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Molecular Genetics & Genomic Medicine Sep 2021Primary microcephaly (PM) is defined as a significant reduction in occipitofrontal circumference (OFC) of prenatal onset. Clinical and genetic heterogeneity of PM...
BACKGROUND
Primary microcephaly (PM) is defined as a significant reduction in occipitofrontal circumference (OFC) of prenatal onset. Clinical and genetic heterogeneity of PM represents a diagnostic challenge.
METHODS
We performed detailed phenotypic and genomic analyses in a large cohort (n = 169) of patients referred for PM and could establish a molecular diagnosis in 38 patients.
RESULTS
Pathogenic variants in ASPM and WDR62 were the most frequent causes in non-consanguineous patients in our cohort. In consanguineous patients, microarray and targeted gene panel analyses reached a diagnostic yield of 67%, which contrasts with a much lower rate in non-consanguineous patients (9%). Our series includes 11 novel pathogenic variants and we identify novel candidate genes including IGF2BP3 and DNAH2. We confirm the progression of microcephaly over time in affected children. Epilepsy was an important associated feature in our PM cohort, affecting 34% of patients with a molecular confirmation of the PM diagnosis, with various degrees of severity and seizure types.
CONCLUSION
Our findings will help to prioritize genomic investigations, accelerate molecular diagnoses, and improve the management of PM patients.
Topics: Cell Cycle Proteins; Child; Consanguinity; Epilepsy; Female; Gene Frequency; Genetic Heterogeneity; Genotype; Humans; Incidence; Male; Microcephaly; Nerve Tissue Proteins; Phenotype
PubMed: 34402213
DOI: 10.1002/mgg3.1768 -
Ophthalmic Genetics Dec 2023Microcephaly and chorioretinopathy (MCCRP) is a rare autosomal recessive (AR) disorder characterized by microcephaly, developmental delay, chorioretinopathy, and visual... (Review)
Review
BACKGROUND
Microcephaly and chorioretinopathy (MCCRP) is a rare autosomal recessive (AR) disorder characterized by microcephaly, developmental delay, chorioretinopathy, and visual impairment. We characterized the long-term phenotype of an additional patient with MCCRP associated with TUBCGP4 pathogenic variants and analysed previously reported cases in the literature.
MATERIALS AND METHODS
Analysis of clinical and genetic data of a patient with TUBGCP4-related MCCRP followed for more than 19 years and literature search for previously reported patients with variants using PubMed, Scopus, and Google Scholar.
RESULTS
Molecular diagnosis using exome sequencing demonstrated two TUBCGP4 variants in trans: c.1669C>T (p.Arg557*) and c.1746 G>T (p.Leu582=). Clinical characteristics included microcephaly, microphthalmia, punched-out chorioretinal lesions, vision impairment, nystagmus, Tetralogy of Fallot and neurodevelopmental delay. Another six previously reported cases of TUBCGP4-related MCCRP were identified. Their clinical and genetic characteristics are compared.
CONCLUSIONS
TUBCGP4-related microcephaly and chorioretinopathy, is a rare autosomal recessive neuro-ophthalmic disorder. Clinical characteristics in our proband have remained stable for two decades. The pathophysiology of this syndrome is not yet fully understood.
Topics: Humans; Microcephaly; Retinal Diseases; Choroid Diseases; Eye; Family; Phenotype; Microtubule-Associated Proteins
PubMed: 37038737
DOI: 10.1080/13816810.2023.2170424 -
Infectious Diseases Now May 2021Identify risk factors for microcephaly and evaluate historical trends of microcephaly and arboviruses to recognize patterns and anomalies that indicate the beginning of...
OBJECTIVE
Identify risk factors for microcephaly and evaluate historical trends of microcephaly and arboviruses to recognize patterns and anomalies that indicate the beginning of the microcephaly epidemic associated with Zika infection.
METHODS
The head circumferences of 62,298 newborns was analyzed to identify cases of microcephaly between 2014 and 2017. We compared the groups of newborns with normal head circumferences and those with microcephaly to identify risk factors. A time series with the incidences of microcephaly was analyzed to assess the appearance of anomalous values in order to identify the beginning of the microcephaly epidemic. Data on the incidence of dengue fever was used to develop a control chart, aiming to identify changes in incidence and seasonality that could suggest the circulation of a new arbovirus.
