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1.
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
2.
Arch Gynecol Obstet ; 302(3): 619-628, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32556516

RESUMO

INTRODUCTION: Neural tube defects (NTDs) are a group of heterogeneous congenital anomalies of the central nervous system (CNS). Acrania is a non-NTD congenital disorder related to the CNS. It can transform into anencephaly through the acrania-exencephaly-anencephaly sequence (AEAS). In AEAS, the cerebral tissue is not protected and is gradually destroyed due to exposure to the harmful effect of amniotic fluid and mechanical injuries. These lead to exencephaly and then into anencephaly. In contrast to primary anencephaly (NTDs), this type of anencephaly authors suggests calling secondary anencephaly. OBJECTIVE: Analysis of the known prenatal ultrasonography (US) signs associated with AEAS. Simultaneously, the authors propose a new sign in the differentiation of acrania from exencephaly and anencephaly, called the "beret" sign. METHODS: It is a two-centre retrospective observational study. As part of the study, 4060 US scans were analyzed. RESULTS: In 10 cases, the absence of calvarium was diagnosed, allowing recognition of either AEAS stages or primary anencephaly. In 5 cases, cerebral structures were enclosed by an inertial rippled thin membrane, with a smooth outer contour. Between the described membrane and the brain structures, a thin anechoic space corresponding to cerebrospinal fluid was observed. This sign was defined as the "beret" sign. In these cases, acrania was diagnosed. In three cases calvarium was missing. The brain structures had an irregular appearance, did not wave and remained motionless. The outer contour was unequal as if divided into lobes. Amniotic fluid was anechoic. Exencephaly was diagnosed in these cases. In two cases calvarium, brain structures, and meninges were missing. The "frog eyes" sign and slightly echogenic amniotic fluid were visible. In this case, anencephaly was diagnosed. CONCLUSIONS: The "beret" sign seems to be a promising tool in the diagnosis of acrania. Furthermore, echogenicity of amniotic fluid could be useful during differentiation between primary and secondary anencephaly.


Assuntos
Anencefalia/diagnóstico por imagem , Defeitos do Tubo Neural/diagnóstico por imagem , Crânio , Ultrassonografia Pré-Natal/métodos , Líquido Amniótico , Anencefalia/complicações , Anencefalia/diagnóstico , Biomarcadores , Encéfalo/anormalidades , Feminino , Humanos , Recém-Nascido , Defeitos do Tubo Neural/complicações , Gravidez , Estudos Retrospectivos , Crânio/anormalidades , Crânio/diagnóstico por imagem , Ultrassonografia
3.
Radiol Clin North Am ; 58(3): 463-474, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32276697

RESUMO

Congenital brain malformations comprise a spectrum of disorders that result from a variety of causes, including genetic abnormalities, ischemia, infections, and toxic exposures. Although most cases are discovered in infancy or childhood, clinically occult abnormalities may prove to be confounding, especially if first encountered later in life on imaging examinations obtained for other indications or in the context of superimposed pathology. This review article provides an overview of congenital brain malformations because they may be encountered at all ages for general radiologists.


Assuntos
Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Diagnóstico por Imagem/métodos , Adulto , Humanos , Lactente
4.
Am J Hum Genet ; 106(5): 623-631, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32275884

RESUMO

Nucleoporins (NUPs) are an essential component of the nuclear-pore complex, which regulates nucleocytoplasmic transport of macromolecules. Pathogenic variants in NUP genes have been linked to several inherited human diseases, including a number with progressive neurological degeneration. We present six affected individuals with bi-allelic truncating variants in NUP188 and strikingly similar phenotypes and clinical courses, representing a recognizable genetic syndrome; the individuals are from four unrelated families. Key clinical features include congenital cataracts, hypotonia, prenatal-onset ventriculomegaly, white-matter abnormalities, hypoplastic corpus callosum, congenital heart defects, and central hypoventilation. Characteristic dysmorphic features include small palpebral fissures, a wide nasal bridge and nose, micrognathia, and digital anomalies. All affected individuals died as a result of respiratory failure, and five of them died within the first year of life. Nuclear import of proteins was decreased in affected individuals' fibroblasts, supporting a possible disease mechanism. CRISPR-mediated knockout of NUP188 in Drosophila revealed motor deficits and seizure susceptibility, partially recapitulating the neurological phenotype seen in affected individuals. Removal of NUP188 also resulted in aberrant dendrite tiling, suggesting a potential role of NUP188 in dendritic development. Two of the NUP188 pathogenic variants are enriched in the Ashkenazi Jewish population in gnomAD, a finding we confirmed with a separate targeted population screen of an international sampling of 3,225 healthy Ashkenazi Jewish individuals. Taken together, our results implicate bi-allelic loss-of-function NUP188 variants in a recessive syndrome characterized by a distinct neurologic, ophthalmologic, and facial phenotype.


