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1.
Texto & contexto enferm ; 29: e20180517, Jan.-Dec. 2020.
Artigo em Inglês | LILACS, BDENF - Enfermagem | ID: biblio-1094554

RESUMO

ABSTRACT Objective: to know how mothers affected by the Zika virus during pregnancy became aware on the diagnosis of Congenital Zika Virus Syndrome in their child and to understand the way in which the communication of the diagnosis was transmitted. Method: a qualitative approach study, with interpretative research, based on the Resilience, Stress, Adjustment and Family Adaptation Model. The research was conducted in a Specialized Rehabilitation Center in a city of Paraíba (Brazil), from June to November 2017, with 40 mothers of children with congenital Zika virus syndrome. The empirical material was produced from a semi-structured script developed by the researcher, related to the different phases and components of the adaptation and resilience process. The findings were submitted to content analysis. Results: two thematic categories were unveiled: The discovery of Congenital Zika Virus Syndrome: period of diagnosis and maternal expectations, and How to communicate the diagnosis: implications for the discovery of Congenital Zika Virus Syndrome. Conclusion: Communication of the diagnosis and professional conduct at the time of information play important roles in re-signifying the meaning of congenital malformation. The interaction established by the health professional and their posture are directly related to the satisfaction about the information received.


RESUMEN Objetivos: conocer de qué manera las madres afectadas por el virus del Zika se enteraron del diagnóstico del Síndrome Congénito del Virus del Zika en sus hijos, y determinar cómo se comunicó el diagnóstico. Método: estudio de enfoque cualitativo, con investigación interpretativa, fundamentado en el Modelo de Resiliencia, Estrés, Ajustes y Adaptación Familiar. La investigación se realizó en un Centro Especializado en Rehabilitación de un municipio da Paraíba (Brasil) entre junio y noviembre de 2017 con 40 madres de niños con el Síndrome Congénito del Virus del Zika. El material empírico se produjo a partir de un guión con carácter semiestructurado desarrollado por la investigadora, relacionado con las diferentes fases y componentes del proceso de adaptación y resiliencia. Los hallazgos se sometieron a análisis de contenido. Resultados: surgieron dos categorías temáticas: La detección del Síndrome Congénito del Virus del Zika: período del diagnóstico y expectativas maternas, y Cómo comunicar el diagnóstico: implicancias al momento de detectar el Síndrome Congénito del Virus del Zika. Conclusión: comunicar el diagnóstico y la conducta profesional al momento de dar la noticia tienen un peso importante en la resignificación del sentido de la malformación congénita. La interacción que establece el profesional de la salud y su postura están directamente relacionadas con el nivel de satisfacción con respecto a la información recibida.


RESUMO Objetivo: conhecer como as mães acometidas pelo Zika vírus na gestação souberam do diagnóstico da Síndrome Congênita do Zika vírus em seu(sua) filho(a) e apreender a forma com que a comunicação do diagnóstico foi transmitida. Método: estudo de abordagem qualitativa, com investigação interpretativa, fundamentado no Modelo de Resiliência, Estresse, Ajustamento e Adaptação Familiar. A pesquisa foi realizada em um Centro Especializado em Reabilitação de um município da Paraíba (Brasil), no período de junho a novembro de 2017, com 40 mães de crianças com a Síndrome Congênita do Zika vírus. O material empírico foi produzido a partir de um roteiro com caráter semiestruturado desenvolvido pela pesquisadora, relacionado com as diferentes fases e componentes do processo de adaptação e resiliência. Os achados foram submetidos à analise de conteúdo. Resultados: foram desveladas duas categorias temáticas: A descoberta da Síndrome Congênita do Zika vírus: período do diagnóstico e expectativas maternas, e A forma da comunicação do diagnóstico: implicações diante da descoberta da Síndrome Congênita do Zika vírus. Conclusão: a comunicação do diagnóstico e a conduta profissional no momento da informação possuem papéis importantes na ressignificação do sentido da malformação congênita. A interação estabelecida pelo profissional de saúde e sua postura estão diretamente relacionadas com a satisfação sobre a informação recebida.


Assuntos
Humanos , Feminino , Saúde da Mulher , Zika virus , Microcefalia , Mães , Sistema Único de Saúde , Diagnóstico
2.
Artigo em Português | PAHO-IRIS | ID: phr-52939

RESUMO

[RESUMO]. Objetivo. Descrever o perfil clínico-epidemiológico dos casos confirmados de microcefalia e/ou alterações do sistema nervoso central (SNC) relacionadas a infecção congênita pelo vírus Zika e outras etiologias infecciosas no estado do Rio de Janeiro no período de novembro de 2015 a julho de 2017. Métodos. Realizou-se um estudo transversal de 298 casos (conforme definição do Ministério da Saúde) notificados à Secretaria de Estado de Saúde do Rio de Janeiro no período estudado. Analisaram-se variáveis demográficas, epidemiológicas, clínicas, radiológicas e laboratoriais, com análise estatística descritiva bivariada e múltipla por regressão logística para estudo de fatores associados ao óbito. Resultados. A idade mediana das mães foi 24 anos; 30,9% relataram febre, e 64,8%, exantema à gestação. A mediana do perímetro cefálico ao nascer foi 29 cm e a do peso foi 2 635 g. O diagnóstico etiológico foi de Zika congênita em 46,0%; de sífilis, toxoplasmose, rubéola, citomegalovírus e vírus herpes simplex (STORCH) em 13,8%, com predomínio da sífilis; e de agente infeccioso não definido em 40,3%. Alterações do SNC diferentes de microcefalia foram descritas em 88,3%, predominando calcificações cerebrais, ventriculomegalia e atrofia cerebral. A letalidade total foi 7,0%, sendo 19,0% nos casos de Zika confirmada laboratorialmente e 22,2% nos de toxoplasmose. Na análise múltipla, o peso ao nascer foi o principal preditor de óbito. Conclusões. Apesar da epidemia de Zika, 13,8% dos casos foram por STORCH. A letalidade e a elevada ocorrência de malformações neurológicas além da microcefalia mostram a gravidade da infecção, com impacto nas famílias e no sistema de saúde.


