóxicos/imunologia , Proteína Supressora de Tumor Von Hippel-Lindau/imunologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/deficiência , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Hipóxia Celular/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/deficiência , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/patologia , Coriomeningite Linfocítica/virologia , Vírus da Coriomeningite Linfocítica/imunologia , Melanoma Experimental/mortalidade , Melanoma Experimental/patologia , Melanoma Experimental/virologia , Camundongos , Camundongos Knockout , Oxigênio/farmacologia , Transdução de Sinais/efeitos dos fármacos , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/virologia , Análise de Sobrevida , Linfócitos T Citotóxicos/patologia , Transcrição Gênica/efeitos dos fármacos , Proteína Supressora de Tumor Von Hippel-Lindau/genéticaRESUMO
Cleft lip/palate is a common orofacial malformation that often leads to speech/language difficulties as well as developmental delays in affected children, despite surgical repair. Our understanding of brain development in these children is limited. This study aimed to analyze prenatal brain development in fetuses with cleft lip/palate and controls. We examined in utero MRIs of 30 controls and 42 cleft lip/palate fetal cases and measured regional brain volumes. Cleft lip/palate was categorized into groups A (cleft lip or alveolus) and B (any combination of clefts involving the primary and secondary palates). Using a repeated-measures regression model with relative brain hemisphere volumes (%), and after adjusting for multiple comparisons, we did not identify significant differences in regional brain growth between group A and controls. Group B clefts had significantly slower weekly cerebellar growth compared with controls. We also observed divergent brain growth in transient brain structures (cortical plate, subplate, ganglionic eminence) within group B clefts, depending on severity (unilateral or bilateral) and defect location (hemisphere ipsilateral or contralateral to the defect). Further research is needed to explore the association between regional fetal brain growth and cleft lip/palate severity, with the potential to inform early neurodevelopmental biomarkers and personalized diagnostics.
Assuntos
Fenda Labial , Fissura Palatina , Feminino , Criança , Gravidez , Humanos , Fenda Labial/diagnóstico por imagem , Fenda Labial/cirurgia , Fissura Palatina/diagnóstico por imagem , Fissura Palatina/cirurgia , Encéfalo/diagnóstico por imagem , Encéfalo/anormalidades , FetoRESUMO
PURPOSE: Niemann-Pick disease type C (NPC) is a rare lysosomal storage disease characterized by progressive neurodegeneration and neuropsychiatric symptoms. This study investigated pathophysiological mechanisms underlying motor deficits, particularly speech production, and cognitive impairment. METHODS: We prospectively phenotyped 8 adults with NPC and age-sex-matched healthy controls using a comprehensive assessment battery, encompassing clinical presentation, plasma biomarkers, hand-motor skills, speech production, cognitive tasks, and (micro-)structural and functional central nervous system properties through magnetic resonance imaging. RESULTS: Patients with NPC demonstrated deficits in fine-motor skills, speech production timing and coordination, and cognitive performance. Magnetic resonance imaging revealed reduced cortical thickness and volume in cerebellar subdivisions (lobule VI and crus I), cortical (frontal, temporal, and cingulate gyri) and subcortical (thalamus and basal ganglia) regions, and increased choroid plexus volumes in NPC. White matter fractional anisotropy was reduced in specific pathways (intracerebellar input and Purkinje tracts), whereas diffusion tensor imaging graph theory analysis identified altered structural connectivity. Patients with NPC exhibited altered activity in sensorimotor and cognitive processing hubs during resting-state and speech production. Canonical component analysis highlighted the role of cerebellar-cerebral circuitry in NPC and its integration with behavioral performance and disease severity. CONCLUSION: This deep phenotyping approach offers a comprehensive systems neuroscience understanding of NPC motor and cognitive impairments, identifying potential central nervous system biomarkers.
