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1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(10): 985-988, 2021 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-34625938

RESUMO

OBJECTIVE: To analyze the clinical phenotype and pathogenic variant in a child diagnosed with mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH). METHODS: Clinical phenotype of the child was reviewed. Whole exome sequencing was carried out for the child. Candidate variant was verified by Sanger sequencing of the family member. RESULTS: The proband manifested dyskinesia, development delay, cerebellar hypoplasia and bilateral hearing impairment. WES results revealed that the proband has carried a pathogenic c.1641_1644delACAA (p.Thr548Trpfs*69) variant of the CASK gene, which was verified by Sanger sequencing to be a de novo variant. CONCLUSION: The c.1641_1644delACAA (p.Thr548Trpfs*69) variant of the CASK gene probably underlay the MICPCH in the proband. Above finding has provided a basis for genetic counseling. WES should be considered for the diagnosis of neurological dysplasia.


Assuntos
Microcefalia , Malformações do Sistema Nervoso , Cerebelo/anormalidades , Criança , Deficiências do Desenvolvimento , Família , Humanos , Retardo Mental Ligado ao Cromossomo X , Microcefalia/genética
2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(10): 973-976, 2021 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-34625935

RESUMO

OBJECTIVE: Two brothes with Seckel's syndrome 1(SCKL1) were reported and a literature review was carried to provide clinical and genetic information of this rare disease. METHODS: Clinical data of the two children were collected, and the peripheral blood was extracted for whole exome sequencing. Literature of the disease were reviewed. RESULTS: The two patients were 11 years and 9.5 years old when examined for short stature. They presented with intrauterine growth retardation, intellectual disability, microcephaly, birdhead-like face and coffee au lait spots. The bone age was more than 2 years behind the chronical age and the growth hormone levels were normal. Whole exome sequencing revealed novel compound heterozygous variants c.1A>G (p.M1?) and c.4853-18A>G of ART gene in both children. CONCLUSION: Children with prenatal onset short stature, developmental delay, microcephaly and special facial featuresshould be considered for the possibility of Seckel's syndrome, whole exome sequencing could help to confirm the clinical diagnosis.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Nanismo , Deficiência Intelectual , Microcefalia , Criança , Nanismo/genética , Humanos , Deficiência Intelectual/genética , Masculino , Microcefalia/genética , Irmãos , Sequenciamento Completo do Exoma
3.
Rev Esc Enferm USP ; 55: e20200507, 2021.
Artigo em Inglês, Português | MEDLINE | ID: mdl-34479309

RESUMO

OBJECTIVE: To review the literature on sleep changes and brain function in children with microcephaly due to Zika virus. METHOD: Systematic review conducted in the databases MEDLINE (PubMed), Scopus, Web of Science, CINAHL, EMBASE, LILACS, and SciELO and the grey databases Google Scholar and OpenGrey. RESULTS: Ten Brazilian primary studies with observational research design were included. These were published between 2017 and 2020 with 516 children with microcephaly due to Zika virus infection aged 4 months to 4 years. Out of these, 4 investigated qualitative aspects of sleep using the questionnaires Brief Infant Sleep Questionnaire or Infant Sleep Questionnaire and 6 investigated changes in brain activities during sleep using the Electroencephalogram or Video-Electroencephalogram exams. The children's quality of sleep was not compromised in most studies. Changes in brain activity during sleep were frequent, with epileptogenic activity being a common finding among the studies. CONCLUSION: The quality of sleep of children with microcephaly due to Zika virus has shown to be similar to that of children with typical development and the presented behavioral changes may be related to changes in electric brain activity.