FINDINGS
Premature newborns, children of mothers under 20 years of age and those born in 2014 and 2015 had a higher risk of microcephaly. Three quarters with anomalous incidences of microcephaly were identified, the first in 2014 and the others in 2015. The dengue fever epidemic curve in 2013 shows persistence of high incidences in atypical periods, suggesting the entry of a new virus in the 3rd and 4th quarters.
CONCLUSIONS
These findings represent epidemiological evidence of the existence of cases of Zika virus between the 2nd quarter of 2013 and the beginning of 2014. The results add new elements to understanding the Zika virus epidemic in the Americas.
Topics: Adult; Americas; Arboviruses; Brazil; Cross-Sectional Studies; Dengue; Epidemics; Female; Humans; Incidence; Infant, Newborn; Male; Microcephaly; Pregnancy; Pregnancy Complications, Infectious; Risk Factors; Young Adult; Zika Virus; Zika Virus Infection
PubMed: 33144264
DOI: 10.1016/j.medmal.2020.10.024 -
Neurobiology of Disease Sep 2023The vacuolar protein sorting-associated protein 13B (VPS13B) is a large and highly conserved protein. Disruption of VPS13B causes the autosomal recessive Cohen syndrome,...
The vacuolar protein sorting-associated protein 13B (VPS13B) is a large and highly conserved protein. Disruption of VPS13B causes the autosomal recessive Cohen syndrome, a rare disorder characterized by microcephaly and intellectual disability among other features, including developmental delay, hypotonia, and friendly-personality. However, the underlying mechanisms by which VPS13B disruption leads to brain dysfunction still remain unexplained. To gain insights into the neuropathogenesis of Cohen syndrome, we systematically characterized brain changes in Vps13b-mutant mice and compared murine findings to 235 previously published and 17 new patients diagnosed with VPS13B-related Cohen syndrome. We showed that Vps13b is differentially expressed across brain regions with the highest expression in the cerebellum, the hippocampus and the cortex with postnatal peak. Half of the Vps13b mice die during the first week of life. The remaining mice have a normal lifespan and display the core phenotypes of the human disease, including microcephaly, growth delay, hypotonia, altered memory, and enhanced sociability. Systematic 2D and 3D brain histo-morphological analyses reveal specific structural changes in the brain starting after birth. The dentate gyrus is the brain region with the most prominent reduction in size, while the motor cortex is specifically thinner in layer VI. The fornix, the fasciculus retroflexus, and the cingulate cortex remain unaffected. Interestingly, these neuroanatomical changes implicate an increase of neuronal death during infantile stages with no progression in adulthood suggesting that VPS13B promotes neuronal survival early in life. Importantly, whilst both sexes were affected, some neuroanatomical and behavioral phenotypes were less pronounced or even absent in females. We evaluate sex differences in Cohen patients and conclude that females are less affected both in mice and patients. Our findings provide new insights about the neurobiology of VPS13B and highlight previously unreported brain phenotypes while defining Cohen syndrome as a likely new entity of non-progressive infantile neurodegeneration.
Topics: Child; Humans; Male; Female; Animals; Mice; Microcephaly; Muscle Hypotonia; Retinal Degeneration; Developmental Disabilities; Phenotype
PubMed: 37573958
DOI: 10.1016/j.nbd.2023.106259 -
Ciencia & Saude Coletiva May 2023In 2015, a range of congenital anomalies resulting from mother-to-child transmission of the zika virus emerged. Later called congenital zika syndrome (CZS), the... (Review)
Review
In 2015, a range of congenital anomalies resulting from mother-to-child transmission of the zika virus emerged. Later called congenital zika syndrome (CZS), the condition includes microcephaly. Since then, around 4,000 children have been affected in 27 countries, with Brazil accounting for the largest proportion of cases. Family caregivers have also been affected. This study analyzes the literature on caregivers of children with CZS and how the disease has affected their everyday lives. We conducted an integrative review using the PubMed, Virtual Health Library, and Embase databases. Thirty-one articles were identified for analysis after screening. The findings were grouped into four categories: a) social impacts - changes in family relationships, life projects, and social life; b) subjective impacts - feelings of resilience, loneliness, grief, overburdening, fear, uncertainty, and spirituality and religion; c) economic and material impacts - loss of income, increased household expenses, change of residence, and unemployment; and d) health impacts - service unpreparedness, selflessness, self-care, changes in nutritional and sleep patterns, and mental health problems, including stress, anxiety and depression.