Assuntos
Alelos , Encéfalo/anormalidades , Proteínas de Drosophila/genética , Anormalidades do Olho/genética , Cardiopatias Congênitas/genética , Mutação com Perda de Função/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Transporte Ativo do Núcleo Celular , Animais , Núcleo Celular/metabolismo , Pré-Escolar , Dendritos/metabolismo , Dendritos/patologia , Drosophila melanogaster , Anormalidades do Olho/mortalidade , Feminino , Fibroblastos , Genes Recessivos , Cardiopatias Congênitas/mortalidade , Humanos , Lactente , Recém-Nascido , Judeus/genética , Masculino , Complexo de Proteínas Formadoras de Poros Nucleares/deficiência , Convulsões/metabolismo , Síndrome , beta Carioferinas/metabolismo
5.
World Neurosurg ; 139: 286-288, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32247796

RESUMO

BACKGROUND: Intracranial fetus in fetu is an extremely rare entity in which a discrete vertebrate fetiform mass is found inside a diamniotic, monochorionic twin. It is a benign mass and can manifest with symptoms owing to mass effect. To establish the diagnosis, a vertebra must be present within the mass. CASE DESCRIPTION: A 5-year-old child presented at a multispecialty hospital with gradual weakness of both lower limbs. Magnetic resonance imaging of the brain revealed a midline intraventricular mass with lobulated margins having both cystic and fatty components with areas of blooming within. A provisional diagnosis of teratoma/primitive neuroectodermal tumor was made. The patient subsequently presented to our hospital with drowsiness and vomiting for 1 day. Noncontrast computed tomography revealed a mass of heterogeneous density occupying the third ventricle. The mass contained a few well-formed long bones representative of the appendicular skeleton and a vertebra-like bone representative of the axial skeleton, fulfilling the Willis criteria. A biopsy sample was taken from the mass; no malignant cells were seen on histopathologic examination. Based on noncontrast computed tomography findings of well-formed long bones and a vertebra and no significant increase in the size of the mass over 2 years, an intracranial fetus in fetu was diagnosed. CONCLUSIONS: Whenever bony structures are identified in an intracranial mass in a pediatric patient, we should always look for bones of the axial skeleton, as this finding will point toward a diagnosis of intracranial fetus in fetu and will help in differentiating it from teratoma, which can have malignant transformation.


Assuntos
Encéfalo/anormalidades , Feto/anormalidades , Pré-Escolar , Humanos , Masculino , Gêmeos Monozigóticos
6.
J Headache Pain ; 21(1): 39, 2020 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-32334532

RESUMO

BACKGROUND: Migraine is a common neurological disorder characterized by a complex physiopathology. We assessed brain morphologic differences in migraine and the possible pathogenetic mechanism underlying this disease. METHODS: We analyzed brain morphologic images of migraine patients, 14 with aura (MwA) [the mean (SD) age was 42.36 (2.95) years (range, 37-47)] and 14 without aura (MwoA) [the mean (SD) age was 43.5 (3.25) years (range, 39-50)] during episodic attack compared with health subjects balanced (HS) [the mean (SD) age was 42.5 (5.17) years (range, 34-51)]. All subjects underwent a Magnetic Resonance Imaging (MRI) examination with a scanner operating at 3.0 T and voxel based morphometry (VBM) approach was used to examine the gray matter volume (GMV). The statistical analysis to compare clinicl characteristics was performed using unpaired t-test an one-way Anova. RESULTS: Total cerebral GMV showed a significant difference between MwA and HS (p = 0.02), and between MwoA and HS (p = 0.003). In addition, not significative differences were found between MwA and MwoA groups (p = 0.17). We found three clusters of regions which showed significant GMV reduction in MwA compared with MwoA. MwA subjects showed a less of GMV in 4 clusters if compared with HS, and MwoA subjects showed a less of GMV in 3 clusters if compared with HS. We observed that MwA and MwoA patients had a significant reduction of GMV in the frontal and temporal lobe and the cerebellum, if compared to HS. The bilateral fusiform gyrus and the cingulate gyrus were increase in MwoA patients compared with HS. CONCLUSION: Our findings could provide a approach to understand possible differences in the pathogenesis of two type of migraine.


