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1.
Braz. j. biol ; 83: e246040, 2023. tab, graf
Artigo em Inglês | LILACS, VETINDEX | ID: biblio-1285610

RESUMO

Abstract 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.


Resumo Microcefalia primária autossômica recessiva (MCPH) é um distúrbio do neurodesenvolvimento caracterizado por uma redução congênita do perímetro cefálico (-3 a -5 DP) e deficiência intelectual não progressiva. O objetivo do estudo foi avaliar mutações patogênicas no gene ASPM a fim de compreender a etiologia e o mecanismo molecular da microcefalia primária. Amostras de sangue foram coletadas de várias famílias em diferentes áreas remotas do Paquistão de fevereiro de 2017 a maio de 2019, que foram identificadas como afetadas com microcefalia primária. A extração do DNA foi realizada pelo método salting-out; a qualidade e a quantidade de DNA foram avaliadas por espectrofotometria e eletroforese em gel de agarose a 1%, respectivamente, na Universidade de Punjab. A análise de mutação foi realizada por sequenciamento completo do exoma do Cologne Center for Genomics, University of Cologne. O sequenciamento de Sanger foi feito na Universidade do Punjab para confirmar a natureza patogênica da mutação. Uma nova mutação de deleção de 4 bp c.3877_3880delGAGA foi detectada no exon 17 do gene ASPM em duas famílias afetadas por microcefalia primária (A e B), que resultou em uma mutação de frame shift no gene seguida por síntese de proteína truncada (pGlu1293Lysfs * 10), bem como a perda do domínio IQ de ligação à calmodulina e o domínio do tipo Armadillo na proteína ASPM. Usando as ferramentas in-silico Mutation Taster, PROVEAN e PolyPhen, o efeito patogênico dessa nova mutação foi testado; foi previsto ser "causador de doenças", com altos escores de patogenicidade. Uma mutação relatada anteriormente no exon 24 (c.9730C > T) do gene ASPM, resultando em truncamento de proteína (p.Arg3244 *) também foi observada na família C. Mutações no gene ASPM são a causa mais comum de MCPH na maioria dos casos . Portanto, a inscrição de famílias afetadas adicionais de áreas remotas do Paquistão ajudaria a identificar ou mapear novas mutações no gene ASPM da microcefalia primária.


Assuntos
Humanos , Microcefalia/genética , Proteínas do Tecido Nervoso/genética , Paquistão , Consanguinidade , Mutação/genética
2.
Methods Mol Biol ; 2583: 13-23, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36418722

RESUMO

Cell cycle progression is a vital aspect of neural development. Repeated cell division in neural progenitor populations amplifies the numbers of specific cell types and is required to prevent growth failure that manifests as microcephaly. Regulated cycling is also required for cell fate specification. Analysis of cell cycle states is a valuable tool to understand the mechanisms underlying brain growth. Here we describe the preparation of cells for immunofluorescent-stained samples and flow cytometry and how to analyze cell cycle progression and cell cycle exit in progenitors. We describe methods as applied to analysis of cerebellar granule neuron progenitors (CGNPs), but similar methods in brain sections can also be applied to other brain neural progenitor populations, such as the hippocampus and subventricular zone.


Assuntos
Microcefalia , Humanos , Citometria de Fluxo , Coloração e Rotulagem , Interneurônios , Divisão Celular
3.
Methods Mol Biol ; 2583: 55-61, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36418725

RESUMO

Neural progenitors show a strong tendency to undergo apoptosis in response to DNA damage, and both impaired DNA repair and increased neural progenitor apoptosis are associated with microcephaly. Here we present an immunohistochemistry-based method for assessing DNA damage and apoptosis in the neonatal mouse brain. These methods are suitable for determining in specific experimental conditions the fractions of cells with DNA double-strand breaks, the fractions of cells undergoing apoptosis, or both. While DNA damage in neural progenitors can trigger apoptosis, inappropriate apoptosis may also result from other processes. Simultaneous analysis of DNA damage and apoptosis in mouse models of microcephaly can determine how genetic instability and cell death contribute to the observed phenotype.