Topics: Pregnancy; Humans; Female; Zika Virus Infection; Pregnancy Complications, Infectious; Infectious Disease Transmission, Vertical; Zika Virus; Microcephaly; Brazil
PubMed: 37194876
DOI: 10.1590/1413-81232023285.14852022 -
BMC Infectious Diseases Oct 2021More than 5 years after the Zika virus (ZIKV) epidemic, Zika infection remains a major concern in regions with high Aedes infestation. The objectives of this study were...
Zika virus infection and microcephaly: spatial analysis and socio-environmental determinants in a region of high Aedes aegypti infestation in the Central-West Region of Brazil.
BACKGROUND
More than 5 years after the Zika virus (ZIKV) epidemic, Zika infection remains a major concern in regions with high Aedes infestation. The objectives of this study were (i) to identify clusters of ZIKV infection and microcephaly, and/or central nervous system (CNS) alterations associated with congenital infection during the epidemic peak in 2016 and subsequently, in 2017 and 2018; (ii) to measure the non-spatial correlation between ZIKV infection and microcephaly and/or CNS alterations associated with congenital infection; and (iii) to analyse the sociodemographic/economic, health, and environmental determinants associated with the incidence of ZIKV in a region of high infestation by Aedes aegypti in the Central-West Region of Brazil.
METHODS
This ecological study analysed 246 municipalities in the state of Goiás (6.9 million inhabitants). The data were obtained from the Information System for Notifiable Diseases (ZIKV cases) and the Public Health Event Registry (microcephaly and/or CNS alterations associated with congenital infection). Incidence rates and prevalence of ZIKA infection were smoothed by an empirical Bayesian estimator (LEbayes), producing the local empirical Bayesian rate (LEBR). In the spatial analysis, ZIKV infection and microcephaly cases were georeferenced by the municipality of residence for 2016 and grouped for 2017 and 2018. Global Moran's I and the Hot Spot Analysis tool (Getis-Ord Gi* statistics) were used to analyse the spatial autocorrelation and clusters of ZIKV infection and microcephaly, respectively. A generalised linear model from the Poisson family was used to assess the association between ecological determinants and the smoothing incidence rate of ZIKV infection.
RESULTS
A total of 9892 cases of acute ZIKV infection and 121 cases of microcephaly were confirmed. The mean LEBR of the ZIKV infection in the 246 municipalities was 22.3 cases/100,000 inhabitants in 2016, and 10.3 cases/100,000 inhabitants in 2017 and 2018. The LEBR of the prevalence rate of microcephaly and/or CNS alterations associated with congenital infection was 7 cases/10,000 live births in 2016 and 2 cases/10,000 live births during 2017-2018. Hotspots of ZIKV infection and microcephaly cases were identified in the capital and neighbouring municipalities in 2016, with new clusters in the following years. In a multiple regression Poisson analysis, ZIKV infection was associated with higher population density, the incidence of dengue, Aedes larvae infestation index, and average rainfall. The important determinant of ZIKV infection incidence reduction was the increase in households attended by endemic disease control agents.
CONCLUSIONS
Our analyses were able to capture, in a more granular way, aspects that make it possible to inform public managers of the sentinel areas identified in the post-epidemic hotspots.
Topics: Aedes; Animals; Bayes Theorem; Brazil; Humans; Microcephaly; Spatial Analysis; Zika Virus; Zika Virus Infection
PubMed: 34706662
DOI: 10.1186/s12879-021-06805-1 -
Methods in Molecular Biology (Clifton,... 2020From its discovery in Uganda in 1947, Zika virus (ZIKV) was considered a relatively innocuous viral pathogen with sporadic and infrequent occurrence of human infection.... (Review)
Review
From its discovery in Uganda in 1947, Zika virus (ZIKV) was considered a relatively innocuous viral pathogen with sporadic and infrequent occurrence of human infection. It was during an outbreak in French Polynesia in 2014 when cases of Guillain-Barré syndrome were identified as a serious complication of ZIKV infection in adults. However, in 2015, ZIKV emerged into and swept through South and Central America infecting millions of people. As part of the latter ZIKV outbreak, in Brazil, cases of microcephaly and other serious congenital complications affecting a large fraction of infants born to mothers infected during pregnancy were first identified and linked to ZIKV. This chapter reviews the history and clinical manifestations of ZIKV infection and mechanisms of immunoprotection. It is notable that, while limited, historical monographs identified most, if not all, of the precepts that are considered as newly discovered.