Assuntos
Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Enxaqueca com Aura/diagnóstico por imagem , Adulto , Cerebelo/anormalidades , Cerebelo/diagnóstico por imagem , Feminino , Substância Cinzenta/anormalidades , Substância Cinzenta/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade
7.
PLoS One ; 15(3): e0230534, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32196525

RESUMO

Dermatoglyphic patterns on the fingers often differ in syndromes and other conditions with a developmental component, compared to the general population. Previous literature on the relationship between orofacial clefts-the most common craniofacial birth defect in humans-and dermatoglyphics is inconsistent, with some studies reporting altered pattern frequencies and/or increased asymmetry and others failing to find differences. To investigate dermatoglyphics in orofacial clefting, we obtained dermatoglyphic patterns in a large multiethnic cohort of orofacial cleft cases (N = 367), their unaffected family members (N = 836), and controls (N = 299). We categorized fingerprint pattern types from males and females who participated at five sites of the Pittsburgh Orofacial Cleft study (Hungary, United States of America (Pennsylvania, Texas), Spain, and Argentina). We also calculated a pattern dissimilarity score for each individual as a measure of left-right asymmetry. We tested for group differences in the number of arches, ulnar and radial loops, and whorls on each individual's hands, and in the pattern dissimilarity scores using ANOVA. After taking sex and site differences into account, we did not find any significant pattern count differences between cleft and non-cleft individuals. Notably, we did observe increased pattern dissimilarity in individuals with clefts, compared to both their unaffected relatives and controls. Increased dermatoglyphic pattern dissimilarity in individuals with nonsyndromic orofacial clefts may reflect a generalized developmental instability.


Assuntos
Encéfalo/anormalidades , Fenda Labial/diagnóstico , Fissura Palatina/diagnóstico , Dermatoglifia , Análise de Variância , Fenda Labial/genética , Fissura Palatina/genética , Estudos de Coortes , Família , Feminino , Humanos , Masculino , Fenótipo , Fatores Sexuais
8.
Sci Adv ; 6(4): eaax0021, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32010779

RESUMO

Lysine acetyltransferase 6A (KAT6A) and its paralog KAT6B form stoichiometric complexes with bromodomain- and PHD finger-containing protein 1 (BRPF1) for acetylation of histone H3 at lysine 23 (H3K23). We report that these complexes also catalyze H3K23 propionylation in vitro and in vivo. Immunofluorescence microscopy and ATAC-See revealed the association of this modification with active chromatin. Brpf1 deletion obliterates the acylation in mouse embryos and fibroblasts. Moreover, we identify BRPF1 variants in 12 previously unidentified cases of syndromic intellectual disability and demonstrate that these cases and known BRPF1 variants impair H3K23 propionylation. Cardiac anomalies are present in a subset of the cases. H3K23 acylation is also impaired by cancer-derived somatic BRPF1 mutations. Valproate, vorinostat, propionate and butyrate promote H3K23 acylation. These results reveal the dual functionality of BRPF1-KAT6 complexes, shed light on mechanisms underlying related developmental disorders and various cancers, and suggest mutation-based therapy for medical conditions with deficient histone acylation.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Ligação a DNA/metabolismo , Histona Acetiltransferases/metabolismo , Histonas/metabolismo , Neoplasias/etiologia , Neoplasias/metabolismo , Transtornos do Neurodesenvolvimento/etiologia , Transtornos do Neurodesenvolvimento/metabolismo , Acetilação , Proteínas Adaptadoras de Transdução de Sinal/genética , Sequência de Aminoácidos , Animais , Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Linhagem Celular , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Suscetibilidade a Doenças , Predisposição Genética para Doença , Histona Acetiltransferases/genética , Humanos , Imagem por Ressonância Magnética , Camundongos , Camundongos Knockout , Modelos Biológicos , Complexos Multiproteicos/metabolismo , Mutação , Neoplasias/diagnóstico , Transtornos do Neurodesenvolvimento/diagnóstico , Fenótipo , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Processamento de Proteína Pós-Traducional , Síndrome
10.
Am J Obstet Gynecol ; 222(6): 610.e1-610.e13, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31954155

