Reduced Head Circumference Research Articles

Evaluating the Concept of Brain Sparing in a High Income Setting, Using Historical Records of Maternal Influenza or Syphilis Infection.

In the context of adverse in utero environments, the fetal brain might be preserved at the expense of other tissues. This trade-off, brain sparing, has not been studied in the context of maternal infection. We investigated cases of maternal syphilis in the early 20th century and influenza during the 1918-1920 pandemic, in the Swiss city of Lausanne, a relatively high-income setting. We tested the brain sparing hypothesis, that head circumference is protected at the expense of birth weight. A total of 8530 individual birth records from 1911 to 1922 from the University Maternity Hospital of Lausanne were used. We fitted generalized linear and additive linear models to explain how neonatal size varies under disease exposure. Influenza reduced head circumference and birth weight among livebirths similarly, by -0.11 and -0.14 standard deviation (SD) units respectively. Conversely, for syphilis-exposed infants, head circumference was affected more than birth weight (-0.61 SD vs. -0.46 SD). Stillborn infants exposed to syphilis experienced a much greater reduction in head circumference (-1.92 SD) than liveborn infants. After adjustment for gestational age, these findings persisted in the case of influenza, but the effects of syphilis were reduced. Furthermore, half of syphilis-exposed infants were born before term, suggesting that lower infant size was partly mediated by shorter gestation. Nevertheless, head circumference among stillbirths exposed to syphilis was still substantially reduced, even after adjustment for gestational age (-1.26 SD). Our findings do not support the brain sparing hypothesis. Moreover, the substantial reduction in head circumference among syphilis-exposed fetuses might help explain why a quarter of them were stillborn.

Ethylene Oxide Hemoglobin Adducts in Cord Blood and Offspring's Size at Birth: The NewGeneris European Cohort Study.

Prenatal ethylene oxide exposure may have adverse effects on fetal development. We examined the relationships between ethylene oxide hemoglobin (Hb) adduct levels and offspring's size at birth in a prospective European mother-child study. This study included 1106 singletons from the NewGeneris project (2006-2010) with ethylene oxide Hb adducts measured in cord blood. We examined the relationships between adduct levels and offspring's size at birth among all infants and separately among infants of nonsmokers, using linear regression models for birth weight and birth head circumference and logarithmic binomial regression models for small for gestational age. We examined potential interactions between CYP2E1 single nucleotide polymorphisms in cord blood and the effects of ethylene oxide Hb adduct levels on offspring birth size. Higher quartiles of adduct levels as a measure of exposure were associated with decreasing birth weight and head circumference in the overall population. Compared to infants in the lowest quartile, those in the highest quartile exhibited lower birth weight (-70.73 g, 95% confidence interval = -141.16, -0.30) and reduced head circumference (-0.30 cm, 95% confidence interval = -0.58, -0.02). We observed similar, albeit less pronounced, patterns among infants of nonsmokers. There was no evidence of an association between ethylene oxide Hb adducts and risk of small for gestational age, nor consistent evidence of an interaction with CYP2E1 polymorphisms on the association between EO Hb adduct levels and offspring's size at birth. Results suggest that higher ethylene oxide Hb adduct levels in cord blood are associated with a reduction in offspring birth size.

Associations between residential environmental characteristics during pregnancy and birthweight and head circumference among term births: The Taiwan birth Cohort study

Exposure to environmental pollutants during pregnancy may cause adverse birth outcomes in newborns. This study examined links between exposure to various residential environmental characteristics during pregnancy and newborn birth weight/head circumference, using the Taiwan Birth Cohort Study (TBCS) database with 14,829 subjects. We conducted simple and multiple linear regression analyses to find out the associations between residential environmental characteristics (molds, environmental tobacco smoke [ETS], household insecticide use, and home renovation or painting) and birth outcomes (birthweight, head circumference), and adjusting for demographics and environmental variables. The standardized beta coefficients were calculated. We also analyzed whether the associations varied by newborn sex and maternal body mass index (BMI). The regression analysis indicated that molds on multiple walls at the residence were significantly associated with lower birthweight (standardized β = −0.025, p = 0.003) and with smaller head circumference (standardized β = −0.023, p = 0.008) than no mold on walls after adjustment. Exposure to ETS did not result in significance for birthweight reduction but a significant reduction in head circumference (standardized β = −0.018, p = 0.047). The birthweight reductions associated with molds were −0.024 SD (standard deviation) for boys and −0.028 SD for girls, whereas the head circumference reduction with molds was sex-specific, being only significant for girls (standardized β = −0.029, p = 0.021). The analysis on BMI-separated data indicated that all significance occurred to mothers having normal BMI. Mold presence correlated significantly with reduced birth weight and head circumference, while ETS exposure only reduced head circumference. Girls and mothers with normal BMI were more affected by these reductions than boys or under/overweight mothers.