[ABSTRACT]. Objective. To describe the clinical and epidemiological profile of cases with confirmed microcephaly or central nervous system (CNS) findings associated with congenital Zika virus infection and other infectious etiologies in the state of Rio de Janeiro, Brazil, from November 2015 to July 2017. Method. A cross-sectional study was performed with 298 cases (as defined by the Ministry of Health) communicated to the Rio de Janeiro State Department of Health in the study period. Demographic, epidemiological, clinical, radiological, and laboratory variables were assessed. Descriptive bivariate and multivariable logistic regression analysis was used to determine the association between specific factors and death outcome. Results. The median age of mothers was 24 years; 30.9% reported fever and 64.8% reported a rash during pregnancy. The median head circumference at birth was 29 cm, and median birth weight was 2 635 g. An etiological diagnosis of congenital Zika was made in 46.0%, whereas 13.8% were diagnosed with syphilis, toxoplasmosis, rubella, cytomegalovirus, and herpes simplex infections (STORCH), with predominance of syphilis, and 40.3% had an unspecified infectious agent. CNS findings other than microcephaly were observed in 88.3%, especially intracranial calcifications, ventriculomegaly, and brain atrophy. Overall lethality was 7.0% — 19.0% in laboratory confirmed Zika cases and 22.2% in toxoplasmosis cases. Multivariable analysis revealed birth weight as the main predictor of death. Conclusions. Despite the Zika epidemic, 13.8% of the studied cases were diagnosed with STORCH. The lethality and high frequency of neurological findings beyond microcephaly reflect severe infection, with impact on families and health care system.


[RESUMEN]. Objetivo. Describir el perfil clínico-epidemiológico de los casos confirmados de microcefalia y de alteraciones del sistema nervioso central (SNC) relacionados con la infección congénita por el virus del Zika y otras etiologías infecciosas en el Estado de Río de Janeiro en el período comprendido entre noviembre del 2015 y julio del 2017. Métodos. Se realizó un estudio transversal de 298 casos (según la definición del Ministerio de Salud) notificados a la Secretaría de Estado de Salud de Río de Janeiro en el período objeto de estudio. Se analizaron variables demográficas, epidemiológicas, clínicas, radiológicas y de laboratorio, con un análisis estadístico descriptivo bivariado y de regresión logística múltiple para estudio de los factores relacionados con la defunción. Resultados. La edad mediana de las madres fue de 24 años; un 30,9% informó fiebre y un 64,8%, exantema durante la gestación. La mediana del perímetro cefálico al nacer fue de 29 cm y la del peso, de 2635 g. El diagnóstico etiológico fue de infección congénita por el virus del Zika en un 46,0%; sífilis, toxoplasmosis, rubéola, infección por citomegalovirus e infección por el virus del herpes simple (STORCH) en un 13,8%, con predominio de sífilis; e infección por un agente infeccioso no definido en un 40,3%. Se describieron alteraciones del SNC diferentes de microcefalia en un 88,3%, con predominio de calcificaciones cerebrales, ventriculomegalia y atrofia cerebral. La letalidad total alcanzó 7,0%; se confirmaron en el laboratorio 19,0% de los casos de infección por el virus del Zika y 22,2% de los casos de toxoplasmosis. En el análisis de regresión logística múltiple, el peso al nacer fue el principal pronóstico de defunción. Conclusiones. A pesar de la epidemia de la infección por el virus del Zika, 13,8% de los casos fueron causados por STORCH. La letalidad y la elevada presencia de malformaciones neurológicas, además de microcefalia, muestran la gravedad de la infección y sus repercusiones para las familias y para el sistema de salud.


Assuntos
Zika virus , Microcefalia , Anormalidades Congênitas , Epidemias , Epidemiologia , Brasil , Microcefalia , Anormalidades Congênitas , Epidemias , Epidemiologia , Brasil , Zika virus , Anormalidades Congênitas , Epidemiologia
3.
Med Sci (Paris) ; 36(10): 866-871, 2020 Oct.
Artigo em Francês | MEDLINE | ID: mdl-33026328

RESUMO

Pathogenic variants of the gene NDE1 (Nuclear Distribution Element 1) in humans lead to microlissencephaly which associates a reduced head circumference and a simplified gyration. Microlissencephaly is the most severe deficit of neurogenesis described to date but its precise physiopathological mechanism is not yet well known. The NDE1 gene encodes a phosphoprotein that is essential to neurogenesis and that is expressed in various cell compartments of neuroblasts. More than 60 interaction partners with NDE1 have been reported, notably various proteins involved in formation of the mitotic spindle, in ciliation, in genome protection of dividing neuroblasts or even in apoptosis (like LIS1, dynein or cohesin), which are all avenues that we explore in this review.