RESUMO

BACKGROUND: Zika virus infection during pregnancy can cause serious birth defects, which include brain and eye abnormalities. The clinical importance of detection of Zika virus RNA in amniotic fluid is unknown. OBJECTIVE: The purpose of this study was to describe patterns of Zika virus RNA testing of amniotic fluid relative to other clinical specimens and to examine the association between Zika virus detection in amniotic fluid and Zika-associated birth defects. Our null hypothesis was that Zika virus detection in amniotic fluid was not associated with Zika-associated birth defects. STUDY DESIGN: We conducted a retrospective cohort analysis of women with amniotic fluid specimens submitted to Colombia's National Institute of Health as part of national Zika virus surveillance from January 2016 to January 2017. Specimens (maternal serum, amniotic fluid, cord blood, umbilical cord tissue, and placental tissue) were tested for the presence of Zika virus RNA with the use of a singleplex or multiplex real-time reverse transcriptase-polymerase chain reaction assay. Birth defect information was abstracted from maternal prenatal and infant birth records and reviewed by expert clinicians. Chi-square and Fisher's exact tests were used to compare the frequency of Zika-associated birth defects (defined as brain abnormalities [with or without microcephaly, but excluding neural tube defects and their associated findings] or eye abnormalities) by frequency of detection of Zika virus RNA in amniotic fluid. RESULTS: Our analysis included 128 women with amniotic fluid specimens. Seventy-five women (58%) had prenatally collected amniotic fluid; 42 women (33%) had amniotic fluid collected at delivery, and 11 women (9%) had missing collection dates. Ninety-one women had both amniotic fluid and other clinical specimens submitted for testing, which allowed for comparison across specimen types. Of those 91 women, 68 had evidence of Zika virus infection based on detection of Zika virus RNA in ≥1 specimen. Testing of amniotic fluid that was collected prenatally or at delivery identified 39 of these Zika virus infections (57%; 15 [22%] infections were identified only in amniotic fluid), and 29 infections (43%) were identified in other specimen types and not amniotic fluid. Among women who were included in the analysis, 89 had pregnancy outcome information available, which allowed for the assessment of the presence of Zika-associated birth defects. Zika-associated birth defects were significantly (P<.05) more common among pregnancies with Zika virus RNA detected in amniotic fluid specimens collected prenatally (19/32 specimens; 59%) than for those with no laboratory evidence of Zika virus infection in any specimen (6/23 specimens; 26%), but the proportion was similar in pregnancies with only Zika virus RNA detected in specimens other than amniotic fluid (10/23 specimens; 43%). Although Zika-associated birth defects were more common among women with any Zika virus RNA detected in amniotic fluid specimens (ie, collected prenatally or at delivery; 21/43 specimens; 49%) than those with no laboratory evidence of Zika virus infection (6/23 specimens; 26%), this comparison did not reach statistical significance (P=.07). CONCLUSION: Testing of amniotic fluid provided additional evidence for maternal diagnosis of Zika virus infection. Zika-associated birth defects were more common among women with Zika virus RNA that was detected in prenatal amniotic fluid specimens than women with no laboratory evidence of Zika virus infection, but similar to women with Zika virus RNA detected in other, nonamniotic fluid specimen types.


Assuntos
Líquido Amniótico/virologia , Encéfalo/anormalidades , Anormalidades do Olho/epidemiologia , Microcefalia/epidemiologia , Complicações Infecciosas na Gravidez/metabolismo , RNA Viral/metabolismo , Infecção por Zika virus/metabolismo , Zika virus/genética , Adulto , Líquido Amniótico/metabolismo , Estudos de Coortes , Colômbia/epidemiologia , Feminino , Sangue Fetal/metabolismo , Sangue Fetal/virologia , Humanos , Recém-Nascido , Malformações do Sistema Nervoso/epidemiologia , Placenta/metabolismo , Placenta/virologia , Gravidez , Complicações Infecciosas na Gravidez/epidemiologia , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Cordão Umbilical/metabolismo , Cordão Umbilical/virologia , Adulto Jovem , Infecção por Zika virus/epidemiologia
11.
Clin Exp Rheumatol ; 38(2): 366-369, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31994478