Complement System Activation Is a Plasma Biomarker Signature during Malaria in Pregnancy.

Malaria in pregnancy (MiP) is a public health problem in malaria-endemic areas, contributing to detrimental outcomes for both mother and fetus. Primigravida and second-time mothers are most affected by severe anemia complications and babies with low birth weight compared to multigravida women. Infected erythrocytes (IE) reach the placenta, activating the immune response by placental monocyte infiltration and inflammation. However, specific markers of MiP result in poor outcomes, such as low birth weight, and intrauterine growth restriction for babies and maternal anemia in women infected with Plasmodium falciparum are limited. In this study, we identified the plasma proteome signature of a mouse model infected with Plasmodium berghei ANKA and pregnant women infected with Plasmodium falciparum infection using quantitative mass spectrometry-based proteomics. A total of 279 and 249 proteins were quantified in murine and human plasma samples, of which 28% and 30% were regulated proteins, respectively. Most of the regulated proteins in both organisms are involved in complement system activation during malaria in pregnancy. CBA anaphylatoxin assay confirmed the complement system activation by the increase in C3a and C4a anaphylatoxins in the infected plasma compared to non-infected plasma. Moreover, correlation analysis showed the association between complement system activation and reduced head circumference in newborns from Pf-infected mothers. The data obtained in this study highlight the correlation between the complement system and immune and newborn outcomes resulting from malaria in pregnancy.

YIPF5 (p.W218R) mutation induced primary microcephaly in rabbits

Primary microcephaly (PMCPH) is a rare autosomal recessive neurodevelopmental disorder with a global prevalence of PMCPH ranging from 0.0013% to 0.15%. Recently, a homozygous missense mutation in YIPF5 (p.W218R) was identified as a causative mutation of severe microcephaly. In this study, we constructed a rabbit PMCPH model harboring YIPF5 (p.W218R) mutation using SpRY-ABEmax mediated base substitution, which precisely recapitulated the typical symptoms of human PMCPH. Compared with wild-type controls, the mutant rabbits exhibited stunted growth, reduced head circumference, altered motor ability, and decreased survival rates. Further investigation based on model rabbit elucidated that altered YIPF5 function in cortical neurons could lead to endoplasmic reticulum stress and neurodevelopmental disorders, interference of the generation of apical progenitors (APs), the first generation of progenitors in the developing cortex. Furthermore, these YIPF5-mutant rabbits support a correlation between unfolded protein responses (UPR) induced by endoplasmic reticulum stress (ERS), and the development of PMCPH, thus providing a new perspective on the role of YIPF5 in human brain development and a theoretical basis for the differential diagnosis and clinical treatment of PMCPH. To our knowledge, this is the first gene-edited rabbit model of PMCPH. The model better mimics the clinical features of human microcephaly than the traditional mouse models. Hence, it provides great potential for understanding the pathogenesis and developing novel diagnostic and therapeutic approaches for PMCPH.

Novel Pathogenic Mutation Mapping of ASPM Gene in Consanguineous Pakistani Families with Primary Microcephaly.

Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by a congenitally reduced head circumference (-3 to -5 SD) and non-progressive intellectual disability. The objective of the study was to evaluate pathogenic mutations in the ASPM gene to understand etiology and molecular mechanism of primary microcephaly. Blood samples were collected from various families across different remote areas of Pakistan from February 2017 to May 2019 who were identified to be affected with primary microcephaly. DNA extraction was performed using the salting-out method; the quality and quantity of DNA were evaluated using spectrophotometry and 1% agarose gel electrophoresis, respectively in University of the Punjab. Mutation analysis was performed by whole exome sequencing from the Cologne Center for Genomics, University of Cologne. Sanger sequencing was done in University of the Punjab to confirm the pathogenic nature of mutation. A novel 4-bp deletion mutation c.3877_3880delGAGA was detected in exon 17 of the ASPM gene in two primary microcephaly affected families (A and B), which resulted in a frame shift mutation in the gene followed by truncated protein synthesis (p.Glu1293Lysfs*10), as well as the loss of the calmodulin-binding IQ domain and the Armadillo-like domain in the ASPM protein. Using the in-silico tools Mutation Taster, PROVEAN, and PolyPhen, the pathogenic effect of this novel mutation was tested; it was predicted to be "disease causing," with high pathogenicity scores. One previously reported mutation in exon 24 (c.9730C>T) of the ASPM gene resulting in protein truncation (p.Arg3244*) was also observed in family C. Mutations in the ASPM gene are the most common cause of MCPH in most cases. Therefore, enrolling additional affected families from remote areas of Pakistan would help in identifying or mapping novel mutations in the ASPM gene of primary microcephaly.

Somatometric alterations and lower APGAR score in indigenous newborns

Introduction: the indigenous population is vulnerable and there is limited understanding of their somatometric indicators and APGAR score at birth. Aim: the objective of the study was to explore the association of the condition of indigenous newborn (INB) on somatometric parameters and APGAR score at birth. Methods: this study employed an exploratory cross-sectional design, utilizing the registry of newborns (NB) from a private clinic. The APGAR score at one minute after birth, as well as nutritional indicators derived from measurements of weight, height, and perimeters, were taken into consideration. The statistical analysis involved the use of logistic regressions. Results: the analysis included 7413 NB (1.8 % INB), 52 % were male and 8.1 % were born preterm (gestational age < 37 weeks). In comparison to non-indigenous NB, the INB group showed a higher risk of malnutrition (8 % vs. 6.3 %; p < 0.001), a greater prevalence of excess weight (7.3 % vs. 1.8 %; p < 0.001), smaller head circumference (33.6 cm vs. 34.1 cm; p = 0.017), smaller abdominal circumference (30.9 cm vs. 31.5 cm; p = 0.011), and a higher occurrence of low APGAR scores (< 7) (8.7 % vs. 1.2 %; p < 0.001). Furthermore, the indigenous condition was independently associated with low birth weight (< 2.500 g) (OR, 0.4; 95 % CI, 0.2; 0.9), excess head circumference (OR, 2.7; 95 % CI, 1.5; 4.7), and APGAR score < 7 points (OR, 8.3; 95 % CI, 4.2; 16.5). Conclusions: the indigenous condition was associated with factors that have adverse effects on the health of NB, including reduced head circumference and suboptimal performance on the APGAR scale. These results emphasize the importance of improving access to and quality of prenatal healthcare services for indigenous communities.

Neuroimaging and Cerebrovascular Changes in Fetuses with Complex Congenital Heart Disease.

Background: Congenital heart diseases (CHDs) are often associated with significant neurocognitive impairment and neurological delay. This study aims to elucidate the correlation between type of CHD and Doppler velocimetry and to investigate the possible presence of fetal brain abnormalities identified by magnetic resonance imaging (MRI). Methods: From July 2010 to July 2020, we carried out a cross-sectional study of 63 singleton pregnancies with a diagnosis of different types of complex CHD: LSOL (left-sided obstructive lesions; RSOL (right-sided obstructive lesions) and MTC (mixed type of CHD). All patients underwent fetal echocardiography, ultrasound evaluation, a magnetic resonance of the fetal brain, and genetic counseling. Results: The analysis of 63 fetuses shows statistically significant results in Doppler velocimetry among the different CHD groups. The RSOL group leads to higher umbilical artery (UA-PI) pressure indexes values, whereas the LSOL group correlates with significantly lower values of the middle cerebral artery (MCA-PI) compared to the other subgroups (p = 0.036), whereas the RSOL group shows a tendency to higher pulsatility indexes in the umbilical artery (UA-PI). A significant correlation has been found between a reduced head circumference (HC) and the presence of brain injury at MRI (p = 0.003). Conclusions: Congenital left- and right-sided cardiac obstructive lesions are responsible for fetal hemodynamic changes and brain growth impairment. The correct evaluation of the central nervous system (CNS) in fetuses affected by CHD could be essential as prenatal screening and the prediction of postnatal abnormalities.

