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PloS One 2019Microcephaly and Zika Virus infection (ZIKV) were declared Public Health Emergencies of International Concern by the World Health Organization in 2016. Brazil was...
Microcephaly and Zika Virus infection (ZIKV) were declared Public Health Emergencies of International Concern by the World Health Organization in 2016. Brazil was considered the epicenter of the outbreak. However, the occurrence of both ZIKV and microcephaly in Brazil was not evenly distributed across the country. To better understand this phenomenon, we investigate regional characteristics at the municipal level that can be associated with the incidence of microcephaly, our response variable, and its relationship with ZIKV and other predictors. All epidemiological data in this study was provided by the Ministry of Health official database (DATASUS). Microcephaly was only confirmed after birth and the diagnostic was made regardless of the mother's ZIKV status. Using exploratory spatial data analysis and spatial autoregressive Tobit models, our results show that microcephaly incidence is significantly, at 95% confidence level, related not only to ZIKV, but also to access to primary care, population size, gross national product, mobility and environmental attributes of the municipalities. There is also a significant spatial autocorrelation of the dependent variable. The results indicate that municipalities that show a high incidence of microcephaly tend to be clustered in space and that incidence of microcephaly varies considerably across regions when correlated only with ZIKV, i.e. that ZIKV alone cannot explain the differences in microcephaly across regions and their correlation is mediated by regional attributes.
Topics: Brazil; Disease Outbreaks; Female; Humans; Infant, Newborn; Male; Microcephaly; Models, Statistical; Spatial Analysis; Zika Virus Infection
PubMed: 31557165
DOI: 10.1371/journal.pone.0222668 -
Development (Cambridge, England) Mar 2017Technologies to differentiate human pluripotent stem cells into three-dimensional organized structures that resemble organs are pushing the frontiers of human disease... (Review)
Review
Technologies to differentiate human pluripotent stem cells into three-dimensional organized structures that resemble organs are pushing the frontiers of human disease modeling and drug development. In response to the global health emergency posed by the Zika virus (ZIKV) outbreak, brain organoids engineered to mimic the developing human fetal brain have been employed to model ZIKV-induced microcephaly. Here, we discuss the advantages of brain organoids over other model systems to study development and highlight recent advances in understanding ZIKV pathophysiology and its underlying pathogenesis mechanisms. We further discuss perspectives on overcoming limitations of current organoid systems for their future use in ZIKV research.
Topics: Animals; Brain; Humans; Microcephaly; Organoids; Zika Virus; Zika Virus Infection
PubMed: 28292840
DOI: 10.1242/dev.140707 -
Clinical Genetics Jul 2023NUSAP1 encodes a cell cycle-dependent protein with key roles in mitotic progression, spindle formation, and microtubule stability. Both over- and under-expression of...
NUSAP1 encodes a cell cycle-dependent protein with key roles in mitotic progression, spindle formation, and microtubule stability. Both over- and under-expression of NUSAP1 lead to dysregulation of mitosis and impaired cell proliferation. Through exome sequencing and Matchmaker Exchange, we identified two unrelated individuals with the same recurrent, de novo heterozygous variant (NM_016359.5 c.1209C > A; p.(Tyr403Ter)) in NUSAP1. Both individuals had microcephaly, severe developmental delay, brain abnormalities, and seizures. The gene is predicted to be tolerant of heterozygous loss-of-function mutations, and we show that the mutant transcript escapes nonsense mediated decay, suggesting that the mechanism is likely dominant-negative or toxic gain of function. Single-cell RNA-sequencing of an affected individual's post-mortem brain tissue indicated that the NUSAP1 mutant brain contains all main cell lineages, and that the microcephaly could not be attributed to loss of a specific cell type. We hypothesize that pathogenic variants in NUSAP1 lead to microcephaly possibly by an underlying defect in neural progenitor cells.
Topics: Humans; Epilepsy; Microcephaly; Mutation; Nervous System Malformations; Neurodevelopmental Disorders
PubMed: 37005340
DOI: 10.1111/cge.14335 -
Archives of Disease in Childhood May 2020The Zika virus outbreak has drawn attention to microcephaly, whose definition is based on head circumference measuring below a percentile or number of SDs below the...
BACKGROUND AND OBJECTIVE
The Zika virus outbreak has drawn attention to microcephaly, whose definition is based on head circumference measuring below a percentile or number of SDs below the mean. The objective of this analysis was to assess how differences in measurement precision might affect prevalence and trends of microcephaly.
METHODS
Data from all births in Uruguay during 2010-2015 were obtained from the Perinatal Information System. The prevalence of births with microcephaly was calculated based on head circumference measurement at birth applying the INTERGROWTH-21 standards for sex and gestational age, and compared by method of ascertaining gestational age.