RESUMO

OBJECTIVES: Chronic non-bacterial osteomyelitis (CNO) is a non-infectious inflammatory disease characterised by uni- or multi-focal bone lytic lesions. CNO mainly affects metaphysis of long bones, pelvis and shoulder girdle. Neurocranium lesions are extremely rare. The objective of the study is to describe the prevalence and clinical manifestations of CNO patients with neurocranium involvement in an Italian cohort of CNO patients. METHODS: This is a retrospective study. Medical records of patients with CNO admitted to eight paediatric rheumatology centres were reviewed. RESULTS: Among 86 patients with CNO enrolled in the study, three of them were female and presented neurocranium involvement - multifocal lesions. Two out of the 3 patients were completely asymptomatic for cranial involvement, while one of the 3 complained of cranial bossing. Cranial involvement was detected with bone scintigraphy and then confirmed by magnetic resonance imaging and/or computed tomography. Two patients presented fever and two with skin manifestations. Laboratory inflammatory markers were increased in two of them. All patients underwent bone biopsy confirming the diagnosis. They all received NSAIDs. Two patients received corticosteroids and then methotrexate and achieved clinical remission, while one patient received pamidronate. CONCLUSIONS: This is the first report of neurocranium involvement in a cohort of patients affected by CNO. In our cohort no patient showed significant signs attributable to cranial involvement.


Assuntos
Encéfalo/anormalidades , Osteomielite , Crânio/anormalidades , Cefalometria , Criança , Doença Crônica , Estudos de Coortes , Feminino , Humanos , Itália , Masculino , Osteomielite/complicações , Prevalência , Estudos Retrospectivos
12.
Sci Adv ; 6(2): eaax9852, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31950080

RESUMO

Holoprosencephaly (HPE) is a congenital forebrain defect often associated with embryonic lethality and lifelong disabilities. Currently, therapeutic and diagnostic options are limited by lack of knowledge of potential disease-causing mutations. We have identified a new mutation in the PRDM15 gene (C844Y) associated with a syndromic form of HPE in multiple families. We demonstrate that C844Y is a loss-of-function mutation impairing PRDM15 transcriptional activity. Genetic deletion of murine Prdm15 causes anterior/posterior (A/P) patterning defects and recapitulates the brain malformations observed in patients. Mechanistically, PRDM15 regulates the transcription of key effectors of the NOTCH and WNT/PCP pathways to preserve early midline structures in the developing embryo. Analysis of a large cohort of patients with HPE revealed potentially damaging mutations in several regulators of both pathways. Our findings uncover an unexpected link between NOTCH and WNT/PCP signaling and A/P patterning and set the stage for the identification of new HPE candidate genes.


Assuntos
Polaridade Celular , Proteínas de Ligação a DNA/genética , Holoprosencefalia/genética , Mutação com Perda de Função/genética , Receptores Notch/metabolismo , Fatores de Transcrição/genética , Via de Sinalização Wnt , Animais , Padronização Corporal/genética , Encéfalo/anormalidades , Encéfalo/embriologia , Polaridade Celular/genética , Estudos de Coortes , Embrião de Mamíferos/anormalidades , Embrião de Mamíferos/metabolismo , Feminino , Deleção de Genes , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Camundongos , Placa Neural/metabolismo , Gravidez , Transcrição Genética , Dedos de Zinco
13.
J Craniofac Surg ; 31(1): 113-116, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31821209

RESUMO

BACKGROUND: Nonsyndromic orofacial clefts (NSOFCs) represent the most common congenital anomalies in the head and neck region. Multiple factors contribute to the occurrence of this anomaly. The etiology of NSOFCs in the Ethiopian population has not been investigated prior to this study. AIMS OF THE STUDY: To assess the role of maternal environmental factors in the occurrence of NSOFCs in the Ethiopian Population. METHODS: The authors used unmatched case control study design and evaluated the role of environmental factors to the occurrence of NSOFCs in the Ethiopian population. The participants were recruited from the same institution (Yekatit 12 Hospital Medical College). The authors studied 760 mothers (359 mothers of children born with NSOFCs and 401 mothers of children born without any congenital anomalies). Univariate and multivariate logistic regression analyses were used to calculate relative risk by odds ratio and 95% confidence interval. RESULTS: Mothers who gave history of bronchial asthma and mothers who were admitted for threatened abortion had a higher risk of delivering a child with NSOFCS P value=0.013; AOR=0.194, 95% CI [0.053-0.712], P value <0.001; AOR= 0.179, 95% CI [0.091-0.352] respectively. Higher number of children with NSOFCs were born to mothers who were exposed to diagnostic X-ray investigation during early pregnancy than those who were not exposed P value 0.048; AOR=0.375, 95% CI [0.142-0.990]. CONCLUSION: Maternal exposure to diagnostic x-ray, maternal chronic illness like bronchial asthma and threatened abortion were found to be associated with the occurrence of NSOFCS in the studied population.