Assuntos
Imagem de Tensor de Difusão , Doença de Niemann-Pick Tipo C , Adulto , Humanos , Doença de Niemann-Pick Tipo C/genética , Doença de Niemann-Pick Tipo C/patologia , Imageamento por Ressonância Magnética/métodos , Cerebelo/diagnóstico por imagem , BiomarcadoresRESUMO
T follicular helper (Tfh) cells are essential in the induction of high-affinity, class-switched antibodies. The differentiation of Tfh cells is a multi-step process that depends upon the co-receptor ICOS and the activation of phosphoinositide-3 kinase leading to the expression of key Tfh cell genes. We report that ICOS signaling inactivates the transcription factor FOXO1, and a Foxo1 genetic deletion allowed for generation of Tfh cells with reduced dependence on ICOS ligand. Conversely, enforced nuclear localization of FOXO1 inhibited Tfh cell development even though ICOS was overexpressed. FOXO1 regulated Tfh cell differentiation through a broad program of gene expression exemplified by its negative regulation of Bcl6. Final differentiation to germinal center Tfh cells (GC-Tfh) was instead FOXO1 dependent as the Foxo1(-/-) GC-Tfh cell population was substantially reduced. We propose that ICOS signaling transiently inactivates FOXO1 to initiate a Tfh cell contingency that is completed in a FOXO1-dependent manner.
Assuntos
Diferenciação Celular/imunologia , Proteínas de Ligação a DNA/biossíntese , Fatores de Transcrição Forkhead/genética , Proteína Coestimuladora de Linfócitos T Induzíveis/imunologia , Linfócitos T Auxiliares-Indutores/citologia , Animais , Ativação Enzimática , Proteína Forkhead Box O1 , Fatores de Transcrição Forkhead/imunologia , Regulação da Expressão Gênica , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6 , Transdução de Sinais , Linfócitos T Auxiliares-Indutores/imunologiaRESUMO
Succinic semialdehyde dehydrogenase deficiency (SSADHD) is an inherited metabolic disorder of γ-aminobutyrate (GABA) catabolism. Cerebral waste clearance along glymphatic perivascular spaces depends on aquaporin 4 (AQP4) water channels, the function of which was shown to be influenced by GABA. Sleep disturbances are associated independently with SSADHD and glymphatic dysfunction. This study aimed to determine whether indices of the hyperGABAergic state characteristic of SSADHD coincide with glymphatic dysfunction and sleep disturbances and to explicate the modulatory effect that GABA may have on the glymphatic system. The study included 42 individuals (21 with SSADHD; 21 healthy controls) who underwent brain MRIs and magnetic resonance spectroscopy (MRS) for assessment of glymphatic dysfunction and cortical GABA, plasma GABA measurements, and circadian clock gene expression. The SSADHD subjects responded to an additional Children's Sleep Habits Questionnaire (CSHQ). Compared with the control group, SSADHD subjects did not differ in sex and age but had a higher severity of enlarged perivascular spaces in the centrum semiovale (p < 0.001), basal ganglia (p = 0.01), and midbrain (p = 0.001), as well as a higher MRS-derived GABA/NAA peak (p < 0.001). Within the SSADHD group, the severity of glymphatic dysfunction was specific for a lower MRS-derived GABA/NAA (p = 0.04) and lower plasma GABA (p = 0.004). Additionally, the degree of their glymphatic dysfunction correlated with the CSHQ-estimated sleep disturbances scores (R = 5.18, p = 0.03). In the control group, EPVS burden did not correlate with age or cerebral and plasma GABA values. The modulatory effect that GABA may exert on the glymphatic system has therapeutic implications for sleep-related disorders and neurodegenerative conditions associated with glymphatic dysfunction.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos , Sistema Glinfático , Imageamento por Ressonância Magnética , Transtornos do Sono-Vigília , Succinato-Semialdeído Desidrogenase , Ácido gama-Aminobutírico , Humanos , Masculino , Feminino , Ácido gama-Aminobutírico/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/fisiopatologia , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Transtornos do Sono-Vigília/fisiopatologia , Sistema Glinfático/fisiopatologia , Criança , Succinato-Semialdeído Desidrogenase/deficiência , Espectroscopia de Ressonância Magnética , Adolescente , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Encéfalo/metabolismo , Aquaporina 4 , Laringoestenose/fisiopatologia , Pré-Escolar , Deficiências do DesenvolvimentoRESUMO
In the field of hereditary spastic paraplegia (HSP), progress in molecular diagnostics needs to be translated into robust phenotyping studies to understand genetic and phenotypic heterogeneity and to support interventional trials. ZFYVE26-associated hereditary spastic paraplegia (HSP-ZFYVE26, SPG15) is a rare, early-onset complex HSP, characterized by progressive spasticity and a variety of other neurological symptoms. While prior reports, often in populations with high rates of consanguinity, have established a general phenotype, there is a lack of systematic investigations and a limited understanding of age-dependent manifestation of symptoms. Here we delineate the clinical, neuroimaging and molecular features of 44 individuals from 36 families, the largest cohort assembled to date. Median age at last follow-up was 23.8 years covering a wide age range (11-61 years). While symptom onset often occurred