Assuntos
Microcefalia , Complicações Infecciosas na Gravidez , Infecção por Zika virus , Zika virus , Brasil , Criança , Feminino , Humanos , Lactente , Gravidez , Sono , Infecção por Zika virus/complicações
4.
Cad Saude Publica ; 37(8): e00271020, 2021.
Artigo em Português | MEDLINE | ID: mdl-34495097

RESUMO

This study aimed to assess the degree of implementation of the response to the emergency of microcephaly associated with Zika virus in Pernambuco State, Brazil. This was a normative evaluative study conducted in the initial epicenter of the public health emergency of international concern, from October 2015 to July 2017. A logical model was produced for the intervention under analysis, with the components of Management, Surveillance, and Care in the dimensions of structure, process, and result, based on technical publications and institutional guidelines, in addition to a corresponding log frame of indicators for assessment. Data were collected through a questionnaire, direct observation, and consultation of official documents. The results showed partial implementation (74.9%) of the response to the microcephaly emergency by the Pernambuco State Health Department, with the process dimension reaching 75% of the expected level and the structure dimension, 74.5%. Surveillance was the only component that was assessed as implemented (81%), although with a shortage of regional and laboratory investments, while Management (74.2%) and Care (68.8%) were partially implemented, with insufficiencies in items related to human resources and physical structure, planning, and evaluation. In conclusion, the response to the public health emergency of international concern involving microcephaly associated with the Zika virus was assessed as partially implemented, with different levels between the intervention´s components, especially surveillance when compared to management and care. The shortcomings signal the need for investments to deal with future public health emergencies, with a view towards more timely and adequate interventions.


Assuntos
Microcefalia , Infecção por Zika virus , Zika virus , Brasil/epidemiologia , Emergências , Humanos , Microcefalia/epidemiologia , Saúde Pública , Infecção por Zika virus/diagnóstico , Infecção por Zika virus/epidemiologia
5.
Med Hypotheses ; 156: 110685, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34592564

RESUMO

Zika virus was declared a national emergency by WHO (World Health Organization) in 2016 when its widespread outbreaks and life-threatening complications were reported, especially in newborns and adults. Numerous studies reported that neuroinflammation is one of the significant root-causes behind its major neurological complications like microcephaly and Guillain-Barré syndrome (GBS). In this hypothesis, we propose Transient Receptor Potential Vanilloid 1 channel (TRPV1) as a major culprit in triggering positive inflammatory loop, ultimately leading to sustained neuroinflammation, one of the key clinical findings in Zika induced microcephalic and GBS patients. Opening of TRPV1 channel also leads to calcium influx and oxidative stress that ultimately results in cellular apoptosis (like Schwann cell in GBS and developing fetal nerve cells in microcephaly), ultimately leading to these complications. Currently, no specific cure exists for these complications. Most of the antiviral candidates are under clinical trials. Though there is no direct research on TRPV1 as a cause of Zika virus's neurological complications, but similarity in mechanisms is undeniable. Thus, exploring pathobiological involvement of TRPV1 channels and various TRPV1 modulators in these complications can possibly prove to be an effective futuristic therapeutic strategy for treatment and management of these life-threatening complications.


Assuntos
Microcefalia , Doenças do Sistema Nervoso , Infecção por Zika virus , Zika virus , Cálcio/metabolismo , Capsaicina , Humanos , Recém-Nascido , Doenças do Sistema Nervoso/tratamento farmacológico , Neurônios/metabolismo , Canais de Cátion TRPV , Zika virus/metabolismo , Infecção por Zika virus/complicações , Infecção por Zika virus/tratamento farmacológico
6.
J Craniofac Surg ; 32(6): 2223-2225, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34516060

RESUMO

BACKGROUND: Microcephaly (MiC) is defined as head circumference (HC) dimensions smaller than the normal standards. OBJECTIVE: To detect MiC with a mathematical formula. MATERIALS AND METHODS: The 0 to 5 years head HC percentile data for girls and boys reported by the World Health Organization were used. To assess early childhood, these growth standards are available on its website for international use. Mathematical formulas best estimating the 3rd percentile curves were defined using basic regression analysis methods. RESULTS: The mathematical models obtained as a result of logarithmic regression analysis with the highest coefficient of determination values (R2 = 0.991 for girls; R2 = 0.991 for boys) were identified as the best model. The formulas of HC = 34.025 + 3.283 ∗ ln (age as months), and HC = 35.475 + 3.14 ∗ ln (age as months) were determined for girls and boys, respectively. A limitation of these formulas is that they do not provide the HC at birth (ln (0) = undetermined). CONCLUSION: Microcephaly can be estimated using the mathematical formulas with a calculator without using percentile scales, mobile applications, software, or the Internet.


