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Clinical Microbiology and Infection :... Jun 2016
Topics: Disease Transmission, Infectious; Guillain-Barre Syndrome; Humans; Microcephaly; Zika Virus; Zika Virus Infection
PubMed: 27067096
DOI: 10.1016/j.cmi.2016.03.032 -
BioMed Research International 2014Autosomal recessive primary microcephaly (MCPH) is a rare hereditary neurodevelopmental disorder characterized by a marked reduction in brain size and intellectual... (Review)
Review
Autosomal recessive primary microcephaly (MCPH) is a rare hereditary neurodevelopmental disorder characterized by a marked reduction in brain size and intellectual disability. MCPH is genetically heterogeneous and can exhibit additional clinical features that overlap with related disorders including Seckel syndrome, Meier-Gorlin syndrome, and microcephalic osteodysplastic dwarfism. In this review, we discuss the key proteins mutated in MCPH. To date, MCPH-causing mutations have been identified in twelve different genes, many of which encode proteins that are involved in cell cycle regulation or are present at the centrosome, an organelle crucial for mitotic spindle assembly and cell division. We highlight recent findings on MCPH proteins with regard to their role in cell cycle progression, centrosome function, and early brain development.
Topics: Animals; Cell Cycle Proteins; Centrosome; Cytoskeletal Proteins; Genetic Heterogeneity; Humans; Intracellular Signaling Peptides and Proteins; Microcephaly; Microtubule-Associated Proteins; Multiprotein Complexes; Mutation; Nerve Tissue Proteins
PubMed: 25548773
DOI: 10.1155/2014/547986 -
Annals of Clinical and Translational... May 2020Defects in ion channels and neurotransmitter receptors are implicated in developmental and epileptic encephalopathy (DEE). Metabotropic glutamate receptor 7 (mGluR7),...
OBJECTIVE
Defects in ion channels and neurotransmitter receptors are implicated in developmental and epileptic encephalopathy (DEE). Metabotropic glutamate receptor 7 (mGluR7), encoded by GRM7, is a presynaptic G-protein-coupled glutamate receptor critical for synaptic transmission. We previously proposed GRM7 as a candidate disease gene in two families with neurodevelopmental disorders (NDDs). One additional family has been published since. Here, we describe three additional families with GRM7 biallelic variants and deeply characterize the associated clinical neurological and electrophysiological phenotype and molecular data in 11 affected individuals from six unrelated families.
METHODS
Exome sequencing and family-based rare variant analyses on a cohort of 220 consanguineous families with NDDs revealed three families with GRM7 biallelic variants; three additional families were identified through literature search and collaboration with a clinical molecular laboratory.
RESULTS
We compared the observed clinical features and variants of 11 affected individuals from the six unrelated families. Identified novel deleterious variants included two homozygous missense variants (c.2671G>A:p.Glu891Lys and c.1973G>A:p.Arg685Gln) and one homozygous stop-gain variant (c.1975C>T:p.Arg659Ter). Developmental delay, neonatal- or infantile-onset epilepsy, and microcephaly were universal. Three individuals had hypothalamic-pituitary-axis dysfunction without pituitary structural abnormality. Neuroimaging showed cerebral atrophy and hypomyelination in a majority of cases. Two siblings demonstrated progressive loss of myelination by 2 years in both and an acquired microcephaly pattern in one. Five individuals died in early or late childhood.
CONCLUSION
Detailed clinical characterization of 11 individuals from six unrelated families demonstrates that rare biallelic GRM7 pathogenic variants can cause DEEs, microcephaly, hypomyelination, and cerebral atrophy.
Topics: Adolescent; Alleles; Atrophy; Child; Child, Preschool; Cohort Studies; Consanguinity; Epilepsy; Female; Humans; Infant; Male; Microcephaly; Neurodevelopmental Disorders; Pedigree; Phenotype; Receptors, Metabotropic Glutamate; Exome Sequencing
PubMed: 32286009
DOI: 10.1002/acn3.51003 -
Journal of Medical Genetics May 2022Minichromosomal maintenance (MCM) complex components 2, 4, 5 and 6 have been linked to human disease with phenotypes including microcephaly and intellectual disability....
BACKGROUND
Minichromosomal maintenance (MCM) complex components 2, 4, 5 and 6 have been linked to human disease with phenotypes including microcephaly and intellectual disability. The MCM complex has DNA helicase activity and is thereby important for the initiation and elongation of the replication fork and highly expressed in proliferating neural stem cells.
METHODS
Whole-exome sequencing was applied to identify the genetic cause underlying the neurodevelopmental disease of the index family. The expression pattern of was characterised by performing quantitative real-time PCR, hybridisation and immunostaining. To prove the disease-causative nature of identified , a proof-of-principle experiment was performed.