in early childhood [median: 24 months, interquartile range (IQR) = 24], a molecular diagnosis was reached at a median age of 18.8 years (IQR = 8), indicating significant diagnostic delay. We demonstrate that most patients present with motor and/or speech delay or learning disabilities. Importantly, these developmental symptoms preceded the onset of motor symptoms by several years. Progressive spasticity in the lower extremities, the hallmark feature of HSP-ZFYVE26, typically presents in adolescence and involves the distal lower limbs before progressing proximally. Spasticity in the upper extremities was seen in 64%. We found a high prevalence of extrapyramidal movement disorders including cerebellar ataxia (64%) and dystonia (11%). Parkinsonism (16%) was present in a subset and showed no sustained response to levodopa. Cognitive decline and neurogenic bladder dysfunction progressed over time in most patients. A systematic analysis of brain MRI features revealed a common diagnostic signature consisting of thinning of the anterior corpus callosum, signal changes of the anterior forceps and non-specific cortical and cerebellar atrophy. The molecular spectrum included 45 distinct variants, distributed across the protein structure without mutational hotspots. Spastic Paraplegia Rating Scale scores, SPATAX Disability Scores and the Four Stage Functional Mobility Score showed moderate strength in representing the proportion of variation between disease duration and motor dysfunction. Plasma neurofilament light chain levels were significantly elevated in all patients (Mann-Whitney U-test, P < 0.0001) and were correlated inversely with age (Spearman's rank correlation coefficient r = -0.65, P = 0.01). In summary, our systematic cross-sectional analysis of HSP-ZFYVE26 patients across a wide age-range, delineates core clinical, neuroimaging and molecular features and identifies markers of disease severity. These results raise awareness to this rare disease, facilitate an early diagnosis and create clinical trial readiness.
Assuntos
Paraplegia Espástica Hereditária , Humanos , Pré-Escolar , Paraplegia Espástica Hereditária/genética , Estudos Transversais , Diagnóstico Tardio , Proteínas/genética , MutaçãoRESUMO
Mild isolated fetal ventriculomegaly (iFVM) is the most common abnormality of the fetal central nervous system. It is characterized by enlargement of one or both of the lateral ventricles (defined as ventricular width greater than 10 mm, but less than 12 mm). Despite its high prevalence, the pathophysiology of iFVM during fetal brain development and the neurobiological substrate beyond ventricular enlargement remain unexplored. In this work, we aimed to establish the relationships between the structural development of transient fetal brain zones/compartments and increased cerebrospinal fluid volume. For this purpose, we used in vivo structural T2-weighted magnetic resonance imaging of 89 fetuses (48 controls and 41 cases with iFVM). Our results indicate abnormal development of transient zones/compartments belonging to both hemispheres (i.e. on the side with and also on the contralateral side without a dilated ventricle) in fetuses with iFVM. Specifically, compared to controls, we observed enlargement of proliferative zones and overgrowth of the cortical plate in iFVM with associated reduction of volumes of central structures, subplate, and fetal white matter. These results indicate that enlarged lateral ventricles might be linked to the development of transient fetal zones and that global brain development should be taken into consideration when evaluating iFVM.
Assuntos
Hidrocefalia , Imageamento por Ressonância Magnética , Gravidez , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Ultrassonografia Pré-Natal/métodos , Hidrocefalia/diagnóstico por imagem , Hidrocefalia/complicações , Hidrocefalia/patologia , Encéfalo/patologia , FetoRESUMO
Non-syndromic, isolated musculoskeletal birth defects (niMSBDs) are among the leading causes of pediatric hospitalization. However, little is known about brain development in niMSBDs. Our study aimed to characterize prenatal brain development in fetuses with niMSBDs and identify altered brain regions compared to controls. We retrospectively analyzed in vivo structural T2-weighted MRIs of 99 fetuses (48 controls and 51 niMSBDs cases). For each group (19-31 and >31 gestational weeks (GW)), we conducted repeated-measures regression analysis with relative regional volume (% brain hemisphere) as a dependent variable (adjusted for age, side, and interactions). Between 19 and 31GW, fetuses with niMSBDs had a significantly (P < 0.001) smaller relative volume of the intermediate zone (-22.9 ± 3.2%) and cerebellum (-16.1 ± 3.5%,) and a larger relative volume of proliferative zones (38.3 ± 7.2%), the ganglionic eminence (34.8 ± 7.3%), and the ventricles (35.8 ± 8.0%). Between 32 and 37 GW, compared to the controls, niMSBDs showed significantly smaller volumes of central regions (-9.1 ± 2.1%) and larger volumes of the cortical plate. Our results suggest there is altered brain development in fetuses with niMSBDs compared to controls (13.1 ± 4.2%). Further basic and translational neuroscience research is needed to better visualize these differences and to characterize the altered development in fetuses with specific niMSBDs.