Assuntos
Microcefalia , Cefalometria , Pré-Escolar , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Masculino , Modelos Teóricos , Análise de Regressão
7.
Eur J Med Genet ; 64(10): 104310, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34400370

RESUMO

MFSD2A, a member of the major facilitator superfamily (MFS), is a transmembrane transporter responsible for the uptake of specific essential fatty acids through the blood-brain barrier (BBB) to the brain. The transporter is crucial for early embryonic brain development and a major factor in the formation and maintenance of the BBB. Mfsd2a-knockout mice show a leakage of the BBB in early embryonic stages and develop a phenotype characterized by microcephaly, cognitive impairment, and anxiety. So far, homozygous or compound heterozygous MFSD2A mutations in humans have only been reported in 13 different families with a total of 28 affected individuals. The phenotypical spectrum of patients with MFSD2A variants is rather broad but all patients present with microcephaly and severe intellectual disability, absent or limited speech, and walking difficulties. Severely affected patients develop seizures and show brain malformations and have, above all, a profound developmental delay hardly reaching any developmental motor milestones. Here, we report on two unrelated individuals with novel homozygous variants in the MFSD2A gene, presenting with severe primary microcephaly, brain malformations, profound developmental delay, and epilepsy, including hypsarrhythmia. Our findings extend the mutational spectrum of the bi-allelic MFSD2A variants causing autosomal recessive primary microcephaly type 15 and broaden the phenotypic spectrum associated with these pathogenic variants emphasizing the role of MFSD2A in early brain development.


Assuntos
Deficiências do Desenvolvimento/genética , Epilepsia/genética , Microcefalia/genética , Fenótipo , Simportadores/genética , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Pré-Escolar , Deficiências do Desenvolvimento/patologia , Epilepsia/patologia , Feminino , Humanos , Lactente , Masculino , Microcefalia/patologia , Mutação
8.
Int J Mol Sci ; 22(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34360805

RESUMO

FAM20C is a gene coding for a protein kinase that targets S-X-E/pS motifs on different phosphoproteins belonging to diverse tissues. Pathogenic variants of FAM20C are responsible for Raine syndrome (RS), initially described as a lethal and congenital osteosclerotic dysplasia characterized by generalized atherosclerosis with periosteal bone formation, characteristic facial dysmorphisms and intracerebral calcifications. The aim of this review is to give an overview of targets and variants of FAM20C as well as RS aspects. We performed a wide phenotypic review focusing on clinical aspects and differences between all lethal (LRS) and non-lethal (NLRS) reported cases, besides the FAM20C pathogenic variant description for each. As new targets of FAM20C kinase have been identified, we reviewed FAM20C targets and their functions in bone and other tissues, with emphasis on novel targets not previously considered. We found the classic lethal and milder non-lethal phenotypes. The milder phenotype is defined by a large spectrum ranging from osteonecrosis to osteosclerosis with additional congenital defects or intellectual disability in some cases. We discuss our current understanding of FAM20C deficiency, its mechanism in RS through classic FAM20C targets in bone tissue and its potential biological relevance through novel targets in non-bone tissues.