Assuntos
Microcefalia , Animais , Camundongos , Dano ao DNA , Encéfalo , Apoptose , Coloração e Rotulagem , Imunofluorescência
4.
Methods Mol Biol ; 2583: 123-125, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36418730

RESUMO

Analysis of single-cell RNA sequencing typically includes the clustering of cells and subsequent determination of the population size of each cluster, relative to the whole. In an experimental setting, two or more conditions are compared to assess changes in cellular composition of the sampled tissue. Cluster populations are frequently normalized to the total number of cells from each replicate in order to facilitate comparisons. After normalization, they become interdependent fractions and therefore cannot be compared using individual t-tests. Here we describe the use of Dirichlet regression to compare changes in cellular composition between two or more conditions when multiple biological replicates (three or more) are sampled under each condition. We provide an example of R code to conduct a similar analysis and interpret the results.


Assuntos
Microcefalia , Análise de Célula Única , Humanos , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Análise por Conglomerados , Sequenciamento Completo do Exoma
5.
Methods Mol Biol ; 2583: 129-148, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36418731

RESUMO

With its sensitivity to soft tissue, MRI is a powerful tool for the study of the neuroanatomical manifestations of a variety of conditions, such as microcephaly-related morbidities that are not easily visualized by other imaging techniques, such as CT. In addition to structural imaging, more recently, researchers have found changes in brain function in a wide range of neurological conditions-highlighting the utility of MRI for the study of microcephaly.In this methods chapter, basic mouse preparation and the acquisition of data for in vivo anatomical MRI will be discussed. Additionally, we will provide our protocol for the perfusion and fixation of brain tissue with gadolinium contrast agent. Following that, the process of optimization of system parameters will be shown for anatomical imaging of in vivo and ex vivo brain tissue. Lastly, the chapter will detail a protocol for fcMRI along with a discussion of considerations specific to functional imaging.


Assuntos
Microcefalia , Animais , Camundongos , Microcefalia/diagnóstico por imagem , Neuroimagem , Imageamento por Ressonância Magnética , Gadolínio , Encéfalo/diagnóstico por imagem
6.
Methods Mol Biol ; 2583: 99-104, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36418728

RESUMO

Droplet-based single-cell RNA-seq (scRNA-seq) requires the addition of bar codes that mark the cell and transcript of origin. Cell-specific bar codes, typically added by cDNA elongation on beads, label each transcript derived from an individual cell. Transcript-specific bar codes serve as unique molecular identifiers and allow for the maintenance of transcript proportions after PCR-based amplification of cDNA. This chapter provides methods for generating bar-coded scRNA-seq libraries after droplet encapsulation.


Assuntos
Microcefalia , Análise de Célula Única , Humanos , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , DNA Complementar/genética , Biblioteca Gênica
7.
Methods Mol Biol ; 2583: 105-121, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36418729

RESUMO

Single-cell transcriptomic analysis (scRNA-seq) can enable researchers to explore the gene expression patterns of thousands of individual cells simultaneously. Processing the complex data generated by scRNA-seq requires specialized computational tools. This chapter focuses on the analytical aspect of scRNA-seq workflow, with a focus on resolving biological signals from large-scale scRNA-seq data produced by the Drop-Seq platform.


Assuntos
Microcefalia , Humanos , Análise de Célula Única , Sequenciamento Completo do Exoma , Pesquisadores , Transcriptoma
8.
Methods Mol Biol ; 2583: 83-97, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36418727

RESUMO

Single-cell RNA sequencing (scRNA-seq) allows for the transcriptomic profiling of a sample tissue with single-cell resolution. The concept of scRNA-seq builds on traditional, "bulk" RNA-seq by recording and preserving the cellular origin of each transcript throughout library preparation. Here we describe an adaptation of the Drop-Seq method (Macosko et al. Cell 161, 1202-1214, 2015), in which nanoliter-scale droplets are used to physically separate dissociated cells, while a cell-specific DNA barcode is simultaneously introduced. Following barcoding, cDNAs can be mixed and pooled while retaining the identity of the cell of origin. The benefit of the Drop-Seq approach is high throughput from relatively small samples of tissue. The method described here is appropriate for processing an input of as few as 150,000 cells, with a final yield of as many as 5000 single-cell transcripts captured.