Assuntos
Encéfalo/anormalidades , Fenda Labial/etiologia , Fissura Palatina/etiologia , Estudos de Casos e Controles , Pré-Escolar , Feminino , Humanos , Lactente , Exposição Materna , Mães , Gravidez , Fatores de Risco
14.
Am J Hum Genet ; 105(6): 1126-1147, 2019 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-31735293

RESUMO

The redox state of the neural progenitors regulates physiological processes such as neuronal differentiation and dendritic and axonal growth. The relevance of endoplasmic reticulum (ER)-associated oxidoreductases in these processes is largely unexplored. We describe a severe neurological disorder caused by bi-allelic loss-of-function variants in thioredoxin (TRX)-related transmembrane-2 (TMX2); these variants were detected by exome sequencing in 14 affected individuals from ten unrelated families presenting with congenital microcephaly, cortical polymicrogyria, and other migration disorders. TMX2 encodes one of the five TMX proteins of the protein disulfide isomerase family, hitherto not linked to human developmental brain disease. Our mechanistic studies on protein function show that TMX2 localizes to the ER mitochondria-associated membranes (MAMs), is involved in posttranslational modification and protein folding, and undergoes physical interaction with the MAM-associated and ER folding chaperone calnexin and ER calcium pump SERCA2. These interactions are functionally relevant because TMX2-deficient fibroblasts show decreased mitochondrial respiratory reserve capacity and compensatory increased glycolytic activity. Intriguingly, under basal conditions TMX2 occurs in both reduced and oxidized monomeric form, while it forms a stable dimer under treatment with hydrogen peroxide, recently recognized as a signaling molecule in neural morphogenesis and axonal pathfinding. Exogenous expression of the pathogenic TMX2 variants or of variants with an in vitro mutagenized TRX domain induces a constitutive TMX2 polymerization, mimicking an increased oxidative state. Altogether these data uncover TMX2 as a sensor in the MAM-regulated redox signaling pathway and identify it as a key adaptive regulator of neuronal proliferation, migration, and organization in the developing brain.


Assuntos
Encefalopatias/patologia , Encéfalo/anormalidades , Deficiências do Desenvolvimento/patologia , Proteínas de Membrana/metabolismo , Mitocôndrias/metabolismo , Tiorredoxinas/metabolismo , Adolescente , Adulto , Encefalopatias/genética , Encefalopatias/metabolismo , Criança , Pré-Escolar , Estudos de Coortes , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/metabolismo , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Proteínas de Membrana/genética , Mitocôndrias/patologia , Oxirredução , Prognóstico , Pele/metabolismo , Pele/patologia , Tiorredoxinas/genética , Transcriptoma
15.
PLoS Genet ; 15(10): e1008357, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31609978

RESUMO

Nonsyndromic orofacial cleft (NSOFC) is a severe birth defect that occurs early in embryonic development and includes the subtypes cleft palate only (CPO), cleft lip only (CLO) and cleft lip with cleft palate (CLP). Given a lack of specific genetic factor analysis for CPO and CLO, the present study aimed to dissect the landscape of genetic factors underlying the pathogenesis of these two subtypes using 6,986 cases and 10,165 controls. By combining a genome-wide association study (GWAS) for specific subtypes of CPO and CLO, as well as functional gene network and ontology pathway analysis, we identified 18 genes/loci that surpassed genome-wide significance (P < 5 × 10-8) responsible for NSOFC, including nine for CPO, seven for CLO, two for both conditions and four that contribute to the CLP subtype. Among these 18 genes/loci, 14 are novel and identified in this study and 12 contain developmental transcription factors (TFs), suggesting that TFs are the key factors for the pathogenesis of NSOFC subtypes. Interestingly, we observed an opposite effect of the genetic variants in the IRF6 gene for CPO and CLO. Moreover, the gene expression dosage effect of IRF6 with two different alleles at the same single-nucleotide polymorphism (SNP) plays important roles in driving CPO or CLO. In addition, PAX9 is a key TF for CPO. Our findings define subtypes of NSOFC using genetic factors and their functional ontologies and provide a clue to improve their diagnosis and treatment in the future.