Assuntos
Anormalidades Múltiplas , Caseína Quinase I , Fissura Palatina , Exoftalmia , Proteínas da Matriz Extracelular , Variação Genética , Microcefalia , Osteosclerose , Fenótipo , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/mortalidade , Anormalidades Múltiplas/patologia , Caseína Quinase I/genética , Caseína Quinase I/metabolismo , Fissura Palatina/genética , Fissura Palatina/metabolismo , Fissura Palatina/mortalidade , Fissura Palatina/patologia , Exoftalmia/genética , Exoftalmia/metabolismo , Exoftalmia/mortalidade , Exoftalmia/patologia , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Humanos , Microcefalia/genética , Microcefalia/metabolismo , Microcefalia/mortalidade , Microcefalia/patologia , Osteosclerose/genética , Osteosclerose/metabolismo , Osteosclerose/mortalidade , Osteosclerose/patologia
9.
Nat Metab ; 3(8): 1109-1124, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34385701

RESUMO

Zika virus (ZIKV) infection during pregnancy can cause microcephaly in newborns, yet the underlying mechanisms remain largely unexplored. Here, we reveal extensive and large-scale metabolic reprogramming events in ZIKV-infected mouse brains by performing a multi-omics study comprising transcriptomics, proteomics, phosphoproteomics and metabolomics approaches. Our proteomics and metabolomics analyses uncover dramatic alteration of nicotinamide adenine dinucleotide (NAD+)-related metabolic pathways, including oxidative phosphorylation, TCA cycle and tryptophan metabolism. Phosphoproteomics analysis indicates that MAPK and cyclic GMP-protein kinase G signaling may be associated with ZIKV-induced microcephaly. Notably, we demonstrate the utility of our rich multi-omics datasets with follow-up in vivo experiments, which confirm that boosting NAD+ by NAD+ or nicotinamide riboside supplementation alleviates cell death and increases cortex thickness in ZIKV-infected mouse brains. Nicotinamide riboside supplementation increases the brain and body weight as well as improves the survival in ZIKV-infected mice. Our study provides a comprehensive resource of biological data to support future investigations of ZIKV-induced microcephaly and demonstrates that metabolic alterations can be potentially exploited for developing therapeutic strategies.


Assuntos
Microcefalia/etiologia , Microcefalia/metabolismo , NAD/metabolismo , Infecção por Zika virus/complicações , Infecção por Zika virus/virologia , Zika virus/fisiologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/virologia , Células Cultivadas , Cromatografia Líquida , Modelos Animais de Doenças , Suscetibilidade a Doenças , Feminino , Metabolômica , Camundongos , Microcefalia/patologia , Neurônios/metabolismo , Gravidez , Proteômica/métodos , Espectrometria de Massas em Tandem
10.
Braz J Biol ; 83: e246040, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34378666

RESUMO

Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by a congenitally reduced head circumference (-3 to -5 SD) and non-progressive intellectual disability. The objective of the study was to evaluate pathogenic mutations in the ASPM gene to understand etiology and molecular mechanism of primary microcephaly. Blood samples were collected from various families across different remote areas of Pakistan from February 2017 to May 2019 who were identified to be affected with primary microcephaly. DNA extraction was performed using the salting-out method; the quality and quantity of DNA were evaluated using spectrophotometry and 1% agarose gel electrophoresis, respectively in University of the Punjab. Mutation analysis was performed by whole exome sequencing from the Cologne Center for Genomics, University of Cologne. Sanger sequencing was done in University of the Punjab to confirm the pathogenic nature of mutation. A novel 4-bp deletion mutation c.3877_3880delGAGA was detected in exon 17 of the ASPM gene in two primary microcephaly affected families (A and B), which resulted in a frame shift mutation in the gene followed by truncated protein synthesis (p.Glu1293Lysfs*10), as well as the loss of the calmodulin-binding IQ domain and the Armadillo-like domain in the ASPM protein. Using the in-silico tools Mutation Taster, PROVEAN, and PolyPhen, the pathogenic effect of this novel mutation was tested; it was predicted to be "disease causing," with high pathogenicity scores. One previously reported mutation in exon 24 (c.9730C>T) of the ASPM gene resulting in protein truncation (p.Arg3244*) was also observed in family C. Mutations in the ASPM gene are the most common cause of MCPH in most cases. Therefore, enrolling additional affected families from remote areas of Pakistan would help in identifying or mapping novel mutations in the ASPM gene of primary microcephaly.