Assuntos
Encéfalo/embriologia , Microcefalia/genética , Proteínas Associadas aos Microtúbulos/genética , Neurogênese/genética , Encéfalo/crescimento & desenvolvimento , Humanos , Microcefalia/patologia , Mitose/genética , Células-Tronco Neurais/fisiologia
4.
Pediatrics ; 146(3)2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32868470

RESUMO

Pediatric care providers, pediatricians, pediatric subspecialty physicians, and other health care providers should be able to recognize children with abnormal head shapes that occur as a result of both synostotic and deformational processes. The purpose of this clinical report is to review the characteristic head shape changes, as well as secondary craniofacial characteristics, that occur in the setting of the various primary craniosynostoses and deformations. As an introduction, the physiology and genetics of skull growth as well as the pathophysiology underlying craniosynostosis are reviewed. This is followed by a description of each type of primary craniosynostosis (metopic, unicoronal, bicoronal, sagittal, lambdoid, and frontosphenoidal) and their resultant head shape changes, with an emphasis on differentiating conditions that require surgical correction from those (bathrocephaly, deformational plagiocephaly/brachycephaly, and neonatal intensive care unit-associated skill deformation, known as NICUcephaly) that do not. The report ends with a brief discussion of microcephaly as it relates to craniosynostosis as well as fontanelle closure. The intent is to improve pediatric care providers' recognition and timely referral for craniosynostosis and their differentiation of synostotic from deformational and other nonoperative head shape changes.


Assuntos
Craniossinostoses/diagnóstico , Acrocefalossindactilia/genética , Fenótipo de Síndrome de Antley-Bixler/genética , Suturas Cranianas/anatomia & histologia , Disostose Craniofacial , Craniossinostoses/classificação , Craniossinostoses/etiologia , Craniossinostoses/cirurgia , Cabeça/anormalidades , Humanos , Lactente , Hipertensão Intracraniana/etiologia , Ilustração Médica , Microcefalia/etiologia , Osteogênese/fisiologia , Fenótipo , Fotografação , Polidactilia/genética , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Procedimentos Cirúrgicos Reconstrutivos , Crânio/anatomia & histologia , Crânio/diagnóstico por imagem , Crânio/crescimento & desenvolvimento , Sinostose/complicações , Sinostose/diagnóstico por imagem
5.
Artigo em Russo | MEDLINE | ID: mdl-32929933

RESUMO

Treatment resistant epileptic encephalopathy (EE) in childhood in a significant amount due to genetic damage or congenital abnormalities of the brain. The literature described a rare microcephalic-capillary malformation syndrome (Microcephaly-capillary malformation, MIC-CAP), manifested from the first month of life by the early onset of treatment-resistant epilepsy, severe progressive microcephaly, spastic tetraparesis, severe delay in psychomotor development, multiple, small-sized capillary angiomas on the body and underdevelopment of the fingers. The boy was diagnosed with a previously described variant of the nucleotide sequence in exon 2 of the STAMBP chr2 gene:74058171rs781694797 188A>G in the homozygous state, leading to the replacement of the amino acid p.Tyr63Cys in 63 protein position. This type of mutation chr2:74058171rs781694797 188A>G was also detected in the father and mother in the heterozygous state. This variant is considered as pathogenic, related to the patient's phenotype. The article presents a literature review of this syndrome and the case report.


Assuntos
Epilepsia , Microcefalia , Malformações Vasculares , Capilares , Criança , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Humanos , Masculino , Mutação , Síndrome , Ubiquitina Tiolesterase/genética
6.
Rev Panam Salud Publica ; 44, sept. 2020
Artigo em Inglês | PAHO-IRIS | ID: phr-52652

RESUMO

Objective. To establish the risk of microcephaly in neonates born to women infected with ZIKV during pregnancy. Methods. A cohort of laboratory-confirmed ZIKV cases of congenital infections (109 mothers infected during pregnancy and 101 newborns) among 308 suspect cases was followed in Belem, Pará, Brazil, from October 2015 to December 2017. Results. A microcephaly risk of 1.98% (95% CI 0.54-6.93%) was found, or 2 cases among the 101 neonates infected with ZIKV during pregnancy. 72% of the pregnant women had ZIKV infection confirmed by RT-qPCR during gestation. Conclusions. Results showed a low incidence of ZIKV-associated birth defects, stillbirth, and miscarriage, which contrasts with previous studies in other Brazilian regions. Previous exposure to yellow fever vaccine and/ or multiserotype DENV infection could be implicated in the protection from ZIKV congenital infection.


Objetivo. Establecer el riesgo de microcefalia en los recién nacidos de mujeres infectadas con ZIKV durante el embarazo. Métodos. Se siguió a una cohorte de casos con infección congénita por ZIKV confirmada por laboratorio (109 madres infectadas durante el embarazo, 101 recién nacidos) conformada a partir de 308 casos sospechosos en Belem, Pará, Brasil, de octubre de 2015 a diciembre de 2017. Resultados. Se encontró un riesgo de microcefalia de 1,98% (IC95% 0,54-6,93%), o 2 casos entre los 101 neonatos infectados con ZIKV durante el embarazo. En el 72% de las mujeres embarazadas se confirmó mediante RT-qPCR la infección por ZIKV durante la gestación. Conclusiones. Los resultados mostraron una baja incidencia de malformaciones congénitas, mortinatos y abortos asociados al ZIKV, lo que contrasta con estudios anteriores de otras regiones de Brasil. La exposición previa a la vacuna contra la fiebre amarilla o la infección previa por varios serotipos de virus del dengue podrían estar implicados en la protección contra la infección congénita por ZIKV.