Assuntos
Microcefalia , Humanos , DNA Complementar/genética , RNA Mensageiro/genética , Análise de Célula Única , Sequenciamento Completo do Exoma
9.
Semin Cell Dev Biol ; 137: 87-95, 2023 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-35915025

RESUMO

Mutations causing dysfunction of tubulins and microtubule-associated proteins, also known as tubulinopathies, are a group of recently described entities that lead to complex brain malformations. Anatomical and functional consequences of the disruption of tubulins include microcephaly, combined with abnormal corticogenesis due to impaired migration or lamination and abnormal growth cone dynamics of projecting and callosal axons. Key imaging features of tubulinopathies are characterized by three major patterns of malformations of cortical development (MCD): lissencephaly, microlissencephaly, and dysgyria. Additional distinctive MRI features include dysmorphism of the basal ganglia, midline commissural structure hypoplasia or agenesis, and cerebellar and brainstem hypoplasia. Tubulinopathies can be diagnosed as early as 21-24 gestational weeks using imaging and neuropathology, with possible extreme microlissencephaly with an extremely thin cortex, lissencephaly with either thick or thin/intermediate cortex, and dysgyria combined with cerebellar hypoplasia, pons hypoplasia and corpus callosum dysgenesis. More than 100 MCD-associated mutations have been reported in TUBA1A, TUBB2B, or TUBB3 genes, whereas fewer than ten are known in other genes such TUBB2A, TUBB or TUBG1. Although these mutations are scattered along the α- and ß-tubulin sequences, recurrent mutations are consistently associated with almost identical cortical dysgenesis. Much of the evidence supports that these mutations alter the dynamic properties and functions of microtubules in several fashions. These include diminishing the abundance of functional tubulin heterodimers, altering GTP binding, altering longitudinal and lateral protofilament interactions, and impairing microtubule interactions with kinesin and/or dynein motors or with MAPs. In this review we discuss the recent advances in our understanding of the effects of mutations of tubulins and microtubule-associated proteins on human brain development and the pathogenesis of malformations of cortical development.


Assuntos
Lisencefalia , Microcefalia , Tubulina (Proteína) , Humanos , Deficiências do Desenvolvimento , Lisencefalia/genética , Lisencefalia/diagnóstico , Proteínas Associadas aos Microtúbulos , Mutação , Tubulina (Proteína)/genética
10.
Methods Mol Biol ; 2583: 149-156, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36418732

RESUMO

Diverse metabolic disorders can disrupt brain growth, and analyzing metabolism in animal models of microcephaly may reveal new mechanisms of pathogenesis. The metabolism of functioning cells in a living organism is constantly changing in response to a changing environment, circadian rhythms, consumed food, drugs, progressing sicknesses, aging, and many other factors. Metabolic profiling can give important insights into the working machinery of the cell. However, a frozen snapshot of the interconnected, complex network of reactions gives very limited information about this system. Flux analysis using stable isotope labels enables more robust metabolic studies that consider interrogate metabolite processing and changes in molecular concentrations over time.


Assuntos
Doenças Metabólicas , Microcefalia , Animais , Camundongos , Ritmo Circadiano/fisiologia , Isótopos , Doenças Metabólicas/diagnóstico , Metabolômica , Microcefalia/complicações
11.
Eur J Med Genet ; 65(12): 104659, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36334884

RESUMO

Pathogenic variants in CENPJ have been first identified in consanguineous Pakistani families with Hereditary Primary Microcephaly type 6 (MCPH6). In addition to primary microcephaly, the CENPJ-related phenotypic spectrum lately included also distinctive and peculiar 'bird-like' craniofacial dysmorphisms, intrauterine and/or postnatal growth retardation, and moderate to severe intellectual disability (ID). These features are also part of the clinical spectrum of Seckel syndrome (SCKL) a genetically heterogeneous neurodevelopmental condition caused by mutations in different genes involved in cell cycle progression. Among these, CENPJ is responsible for type 4 Seckel syndrome (SCKL4). The literature reports two individuals affected by SCKL4 suffering from seizures and other two individuals with other brain malformations in addition to microcephaly. However, neither epilepsy nor brain malformations are described in detail and genotype-phenotype information remains limited. We describe the first Caucasian affected with SCKL4 and harboring a novel, homozygous mutation in CENPJ. We detail the clinical and neuroradiological findings including structural focal epilepsy and a severe brain malformation (i.e., hydranencephaly) that was never associated with SCKL4 to date.