Assuntos
Microcefalia , Proteínas do Tecido Nervoso , Consanguinidade , Humanos , Microcefalia/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Paquistão
11.
eNeuro ; 8(5)2021.
Artigo em Inglês | MEDLINE | ID: mdl-34272257

RESUMO

Prenatal exposure to Zika virus (ZIKV) can result in microencephaly and congenital Zika syndrome, although some brain cells and structures are spared by the virus for unknown reasons. Here, a novel murine model of fetal ZIKV infection incorporating intraventricular infection and cell type-specific in utero electroporation (IUE) was used to identify the time course of ZIKV infection and to determine the identity of cells that are initially infected or spared during neocortical neurogenesis. In vivo time course studies revealed the presence of ZIKV in apical radial glial cells (aRGCs) at early time points following virus exposure, while basal intermediate progenitor cells (bIPCs) became maximally (ZIKV+) after 3 d of virus exposure. ZIKV-infected fetal brains exhibited microencephaly as early as 1 d following infection, regardless of developmental age. This change in brain size was caused in part by apoptosis and reduced proliferation that persisted until birth. While 60% of aRGC basal fibers were perturbed during infection, 40% retained normal morphology, indicating that aRGCs are not uniformly vulnerable to ZIKV infection. To investigate this heterogeneous vulnerability, we performed genetic fate mapping using cell type-specific probes derived from a mouse embryonic day (E)15.5 neocortical wall single-cell RNA sequencing (scRNAseq) dataset. The results indicate that one class of aRGCs preferentially express the putative ZIKV entry receptor AXL and that these cells are more vulnerable to ZIKV infection than other aRGC subtypes with low AXL expression. Together, these data uncover crucial temporal and cellular details of ZIKV fetal brain infection for prevention strategies and for management of congenital Zika syndrome.


Assuntos
Microcefalia , Células-Tronco Neurais , Infecção por Zika virus , Zika virus , Animais , Feminino , Camundongos , Gravidez , Prosencéfalo
12.
Nat Commun ; 12(1): 4067, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34210973

RESUMO

Ataxia Telangiectasia and Rad3-related (ATR) protein, as a key DNA damage response (DDR) regulator, plays an essential function in response to replication stress and controls cell viability. Hypomorphic mutations of ATR cause the human ATR-Seckel syndrome, characterized by microcephaly and intellectual disability, which however suggests a yet unknown role for ATR in non-dividing cells. Here we show that ATR deletion in postmitotic neurons does not compromise brain development and formation; rather it enhances intrinsic neuronal activity resulting in aberrant firing and an increased epileptiform activity, which increases the susceptibility of ataxia and epilepsy in mice. ATR deleted neurons exhibit hyper-excitability, associated with changes in action potential conformation and presynaptic vesicle accumulation, independent of DDR signaling. Mechanistically, ATR interacts with synaptotagmin 2 (SYT2) and, without ATR, SYT2 is highly upregulated and aberrantly translocated to excitatory neurons in the hippocampus, thereby conferring a hyper-excitability. This study identifies a physiological function of ATR, beyond its DDR role, in regulating neuronal activity.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Neurônios/metabolismo , Animais , Proteínas Mutadas de Ataxia Telangiectasia/genética , Linhagem Celular , Nanismo , Fármacos Atuantes sobre Aminoácidos Excitatórios , Facies , Hipocampo , Camundongos , Microcefalia , Mutação , Células de Purkinje , Transdução de Sinais , Sinaptotagmina II/metabolismo
13.
Nat Commun ; 12(1): 4284, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34257281