Assuntos
Encéfalo/anormalidades , Fenda Labial/genética , Fissura Palatina/genética , Fatores Reguladores de Interferon/genética , Fator de Transcrição PAX9/genética , Alelos , Encéfalo/fisiopatologia , Fenda Labial/fisiopatologia , Fissura Palatina/fisiopatologia , Dosagem de Genes/genética , Regulação da Expressão Gênica/genética , Redes Reguladoras de Genes/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único/genética
16.
Neurology ; 93(14): e1360-e1373, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31484711

RESUMO

OBJECTIVE: To better evaluate the imaging spectrum of subcortical heterotopic gray matter brain malformations (subcortical heterotopia [SUBH]), we systematically reviewed neuroimaging and clinical data of 107 affected individuals. METHODS: SUBH is defined as heterotopic gray matter, located within the white matter between the cortex and lateral ventricles. Four large brain malformation databases were searched for individuals with these malformations; data on imaging, clinical outcomes, and results of molecular testing were systematically reviewed and integrated with all previously published subtypes to create a single classification system. RESULTS: Review of the databases revealed 107 patients with SUBH, the large majority scanned during childhood (84%), including more than half before 4 years (59%). Although most individuals had cognitive or motor disability, 19% had normal development. Epilepsy was documented in 69%. Additional brain malformations were common and included abnormalities of the corpus callosum (65/102 [64%]), and, often, brainstem or cerebellum (47/106 [44%]). Extent of the heterotopic gray matter brain malformations (unilateral or bilateral) did not influence the presence or age at onset of seizures. Although genetic testing was not systematically performed in this group, the sporadic occurrence and frequent asymmetry suggests either postzygotic mutations or prenatal disruptive events. Several rare, bilateral forms are caused by mutations in genes associated with cell proliferation and polarity (EML1, TUBB, KATNB1, CENPJ, GPSM2). CONCLUSION: This study reveals a broad clinical and imaging spectrum of heterotopic malformations and provides a framework for their classification.


Assuntos
Encefalopatias/classificação , Encefalopatias/diagnóstico por imagem , Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Substância Cinzenta/anormalidades , Substância Cinzenta/diagnóstico por imagem , Adolescente , Adulto , Encefalopatias/etiologia , Criança , Pré-Escolar , Bases de Dados Factuais/classificação , Bases de Dados Factuais/tendências , Feminino , Humanos , Lactente , Recém-Nascido , Imagem por Ressonância Magnética/classificação , Masculino , Adulto Jovem
17.
PLoS Negl Trop Dis ; 13(9): e0007721, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31545803

RESUMO

This study aimed to assess the impact of the Zika epidemic on the registration of birth defects in Brazil. We used an interrupted time series analysis design to identify changes in the trends in the registration of congenital anomalies. We obtained monthly data from Brazilian Live Birth Information System and used two outcome definitions: 1) rate of congenital malformation of the brain and eye (likely to be affected by Zika and its complications) 2) rate of congenital malformation not related to the brain or eye unlikely to be causally affected by Zika. The period between maternal infection with Zika and diagnosis of congenital abnormality attributable to the infection is around six months. We therefore used September 2015 as the interruption point in the time series, six months following March 2015 when cases of Zika started to increase. For the purposes of this analysis, we considered the period from January 2010 to September 2015 to be "pre-Zika event," and the period from just after September 2015 to December 2017 to be "post-Zika event." We found that immediately after the interruption point, there was a great increase in the notification rate of congenital anomalies of 14.9/10,000 live births in the brain and eye group and of 5.2/10,000 live births in the group not related with brain or eye malformations. This increase in reporting was in all regions of the country (except in the South) and especially in the Northeast. In the period "post-Zika event", unlike the brain and eye group which showed a monthly decrease, the group without brain or eye malformations showed a slow but significant increase (relative to the pre-Zika trend) of 0.2/10,000 live births. These findings suggest an overall improvement in the registration of birth malformations, including malformations that were not attributed to Zika, during and after the Zika epidemic.