Topics: Adult; Central America; Disease Outbreaks; Female; Guillain-Barre Syndrome; History, 20th Century; History, 21st Century; Humans; Infant; Infant, Newborn; Microcephaly; Pregnancy; South America; Uganda; Zika Virus; Zika Virus Infection
PubMed: 32367354
DOI: 10.1007/978-1-0716-0581-3_1 -
Transactions of the Royal Society of... Mar 2023Northeast Brazil has the world's highest rate of Zika-related microcephaly. However, Zika case counts cannot accurately describe burden because mandatory reporting was...
BACKGROUND
Northeast Brazil has the world's highest rate of Zika-related microcephaly. However, Zika case counts cannot accurately describe burden because mandatory reporting was only established when the epidemic was declining in the region.
METHODS
To advance the study of the Zika epidemic, we identified hotspots of Zika in Pernambuco state, Northeast Brazil, using Aedes-borne diseases (dengue, chikungunya and Zika) and microcephaly data. We used Kulldorff's Poisson purely spatial scan statistic to detect low- and high-risk clusters for Aedes-borne diseases (2014-2017) and for microcephaly (2015-2017), separately. Municipalities were classified according to a proposed gradient of Zika burden during the epidemic, based on the combination of cluster status in each analysis and considering the strength of the evidence.
RESULTS
We identified 26 Aedes-borne diseases clusters (11 high-risk) and 5 microcephaly clusters (3 high-risk) in Pernambuco. According to the proposed Zika burden gradient, our results indicate that the northeast of Pernambuco and the Sertão region were hit hardest by the Zika epidemic. The first is the most populous area of Pernambuco, while the second has one of the highest rates of social and economic inequality in Brazil.
CONCLUSION
We successfully identified possible hidden Zika hotspots using a simple methodology combining Aedes-borne diseases and microcephaly information.
Topics: Animals; Humans; Microcephaly; Brazil; Zika Virus Infection; Zika Virus; Spatial Analysis; Aedes
PubMed: 36326785
DOI: 10.1093/trstmh/trac099 -
Birth Defects Research Sep 2020Zika virus was first identified in Uganda in 1947 but received little attention until 2015 when a large outbreak of Zika virus illness followed by an increased number of...
Zika virus was first identified in Uganda in 1947 but received little attention until 2015 when a large outbreak of Zika virus illness followed by an increased number of babies born with microcephaly occurred in Brazil. Zika virus spread rapidly throughout the Americas, and in 2016 was identified as a cause of microcephaly and other serious birth defects. Since that time, much has been learned about the Zika virus. The virus is primarily spread by the bite of Aedes species mosquitoes; however, other forms of transmission (e.g., sexual and intrauterine) have been recognized. Although postnatal Zika virus infection typically causes mild or no symptoms, effects on infants born to prenatally infected mothers can be severe and include structural birth defects and neurodevelopmental effects. The risk of a structural birth defect among infants born to mothers with confirmed or suspected Zika virus infection during pregnancy has ranged from 5 to 10%. The timing of Zika infection during pregnancy affects risk, with higher risks with the first-trimester infection. Neurodevelopmental effects are seen even in infants who appear normal in the newborn period. Although cases of Zika virus infection have fallen in the Americas, the Zika virus remains an active threat in some regions of the world. The development of a Zika vaccine will require continued focus and investment. Until a Zika vaccine is available, prevention efforts for pregnant women include avoidance of travel to areas with active Zika transmission, avoidance of mosquito bites for those living in or traveling to areas with Zika transmission, and protection against sexual transmission.
Topics: Animals; Female; Humans; Infant; Infant, Newborn; Microcephaly; Parturition; Pregnancy; Teratogens; United States; Zika Virus; Zika Virus Infection
PubMed: 32830420
DOI: 10.1002/bdr2.1781 -
Aging Oct 2021
Topics: Brain; Cell Cycle Proteins; Cytoskeletal Proteins; Humans; Microcephaly; Organ Size
PubMed: 34705666
DOI: 10.18632/aging.203658