RESUMO

The translocase of the outer mitochondrial membrane TOM constitutes the organellar entry gate for nearly all precursor proteins synthesized on cytosolic ribosomes. Thus, TOM presents the ideal target to adjust the mitochondrial proteome upon changing cellular demands. Here, we identify that the import receptor TOM70 is targeted by the kinase DYRK1A and that this modification plays a critical role in the activation of the carrier import pathway. Phosphorylation of TOM70Ser91 by DYRK1A stimulates interaction of TOM70 with the core TOM translocase. This enables transfer of receptor-bound precursors to the translocation pore and initiates their import. Consequently, loss of TOM70Ser91 phosphorylation results in a strong decrease in import capacity of metabolite carriers. Inhibition of DYRK1A impairs mitochondrial structure and function and elicits a protective transcriptional response to maintain a functional import machinery. The DYRK1A-TOM70 axis will enable insights into disease mechanisms caused by dysfunctional DYRK1A, including autism spectrum disorder, microcephaly and Down syndrome.


Assuntos
Transtorno do Espectro Autista/metabolismo , Mitocôndrias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Transtorno do Espectro Autista/genética , Citosol/metabolismo , Síndrome de Down/genética , Síndrome de Down/metabolismo , Humanos , Microcefalia/genética , Microcefalia/metabolismo , Mitocôndrias/genética , Proteínas de Transporte da Membrana Mitocondrial/genética , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética
14.
Eur J Med Genet ; 64(9): 104282, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34284163

RESUMO

The Forkhead transcription factor FOXG1 is a prerequisite for telencephalon development in mammals and is an essential factor controlling expansion of the dorsal telencephalon by promoting neuron and interneuron production. Heterozygous FOXG1 gene mutations cause FOXG1 syndrome characterized by severe intellectual disability, motor delay, dyskinetic movements and epilepsy. Neuroimaging studies in patients disclose constant features including microcephaly, corpus callosum dysgenesis and delayed myelination. Currently, investigative research on the underlying pathophysiology relies on mouse models only and indicates that de-repression of FOXG1 target genes may cause premature neuronal differentiation at the expense of the progenitor pool, patterning and migration defects with impaired formation of cortico-cortical projections. It remains an open question to which extent this recapitulates the neurodevelopmental pathophysiology in FOXG1-haploinsufficient patients. To close this gap, we performed neuropathological analyses in two foetal cases with FOXG1 premature stop codon mutations interrupted during the third trimester of the pregnancy for microcephaly and corpus callosum dysgenesis. In these foetuses, we observed cortical lamination defects and decreased neuronal density mainly affecting layers II, III and V that normally give rise to cortico-cortical and inter-hemispheric axonal projections. GABAergic interneurons were also reduced in number in the cortical plate and persisting germinative zones. Additionally, we observed more numerous PDGFRα-positive oligodendrocyte precursor cells and fewer Olig2-positive pre-oligodendrocytes compared to age-matched control brains, arguing for delayed production and differentiation of oligodendrocyte lineage leading to delayed myelination. These findings provide key insights into the human pathophysiology of FOXG1 syndrome.


Assuntos
Agenesia do Corpo Caloso/genética , Axônios/patologia , Fatores de Transcrição Forkhead/genética , Microcefalia/genética , Proteínas do Tecido Nervoso/genética , Transtornos do Neurodesenvolvimento/genética , Neurogênese , Oligodendroglia/patologia , Feto Abortado/metabolismo , Feto Abortado/patologia , Adulto , Agenesia do Corpo Caloso/patologia , Axônios/metabolismo , Encéfalo/embriologia , Encéfalo/metabolismo , Encéfalo/patologia , Códon sem Sentido , Feminino , Fatores de Transcrição Forkhead/metabolismo , Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/patologia , Humanos , Interneurônios/metabolismo , Interneurônios/patologia , Microcefalia/patologia , Bainha de Mielina/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Transtornos do Neurodesenvolvimento/patologia , Oligodendroglia/metabolismo , Linhagem , Gravidez , Síndrome
15.
Cien Saude Colet ; 26(6): 2271-2280, 2021.
Artigo em Português | MEDLINE | ID: mdl-34231737