Assuntos
Encéfalo , Cérebro , Gravidez , Feminino , Humanos , Criança , Estudos Retrospectivos , Feto , Desenvolvimento Fetal , Imageamento por Ressonância Magnética/métodos , Idade GestacionalRESUMO
PHACE (posterior fossa malformations, hemangiomas, arterial anomalies, cardiac anomalies, eye anomalies) association has many recognized clinical features. A link between PHACE and non-vascular intracranial lesions has not been well-described. We report three pediatric patients with PHACE and non-vascular intracranial lesions.
Assuntos
Anormalidades Múltiplas , Coartação Aórtica , Anormalidades do Olho , Síndromes Neurocutâneas , Humanos , Criança , Lactente , Síndromes Neurocutâneas/diagnóstico , Síndromes Neurocutâneas/patologia , Coartação Aórtica/complicações , Coartação Aórtica/diagnóstico , Coartação Aórtica/patologia , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/patologiaRESUMO
Varicella-zoster virus (VZV) is a medically important alphaherpesvirus that induces fusion of the virion envelope and the cell membrane during entry, and between cells to form polykaryocytes within infected tissues during pathogenesis. All members of the Herpesviridae, including VZV, have a conserved core fusion complex composed of glycoproteins, gB, gH and gL. The ectodomain of the primary fusogen, gB, has five domains, DI-V, of which DI contains the fusion loops needed for fusion function. We recently demonstrated that DIV is critical for fusion initiation, which was revealed by a 2.8Å structure of a VZV neutralizing mAb, 93k, bound to gB and mutagenesis of the gB-93k interface. To further assess the mechanism of mAb 93k neutralization, the binding site of a non-neutralizing mAb to gB, SG2, was compared to mAb 93k using single particle cryogenic electron microscopy (cryo-EM). The gB-SG2 interface partially overlapped with that of gB-93k but, unlike mAb 93k, mAb SG2 did not interact with the gB N-terminus, suggesting a potential role for the gB N-terminus in membrane fusion. The gB ectodomain structure in the absence of antibody was defined at near atomic resolution by single particle cryo-EM (3.9Å) of native, full-length gB purified from infected cells and by X-ray crystallography (2.4Å) of the transiently expressed ectodomain. Both structures revealed that the VZV gB N-terminus (aa72-114) was flexible based on the absence of visible structures in the cryo-EM or X-ray crystallography data but the presence of gB N-terminal peptides were confirmed by mass spectrometry. Notably, N-terminal residues 109KSQD112 were predicted to form a small α-helix and alanine substitution of these residues abolished cell-cell fusion in a virus-free assay. Importantly, transferring the 109AAAA112 mutation into the VZV genome significantly impaired viral propagation. These data establish a functional role for the gB N-terminus in membrane fusion broadly relevant to the Herpesviridae.