Assuntos
Infecção por Zika virus , Complicações na Gravidez , Microcefalia , Infecção por Zika virus , Microcefalia , Complicações Infecciosas na Gravidez , Brasil
7.
PLoS Genet ; 16(9): e1008916, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32877400

RESUMO

Some imprinted genes exhibit parental origin specific expression bias rather than being transcribed exclusively from one copy. The physiological relevance of this remains poorly understood. In an analysis of brain-specific allele-biased expression, we identified that Trappc9, a cellular trafficking factor, was expressed predominantly (~70%) from the maternally inherited allele. Loss-of-function mutations in human TRAPPC9 cause a rare neurodevelopmental syndrome characterized by microcephaly and obesity. By studying Trappc9 null mice we discovered that homozygous mutant mice showed a reduction in brain size, exploratory activity and social memory, as well as a marked increase in body weight. A role for Trappc9 in energy balance was further supported by increased ad libitum food intake in a child with TRAPPC9 deficiency. Strikingly, heterozygous mice lacking the maternal allele (70% reduced expression) had pathology similar to homozygous mutants, whereas mice lacking the paternal allele (30% reduction) were phenotypically normal. Taken together, we conclude that Trappc9 deficient mice recapitulate key pathological features of TRAPPC9 mutations in humans and identify a role for Trappc9 and its imprinting in controlling brain development and metabolism.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Microcefalia/genética , Obesidade/genética , Animais , Criança , Feminino , Regulação da Expressão Gênica , Frequência do Gene , Impressão Genômica , Heterozigoto , Homozigoto , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Herança Materna , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microcefalia/metabolismo , Mutação , Obesidade/metabolismo , Fenótipo
8.
BMC Med Genet ; 21(1): 182, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32943010

RESUMO

BACKGROUND: Mandibulofacial dysostosis with microcephaly (MFDM) is a rare autosomal dominant genetic disease characterized by intellectual and growth retardations, as well as major microcephaly, induced by missense and splice site variants or microdeletions in the EFTUD2 gene. CASE PRESENTATION: Here, we investigate the case of a young girl with symptoms of MFDM and a normal karyotype. Whole-exome sequencing of the family was performed to identify genetic alterations responsible for this phenotype. We identified a de novo synonymous variant in the EFTUD2 gene. We demonstrated that this synonymous variant disrupts the donor splice-site in intron 9 resulting in the skipping of exon 9 and a frameshift that leads to a premature stop codon. CONCLUSIONS: We present the first case of MFDM caused by a synonymous variant disrupting the donor splice site, leading to exon skipping.


Assuntos
Disostose Mandibulofacial/genética , Microcefalia/genética , Mutação , Fatores de Alongamento de Peptídeos/genética , Processamento de RNA , Ribonucleoproteína Nuclear Pequena U5/genética , Sequência de Bases , Criança , Feminino , Humanos , Cariótipo , Fenótipo
9.
Pediatrics ; 146(3)2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32820067

RESUMO

An 11-week-old unvaccinated, term Amish boy initially presented with poor feeding, microcephaly, failure to thrive, and developmental delays. His physical examination was significant for both weight and head circumference being less than the third percentile, and he was noted to have micrognathia, truncal hypotonia, and head lag. He was admitted to the pediatric hospital medicine service for further diagnostic evaluation. Laboratory studies assessing for endocrinological and metabolic etiologies yielded negative results, and imaging studies (including a chest radiograph, echocardiogram, and abdominal ultrasound) were normal. However, intracranial calcifications were noted on a head ultrasound. The etiology of his constellation of symptoms was initially thought to be infectious, but the ultimate diagnosis was not made until after discharge from the pediatric hospital medicine service.


Assuntos
Doenças Autoimunes do Sistema Nervoso/diagnóstico por imagem , Calcinose/diagnóstico por imagem , Microcefalia/diagnóstico por imagem , Hipotonia Muscular/diagnóstico por imagem , Malformações do Sistema Nervoso/diagnóstico por imagem , Doenças Autoimunes do Sistema Nervoso/sangue , Doenças Autoimunes do Sistema Nervoso/complicações , Calcinose/sangue , Calcinose/complicações , Cefalometria/métodos , Humanos , Lactente , Masculino , Microcefalia/sangue , Microcefalia/complicações , Hipotonia Muscular/sangue , Hipotonia Muscular/complicações , Malformações do Sistema Nervoso/sangue , Malformações do Sistema Nervoso/complicações
10.
Value Health ; 23(7): 969-976, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32762999