DNA Replication proteins in primary microcephaly syndromes.

Improper expansion of neural stem and progenitor cells during brain development manifests in primary microcephaly. This disease is characterized by a reduced head circumference, which correlates with a reduction in brain size. This often corresponds to a general underdevelopment of the brain and entails cognitive, behavioral and motoric retardation. In the past decade significant research efforts have been undertaken to identify genes and the molecular mechanisms underlying microcephaly. One such gene set encompasses factors required for DNA replication. Intriguingly, a growing body of evidence indicates that a substantial number of these genes mediate faithful centrosome and cilium function in addition to their canonical function in genome duplication. Here, we summarize, which DNA replication factors are associated with microcephaly syndromes and to which extent they impact on centrosomes and cilia.

Autosomal Recessive Primary Microcephaly: Not Just a Small Brain.

Microcephaly or reduced head circumference results from a multitude of abnormal developmental processes affecting brain growth and/or leading to brain atrophy. Autosomal recessive primary microcephaly (MCPH) is the prototype of isolated primary (congenital) microcephaly, affecting predominantly the cerebral cortex. For MCPH, an accelerating number of mutated genes emerge annually, and they are involved in crucial steps of neurogenesis. In this review article, we provide a deeper look into the microcephalic MCPH brain. We explore cytoarchitecture focusing on the cerebral cortex and discuss diverse processes occurring at the level of neural progenitors, early generated and mature neurons, and glial cells. We aim to thereby give an overview of current knowledge in MCPH phenotype and normal brain growth.

Mutation screening of multiple Pakistani MCPH families revealed novel and recurrent protein-truncating mutations of ASPM.

Autosomal primary microcephaly (MCPH) is a heterogenetic disorder that affects brain's cerebral cortex size and leads to a reduction in the cranial vault. Along with the hallmark feature of reduced head circumference, microcephalic patients also exhibit a variable degree of intellectual disability as well. Genetic studies have reported 28 MCPH genes, most of which produce microtubule-associated proteins and are involved in cell division. Herein this study, 14 patients from seven Pashtun origin Pakistani families of primary microcephaly were analyzed. Mutation analysis was performed through targeted Sanger DNA sequencing on the basis of phenotype-linked genetic makeup. Genetic analysis in one family found a novel pathogenic DNA change in the abnormal spindle microtubule assembly (ASPM) gene (NM_018136.4:c.3871dupGA), while the rest of the families revealed recurrent nonsense mutation c.3978G>A (p.Trp1326*) in the same gene. The novel reported frameshift insertion presumably truncates the protein p.(Lys1291Glyfs*14) and deletes the N-terminus domains. Identification of novel ASPM-truncating mutation expands the mutational spectrum of the ASPM gene, while mapping of recurrent mutation c.3978G>A (p.Trp1326*) will aid in establishing its founder effect in the Khyber Pakhtunkhwa (KPK) inhabitant population of Pakistan and should be suggestively screened for premarital counseling of MCPH susceptible families. Most of the recruited families are related to first-degree consanguinity. Hence, all the family elders were counseled to avoid intrafamilial marriages.

Whole exome sequencing identifies a novel mutation in ASPM and ultra-rare mutation in CDK5RAP2 causing Primary microcephaly in consanguineous Pakistani families.