RESUMO

In 2015, there was an epidemic of microcephaly in Brazil that was associated with infection by the Zika virus. The condition of these children obliged the parents to embark on a quest in search of treatment. The scope of this study was to establish the therapeutic itinerary pursued in healthcare sectors by parents and/or caregivers of children with microcephaly due to the Zika virus. It involved qualitative research, conducted at a Center of Reference on Neurodevelopment between April 2017 and February 2018, with parents and/or caregivers of children with microcephaly caused by the Zika virus. The sample complied with the criteria of saturation. Twenty semi-structured interviews were conducted, recorded, and transcribed, and content analysis was applied. The results revealed disorientation and uncertainties in the search for care in the health sector. The most sought-after sector was the professional sector, followed by the informal sector. The information conveyed in the media and social networks, which constitute part of the informal sector, helped to clarify the significance of microcephaly and the Zika virus and assisted in the search for treatment. Care in the healthcare network was marked by difficulties and, faced with a new and emergency situation, the route between diagnosis and treatment was arduous.


Assuntos
Microcefalia , Complicações Infecciosas na Gravidez , Infecção por Zika virus , Zika virus , Brasil/epidemiologia , Criança , Feminino , Humanos , Microcefalia/epidemiologia , Gravidez , Infecção por Zika virus/complicações , Infecção por Zika virus/epidemiologia
16.
Recurso na Internet em Português | LIS - Localizador de Informação em Saúde | ID: lis-48260

RESUMO

Cientistas do Instituto de Química da USP e da Fiocruz do Rio de Janeiro e da Bahia identificaram consideráveis alterações lipídicas no plasma de recém-nascidos com exposição pré-natal ao vírus da zika.


Assuntos
Microcefalia/diagnóstico , Microcefalia/prevenção & controle , Zika virus , Recém-Nascido/líquido cefalorraquidiano , Infecção por Zika virus/prevenção & controle , Insuficiência Placentária/diagnóstico
17.
J AAPOS ; 25(3): 158.e1-158.e8, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34082114

RESUMO

PURPOSE: To analyze the spectrum of ophthalmologic manifestations in a large sample of children with congenital Zika syndrome (CZS) in Brazil. METHODS: The medical records of infants born in the states of Pernambuco, Bahia, and Rio de Janeiro, Brazil, between December 2015 and December 2016 with clinical manifestations of CZS and positive reverse transcription polymerase-chain-reaction (RT-PCR) and/or serology for the Zika virus were reviewed retrospectively. Data were collected from the record of the first ophthalmological assessment, performed on admission. Children with other congenital infectious diseases, genetic conditions, and incomplete medical records were excluded. RESULTS: A total of 469 infants (242 female [51.6%]) were included. Mean age at examination was 5.0 ± 7.1 months (range, 0.0-36.0 months). Of the 469 infants, 197 (42.0%) were from Rio de Janeiro, 144 (30.7%) from Pernambuco, and 128 (27.3%) from Bahia States. Microcephaly at birth was detected in 214 (45.6%) children; 62 cases (29.0%) were severe. Pernambuco had significantly more children born with microcephaly compared with Bahia and Rio de Janeiro (P < 0.001). Ocular manifestations were found in 269 of 938 eyes (28.7%; 148/469 children [31.6%]). The main ocular alterations were optic nerve pallor in 122 of 938 eyes (13.0%), focal pigment mottling in 112 eyes (11.9%), and chorioretinal scars in 101 eyes (10.8%). A higher prevalence of ocular manifestations was seen in Pernambuco (P < 0.001). No microcephaly was observed in 252 of 466 children (54.1%); of these, 19 children (7.5%) had funduscopic findings. CONCLUSIONS: One-third of children with CZS had ocular manifestations. Children from Pernambuco were more affected. Ocular abnormalities were found in 7.5% of children without microcephaly.