Assuntos
Herpesvirus Humano 3/fisiologia , Melanoma/metabolismo , Fusão de Membrana , Proteínas do Envelope Viral/metabolismo , Internalização do Vírus , Sequência de Aminoácidos , Cristalografia por Raios X , Humanos , Melanoma/virologia , Modelos Moleculares , Mutação , Ligação Proteica , Conformação Proteica , Domínios Proteicos , Homologia de Sequência , Células Tumorais Cultivadas , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/genéticaRESUMO
During infection, naive CD8(+) T cells differentiate into effector cells, which are armed to eliminate pathogens, and memory cells, which are poised to protect against reinfection. The transcriptional program that regulates terminal differentiation into short-lived effector-memory versus long-lived memory cells is not clearly defined. Through the use of mice expressing reporters for the DNA-binding inhibitors Id2 and Id3, we identified Id3(hi) precursors of long-lived memory cells before the peak of T cell population expansion or upregulation of cell-surface receptors that indicate memory potential. Deficiency in Id2 or Id3 resulted in loss of distinct CD8(+) effector and memory populations, which demonstrated unique roles for these inhibitors of E-protein transcription factors. Furthermore, cytokines altered the expression of Id2 and Id3 differently, which provides insight into how external cues influence gene expression.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Regulação da Expressão Gênica , Memória Imunológica/imunologia , Proteína 2 Inibidora de Diferenciação/metabolismo , Proteínas Inibidoras de Diferenciação/metabolismo , Subpopulações de Linfócitos T/imunologia , Transcrição Gênica , Animais , Linfócitos T CD8-Positivos/citologia , Diferenciação Celular/imunologia , Citocinas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Infecções/genética , Infecções/imunologia , Infecções/microbiologia , Proteína 2 Inibidora de Diferenciação/genética , Proteínas Inibidoras de Diferenciação/genética , Lectinas Tipo C , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Receptores Imunológicos/metabolismo , Subpopulações de Linfócitos T/citologia , Transcrição Gênica/efeitos dos fármacosRESUMO
NUSAP1 encodes a cell cycle-dependent protein with key roles in mitotic progression, spindle formation, and microtubule stability. Both over- and under-expression of NUSAP1 lead to dysregulation of mitosis and impaired cell proliferation. Through exome sequencing and Matchmaker Exchange, we identified two unrelated individuals with the same recurrent, de novo heterozygous variant (NM_016359.5 c.1209C > A; p.(Tyr403Ter)) in NUSAP1. Both individuals had microcephaly, severe developmental delay, brain abnormalities, and seizures. The gene is predicted to be tolerant of heterozygous loss-of-function mutations, and we show that the mutant transcript escapes nonsense mediated decay, suggesting that the mechanism is likely dominant-negative or toxic gain of function. Single-cell RNA-sequencing of an affected individual's post-mortem brain tissue indicated that the NUSAP1 mutant brain contains all main cell lineages, and that the microcephaly could not be attributed to loss of a specific cell type. We hypothesize that pathogenic variants in NUSAP1 lead to microcephaly possibly by an underlying defect in neural progenitor cells.
Assuntos
Epilepsia , Microcefalia , Malformações do Sistema Nervoso , Transtornos do Neurodesenvolvimento , Humanos , Microcefalia/genética , Microcefalia/patologia , Mutação/genética , Transtornos do Neurodesenvolvimento/genéticaRESUMO
BACKGROUND: MRI is the gold standard test to define brain injury in infants with neonatal encephalopathy(NE). As imaging findings evolve considerably over the first week, early imaging may not fully reflect the final nature of the injury. This study aimed to compare day 4 versus second week MRI in infants with NE. METHODS: Retrospective cohort study including infants who received therapeutic hypothermia(TH) for NE and had two MRIs: early (≤7days) and late (>7days). MRIs were clinically reported and also reviewed by study investigators. RESULTS: 94infants with NE were included (40mild,49moderate,5severe). Twenty-four infants(26%) had a normal early scan of which 3/24(13%) had injury noted on repeat MRI. Seventy infants(74%) had abnormal findings noted on early MRI, of which 4/70(6%) had further evolution of injury while 11/70(16%) had complete resolution of findings. Applying a grading system resulted in a change of grade in 7 infants. CONCLUSION: In infants who received TH for NE, 19% had changes noted between their early and late MRIs. While the impact on predicting neurodevelopmental outcome was not studied, relying solely on early MRI may overestimate injury in a proportion of infants and miss injury in others. Combining early and late MRI allows for better characterization of injury. IMPACT: MRI is the gold standard tool to define brain injury in infants with NE, however, imaging findings evolve considerably over the first week of life. Most centers perform a single MRI on day 4 after rewarming. In our cohort, 19% of infants had a notable change in their MRI findings between early (within the first week) and late (beyond the first week) scans. Relying solely on early MRI may overestimate injury in a proportion of infants and miss injury in others. Combining early and late MRI following hypothermia allows for better characterization of brain injury.
