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Genes Dec 2021Congenital microcephaly causes smaller than average head circumference relative to age, sex and ethnicity and is most usually associated with a variety of...
Congenital microcephaly causes smaller than average head circumference relative to age, sex and ethnicity and is most usually associated with a variety of neurodevelopmental disorders. The underlying etiology is highly heterogeneous and can be either environmental or genetic. Disruption of any one of multiple biological processes, such as those underlying neurogenesis, cell cycle and division, DNA repair or transcription regulation, can result in microcephaly. This etiological heterogeneity manifests in a clinical variability and presents a major diagnostic and therapeutic challenge, leaving an unacceptably large proportion of over half of microcephaly patients without molecular diagnosis. To elucidate the clinical and genetic landscapes of congenital microcephaly, we sequenced the exomes of 191 clinically diagnosed patients with microcephaly as one of the features. We established a molecular basis for microcephaly in 71 patients (37%), and detected novel variants in five high confidence candidate genes previously unassociated with this condition. We report a large number of patients with mutations in tubulin-related genes in our cohort as well as higher incidence of pathogenic mutations in genes. Our study expands the phenotypic and genetic landscape of microcephaly, facilitating differential clinical diagnoses for disorders associated with most commonly disrupted genes in our cohort.
Topics: Adolescent; Child; Child, Preschool; Female; Gene Regulatory Networks; Humans; Infant; Infant, Newborn; Male; Microcephaly; Mutation; Pedigree; Sequence Analysis, DNA; Exome Sequencing
PubMed: 34946966
DOI: 10.3390/genes12122014 -
Scientific Reports Apr 2021Not every neonate with congenital Zika virus (ZIKV) infection (CZI) is born with microcephaly. We compared inflammation mediators in CSF (cerebrospinal fluid obtained...
Not every neonate with congenital Zika virus (ZIKV) infection (CZI) is born with microcephaly. We compared inflammation mediators in CSF (cerebrospinal fluid obtained from lumbar puncture) between ZIKV-exposed neonates with/without microcephaly (cases) and controls. In Brazil, in the same laboratory, we identified 14 ZIKV-exposed neonates during the ZIKV epidemic (2015-2016), 7(50%) with and 7(50%) without microcephaly, without any other congenital infection, and 14 neonates (2017-2018) eligible to be controls and to match cases. 29 inflammation mediators were measured using Luminex immunoassay and multidimensional analyses were employed. Neonates with ZIKV-associated microcephaly presented substantially higher degree of inflammatory perturbation, associated with uncoupled inflammatory response and decreased correlations between concentrations of inflammatory biomarkers. The groups of microcephalic and non-microcephalic ZIKV-exposed neonates were distinguished from the control group (area under curve [AUC] = 1; P < 0.0001). Between controls and those non-microcephalic exposed to ZIKV, IL-1β, IL-3, IL-4, IL-7 and EOTAXIN were the top CSF markers. By comparing the microcephalic cases with controls, the top discriminant scores were for IL-1β, IL-3, EOTAXIN and IL-12p70. The degree of inflammatory imbalance may be associated with microcephaly in CZI and it may aid additional investigations in experimental pre-clinical models testing immune modulators in preventing extensive damage of the Central Nervous System.
Topics: Biomarkers; Brazil; Case-Control Studies; Female; Follow-Up Studies; Humans; Infant, Newborn; Inflammation Mediators; Male; Microcephaly; Pregnancy; Pregnancy Complications, Infectious; Prognosis; Prospective Studies; Retrospective Studies; Zika Virus; Zika Virus Infection
PubMed: 33875756
DOI: 10.1038/s41598-021-87895-4 -
CNS Neuroscience & Therapeutics Dec 2023Christianson syndrome (CS) is caused by mutations in SLC9A6 and is characterized by global developmental delay, epilepsy, hyperkinesis, ataxia, microcephaly, and...