Assuntos
Nanismo , Hidranencefalia , Deficiência Intelectual , Microcefalia , Humanos , Microcefalia/genética , Microcefalia/patologia , Nanismo/genética , Facies , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Mutação , Proteínas Associadas aos Microtúbulos/genética
12.
Am J Med Genet A ; 188(12): 3432-3447, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36367278

RESUMO

Verheij syndrome (VRJS) is a rare craniofacial spliceosomopathy presenting with craniofacial dysmorphism, multiple congenital anomalies and variable neurodevelopmental delay. It is caused by single nucleotide variants (SNVs) in PUF60 or interstitial deletions of the 8q24.3 region. PUF60 encodes a splicing factor which forms part of the spliceosome. To date, 36 patients with a sole diagnosis of VRJS due to disease-causing PUF60 SNVs have been reported in peer-reviewed publications. Although the depth of their phenotyping has varied greatly, they exhibit marked phenotypic heterogeneity. We report 10 additional unrelated patients, including the first described patients of Khmer, Indian, and Vietnamese ethnicities, and the eldest patient to date, with 10 heterozygous PUF60 variants identified through exome sequencing, 8 previously unreported. All patients underwent deep phenotyping identifying variable dysmorphism, growth delay, neurodevelopmental delay, and multiple congenital anomalies, including several unique features. The eldest patient is the only reported individual with a germline variant and neither neurodevelopmental delay nor intellectual disability. In combining these detailed phenotypic data with that of previously reported patients (n = 46), we further refine the known frequencies of features associated with VRJS. These include neurodevelopmental delay/intellectual disability (98%), axial skeletal anomalies (74%), appendicular skeletal anomalies (73%), oral anomalies (68%), short stature (66%), cardiac anomalies (63%), brain malformations (48%), hearing loss (46%), microcephaly (41%), colobomata (38%), and other ocular anomalies (65%). This case series, incorporating three patients from previously unreported ethnic backgrounds, further delineates the broad pleiotropy and mutational spectrum of PUF60 pathogenic variants.


Assuntos
Anormalidades Múltiplas , Deficiência Intelectual , Microcefalia , Fatores de Processamento de RNA , Proteínas Repressoras , Humanos , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Microcefalia/diagnóstico , Microcefalia/genética , Fenótipo , Proteínas Repressoras/genética , Fatores de Processamento de RNA/genética , Spliceossomos/genética , Spliceossomos/patologia
13.
BMC Med Genomics ; 15(1): 236, 2022 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-36348459

RESUMO

BACKGROUND: The etiology of intellectual disabilities is diverse and includes both genetic and environmental factors. The genetic causes of intellectual disabilities range from chromosomal aberrations to single gene disorders. The TRAPPC9 gene has been reported to cause autosomal recessive forms of intellectual disabilities in 56 patients from consanguineous and non-consanguineous families around the world. METHODS: We analyzed two siblings with intellectual disability, microcephaly and delayed motor and speech development from a consanguineous Sudanese family. Genomic DNA was screened for mutations using NGS panel (NextSeq500 Illumina) testing 173 microcephaly associated genes in the Molecular Genetics service in Robert Debre hospital in Paris, France. RESULTS: A novel homozygous mutation (NM_031466.7 (TRAPPC9):c.2288dup, p. (Val764Glyfs*7) in exon 14 of TRAPPC9 gene was found in the two patients. The mutation was predicted to cause nonsense mediated decay (NSMD) using SIFT prediction tool. The variant has not been found in either gnomAD or Exac databases. Both parents were heterozygous (carriers) to the mutation. CONCLUSION: This is the first study to report patients with TRAPPC9-related disorder from Sub-Saharan Africa.