Assuntos
Lesões Encefálicas , Hipotermia Induzida , Hipóxia-Isquemia Encefálica , Doenças do Recém-Nascido , Recém-Nascido , Humanos , Lactente , Estudos Retrospectivos , Hipóxia-Isquemia Encefálica/diagnóstico por imagem , Hipóxia-Isquemia Encefálica/terapia , Imageamento por Ressonância Magnética/métodos , Doenças do Recém-Nascido/terapia , Lesões Encefálicas/complicações , Lesões Encefálicas/diagnóstico por imagem , Lesões Encefálicas/terapia , Hipotermia Induzida/métodosRESUMO
BACKGROUND: The incidence of cerebral sinovenous thrombosis (CSVT) in infants receiving therapeutic hypothermia for neonatal encephalopathy remains controversial. The aim of this study was to identify if the routine use of magnetic resonance venography (MRV) in term-born infants receiving hypothermia is associated with diagnostic identification of CSVT. METHODS: We performed a retrospective review of 291 infants who received therapeutic hypothermia from January 2014 to March 2020. Demographic and clinical data, as well as the incidence of CSVT, were compared between infants born before and after adding routine MRV to post-rewarming magnetic resonance imaging (MRI). RESULTS: Before routine inclusion of MRV, 209 babies were cooled, and 25 (12%) underwent MRV. Only one baby (0.5%) was diagnosed with CSVT in that period, and it was detected by structural MRI, then confirmed with MRV. After the inclusion of routine MRV, 82 infants were cooled. Of these, 74 (90%) had MRV and none were diagnosed with CSVT. CONCLUSION: CSVT is uncommon in our cohort of infants receiving therapeutic hypothermia for neonatal encephalopathy. Inclusion of routine MRV in the post-rewarming imaging protocol was not associated with increased detection of CSVT in this population. IMPACT: Cerebral sinovenous thrombosis (CSVT) in infants with NE receiving TH may not be as common as previously indicated. The addition of MRV to routine post-rewarming imaging protocol did not lead to increased detection of CSVT in infants with NE. Asymmetry on MRV of the transverse sinus is a common anatomic variant. MRI alone may be sufficient in indicating the presence of CSVT.
Assuntos
Encefalopatias , Hipotermia Induzida , Trombose dos Seios Intracranianos , Trombose , Recém-Nascido , Humanos , Lactente , Flebografia/efeitos adversos , Trombose dos Seios Intracranianos/diagnóstico por imagem , Trombose dos Seios Intracranianos/terapia , Imageamento por Ressonância Magnética , Hipotermia Induzida/efeitos adversos , Encefalopatias/complicações , Espectroscopia de Ressonância Magnética , Trombose/complicaçõesRESUMO
Post-zygotically acquired genetic variants, or somatic variants, that arise during cortical development have emerged as important causes of focal epilepsies, particularly those due to malformations of cortical development. Pathogenic somatic variants have been identified in many genes within the PI3K-AKT-mTOR-signalling pathway in individuals with hemimegalencephaly and focal cortical dysplasia (type II), and more recently in SLC35A2 in individuals with focal cortical dysplasia (type I) or non-dysplastic epileptic cortex. Given the expanding role of somatic variants across different brain malformations, we sought to delineate the landscape of somatic variants in a large cohort of patients who underwent epilepsy surgery with hemimegalencephaly or focal cortical dysplasia. We evaluated samples from 123 children with hemimegalencephaly (n = 16), focal cortical dysplasia type I and related phenotypes (n = 48), focal cortical dysplasia type II (n = 44), or focal cortical dysplasia type III (n = 15). We performed high-depth exome sequencing in brain tissue-derived DNA from each case and identified somatic single nucleotide, indel and large copy number variants. In 75% of individuals with hemimegalencephaly and 29% with focal cortical dysplasia type II, we identified pathogenic variants in PI3K-AKT-mTOR pathway genes. Four of 48 cases with focal cortical dysplasia type I (8%) had a likely pathogenic variant in SLC35A2. While no other gene had multiple disease-causing somatic variants across the focal cortical dysplasia type I cohort, four individuals in this group had a single pathogenic or likely pathogenic somatic variant in CASK, KRAS, NF1 and NIPBL, genes previously associated with neurodevelopmental disorders. No rare pathogenic or likely pathogenic somatic variants in any neurological disease genes like those identified in the focal cortical dysplasia type I cohort were found in 63 neurologically normal controls (P = 0.017), suggesting a role for these novel variants. We also identified a somatic loss-of-function variant in the known epilepsy gene, PCDH19, present in a small number of alleles in the dysplastic tissue from a female patient with focal cortical dysplasia IIIa with hippocampal sclerosis. In contrast to focal cortical dysplasia type II, neither focal cortical dysplasia type I nor III had somatic variants in genes that converge on a unifying biological pathway, suggesting greater genetic heterogeneity compared to type II. Importantly, we demonstrate that focal cortical dysplasia types I, II and III are associated with somatic gene variants across a broad range of genes, many associated with epilepsy in clinical syndromes caused by germline variants, as well as including some not previously associated with radiographically evident cortical brain malformations.