RESUMO

OBJECTIVES: In this systematic review, we synthesize the current evidence on health-related quality of life (HRQoL) for the two of the most relevant outcomes of Zika virus infection in humans, microcephaly and Guillain-Barré Syndrome (GBS). METHODS: We searched the following databases: MEDLINE, Embase, CINAHL, LILACS, WHO's ICTRP clinical trials registries database and PROSPERO. Search terms included quality of life, microcephaly, and Guillain-Barré Syndrome. We included primary studies where HRQoL was quantitatively assessed for microcephaly and GBS using validated instruments. We used the Joanna Briggs Institute Critical Appraisal Tools to assess the risk of bias of individual studies. RESULTS: From a total of 1,657 abstracts screened and 66 full texts reviewed, 21 studies met the eligibility criteria; one study for microcephaly and 20 for GBS. Adjusted disutilities for microcephaly compared to a normative childhood utility ranged from -0.745 to -0.820. For GBS, time traded-off the expected lifetime ranged from 16 days to 3 years. HRQoL follows the clinical course of GBS, with lower scores in the first months, recovery within the first year post onset, and stabilization after one year. CONCLUSIONS: Included studies reported a wide range of HRQoL for GBS, due in part to a high level of heterogeneity in methods, inclusion criteria, follow-up and reporting of results. Opportunities exist for primary studies assessing the longitudinal HRQoL over the entire course of the diseases to inform clinical practice, economic evaluations and health policy.


Assuntos
Qualidade de Vida , Infecção por Zika virus/complicações , Criança , Síndrome de Guillain-Barré/epidemiologia , Síndrome de Guillain-Barré/virologia , Humanos , Microcefalia/epidemiologia , Microcefalia/virologia , Fatores de Tempo , Infecção por Zika virus/epidemiologia
11.
PLoS One ; 15(8): e0237392, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32804962

RESUMO

BACKGROUND: Birth defects surveillance in the United States is conducted principally by review of routine but lagged reporting to statewide congenital malformations registries of diagnoses by hospitals or other health care providers, a process that is not designed to rapidly detect changes in prevalence. Health information exchange (HIE) systems are well suited for rapid surveillance, but information is limited about their effectiveness at detecting birth defects. We evaluated HIE data to detect microcephaly diagnosed at birth during January 1, 2013-December 31, 2015 before known introduction of Zika virus in North America. METHODS: Data from an HIE system were queried for microcephaly diagnostic codes on day of birth or during the first two days after birth at three Bronx hospitals for births to New York City resident mothers. Suspected cases identified by HIE data were compared with microcephaly cases that had been identified through direct inquiry of hospital records and confirmed by chart abstraction in a previous study of the same cohort. RESULTS: Of 16,910 live births, 43 suspected microcephaly cases were identified through an HIE system compared to 67 confirmed cases that had been identified as part of the prior study. A total of 39 confirmed cases were found by both studies (sensitivity = 58.21%, 95% CI: 45.52-70.15%; positive predictive value = 90.70%, 95% CI: 77.86-97.41%; negative predictive value = 99.83%, 95% CI: 99.76-99.89% for HIE data). CONCLUSION: Despite limitations, HIE systems could be used for rapid newborn microcephaly surveillance, especially in the many jurisdictions where more labor-intensive approaches are not feasible. Future work is needed to improve electronic medical record documentation quality to improve sensitivity and reduce misclassification.


Assuntos
Troca de Informação em Saúde/estatística & dados numéricos , Microcefalia/epidemiologia , Hospitais/estatística & dados numéricos , Humanos , Cidade de Nova Iorque/epidemiologia
12.
Nucleic Acids Res ; 48(16): 9135-9146, 2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32735676

RESUMO

Microcephalin 1 (MCPH1) was identified from genetic mutations in patients with primary autosomal recessive microcephaly. In response to DNA double-strand breaks (DSBs), MCPH1 forms damage-induced foci and recruits BRCA2-RAD51 complex, a key component of the DSB repair machinery for homologous recombination (HR), to damage sites. Accordingly, the efficiency of HR is significantly attenuated upon depletion of MCPH1. The biochemical characteristics of MCPH1 and its functional interaction with the HR machinery had remained unclear due to lack of highly purified MCPH1 recombinant protein for functional study. Here, we established a mammalian expression system to express and purify MCPH1 protein. We show that MCPH1 is a bona fide DNA-binding protein and provide direct biochemical analysis of this MCPH family protein. Furthermore, we reveal that MCPH1 directly interacts with RAD51 at multiple contact points, providing evidence for how MCPH1 physically engages with the HR machinery. Importantly, we demonstrate that MCPH1 enhances the stability of RAD51 on single-strand DNA, a prerequisite step for RAD51-mediated recombination. Single-molecule tethered particle motion analysis showed a ∼2-fold increase in the lifetime of RAD51-ssDNA filaments in the presence of MCPH1. Thus, our study demonstrates direct crosstalk between microcephaly protein MCPH1 and the recombination component RAD51 for DSB repair.


Assuntos
Proteína BRCA2/genética , Proteínas de Ciclo Celular/genética , Proteínas do Citoesqueleto/genética , Microcefalia/genética , Rad51 Recombinase/genética , Citoesqueleto/genética , Quebras de DNA de Cadeia Dupla , Dano ao DNA/genética , Reparo do DNA/genética , DNA de Cadeia Simples/genética , Proteínas de Ligação a DNA/genética , Instabilidade Genômica/genética , Recombinação Homóloga/genética , Humanos , Microcefalia/patologia , Nucleoproteínas/genética
13.
Artigo em Inglês | MEDLINE | ID: mdl-32844907