Assuntos
Anormalidades Congênitas/epidemiologia , Sistema de Registros/normas , Infecção por Zika virus/complicações , Encéfalo/anormalidades , Brasil/epidemiologia , Anormalidades Congênitas/virologia , Coleta de Dados/normas , Epidemias/estatística & dados numéricos , Anormalidades do Olho/epidemiologia , Feminino , Humanos , Análise de Séries Temporais Interrompida , Gravidez , Complicações Infecciosas na Gravidez/epidemiologia , Complicações Infecciosas na Gravidez/virologia , Zika virus , Infecção por Zika virus/epidemiologia
19.
J Med Eng Technol ; 43(5): 279-286, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31502902

RESUMO

This paper presents an advanced approach for foetal brain abnormalities diagnostic by integrating significant biometric features in the identification process. In foetal anomaly diagnosis, manual evaluation of foetal behaviour in ultrasound images is a subjective, slow and error-prone task, especially in the preliminary treatment phases. The effectiveness of this appearance is strictly subject to the attention and the experience of gynaecologists. In this case, automatic methods of image analysis offer the possibility of obtaining a homogeneous, objective and above all fast diagnosis of the foetal head in order to identify pregnancy behaviour. Indeed, we propose a computerised diagnostic method based on morphological characteristics and a supervised classification method to categorise subjects into two groups: normal and affected cases. The presented method is validated on a real integrated microcephaly and dolichocephaly cases. The studied database contains the same gestational age of both normal and abnormal foetuses. The results show that the use of a support vector machine (SVM) classifier is an effective way to enhance recognition and detection for rapid and accurate foetal head diagnostic.


Assuntos
Encéfalo/anormalidades , Cabeça/diagnóstico por imagem , Processamento de Imagem Assistida por Computador , Diagnóstico Pré-Natal , Máquina de Vetores de Suporte , Biometria , Bases de Dados Factuais , Feto , Idade Gestacional , Humanos , Ultrassonografia
20.
Hum Mol Genet ; 28(20): 3391-3405, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31363758

RESUMO

Reversible detyrosination of tubulin, the building block of microtubules, is crucial for neuronal physiology. Enzymes responsible for detyrosination were recently identified as complexes of vasohibins (VASHs) one or two with small VASH-binding protein (SVBP). Here we report three consanguineous families, each containing multiple individuals with biallelic inactivation of SVBP caused by truncating variants (p.Q28* and p.K13Nfs*18). Affected individuals show brain abnormalities with microcephaly, intellectual disability and delayed gross motor and speech development. Immunoblot testing in cells with pathogenic SVBP variants demonstrated that the encoded proteins were unstable and non-functional, resulting in a complete loss of VASH detyrosination activity. Svbp knockout mice exhibit drastic accumulation of tyrosinated tubulin and a reduction of detyrosinated tubulin in brain tissue. Similar alterations in tubulin tyrosination levels were observed in cultured neurons and associated with defects in axonal differentiation and architecture. Morphological analysis of the Svbp knockout mouse brains by anatomical magnetic resonance imaging showed a broad impact of SVBP loss, with a 7% brain volume decrease, numerous structural defects and a 30% reduction of some white matter tracts. Svbp knockout mice display behavioural defects, including mild hyperactivity, lower anxiety and impaired social behaviour. They do not, however, show prominent memory defects. Thus, SVBP-deficient mice recapitulate several features observed in human patients. Altogether, our data demonstrate that deleterious variants in SVBP cause this neurodevelopmental pathology, by leading to a major change in brain tubulin tyrosination and alteration of microtubule dynamics and neuron physiology.


Assuntos
Encéfalo/anormalidades , Encéfalo/metabolismo , Proteínas de Ciclo Celular/metabolismo , Neurônios/metabolismo , Tubulina (Proteína)/metabolismo , Animais , Proteínas de Transporte/metabolismo , Disfunção Cognitiva/genética , Disfunção Cognitiva/metabolismo , Feminino , Humanos , Immunoblotting , Imagem por Ressonância Magnética , Camundongos , Microcefalia/genética , Microcefalia/metabolismo , Tirosina/metabolismo
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