RESULTS
Rounding and digit preference was observed: 74% of head circumference measurements were reported as a whole centimetre value. The prevalence of births varied substantially by the criterion used to define microcephaly (<3 SD, <2 SD, <3rd percentile for gestational age) and could be halved or doubled based on adding or subtracting a half-centimetre from all reported head circumference measurements. If 4 days were added to gestational age calculations, rather than using completed gestational weeks (without days) for gestational age reporting, the prevalence was 1.7-2 times higher.
DISCUSSION
Rounding in measurement of head circumference and reporting preferences of gestational age may have contributed to a lower prevalence of microcephaly than expected in this population. Differences in head circumference measurement protocols and gestational age dating have the potential to affect the prevalence of babies reported with microcephaly, and this limitation should be acknowledged when interpreting head circumference data collected for surveillance.
Topics: Cephalometry; Dimensional Measurement Accuracy; Humans; Infant, Newborn; Microcephaly; Prevalence; Uruguay; Zika Virus Infection
PubMed: 31836636
DOI: 10.1136/archdischild-2019-317678 -
Fetal Diagnosis and Therapy 2011Fetuses with congenital cytomegalovirus infection may remain asymptomatic or present with a wide range of brain pathologies. These findings are not always obvious but... (Review)
Review
Fetuses with congenital cytomegalovirus infection may remain asymptomatic or present with a wide range of brain pathologies. These findings are not always obvious but may on some occasions be demonstrated by ultrasound and MRI, they include ventriculomegaly, microcephaly, increased periventricular echogenicity, calcifications, periventricular pseudocysts, intraventricular synechia, malformations of cortical development, cerebellar lesions and T2 abnormal temporal signals. The purpose of this mini-review is to describe US and MRI findings characteristic of congenital cytomegalovirus infection, with particular emphasis on their time of appearance, frequency and specificity.
Topics: Calcinosis; Cerebellum; Cytomegalovirus Infections; Female; Fetal Diseases; Humans; Hydrocephalus; Magnetic Resonance Imaging; Microcephaly; Pregnancy; Ultrasonography
PubMed: 21088375
DOI: 10.1159/000321346 -
Neurology Aug 2018To investigate the morphology of the retina and optic nerve (ON) in microcephaly.
OBJECTIVE
To investigate the morphology of the retina and optic nerve (ON) in microcephaly.
METHODS
This was a prospective case-control study including 27 patients with microcephaly and 27 healthy controls. All participants underwent ophthalmologic examination and handheld optical coherence tomography (OCT) of the macula and ON head. The thickness of individual retinal layers was quantified at the foveal center and the parafovea (1,000 μm nasal and temporal to the fovea). For the ON head, disc diameter, cup diameter, cup-to-disc ratio, cup depth, horizontal rim diameter, rim area, peripapillary retinal thickness, and retinal nerve fiber layer thickness were measured.
RESULTS
Seventy-eight percent of patients had ophthalmologic abnormalities, mainly nystagmus (56%) and strabismus (52%). OCT abnormalities were found in 85% of patients. OCT revealed disruption of the ellipsoid zone, persistent inner retinal layers, and irregular foveal pits. Parafoveal retinal thickness was significantly reduced in patients with microcephaly compared to controls, nasally (307 ± 44 vs 342 ± 19 μm, = 0.001) and temporally (279 ± 56 vs 325 ± 16 μm, < 0.001). There was thinning of the ganglion cell layer and the inner segments of the photoreceptors in microcephaly. Total peripapillary retinal thickness was smaller in patients with microcephaly compared to controls for both temporal (275 vs 318 μm, < 0.001) and nasal sides (239 vs 268 μm, = 0.013).
CONCLUSIONS
Retinal and ON anomalies in microcephaly likely reflect retinal cell reduction and lamination alteration due to impaired neurogenic mitosis. OCT allows diagnosis and quantification of retinal and ON changes in microcephaly even if they are not detected on ophthalmoscopy.
Topics: Adolescent; Case-Control Studies; Child; Child, Preschool; Female; Humans; Male; Microcephaly; Optic Nerve; Prospective Studies; Retina; Tomography, Optical Coherence
PubMed: 29997194
DOI: 10.1212/WNL.0000000000005950 -
Birth Defects Research. Part A,... Nov 2016The current surveillance systems for congenital microcephaly are necessary to monitor the impact of Zika virus (ZIKV) on the developing human brain, as well as the ZIKV...