Assuntos
Deficiência Intelectual , Microcefalia , Humanos , Deficiência Intelectual/genética , Microcefalia/genética , Proteínas de Transporte/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mutação , Linhagem
14.
Nat Commun ; 13(1): 6664, 2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36333305

RESUMO

Embryonic development is dictated by tight regulation of DNA replication, cell division and differentiation. Mutations in DNA repair and replication genes disrupt this equilibrium, giving rise to neurodevelopmental disease characterized by microcephaly, short stature and chromosomal breakage. Here, we identify biallelic variants in two components of the RAD18-SLF1/2-SMC5/6 genome stability pathway, SLF2 and SMC5, in 11 patients with microcephaly, short stature, cardiac abnormalities and anemia. Patient-derived cells exhibit a unique chromosomal instability phenotype consisting of segmented and dicentric chromosomes with mosaic variegated hyperploidy. To signify the importance of these segmented chromosomes, we have named this disorder Atelís (meaning - incomplete) Syndrome. Analysis of Atelís Syndrome cells reveals elevated levels of replication stress, partly due to a reduced ability to replicate through G-quadruplex DNA structures, and also loss of sister chromatid cohesion. Together, these data strengthen the functional link between SLF2 and the SMC5/6 complex, highlighting a distinct role for this pathway in maintaining genome stability.


Assuntos
Proteínas de Ciclo Celular , Microcefalia , Humanos , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Microcefalia/genética , Reparo do DNA/genética , Cromossomos/metabolismo , Instabilidade Genômica , Proteínas de Ligação a DNA/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Cromossômicas não Histona/metabolismo
15.
Eur J Med Genet ; 65(12): 104653, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36330903

RESUMO

Adams-Oliver syndrome (AOS) is diagnosed in presence of aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD). The autosomal recessive (AR) DOCK6-related form of AOS is most often associated with a severe phenotype including also central nervous system and ocular abnormalities. We report a sister and brother with different expression of the phenotype. Both were compound heterozygous pathogenic variants in the DOCK6 gene, including a heterozygous c.5939+2T > C intronic variant that was maternally inherited, and a heterozygous deletion of exons 10 to 21 that was paternally inherited. The sister had microcephaly, periventricular calcifications, minor retinal vasculopathy, and mild impaired neurodevelopment, but only very subtle limb abnormalities and no ACC. Her brother showed a classical DOCK6-related AOS phenotype, including a severe bilateral peripheral ischemic retinopathy. From a review of 22 molecularly confirmed cases with DOCK6-related AOS with ophthalmic examination, we found that 16 of them had retinal vascular pathology (72.7%), confirming as the major ocular anomaly. Documented intrafamilial variability in our family and the evidence revised from previous reports, confirm that AR DOCK6-related AOS expressivity can produce a "milder" phenotype without ACC or TTLD, which could be underdiagnosed in simplex cases because it is difficult to recognize out of a familial context. Therefore, in order to know its real magnitude is required the future inclusion of DOCK6 gene in NGS panels directed to the study of simplex cases of patients with microcephaly, periventricular calcifications, retinal vasculopathy, and/or cardiovascular defects.


Assuntos
Displasia Ectodérmica , Deformidades Congênitas dos Membros , Microcefalia , Feminino , Humanos , Masculino , Variação Biológica da População , Displasia Ectodérmica/genética , Displasia Ectodérmica/diagnóstico , Fatores de Troca do Nucleotídeo Guanina/genética , Deformidades Congênitas dos Membros/genética , Deformidades Congênitas dos Membros/diagnóstico , Microcefalia/genética , Couro Cabeludo
16.
Seizure ; 103: 92-98, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36368189