Assuntos
Microcefalia , Complicações Infecciosas na Gravidez , Infecção por Zika virus , Zika virus , Brasil/epidemiologia , Criança , Feminino , Humanos , Lactente , Recém-Nascido , Microcefalia/epidemiologia , Gravidez , Estudos Retrospectivos , Zika virus/genética , Infecção por Zika virus/complicações , Infecção por Zika virus/diagnóstico , Infecção por Zika virus/epidemiologia
18.
J Cell Biol ; 220(8)2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34137788

RESUMO

Mutations in the WDR62 gene cause primary microcephaly, a pathological condition often associated with defective cell division that results in severe brain developmental defects. The precise function and localization of WDR62 within the mitotic spindle is, however, still under debate, as it has been proposed to act either at centrosomes or on the mitotic spindle. Here we explored the cellular functions of WDR62 in human epithelial cell lines using both short-term siRNA protein depletions and long-term CRISPR/Cas9 gene knockouts. We demonstrate that WDR62 localizes at spindle poles, promoting the recruitment of the microtubule-severing enzyme katanin. Depletion or loss of WDR62 stabilizes spindle microtubules due to insufficient microtubule minus-end depolymerization but does not affect plus-end microtubule dynamics. During chromosome segregation, WDR62 and katanin promote efficient poleward microtubule flux and favor the synchronicity of poleward movements in anaphase to prevent lagging chromosomes. We speculate that these lagging chromosomes might be linked to developmental defects in primary microcephaly.


Assuntos
Adenosina Trifosfatases/metabolismo , Proteínas de Ciclo Celular/metabolismo , Segregação de Cromossomos , Microtúbulos/enzimologia , Proteínas do Tecido Nervoso/metabolismo , Polos do Fuso/enzimologia , Adenosina Trifosfatases/genética , Proteínas de Ciclo Celular/genética , Células HeLa , Humanos , Microcefalia/genética , Microcefalia/metabolismo , Microscopia Confocal , Microscopia de Fluorescência , Microtúbulos/genética , Proteínas do Tecido Nervoso/genética , Ligação Proteica , Transporte Proteico , Transdução de Sinais , Polos do Fuso/genética , Fatores de Tempo
19.
J Cell Biol ; 220(8)2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34137789

RESUMO

WDR62 is a microcephaly-related, microtubule (MT)-associated protein (MAP) that localizes to the spindle pole and regulates spindle organization, but the underlying mechanisms remain elusive. Here, we show that WDR62 regulates spindle dynamics by recruiting katanin to the spindle pole and further reveal a TPX2-Aurora A-WDR62-katanin axis in cells. By combining cellular and in vitro experiments, we demonstrate that WDR62 shows preference for curved segments of dynamic GDP-MTs, as well as GMPCPP- and paclitaxel-stabilized MTs, suggesting that it recognizes extended MT lattice. Consistent with this property, WDR62 alone is inefficient in recruiting katanin to GDP-MTs, while WDR62 complexed with TPX2/Aurora A can potently promote katanin-mediated severing of GDP-MTs in vitro. In addition, the MT-binding affinity of WDR62 is autoinhibited through JNK phosphorylation-induced intramolecular interaction. We propose that WDR62 is an atypical MAP and functions as an adaptor protein between its recruiting factor TPX2/Aurora A and the effector katanin to orchestrate the regulation of spindle dynamics.


Assuntos
Aurora Quinase A/metabolismo , Proteínas de Ciclo Celular/metabolismo , Katanina/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Fuso Acromático/enzimologia , Aurora Quinase A/genética , Proteínas de Ciclo Celular/genética , Células HEK293 , Células HeLa , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Katanina/genética , Cinética , Microcefalia/enzimologia , Microcefalia/genética , Microscopia de Fluorescência , Proteínas Associadas aos Microtúbulos/genética , Proteínas do Tecido Nervoso/genética , Paclitaxel/farmacologia , Fosforilação , Ligação Proteica , Transporte Proteico , Transdução de Sinais , Fuso Acromático/efeitos dos fármacos , Fuso Acromático/genética , Moduladores de Tubulina/farmacologia
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