RESULTS
We reported that the homozygous missense variant c.793G>A/p.A265T (g.7:99695841C>T, NM_005916.4) in was associated with autosomal recessive primary microcephaly (MCPH), severe intellectual disability and behavioural abnormalities in a consanguineous pedigree with three affected individuals. We found concordance between the spatiotemporal expression pattern of in mice and a proliferative state: expression was higher in early mouse developmental stages and in proliferative zones of the brain. Accordingly, Mcm7/MCM7 levels were detectable particularly in undifferentiated mouse embryonal stem cells and human induced pluripotent stem cells compared with differentiated neurons. We further demonstrate that the downregulation of in mouse neuroblastoma cells reduces cell viability and proliferation, and, as a proof-of-concept, that this is counterbalanced by the overexpression of wild-type but not mutant .
CONCLUSION
We report mutations of as a novel cause of autosomal recessive MCPH and intellectual disability and highlight the crucial function of MCM7 in nervous system development.
Topics: Animals; Humans; Induced Pluripotent Stem Cells; Intellectual Disability; Mice; Microcephaly; Minichromosome Maintenance Complex Component 7; Mutation; Nervous System Malformations; Pedigree
PubMed: 34059554
DOI: 10.1136/jmedgenet-2020-107518 -
Nature Communications Jan 2022Primary microcephaly and megalencephaly are severe brain malformations defined by reduced and increased brain size, respectively. Whether these two pathologies arise...
Primary microcephaly and megalencephaly are severe brain malformations defined by reduced and increased brain size, respectively. Whether these two pathologies arise from related alterations at the molecular level is unclear. Microcephaly has been largely associated with centrosomal defects, leading to cell death. Here, we investigate the consequences of WDR81 loss of function, which causes severe microcephaly in patients. We show that WDR81 regulates endosomal trafficking of EGFR and that loss of function leads to reduced MAP kinase pathway activation. Mouse radial glial progenitor cells knocked-out for WDR81 exhibit reduced proliferation rate, subsequently leading to reduced brain size. These proliferation defects are rescued in vivo by expressing a megalencephaly-causing mutant form of Cyclin D2. Our results identify the endosomal machinery as an important regulator of proliferation rates and brain growth, demonstrating that microcephaly and megalencephaly can be caused by opposite effects on the proliferation rate of radial glial progenitors.
Topics: Animals; Brain; Cell Proliferation; Cells, Cultured; Endosomes; Green Fluorescent Proteins; Humans; MAP Kinase Signaling System; Megalencephaly; Mice; Microcephaly; Nerve Tissue Proteins; Nervous System Malformations; Neural Stem Cells; Neuroglia; Protein Transport; Transport Vesicles
PubMed: 35013230
DOI: 10.1038/s41467-021-27705-7 -
European Journal of Human Genetics :... Jan 2020Stromme syndrome.Jejunal atresia with microcephaly and ocular anomalies.Apple peel syndrome with microcephaly and ocular anomalies.Ciliopathy phenotype.Primary...
Stromme syndrome.Jejunal atresia with microcephaly and ocular anomalies.Apple peel syndrome with microcephaly and ocular anomalies.Ciliopathy phenotype.Primary microcephaly and intellectual disability.OMIM# of the disease 243605.Name of the analysed genes or DNA/chromosome segments CENPF.OMIM# of the gene(s) 600236.Review of the analytical and clinical validity as well as of the clinical utility of DNA-based testing for mutations in CENPF genes in diagnostic, prenatal settings, and for risk assessment in relatives.
Topics: Chromosomal Proteins, Non-Histone; Eye Abnormalities; Genetic Testing; Humans; Intestinal Atresia; Microcephaly; Microfilament Proteins; Mutation; Phenotype; Sensitivity and Specificity
PubMed: 31488893
DOI: 10.1038/s41431-019-0498-y -
Brazilian Journal of Medical and... 2016Zika virus (ZIKV), a mosquito-borne flavivirus, belongs to the Flaviviridae family, genus Flavivirus. ZIKV was initially isolated in 1947 from a sentinel monkey in the... (Review)
Review
Zika virus (ZIKV), a mosquito-borne flavivirus, belongs to the Flaviviridae family, genus Flavivirus. ZIKV was initially isolated in 1947 from a sentinel monkey in the Zika forest, Uganda. Little clinical importance was attributed to ZIKV, once only few symptomatic cases were reported in some African and Southeast Asiatic countries. This situation changed in 2007, when a large outbreak was registered on the Yap Island, Micronesia, caused by the Asian ZIKV lineage. Between 2013 and 2014, ZIKV spread explosively and caused many outbreaks in different islands of the Southern Pacific Ocean and in 2015 autochthonous transmission was reported in Brazil. Currently, Brazil is the country with the highest number of ZIKV-positive cases in Latin America. Moreover, for the first time after the discovery of ZIKV, the Brazilian scientists are studying the possibility for the virus to cause severe congenital infection related to microcephaly and serious birth defects due to the time-spatial coincidence of the alarming increase of newborns with microcephaly and the Brazilian ZIKV epidemic. The present review summarizes recent information for ZIKV epidemiology, clinical picture, transmission, diagnosis and the consequences of this emerging virus in Brazil.