RESUMO

OBJECTIVES: To verify characteristics associated with drug resistant epilepsy in children up to 36 months of age with Congenital Zika Syndrome (CZS). METHODS: This is a prospective cohort study with children aged up to 36 months diagnosed with CZS. Obstetric, demographic, phenotype and other clinical signs, cranial tomography, growth and motor development of the children were collected. RESULTS: Of a total of 109 children diagnosed with CZS, 100 (91.7%) had epilepsy and 68 (68%) with drug resistant seizures. The types of seizures associated with drug resistant epilepsy were focal seizures from the occipital lobe, generalized tonic and generalized tonic-clonic seizures. There was an association between drug resistant epilepsy and microcephaly at birth, severe microcephaly at birth, excess nuchal skin, ventriculomegaly, reduced brain parenchyma volume, and hypoplasia or malformation of the cerebellum. Difficulty sleeping, irritability, continuous crying, dysphagia and gross motor function were clinical signs associated with drug resistant epilepsy, as were the presence of ocular abnormalities, low head circumference in the first year of life and low weight in the first six months. CONCLUSIONS: The prevalence of drug resistant epilepsy in children up to 36 months with CZS was 62.4% and was associated with the severity of the child's neurological damage, with emphasis on the reduction of brain parenchyma volume and damage to the cerebellum.


Assuntos
Epilepsia Resistente a Medicamentos , Microcefalia , Malformações do Sistema Nervoso , Complicações Infecciosas na Gravidez , Infecção por Zika virus , Zika virus , Humanos , Gravidez , Feminino , Infecção por Zika virus/complicações , Infecção por Zika virus/epidemiologia , Microcefalia/diagnóstico por imagem , Microcefalia/epidemiologia , Epilepsia Resistente a Medicamentos/diagnóstico por imagem , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Epilepsia Resistente a Medicamentos/epidemiologia , Estudos Prospectivos , Complicações Infecciosas na Gravidez/epidemiologia , Malformações do Sistema Nervoso/complicações , Convulsões/complicações , Brasil/epidemiologia
17.
PLoS Biol ; 20(11): e3001856, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36318514

RESUMO

Feingold syndrome type 1, caused by loss-of-function of MYCN, is characterized by varied phenotypes including esophageal and duodenal atresia. However, no adequate model exists for studying the syndrome's pathological or molecular mechanisms, nor is there a treatment strategy. Here, we developed a zebrafish Feingold syndrome type 1 model with nonfunctional mycn, which had severe intestinal atresia. Single-cell RNA-seq identified a subcluster of intestinal cells that were highly sensitive to Mycn, and impaired cell proliferation decreased the overall number of intestinal cells in the mycn mutant fish. Bulk RNA-seq and metabolomic analysis showed that expression of ribosomal genes was down-regulated and that amino acid metabolism was abnormal. Northern blot and ribosomal profiling analysis showed abnormal rRNA processing and decreases in free 40S, 60S, and 80S ribosome particles, which led to impaired translation in the mutant. Besides, both Ribo-seq and western blot analysis showed that mTOR pathway was impaired in mycn mutant, and blocking mTOR pathway by rapamycin treatment can mimic the intestinal defect, and both L-leucine and Rheb, which can elevate translation via activating TOR pathway, could rescue the intestinal phenotype of mycn mutant. In summary, by this zebrafish Feingold syndrome type 1 model, we found that disturbance of ribosomal biogenesis and blockage of protein synthesis during development are primary causes of the intestinal defect in Feingold syndrome type 1. Importantly, our work suggests that leucine supplementation may be a feasible and easy treatment option for this disease.


Assuntos
Microcefalia , Peixe-Zebra , Animais , Proteína Proto-Oncogênica N-Myc , Peixe-Zebra/metabolismo , Microcefalia/genética , Serina-Treonina Quinases TOR/metabolismo , Leucina
18.
PLoS One ; 17(11): e0276931, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36318578

RESUMO

The effects of congenital Zika syndrome (CZS) on the tooth development of infected children are not well known. The aim of this study was to analyze the association of CZS with dental alterations in children with microcephaly seen at a referral hospital in Rio Grande do Norte, Brazil. The chronology and sequence of tooth eruption and the presence of dental alterations were evaluated by a single calibrated examiner (kappa > 0.80) in 62 children aged 7 to 35 months with microcephaly associated with CZS and other congenital infections. Medical data of the mother and child were collected from the records and the parents responded to a socioeconomic questionnaire. Descriptive analysis and Fisher's exact test were used (5% significance level). The mean age of the children was 26.4 months (SD = 7.52). The mean weight and head circumference at birth were 2,593 g (SD = 0.60) and 29.6 cm (SD = 2.48), respectively. Microcephaly was associated with congenital Zika virus infection in 79% of cases and with other congenital infections in 21%. No significant association was found between CZS and alterations in the chronology (p = 1.00) or sequence of tooth eruption (p = 0.16) or changes in enamel development (p = 1.00). In conclusion, children with microcephaly exhibit a delay and alterations in the sequence of tooth eruption of primary teeth, as well as developmental defects of enamel, which are not associated with Zika virus infection.