ABSTRACTBackground & Objectives:Primary Microcephaly (MCPH) is a rare neurogenetic disease, manifesting congenitally reduced head circumference and non-progressive intellectual disability (ID). To date, twenty-eight genes with biallelic mutations have been reported for this disorder. The study aimed for molecular genetic characterization of Pakistani families segregating MCPH.Methods:We studied two unrelated consanguineous families (family A and B) presenting >2 patients with diagnostic symptoms of MCPH, born to asymptomatic parents. We employed whole-exome sequencing (WES) of probands to find putative causal mutations. The candidate variants were further confirmed and analyzed for co-segregation by Sanger sequencing of all available members of each family. This study was conducted at Government College University, Faisalabad, Pakistan, and Cologne Center for Genomics (CCG), University of Cologne, Germany; during 2017-2020.Results:We identified a novel homozygous variant c.10097_10098delGA, p.(Gly3366Glufs*19) in exon 26 of ASPM gene in family A which presents with moderate intellectual disability, speech impairment, visual abnormalities, seizures, and ptyalism. Family B was found to segregate nonsense, homozygous variant c.448C>T p.(Arg150*) in CDK5RAP2. The patients also exhibited mild to severe seizures without ptyalism that has not been previously reported in patients with mutations in the CDK5RAP2 gene.Conclusion:We report a novel mutation in ASPM and ultra-rare mutation in the CDK5RAP2 gene, both causing primary microcephaly. The study expands the mutational spectrum of the ASPM gene to 212, and also adds to the clinical spectrum of CDK5RAP2 mutations. It also demonstrated the utility of WES in the investigation and genetic diagnosis of genetically heterogeneous disorders like MCPH. These findings would aid in diagnostic and preventive strategies including carrier screening, cascade testing, and genetic counselling.

RAB33B and PCNT variants in two Pakistani families with skeletal dysplasia and short stature

BackgroundSkeletal dysplasia is a heterogeneous group of disorders resulting from different genetic variants in humans. The current study was designed to identify the genetic causes of skeletal dysplasia and short stature in two consanguineous families from Pakistan, both comprised of multiple affected individuals. Patients in one family had proportionate short stature with reduced head circumference while affected individuals in the other family had disproportionate short stature.MethodsClinical data were obtained and radiological examinations of the index patients were completed. Whole genome sequencing for probands from both families were performed followed by Sanger sequencing to confirm segregation of identified variants in the respective families. In-silico pathogenicity score prediction for identified variant and amino acid conservation analysis was completed.ResultsWhole Genome Sequencing identified a known biallelic variant c.6176_6189delGTCAGCTGCCGAAG; p.(Gln2060ArgfsTer48) in PCNT gene and a novel biallelic variant c.174delC; p.(Asp60ThrfsTer7) in RAB33B gene respectively in affected members of the two families. Clinical imaging revealed platyspondyly and varus deformity in the legs of the affected members in the first family. Radiographs indicated severe platyspondyly, genu valgus deformity of legs and pectus carinatum for the patients in the second family.ConclusionIn this study we report the phenotypes and genetic variants in two unrelated families with two distinct forms of skeletal dysplasia. This study strengthens the previous findings that patients harboring PCNT variants are phenotypically homogeneous and also extends the genotypic spectrum of RAB33B variants.

Adverse pregnancy outcomes are associated with Plasmodium vivax malaria in a prospective cohort of women from the Brazilian Amazon.

Malaria in Brazil represents one of the highest percentages of Latin America cases, where approximately 84% of infections are attributed to Plasmodium (P.) vivax. Despite the high incidence, many aspects of gestational malaria resulting from P. vivax infections remain poorly studied. As such, we aimed to evaluate the consequences of P. vivax infections during gestation on the health of mothers and their neonates in an endemic area of the Amazon. We have conducted an observational cohort study in Brazilian Amazon between January 2013 and April 2015. 600 pregnant women were enrolled and followed until delivery. After applying exclusion criteria, 329 mother-child pairs were included in the analysis. Clinical data regarding maternal infection, newborn's anthropometric measures, placental histopathological characteristics, and angiogenic and inflammatory factors were evaluated. The presence of plasma IgG against the P. vivax (Pv) MSP119 protein was used as marker of exposure and possible associations with pregnancy outcomes were analyzed. Multivariate logistic regression analysis revealed that P. vivax infections during the first trimester of pregnancy are associated with adverse gestational outcomes such as premature birth (adjusted odds ratio [aOR] 8.12, 95% confidence interval [95%CI] 2.69-24.54, p < 0.0001) and reduced head circumference (aOR 3.58, 95%CI 1.29-9.97, p = 0.01). Histopathology analysis showed marked differences between placentas from P. vivax-infected and non-infected pregnant women, especially regarding placental monocytes infiltrate. Placental levels of vasomodulatory factors such as angiopoietin-2 (ANG-2) and complement proteins such as C5a were also altered at delivery. Plasma levels of anti-PvMSP119 IgG in infected pregnant women were shown to be a reliable exposure marker; yet, with no association with improved pregnancy outcomes. This study indicates that P. vivax malaria during the first trimester of pregnancy represents a higher likelihood of subsequent poor pregnancy outcomes associated with marked placental histologic modification and angiogenic/inflammatory imbalance. Additionally, our findings support the idea that antibodies against PvMSP119 are not protective against poor pregnancy outcomes induced by P. vivax infections.