The current surveillance systems for congenital microcephaly are necessary to monitor the impact of Zika virus (ZIKV) on the developing human brain, as well as the ZIKV prevention efforts. However, these congenital microcephaly surveillance systems are insufficient. Abnormalities of neuronal differentiation, development and migration may occur among infants with normal head circumference who have intrauterine exposure to ZIKV. Therefore, surveillance for congenital microcephaly does not ascertain many of the infants seriously impacted by congenital ZIKV infection. Furthermore, many infants with normal head circumference and with malformations of the brain cortex do not have clinical manifestations of their congenital malformations until several months to many years after birth, when they present with clinical manifestations such as seizures/epilepsy, developmental delays with or without developmental regression, and/or motor impairment. In response to the ZIKV threat, public health surveillance systems must be enhanced to ascertain a wide variety of congenital brain malformations, as well as their clinical manifestations that lead to diagnostic brain imaging. Birth Defects Research (Part A) 106:869-874, 2016. © 2016 The Authors Birth Defects Research Part A: Clinical and Molecular Teratology Published by Wiley Periodicals, Inc.
Topics: Brain; Humans; Microcephaly; Zika Virus; Zika Virus Infection
PubMed: 27891785
DOI: 10.1002/bdra.23582 -
Viruses Apr 2021The emergence of the Zika virus (ZIKV) mirrors its evolutionary nature and, thus, its ability to grow in diversity or complexity (i.e., related to genome, host response,... (Review)
Review
The emergence of the Zika virus (ZIKV) mirrors its evolutionary nature and, thus, its ability to grow in diversity or complexity (i.e., related to genome, host response, environment changes, tropism, and pathogenicity), leading to it recently joining the circle of closed congenital pathogens. The causal relation of ZIKV to microcephaly is still a much-debated issue. The identification of outbreak foci being in certain endemic urban areas characterized by a high-density population emphasizes that mixed infections might spearhead the recent appearance of a wide range of diseases that were initially attributed to ZIKV. Globally, such coinfections may have both positive and negative effects on viral replication, tropism, host response, and the viral genome. In other words, the possibility of coinfection may necessitate revisiting what is considered to be known regarding the pathogenesis and epidemiology of ZIKV diseases. ZIKV viral coinfections are already being reported with other arboviruses (e.g., chikungunya virus (CHIKV) and dengue virus (DENV)) as well as congenital pathogens (e.g., human immunodeficiency virus (HIV) and cytomegalovirus (HCMV)). However, descriptions of human latent viruses and their impacts on ZIKV disease outcomes in hosts are currently lacking. This review proposes to select some interesting human latent viruses (i.e., herpes simplex virus 2 (HSV-2), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), human parvovirus B19 (B19V), and human papillomavirus (HPV)), whose virological features and co-exposition with ZIKV may provide evidence of the syndemism process, shedding some light on the emergence of the ZIKV-induced global congenital syndrome in South America.
Topics: Biological Coevolution; Coinfection; Disease Reservoirs; Humans; Microcephaly; South America; Viral Tropism; Virus Diseases; Virus Latency; Virus Replication; Zika Virus; Zika Virus Infection
PubMed: 33924398
DOI: 10.3390/v13040669 -
Aging Oct 2021
Topics: Brain; Cell Cycle Proteins; Cytoskeletal Proteins; Humans; Microcephaly; Organ Size
PubMed: 34705666
DOI: 10.18632/aging.203658 -
International Journal of Molecular... Aug 2017Zika virus is an emergent flavivirus transmitted by genus mosquitoes that recently reached the Americas and was soon implicated in an increase of microcephaly... (Meta-Analysis)
Meta-Analysis Review
Zika virus is an emergent flavivirus transmitted by genus mosquitoes that recently reached the Americas and was soon implicated in an increase of microcephaly incidence. The objective of the present study is to systematically review the published data and perform a meta-analysis to estimate the prevalence of microcephaly in babies born to Zika virus-infected women during pregnancy. We searched PubMed and Cochrane databases, included cohort studies, and excluded case reports and case series publications. We extracted sample sizes and the number of microcephaly cases from eight studies, which permitted a calculation of prevalence rates that are pooled in a random-effects model meta-analysis. We estimated the prevalence of microcephaly of 2.3% (95% CI = 1.0-5.3%) among all pregnancies. Limitations include mixed samples of women infected at different pregnancy times, since it is known that infection at the first trimester is associated with higher risk to congenital anomalies. The estimates are deceptively low, given the devastating impact the infection causes over children and their families. We hope our study contributes to public health knowledge to fight Zika virus epidemics to protect mothers and their newborns.
Topics: Female; Humans; Infant; Infant, Newborn; Microcephaly; Prevalence; Zika Virus; Zika Virus Infection
PubMed: 28783051
DOI: 10.3390/ijms18081714