Assuntos
Epilepsia , Hemimegalencefalia , Malformações do Desenvolvimento Cortical , Caderinas , Proteínas de Ciclo Celular , Feminino , Humanos , Malformações do Desenvolvimento Cortical do Grupo I , Mutação , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Protocaderinas , Serina-Treonina Quinases TORRESUMO
PCDH19 is a common epilepsy gene causing medication resistant epilepsy with fever-related seizures. Traditionally, patients with PCDH19-related epilepsy have not been considered surgical candidates. This retrospective review evaluated three patients with pathogenic variants in PCDH19 who presented with seizures in childhood, had one seizure semiology, became medication resistant, and had concordant imaging, seizure semiology and electrographic findings. All three patients ultimately underwent temporal lobectomy, resulting in seizure freedom. These findings suggest epilepsy surgery can be an effective treatment option for select patients with PCDH19-related epilepsy and a single seizure semiology.
Assuntos
Epilepsia , Convulsões Febris , Humanos , Caderinas/genética , Protocaderinas , Epilepsia/genética , Epilepsia/cirurgia , Convulsões/genética , Estudos RetrospectivosRESUMO
Magnetic resonance imaging has emerged as a preferred modality in pediatric imaging because of its high soft-tissue contrast and the lack of ionizing radiation. It is important to recognize that despite its many advantages, several challenges to performing neonatal MRI arise from the lack of patient compliance and the small size of the anatomy. This manuscript presents the approach to patient preparation used at the authors' institution, summarizes general principles of image optimization and hardware selection, and reviews common indications across various organ systems. This manuscript also incorporates input from our pediatric-trained MRI technologists, in an attempt to compile a practical guideline covering all major aspects of neonatal MRI, from its execution to its interpretation.
Assuntos
Imageamento por Ressonância Magnética , Cooperação do Paciente , Recém-Nascido , Criança , Humanos , Imageamento por Ressonância Magnética/métodosRESUMO
OBJECTIVE: This study aimed to describe the evolution of amplitude-integrated electroencephalography (aEEG) in neonatal encephalopathy (NE) during therapeutic hypothermia (TH) and evaluate the association between aEEG parameters and magnetic resonance imaging (MRI) injury. STUDY DESIGN: aEEG data of infants who underwent TH were reviewed for background, sleep wake cycling (SWC), and seizures. Conventional electroencephalography (cEEG) background was assessed from the reports. Discordance of background on aEEG and cEEG was defined if there was a difference in the severity of the background. MRI injury (total score ≥ 5) was assessed by using the Weeke scoring system. RESULTS: A total of 46 infants were included; 23 (50%) with mild NE and 23 (50%) with moderate to severe NE. Comparing mild NE with moderate to severe NE, the initial aEEG background differed with more mild being continuous (70 vs. 52%), with fewer being discontinuous (0 vs. 22%) and flat tracing (0 vs. 4%), whereas burst suppression (4 vs. 4%) and low voltage (26 vs. 18%) did not differ. There was a notably common discordance between the background assessment on cEEG with aEEG in 82% with continuous and 40% low voltage aEEG background. MRI abnormalities were identified in four infants with mild NE and seven infants with moderate to severe NE. MRI injury was associated with aEEG seizures in infants with moderate to severe NE. CONCLUSION: aEEG seizures are useful to predict MRI injury in moderate to severe NE infants. There is a large discrepancy between aEEG, cEEG, and MRI in neonates treated by TH. KEY POINTS: · MRI injury was identified in 29% of moderate NE infants and in 50% of severe NE infants.. · aEEG seizures were associated with MRI injury in the moderate to severe NE infants.. · MRI injury was identified in 16% infants with mild NE.. · Mild NE infants with normal aEEG were unlikely to have MRI injury.. · There was a large discrepancy between aEEG, cEEG, and MRI in infants treated by TH..