The sex-specific association between maternal urinary paraben levels and offspring size at birth

Parabens are a group of antimicrobial preservatives applied in an extensive range of products and are suspected to impair fetal growth because of their disrupting effect on the endocrine system. We aimed to examine maternal urinary paraben concentrations and their neonates' outcome indexes. Methylparaben (MP), ethylparaben (EP), propylparaben (PP), and butylparaben (BP) concentrations were measured in 105 maternal urine samples collected before delivery. Length, weight, and head circumference at birth were extracted from the mothers' delivery files. A multivariable linear regression analysis was performed to evaluate the association between paraben levels and neonatal anthropometric indices. The median levels of urinary parabens, especially BP, were higher than those in other countries. Prenatal urinary concentration of MP and BP showed a significantly positive association with birth weight in all neonates (β = 0.79, 95% CI: 0.16, 1.41, and β = 8.56, 95% CI: 3.95, 13.17, respectively), while these chemicals showed a significant negative association with head circumference (β = - 0.002, 95% CI: - 0.004, - 0.000, and β = - 0.016, 95% CI: - 0.030, - 0.002, respectively). A significant positive association between MP and birth length was also found (β = 0.004, 95% CI: 0.00, 0.00) in all the neonates. In sex-stratified adjusted models, MP and BP were found to be associated, respectively, with higher birth length and weight in male neonates (β = 0.008, 95% CI: - 0.001, 0.017, and β = 7.948, 95% CI: 1.045, 14.851). In girls, maternal urinary MP, PP, and BP were associated with increased birth weight (β = 0.831, 95% CI: 0.043, 1.620; β = 4.178, 95% CI: 0.877, 7.480; and β = 10.821, 95% CI: 3.545, 18.097, respectively), and MP and BP were associated with reduced head circumference at birth (β = - 0.003, 95% CI: - 0.005, - 0.001, and β = - 0.035, 95% CI: - 0.055, - 0.016). These results revealed potential impacts between neonatal growth and maternal exposure to parabens. However, these findings should be interpreted while considering the limitations of the present study.

Does the food processing contaminant acrylamide cause developmental neurotoxicity? A review and identification of knowledge gaps

There is a worldwide concern on adverse health effects of dietary exposure to acrylamide (AA) due to its presence in commonly consumed foods. AA is formed when carbohydrate rich foods containing asparagine and reducing sugars are prepared at high temperatures and low moisture conditions. Upon oral intake, AA is rapidly absorbed and distributed to all organs. AA is a known human neurotoxicant that can reach the developing foetus via placental transfer and breast milk. Although adverse neurodevelopmental effects have been observed after prenatal AA exposure in rodents, adverse effects of AA on the developing brain has so far not been studied in humans. However, epidemiological studies indicate that gestational exposure to AA impair foetal growth and AA exposure has been associated with reduced head circumference of the neonate. Thus, there is an urgent need for further research to elucidate whether pre- and perinatal AA exposure in humans might impair neurodevelopment and adversely affect neuronal function postnatally. Here, we review the literature with emphasis on the identification of critical knowledge gaps in relation to neurodevelopmental toxicity of AA and its mode of action and we suggest research strategies to close these gaps to better protect the unborn child.

Whole Exome Sequencing Identifies Three Novel Mutations in the ASPM Gene From Saudi Families Leading to Primary Microcephaly.

Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental defect that is characterized by reduced head circumference at birth along with non-progressive intellectual disability. Till date, 25 genes related to MCPH have been reported so far in humans. The ASPM (abnormal spindle-like, microcephaly-associated) gene is among the most frequently mutated MCPH gene. We studied three different families having primary microcephaly from different regions of Saudi Arabia. Whole exome sequencing (WES) and Sanger sequencing were done to identify the genetic defect. Collectively, three novel variants were identified in the ASPM gene from three different primary microcephaly families. Family 1, showed a deletion mutation leading to a frameshift mutation c.1003del. (p.Val335*) in exon 3 of the ASPM gene and family 2, also showed deletion mutation leading to frameshift mutation c.1047del (p.Gln349Hisfs*18), while in family 3, we identified a missense mutation c.5623A>G leading to a change in protein (p.Lys1875Glu) in exon 18 of the ASPM gene underlying the disorder. The identified respective mutations were ruled out in 100 healthy control samples. In conclusion, we found three novel mutations in the ASPM gene in Saudi families that will help to establish a disease database for specified mutations in Saudi population and will further help to identify strategies to tackle primary microcephaly in the kingdom.

The effects of prenatal cigarette and e-cigarette exposure on infant neurobehaviour: A comparison to a control group

BackgroundInfant neurobehaviour provides an insight into the development of the central nervous system during infancy, with behavioural abnormalities highlighting a cause for concern. Research has demonstrated that prenatal exposure to cigarettes leads to deficits within neurobehavioural development, along with negative birth outcomes detrimental to subsequent development. With the growing use of e-cigarettes amongst pregnant women, this study explores how prenatal e-cigarette exposure compares to prenatal cigarette exposure.MethodsEighty-three infants were involved in the study, either exposed prenatally to cigarettes or e-cigarettes or not exposed to either. Differences were assessed between these three groups for birth outcomes and scores on the Neonatal Behavioural Assessment Scale (NBAS) at one month of age.FindingsBoth cigarette and e-cigarette exposed infants had a significantly greater number of abnormal reflexes (p = ·001; p = ·002). For both self-regulation and motor maturity, cigarette exposed infants performed significantly worse (p = ·010; p = ·002), with e-cigarette exposed infants having decreased motor maturity (p = ·036) abilities and marginally decreased for self-regulation (p = ·057). Birth outcomes, namely birthweight, gestation and head circumference, did not differ for e-cigarette exposed infants compared with infants who were not prenatally exposed to nicotine. Cigarette exposed infants had a significantly lower birthweight (p = ·021) and reduced head circumference (p = ·008) in comparison to non-exposed infants.InterpretationTo our knowledge, this is the first research study assessing a neurological outcome as a result of e-cigarette exposure. Findings of this have potentially important implications for public health policies regarding the safety and use of e-cigarettes throughout pregnancy.FundingThis research was funded by a doctoral training partnership scholarship via the ESRC, ES/P000762/1.

Microlissencephaly due to pathogenic variants of NDE1: from pathology to normal brain development

Pathogenic variants of the gene NDE1 (Nuclear Distribution Element 1) in humans lead to microlissencephaly which associates a reduced head circumference and a simplified gyration. Microlissencephaly is the most severe deficit of neurogenesis described to date but its precise physiopathological mechanism is not yet well known. The NDE1 gene encodes a phosphoprotein that is essential to neurogenesis and that is expressed in various cell compartments of neuroblasts. More than 60 interaction partners with NDE1 have been reported, notably various proteins involved in formation of the mitotic spindle, in ciliation, in genome protection of dividing neuroblasts or even in apoptosis (like LIS1, dynein or cohesin), which are all avenues that we explore in this review.

Understanding microcephaly through the study of centrosome regulation in Drosophila neural stem cells.

Microcephaly is a rare, yet devastating, neurodevelopmental condition caused by genetic or environmental insults, such as the Zika virus infection. Microcephaly manifests with a severely reduced head circumference. Among the known heritable microcephaly genes, a significant proportion are annotated with centrosome-related ontologies. Centrosomes are microtubule-organizing centers, and they play fundamental roles in the proliferation of the neuronal progenitors, the neural stem cells (NSCs), which undergo repeated rounds of asymmetric cell division to drive neurogenesis and brain development. Many of the genes, pathways, and developmental paradigms that dictate NSC development in humans are conserved in Drosophila melanogaster. As such, studies of Drosophila NSCs lend invaluable insights into centrosome function within NSCs and help inform the pathophysiology of human microcephaly. This mini-review will briefly survey causative links between deregulated centrosome functions and microcephaly with particular emphasis on insights learned from Drosophila NSCs.