Assuntos
Microcefalia , Complicações Infecciosas na Gravidez , Anormalidades Dentárias , Infecção por Zika virus , Zika virus , Recém-Nascido , Criança , Feminino , Humanos , Pré-Escolar , Gravidez , Infecção por Zika virus/complicações , Brasil , Mães
19.
BMC Public Health ; 22(1): 2069, 2022 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-36371150

RESUMO

BACKGROUND: Congenital anomalies are associated with several clinical and epidemiological complications. Following the Zika epidemic onset in Latin America, the incidence of congenital anomalies increased in Brazil. This study aimed to determine the frequency of congenital anomalies in one Brazilian state and assess potential factors associated with them. METHODS: This cross-sectional descriptive study was based on data concerning congenital anomalies recorded in the Brazilian Live-Born Information System during the Zika epidemic in Mato Grosso do Sul state from 2015 to 2018. Congenital anomalies were stratified according to year of birth and classified using ICD-10 categories. RESULTS: In total, 1,473 (0.85%) anomalies were registered. Within the number of cases recorded, microcephaly showed the greatest frequency and variations, with a 420% increase observed in the number of cases from 2015 to 2016. We identified an increase in the incidence of central nervous system anomalies, with the highest peak observed in 2016 followed by a subsequent decrease. Musculoskeletal, nervous, and cardiovascular system anomalies, and eye, ear, face, and neck anomalies represented 73.9% of all recorded anomalies. There was an increased chance of congenital anomalies in uneducated (odds ratio [OR] 5.56, 95% confidence interval [CI] 2.61-11.84) and Indigenous (OR 1.32, 95% CI 1.03-1.69) women, as well as among premature births (OR 2.74, 95% CI 2.39-3.13). CONCLUSIONS: We estimated the incidence of congenital anomalies during the Zika epidemic. Our findings could help to support future research and intervention strategies in health facilities to better identify and assist children born with congenital anomalies.


Assuntos
Microcefalia , Complicações Infecciosas na Gravidez , Infecção por Zika virus , Zika virus , Gravidez , Criança , Feminino , Humanos , Estudos Transversais , Complicações Infecciosas na Gravidez/epidemiologia , Microcefalia/epidemiologia , Brasil/epidemiologia
20.
Rev. Ciênc. Plur ; 8(3): 24605, out. 2022. ilus, tab
Artigo em Português | LILACS, BBO - Odontologia | ID: biblio-1399020

RESUMO

Introdução: a importância diagnóstica do Zika vírus reside na capacidade de transmissão vertical e seu elevado potencial teratogênico, que tem resultado em anormalidades congênitas cerebrais. Dentre as anomalias congênitas em fetos advindas do contagio do vírus na gestação, a de maior destaque é a microcefalia, sugerindo assim uma nova síndrome congênita: Síndrome Congênita do Zika. Objetivo:gerar um debate sobre o enfrentamento dos desafios no cuidado a crianças com Síndrome Congênita do Zika dentro da Atenção Primária a Saúde no Brasil, sob luz dos pressupostos dos seus atributos essências e derivados. Metodologia:trata-se de um ensaio teórico e analítico, apresentado na forma de exposição reflexiva, foi realizado revisão da literatura da área que contou com busca nas bases eletrônicas de dados da Biblioteca Virtual em Saúde Pública; Biblioteca Virtual em Saúde, englobando as fontes de informação da LILACS, SCIELOe Google Acadêmico. Foram utilizados os descritores 'atenção primária a saúde' articulado à palavra-chave 'atributos' pelo operador booleano AND. Resultados:A Atenção Primária ainda enfrenta muitos desafios para que possa desempenhar seu papel de organizadora do sistema e coordenadora do cuidado em saúde para o público com Síndrome Congênita do Zika, porém destaca-se a abordagem que reconhece a importância da família com adoção do modelo da Classificação Internacional de Funcionalidade e Incapacidade em Saúde na orientaçãodos casos. Conclusão:O presente estudo permitiu dar início ao debate da importância da Atenção Primária à Saúde na condução do público acometido pela Síndrome Congênita do Zika a partir do ano de 2015 no Brasil, merecendo destaque a necessidade de tomadade decisão relativo à melhoria quanto ao posicionamento de responsabilização por este usuário, tanto por parte das equipes de saúde da família quanto pelos gestores (AU).