RESUMO

This study analyzed possible associations between the trimester of maternal Zika virus infection (ZIKV) in pregnancy, severity of brain computed tomography (CT) findings and the presence of microcephaly at birth in children with Congenital Zika Syndrome (CZS). It was an analytical study in a cohort of children with CZS. Symptoms of maternal infection were dichotomized into the 1st trimester of pregnancy and other trimesters. Head circumference (HC) at birth was used to calculate the z-score. Mild microcephaly was defined as HC between 2 and ≥3 standard deviations (SD) below the mean for each gestational age and sex, and severe microcephaly when HC <3 SD below average. Brain CT images were evaluated by two radiologists and classified, according to the severity, into mild, moderate and severe. Fisher's exact, Mann-Whitney and Kruskal-Wallis tests were used to verify the associations between variables. In 108 children, maternal infection in the 1st trimester of pregnancy was associated with more severe brain CT abnormalities (p=0.038), greater severity of microcephaly at birth (p=0.013) and lower HC z-scores at birth (p=0.021). The severity of brain CT lesions was also associated with lower HC z-scores at birth (p<0.001). Maternal ZIKV infection during the first trimester of pregnancy proved to be an important risk factor for a more severe spectrum of CZS, as it is associated with more severe brain CT abnormalities and, consequently, with lower HC z-scores at birth.


Assuntos
Encéfalo/diagnóstico por imagem , Microcefalia/virologia , Primeiro Trimestre da Gravidez , Tomografia Computadorizada por Raios X/métodos , Infecção por Zika virus/diagnóstico , Zika virus , Adulto , Feminino , Humanos , Recém-Nascido , Gravidez , Complicações Infecciosas na Gravidez/epidemiologia , Trimestres da Gravidez , Índice de Gravidade de Doença , Infecção por Zika virus/congênito , Infecção por Zika virus/epidemiologia
14.
N Engl J Med ; 383(6): 537-545, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32757522

RESUMO

BACKGROUND: In 2015 and 2016, Colombia had a widespread outbreak of Zika virus. Data from two national population-based surveillance systems for symptomatic Zika virus disease (ZVD) and birth defects provided complementary information on the effect of the Zika virus outbreak on pregnancies and infant outcomes. METHODS: We collected national surveillance data regarding cases of pregnant women with ZVD that were reported during the period from June 2015 through July 2016. The presence of Zika virus RNA was identified in a subgroup of these women on real-time reverse-transcriptase-polymerase-chain-reaction (rRT-PCR) assay. Brain or eye defects in infants and fetuses and other adverse pregnancy outcomes were identified among the women who had laboratory-confirmed ZVD and for whom data were available regarding pregnancy outcomes. We compared the nationwide prevalence of brain and eye defects during the outbreak with the prevalence both before and after the outbreak period. RESULTS: Of 18,117 pregnant women with ZVD, the presence of Zika virus was confirmed in 5926 (33%) on rRT-PCR. Of the 5673 pregnancies with laboratory-confirmed ZVD for which outcomes had been reported, 93 infants or fetuses (2%) had brain or eye defects. The incidence of brain or eye defects was higher among pregnancies in which the mother had an onset of ZVD symptoms in the first trimester than in those with an onset during the second or third trimester (3% vs. 1%). A total of 172 of 5673 pregnancies (3%) resulted in pregnancy loss; after the exclusion of pregnancies affected by birth defects, 409 of 5426 (8%) resulted in preterm birth and 333 of 5426 (6%) in low birth weight. The prevalence of brain or eye defects during the outbreak was 13 per 10,000 live births, as compared with a prevalence of 8 per 10,000 live births before the outbreak and 11 per 10,000 live births after the outbreak. CONCLUSIONS: In pregnant women with laboratory-confirmed ZVD, brain or eye defects in infants or fetuses were more common during the Zika virus outbreak than during the periods immediately before and after the outbreak. The frequency of such defects was increased among women with a symptom onset early in pregnancy. (Funded by the Colombian Instituto Nacional de Salud and the Centers for Disease Control and Prevention.).


Assuntos
Encéfalo/anormalidades , Surtos de Doenças , Anormalidades do Olho/epidemiologia , Complicações Infecciosas na Gravidez , Infecção por Zika virus/complicações , Zika virus/isolamento & purificação , Adolescente , Adulto , Colômbia/epidemiologia , Feminino , Doenças Fetais/epidemiologia , Feto/anormalidades , Geografia Médica , Humanos , Incidência , Recém-Nascido , Masculino , Microcefalia/epidemiologia , Distribuição de Poisson , Gravidez , Complicações Infecciosas na Gravidez/epidemiologia , Resultado da Gravidez , Prevalência , RNA Viral/sangue , Reação em Cadeia da Polimerase em Tempo Real , Adulto Jovem , Zika virus/genética , Infecção por Zika virus/epidemiologia
15.
Nat Commun ; 11(1): 4038, 2020 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-32788587

RESUMO

Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Here, we identify biallelic missense and frameshift mutations in NARS1 in seven patients from three unrelated families with microcephaly and neurodevelopmental delay. Patient cells show reduced NARS1 protein, impaired NARS1 activity and impaired global protein synthesis. Cortical brain organoid modeling shows reduced proliferation of radial glial cells (RGCs), leading to smaller organoids characteristic of microcephaly. Single-cell analysis reveals altered constituents of both astrocytic and RGC lineages, suggesting a requirement for NARS1 in RGC proliferation. Our findings demonstrate that NARS1 is required to meet protein synthetic needs and to support RGC proliferation in human brain development.