BACKGROUND
Christianson syndrome (CS) is caused by mutations in SLC9A6 and is characterized by global developmental delay, epilepsy, hyperkinesis, ataxia, microcephaly, and behavioral disorder. However, the molecular mechanism by which these SLC9A6 mutations cause CS in humans is not entirely understood, and there is no objective method to determine the pathogenicity of single SLC9A6 variants.
METHODS
Trio-based whole exome sequencing (WES) was carried out on two individuals with suspicion of CS. qRT-PCR, western blot analysis, filipin staining, lysosomal enzymatic assays, and electron microscopy examination, using EBV-LCLs established from the two patients, were performed.
RESULTS
Trio-based WES identified a hemizygous SLC9A6 c.1560dupT, p.T521Yfs*23 variant in proband 1 and a hemizygous SLC9A6 c.608delA, p.H203Lfs*10 variant in proband 2. Both children exhibited typical phenotypes associated with CS. Expression analysis in EBV-LCLs derived from the two patients showed a significant decrease in mRNA levels and no detectable normal NHE6 protein. EBV-LCLs showed a statistically significant increase in unesterified cholesterol in patient 1, but only non-significant increase in patient 2 when stained with filipin. Activities of lysosomal enzymes (β-hexosaminidase A, β-hexosaminidase A + B, β-galactosidase, galactocerebrosidase, arylsulfatase A) of EBV-LCLs did not significantly differ between the two patients and six controls. Importantly, by electron microscopy we detected an accumulation of lamellated membrane structures, deformed mitochondria, and lipid droplets in the patients' EBV-LCLs.
CONCLUSIONS
The SLC9A6 p.T521Yfs*23 and p.H203Lfs*10 variants in our patients result in loss of NHE6. Alterations of mitochondria and lipid metabolism may play a role in the pathogenesis of CS. Moreover, the combination of filipin staining with electron microscopy examination of patient lymphoblastoid cells can serve as a useful complementary diagnostic method for CS.
Topics: Child; Humans; Ataxia; beta-N-Acetylhexosaminidases; Epilepsy; Filipin; Microcephaly
PubMed: 37381736
DOI: 10.1111/cns.14329 -
PloS One 2020Since 2015 Brazil has experienced the social repercussions of the Zika virus epidemic, thus raising a debate about: difficulties of diagnosis; healthcare access for...
Since 2015 Brazil has experienced the social repercussions of the Zika virus epidemic, thus raising a debate about: difficulties of diagnosis; healthcare access for children with Zika Congenital Syndrome (ZCS); the search for benefits by affected families; social and gender inequalities; and a discussion on reproductive rights, among others. The objective of this article is to analyse access to specialized health services for the care of children born with ZCS in three North-eastern states of Brazil. This is an exploratory cross-sectional study which analyses recorded cases of microcephaly at the municipal level between 2015 and 2017. Most of the cases of ZCS were concentrated on the Northeast coast. Rio Grande do Norte and Paraiba had the highest incidence of microcephaly in the study period. The states of Bahia, Paraiba and Rio Grande do Norte were selected for their high incidence of microcephaly due to the Zika Virus. Socio-territorial vulnerability was stratified using access to microcephaly diagnosis and treatment indicators. The specialized care network was mapped according to State Health Secretaries Protocols. A threshold radius of 100 km was stablished as the maximum distance from municipalities centroids to specialised health care for children with microcephaly. Prenatal coverage was satisfactory in most of the study area, although availability of ultrasound equipment was uneven within states and health regions. Western Bahia had the lowest coverage of ultrasound equipment and lacked health rehabilitation services. ZCS's specialized health services were spread out over large areas, some of which were outside the affected patients' home municipalities, so displacements were expensive and very time consuming, representing an extra burden for the affected families. This study is the first to address accessibility of children with microcephaly to specialised health care services and points to the urgent need to expand coverage of these services in Brazil, especially in the northeastern states, which are most affected by the epidemic.