Introduction:the diagnostic importance of the Zika virus lies in its capacity for vertical transmission and its high teratogenic potential, which has resulted in congenital brain abnormalities. Among the congenital anomaliesin fetuses resulting from the contagion of the virus during pregnancy, the most prominent is microcephaly, thus suggesting a new congenital syndrome: Congenital Zika Syndrome. Objective:to generate a debate on facing the challenges in caring for childrenwith Congenital Zika Syndrome within Primary Health Care in Brazil, in the light of the assumptions of its essential and derived attributes. Methodology:this is a theoretical and analytical essay, presented in the form of a reflective exposition, a literature review was carried out in the area, which included a search in the electronic databases of the Virtual Public Health Library; Virtual Health Library, encompassing LILACS, SCIELOand Academic Googleinformation sources. The descriptors 'primary healthcare' articulated to the keyword 'attributes' by the Boolean operator AND were used. Results:The Primary Health Carestill faces many challenges so that it can play its role of organizer of the system and coordinator of health care for the public with Congenital Zika Syndrome, but the approach that recognizes the importance of the family with the adoption of the model of International Classification of Functioning and Disability in Health in case orientation. Conclusion:The present study allowed us to start the debate on the importance of Primary Health Care in guiding the public affected by the Congenital Zika Syndrome from the year 2015 in Brazil, highlighting the need for decision-making regarding the improvement of the positioning responsibility for this user, both by the family health teams and by the managers (AU).


Introducción:la importancia diagnóstica del virus Zika radica en su capacidad de transmisión vertical y su alto potencial teratogénico, lo que hayresultado en anomalías cerebrales congénitas. Entre las anomalías congénitas en fetos derivadas del contagio del virus durante el embarazo, la más destacada es la microcefalia, sugiriendo así un nuevo síndrome congénito: el Síndrome Congénito Zika. Objetivo:generar un debate sobre el enfrentamiento de los desafíos en el cuidado de niños con Síndrome Congénito de Zika en la Atención Primaria de Salud en Brasil, a la luz de los supuestos de sus atributos esenciales y derivados. Metodología:se trata de un ensayo teórico y analítico, presentado en forma de exposición reflexiva, se realizó una revisión bibliográfica en el área, que incluyó una búsqueda en las bases de datos electrónicas de la Biblioteca Virtual en Salud Pública; Biblioteca Virtual en Salud, confuentes de información LILACS, SCIELOy Google académico. Se utilizaron los descriptores 'atención primaria de salud' articulados a la palabra clave 'atributos' por el operador booleano AND. Resultados:La Atención Primaria de Saludaún enfrenta muchos desafíos para que pueda desempeñar su papel de organizador del sistema y coordinador de la atención a la salud de la población con Síndrome Congénito de Zika, pero el abordaje que reconoce la importancia de la familia con la adopción del modelo de Clasificación Internacional de Funcionamiento y Discapacidad en Salud en la orientación de casos. Conclusión:El presente estudio permitió iniciar el debate sobre la importancia de la Atención Primaria de Salud en la orientación del público afectado por el Síndrome Congénito de Zika a partir del año 2015 en Brasil, destacando la necesidad de la toma de decisiones sobre la mejora del posicionamiento de la responsabilidad por este usuario, tanto por los equipos de salud de la familia como por los gestores (AU).


Assuntos
Humanos , Atenção Primária à Saúde , Anormalidades Congênitas/patologia , Estratégias de Saúde Nacionais , Saúde da Família , Infecção por Zika virus/congênito , Saúde Pública , Microcefalia/diagnóstico
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