Assuntos
Aspartato-tRNA Ligase/deficiência , Aspartato-tRNA Ligase/genética , Córtex Cerebral/patologia , Microcefalia/genética , Células-Tronco Neurais/patologia , Organoides/patologia , Aminoacil-RNA de Transferência/genética , Adolescente , Adulto , Sequência de Bases , Diferenciação Celular , Proliferação de Células , Tamanho Celular , Sobrevivência Celular , Criança , Família , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Células HEK293 , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Antígeno Ki-67/metabolismo , Masculino , Mutação/genética , Células-Tronco Neurais/metabolismo , Neuroglia/metabolismo , Linhagem , Adulto Jovem
16.
Arq Neuropsiquiatr ; 78(7): 403-411, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32627805

RESUMO

BACKGROUND: The congenital Zika syndrome involves structural brain changes, including ventriculomegaly, thin cerebral cortices, abnormal gyral pattern, cortical malformations, hypoplasia of the corpus callosum, myelination delay, subcortical diffuse calcifications, brainstem hypoplasia, and microcephaly in newborns. OBJECTIVE: This study aimed to describe the clinical characteristics of children with congenital Zika syndrome; to compare the outcomes of infants infected in the first (1T, n=20) and second trimesters of pregnancy (2T, n=11); to investigate correlations between birth weight, birth and follow-up head circumference, birth gestational age, and gross motor scores. METHODS: Participants were evaluated with Alberta Infant Motor Scale (AIMS) and part A of the Gross Motor Function Measure (GMFM-A). ANOVA compared head circumference, birth gestational age, birth weight, and gross motor performance of 1T and 2T. RESULTS: The correlations were investigated by Pearson correlation coefficients. ANOVA showed differences in birth and follow-up head circumferences. Head circumference was smaller in 1T, compared to 2T. Motor performance was classified as below the fifth percentile in AIMS in all children and 1T showed lower scores in prone, sitting, and total AIMS score, compared to 2T. Children ranged from 8 to 78% on GMFM-A and there was a poorer motor performance of 1T. Nineteen children showed hypertonia, six showed normal tone and six showed hypotonia. Birth head circumference was correlated with AIMS prone postural control. Follow-up head circumference was correlated to prone, supine and total AIMS scores. Smaller head circumference at birth and follow-up denoted poorer postural control. DISCUSSION: Children with congenital Zika syndrome showed microcephaly at birth and follow-up. Smaller head circumferences and poorer motor outcomes were observed in 1T. Infants showed poor visual and motor outcomes. Moderate positive correlations between birth and follow-up head circumference and gross motor function were found.


Assuntos
Microcefalia/virologia , Infecção por Zika virus/diagnóstico , Zika virus/isolamento & purificação , Encéfalo , Cefalometria , Criança , Feminino , Humanos , Lactente , Recém-Nascido , Imagem por Ressonância Magnética , Microcefalia/diagnóstico , Destreza Motora , Gravidez , Complicações Infecciosas na Gravidez , Infecção por Zika virus/complicações , Infecção por Zika virus/congênito
17.
BMC Med Genet ; 21(1): 140, 2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32605629

RESUMO

BACKGROUND: Cohen syndrome, an autosomal recessive syndrome, is a rare syndrome with diverse clinical manifestations including failure to thrive, hypotonia, hypermobile joints, microcephaly, intellectual disabilities, craniofacial and limb anomalies, neutropenia and a friendly character. It is associated with mutations of the vacuolar protein sorting 13 homolog B (VPS13B) gene, which is involved in the development of the ocular, hematological and central nervous systems. This gene encodes a transmembrane protein playing a crucial role in preserving the integrity of the Golgi complex. To date, more than 150 mutations of VPS13B have been reported in over 200 Cohen syndrome patients. Missense or nonsense mutations are the most common mutations. CASE PRESENTATION: A 4-year-old girl, born to consanguineous parents, was referred to the pediatric clinical immunology outpatient clinic for investigation of recurrent neutropenia with a history of recurrent infections in the past year. On physical examination, she had the characteristic facial features of Cohen syndrome, developmental delay and speech disorder. She had a cheerful disposition, and her mother gave a history of feeding difficulties in her first months of life. She did not present any ophthalmologic or cardiac abnormalities. Her lab results revealed moderate neutropenia. Serum IgG, IgM, IgA and IgE levels were normal. She fulfilled the clinical diagnostic criteria for Cohen syndrome. WES revealed a novel homozygous frameshift variant in VPS13B (LRG_351t1: c.7095del; p.Ser2366AlafsTer49). Currently, she is not experiencing any severe problem, and she undergoes irregular medical treatment once her neutrophil count decreases under the normal limit. Her verbal and motor abilities have improved as a result of speech and occupational therapies. CONCLUSION: We reported a novel homozygous frameshift variant in VPS13B (LRG_351t1: c.7095del; p.Ser2366AlafsTer49) in a 4-year-old girl with Cohen syndrome. Cohen syndrome should be considered in differential diagnosis of any child with intellectual disability and neutropenia.