Topics: Brazil; Child; Child, Preschool; Cross-Sectional Studies; Epidemics; Female; Geography, Medical; Health Services Accessibility; Humans; Infant; Male; Microcephaly; Pregnancy; Pregnancy Complications, Infectious; Socioeconomic Factors; Zika Virus; Zika Virus Infection
PubMed: 32634152
DOI: 10.1371/journal.pone.0235010 -
Pediatrics Feb 2018The association between Zika virus infection during pregnancy and severe birth defects in infants has led to worldwide attention focused on the mechanisms of the disease... (Review)
Review
The association between Zika virus infection during pregnancy and severe birth defects in infants has led to worldwide attention focused on the mechanisms of the disease and the prevention of future exposure. Surveillance efforts around the world continue with the goal of identifying and monitoring all potentially exposed women and their newborns. For infants who were born with congenital Zika syndrome (CZS) and their families, an uncertain future awaits. As infants who were born with CZS during the most recent outbreak enter their second year of life, new developments in the outcomes of the condition continue to unfold, providing some insight into the likely long-term sequalae. In this article, I review the literature on emerging findings regarding the impact of CZS on the developing infant and provide some predictions regarding the long-term outcomes and lifetime needs of these children and their families.
Topics: Brain; Child Development; Female; Humans; Infant; Infant Behavior; Infant, Newborn; Microcephaly; Pregnancy; Pregnancy Complications, Infectious; Zika Virus; Zika Virus Infection
PubMed: 29437048
DOI: 10.1542/peds.2017-2038D -
Clinics (Sao Paulo, Brazil) 2019To describe the nutritional profile of newborns with microcephaly and factors associated with worse outcomes during the first 14 days of life.
OBJECTIVE
To describe the nutritional profile of newborns with microcephaly and factors associated with worse outcomes during the first 14 days of life.
METHODS
This investigation is a longitudinal, descriptive study carried out in 21 full-term neonates exposed vertically to the Zika virus and hospitalized in a neonatal intensive care unit from February to September 2016. Patients receiving parenteral nutrition were excluded. Data analysis was performed using a generalized estimating equation model and Student's t-test to evaluate the association between worsening weight-for-age z-scores and independent clinical, sociodemographic and nutritional variables during hospitalization, with p<0.05 indicating significance.
RESULTS
During hospitalization, there was a decrease in the mean values of the weight-for-age z-scores. The factors associated with worse nutritional outcomes were symptomatic exposure to the Zika virus, low maternal schooling, absence of maternal income and consumption of infant formula (p<0.05). Calcification and severe microcephaly were also associated with poor nutritional outcomes. Energy and macronutrient consumption remained below the recommendations and had an upward trend during hospitalization.
CONCLUSION
The presence of cerebral calcification, the severity of microcephaly and symptomatic maternal exposure to Zika virus affected the nutritional status of newborns. In terms of nutritional factors, human milk intake had a positive impact, reducing weight loss in the first days of life. Other known factors, such as income and maternal schooling, were still associated with a poor nutritional status.
Topics: Adolescent; Adult; Female; Humans; Infant, Newborn; Longitudinal Studies; Male; Microcephaly; Nutritional Status; Risk Factors; Severity of Illness Index; Socioeconomic Factors; Young Adult; Zika Virus Infection
PubMed: 31644665
DOI: 10.6061/clinics/2019/e798 -
The New England Journal of Medicine Jul 2016
Topics: Brazil; Disease Outbreaks; Female; Humans; Microcephaly; Pregnancy; Pregnancy Complications, Infectious; Zika Virus; Zika Virus Infection
PubMed: 27222919
DOI: 10.1056/NEJMp1605367 -
Cadernos de Saude Publica 2021This study aimed to compare the anthropometric measurements and body proportionalities of neonates born before the Zika virus epidemic with those born during this...