Topics: Animals; Brazil; Epidemics; Humans; Infant, Newborn; Microcephaly; Zika Virus; Zika Virus Infection
PubMed: 27143174
DOI: 10.1590/1414-431X20165420 -
BMC Pregnancy and Childbirth Mar 2021Prevalence of neonatal microcephaly in populations without Zika-epidemics is sparse. The study aimed to report baseline prevalence of congenital microcephaly and its...
BACKGROUND
Prevalence of neonatal microcephaly in populations without Zika-epidemics is sparse. The study aimed to report baseline prevalence of congenital microcephaly and its relationship with prenatal factors in an area at risk of Zika outbreak.
METHODS
This study included singletons born after 24 gestational weeks in 2017-2018 at four hospitals in Guangzhou, China. Microcephaly was defined as a head circumference at birth >3SD below the mean for sex and gestational age. Prevalence of microcephaly was estimated by binomial exact method. Multivariable logistic regression was used to examine the associations of microcephaly with prenatal factors. The population attributable fraction (PAF) for associated risk factors was calculated.
RESULTS
Of 46,610 live births included, 154 (3.3, 95% CI 2.8-3.9 per 1000 live births) microcephalies were identified. Maternal hepatitis B virus carriers (HBV, OR 1.80, 95% CI 1.05-3.10) and primipara (OR 2.68, 95% CI 1.89-3.81) had higher risk of having a microcephalic baby. Higher prevalence of microcephaly was observed in women who had premature labor (OR 1.98, 95% CI 1.17-3.34) and had a baby with fetal growth restriction (OR 16.38, 95% CI 11.81-22.71). Four identified factors (HBV, primiparity, preterm labor, and fetal growth restriction) contributed to 66.4% of the risk of microcephaly.
CONCLUSIONS
The prevalence of microcephaly in Guangzhou was higher than expected. This study identified four prenatal risk factors that, together, contributed to two-thirds of the increased risk of microcephaly. This is the first reported association between maternal HBV carrier status and microcephaly.
Topics: Adult; China; Female; Fetal Growth Retardation; Gestational Age; Hepatitis B; Humans; Infant, Newborn; Infant, Newborn, Diseases; Microcephaly; Parity; Pregnancy; Pregnancy Complications, Infectious; Premature Birth; Prevalence; Risk Assessment; Risk Factors; Zika Virus; Zika Virus Infection
PubMed: 33731027
DOI: 10.1186/s12884-021-03705-9 -
Cell Cycle (Georgetown, Tex.) Feb 2017
Topics: Animals; Cell Cycle; Cell Nucleus; Humans; Microcephaly; Models, Biological; Mutation; Rats
PubMed: 27792466
DOI: 10.1080/15384101.2016.1252591 -
PLoS Neglected Tropical Diseases Apr 2018Although the Zika virus (ZIKV) epidemic ceased to be a public health emergency by the end of 2016, studies to improve knowledge about this emerging disease are still...
BACKGROUND
Although the Zika virus (ZIKV) epidemic ceased to be a public health emergency by the end of 2016, studies to improve knowledge about this emerging disease are still needed, especially those investigating a causal relationship between ZIKV in pregnant women and microcephaly in neonates. However, there are still many challenges in describing the relationship between ZIKV and microcephaly. The few studies focusing on the epidemiological profile of ZIKV and its changes over time are largely limited to systematic reviews of case reports and dispersal mapping of ZIKV spread over time without quantitative methods to analyze patterns and their covariates. Since Brazil has been at the epicenter of the ZIKV epidemic, this study examines the geospatial association between ZIKV and microcephaly in Brazil.
METHODS
Our study is categorized as a retrospective, ecological study based on secondary databases. Data were obtained from January to December 2016, from the following data sources: Brazilian System for Epidemiological Surveillance, Disease Notification System, System for Specialized Management Support, and Brazilian Institute of Geography and Statistics. Data were aggregated by municipality. Incidence rates were estimated per 100,000 inhabitants. Analyses consisted of mapping the aggregated incidence rates of ZIKV and microcephaly, followed by a Getis-Ord-Gi spatial cluster analysis and a Bivariate Local Moran's I analysis.
RESULTS
The incidence of ZIKV cases is changing the virus's spatial pattern, shifting from Brazil's Northeast region to the Midwest and North regions. The number of municipalities in clusters of microcephaly incidence is also shifting from the Northeast region to the Midwest and North, after a time lag is considered. Our findings suggest an increase in microcephaly incidence in the Midwest and North regions, associated with high levels of ZIKV infection months before.
CONCLUSION
The greatest burden of microcephaly shifted from the Northeast to other Brazilian regions at the beginning of 2016. Brazil's Midwest region experienced an increase in microcephaly incidence associated with ZIKV incidence. This finding highlights an association between an increase in ZIKV infection with a rise in microcephaly cases after approximately three months.
Topics: Brazil; Female; Humans; Infant; Infant, Newborn; Male; Microcephaly; Retrospective Studies; Zika Virus; Zika Virus Infection
PubMed: 29694351
DOI: 10.1371/journal.pntd.0006392