Assuntos
Dedos/anormalidades , Deficiência Intelectual/genética , Microcefalia/genética , Hipotonia Muscular/genética , Mutação/genética , Miopia/genética , Obesidade/genética , Degeneração Retiniana/genética , Proteínas de Transporte Vesicular/genética , Pré-Escolar , Deficiências do Desenvolvimento/genética , Feminino , Humanos , Fenótipo
18.
PLoS Negl Trop Dis ; 14(7): e0008413, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32628667

RESUMO

Global Zika virus (ZIKV) outbreaks and their link to microcephaly have raised major public health concerns. However, the mechanism of maternal-fetal transmission remains largely unknown. In this study, we determined the role of yolk sac (YS) microglial progenitors in a mouse model of ZIKV vertical transmission. We found that embryonic (E) days 6.5-E8.5 were a critical window for ZIKV infection that resulted in fetal demise and microcephaly, and YS microglial progenitors were susceptible to ZIKV infection. Ablation of YS microglial progenitors significantly reduced the viral load in both the YS and the embryonic brain. Taken together, these results support the hypothesis that YS microglial progenitors serve as "Trojan horses," contributing to ZIKV fetal brain dissemination and congenital brain defects.


Assuntos
Feto/patologia , Microcefalia/patologia , Microglia/virologia , Complicações Infecciosas na Gravidez/patologia , Infecção por Zika virus/patologia , Zika virus/isolamento & purificação , Animais , Encéfalo/virologia , Modelos Animais de Doenças , Feminino , Feto/virologia , Humanos , Transmissão Vertical de Doença Infecciosa , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microcefalia/embriologia , Microcefalia/virologia , Microglia/metabolismo , Gravidez , Complicações Infecciosas na Gravidez/virologia , Carga Viral , Zika virus/fisiologia , Infecção por Zika virus/transmissão , Infecção por Zika virus/virologia
19.
Artigo em Inglês | MEDLINE | ID: mdl-32667392

RESUMO

Severe neurological problems and other special manifestations such as high prevalence of structural cardiac changes has been described in infants vertically exposed to the Zika virus (ZIKV) and has been called congenital Zika virus syndrome (CZS). Previous studies have shown that the 24-hour Holter heart rate variability (HRV) analysis allows the prediction of worse outcomes in infants with neurological impairment and higher risk of sudden infant death syndrome (SIDS), hypertension, diabetes mellitus and other cardiovascular diseases. This study describes the 24-hour Holter findings of infants with confirmed vertical exposure to the ZIKV by positive polymerase chain reaction (PCR) assays in the mother's blood during pregnancy and/or in the urine or cerebrospinal fluid of the newborn. Data analysis was descriptive and included two subgroups according to the presence of fetal distress, positive PCR to ZIKV in the newborn, CZS and severe microcephaly. Heart rate, pauses, arrhythmias, ST segment and QT interval analyses and HRV evaluation through R-R, SDNN, pNN50 and rMMSD were described. The Mann-Whitney test was performed to assess differences between the two subgroups. The sample consisted of 15 infants with a mean age of 16 months, nine of whom were male. No arrhythmias or QT interval changes were observed. The comparison of HRV through the Mann-Whitney test showed a significant difference between patients with and without CZS, with and without severe microcephaly, with lower HRV in the groups with severe microcephaly and CZS. The study suggests that there is an increased risk of SIDS and cardiovascular diseases in this group of patients.


Assuntos
Transmissão Vertical de Doença Infecciosa , Malformações do Sistema Nervoso/etiologia , Complicações Infecciosas na Gravidez/virologia , Infecção por Zika virus/complicações , Zika virus/isolamento & purificação , Doenças Cardiovasculares/etiologia , Feminino , Frequência Cardíaca , Humanos , Lactente , Recém-Nascido , Masculino , Microcefalia/etiologia , Reação em Cadeia da Polimerase , Gravidez , Morte Súbita do Lactente , Zika virus/genética , Infecção por Zika virus/congênito
20.
PLoS One ; 15(7): e0235655, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32628740

RESUMO

Biallelic variants in RNU4ATAC, a non-coding gene transcribed into the minor spliceosome component U4atac snRNA, are responsible for three rare recessive developmental diseases, namely Taybi-Linder/MOPD1, Roifman and Lowry-Wood syndromes. Next-generation sequencing of clinically heterogeneous cohorts (children with either a suspected genetic disorder or a congenital microcephaly) recently identified mutations in this gene, illustrating how profoundly these technologies are modifying genetic testing and assessment. As RNU4ATAC has a single non-coding exon, the bioinformatic prediction algorithms assessing the effect of sequence variants on splicing or protein function are irrelevant, which makes variant interpretation challenging to molecular diagnostic laboratories. In order to facilitate and improve clinical diagnostic assessment and genetic counseling, we present i) an update of the previously reported RNU4ATAC mutations and an analysis of the genetic variations affecting this gene using the Genome Aggregation Database (gnomAD) resource; ii) the pathogenicity prediction performances of scores computed based on an RNA structure prediction tool and of those produced by the Combined Annotation Dependent Depletion tool for the 285 RNU4ATAC variants identified in patients or in large-scale sequencing projects; iii) a method, based on a cellular assay, that allows to measure the effect of RNU4ATAC variants on splicing efficiency of a minor (U12-type) reporter intron. Lastly, the concordance of bioinformatic predictions and cellular assay results was investigated.


Assuntos
RNA Nuclear Pequeno/metabolismo , Spliceossomos/metabolismo , Criança , Bases de Dados Genéticas , Nanismo/genética , Nanismo/patologia , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/patologia , Fibroblastos/citologia , Fibroblastos/metabolismo , Variação Genética , Humanos , Microcefalia/genética , Microcefalia/patologia , Conformação de Ácido Nucleico , Osteocondrodisplasias/genética , Osteocondrodisplasias/patologia , Processamento de RNA , RNA Nuclear Pequeno/química , RNA Nuclear Pequeno/genética
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