This study aimed to compare the anthropometric measurements and body proportionalities of neonates born before the Zika virus epidemic with those born during this period. We compared 958 neonates born during the pre-Zika epidemic with 264 neonates born during the epidemic period. The newborns had their head circumference, weight, and length classified according to the Fenton & Kim growth chart. We considered disproportionate those individuals that presented microcephaly and adequate weight or length for sex and gestational age, and those whose head circumferences were lower than the ratio ((length / 2) + 9.5) - 2.5cm. We estimated the frequencies of Zika positivity and brain imaging findings among neonates with microcephaly born during the epidemic period, concerning the anthropometric and body proportionality parameters. Low weight and proportionate microcephaly were similar among newborns from both periods. However, the frequencies of newborns with microcephaly with a very low length and disproportionate microcephaly were higher among the neonates of the epidemic period with brain abnormalities and positive for Zika virus. We conclude that, at birth, the disproportion between head circumference and length can be an indicator of the severity of microcephaly caused by congenital Zika.
Topics: Brazil; Cephalometry; Humans; Infant, Newborn; Microcephaly; Zika Virus; Zika Virus Infection
PubMed: 34852159
DOI: 10.1590/0102-311X00228520 -
Cells Mar 2023The () gene was discovered about 40 years ago and shown to be required for both mitotic and meiotic cell division. Subsequent studies showed that is highly conserved... (Review)
Review
The () gene was discovered about 40 years ago and shown to be required for both mitotic and meiotic cell division. Subsequent studies showed that is highly conserved and that mutations in its human ortholog (; or ) are the most common cause of autosomal recessive primary microcephaly. This finding greatly stimulated research on and its fly and mouse () orthologs. The three Asp orthologous proteins bind the microtubules (MTs) minus ends during cell division and also function in interphase nuclei. Investigations on different cell types showed that Asp/Aspm/ASPM depletion disrupts one or more of the following mitotic processes: aster formation, spindle pole focusing, centrosome-spindle coupling, spindle orientation, metaphase-to-anaphase progression, chromosome segregation, and cytokinesis. In addition, ASPM physically interacts with components of the DNA repair and replication machineries and is required for the maintenance of chromosomal DNA stability. We propose the working hypothesis that the // genes play the same conserved functions in , mouse, and human cells. Human microcephaly is a genetically heterogeneous disorder caused by mutations in 30 different genes that play a variety of functions required for cell division and chromosomal DNA integrity. Our hypothesis postulates that recapitulates the functions of most human microcephaly genes and provides a justification for why is the most frequently mutated gene in autosomal recessive primary microcephaly.
Topics: Animals; Humans; Mice; DNA; Drosophila; Microcephaly; Mitosis; Nerve Tissue Proteins; Microtubule-Associated Proteins
PubMed: 36980263
DOI: 10.3390/cells12060922 -
Trends in Cell Biology Aug 2011Autosomal recessive primary microcephaly (MCPH) is characterized by small brain size as a result of deficient neuron production in the developing cerebral cortex.... (Review)
Review
Autosomal recessive primary microcephaly (MCPH) is characterized by small brain size as a result of deficient neuron production in the developing cerebral cortex. Although MCPH is a rare disease, the questions surrounding its etiology strike at the core of stem cell biology. The seven genes implicated in MCPH all encode centrosomal proteins and disruption of the MCPH gene Cdk5rap2 in mice revealed its role in neural progenitor proliferation and in maintaining normal centriole replication control. We discuss here the impact that centrosome regulation has upon neural progenitors in the developing brain. We integrate the impact of centriole replication defects with the functions of Cdk5rap2 and other MCPH proteins, propose mechanisms for progenitor loss in MCPH, and discuss links to two other microcephaly syndromes.
Topics: Animals; Centrosome; Humans; Intracellular Signaling Peptides and Proteins; Mice; Microcephaly; Microtubule-Associated Proteins; Nerve Tissue Proteins; Spindle Apparatus
PubMed: 21632253
DOI: 10.1016/j.tcb.2011.04.007