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DYRK1A, a ubiquitously expressed kinase, is linked to the dominant intellectual developmental disorder, microcephaly, and Down syndrome in humans. It regulates numerous cellular processes such as cell cycle, vesicle trafficking, and microtubule assembly. DYRK1A is a critical regulator of organ growth; however, how it regulates organ growth is not fully understood. Here, we show that the knockdown of DYRK1A in mammalian cells results in reduced cell size, which depends on mTORC1. Using proteomic approaches, we found that DYRK1A interacts with the tuberous sclerosis complex (TSC) proteins, namely TSC1 and TSC2, which negatively regulate mTORC1 activation. Furthermore, we show that DYRK1A phosphorylates TSC2 at T1462, a modification known to inhibit TSC activity and promote mTORC1 activity. We also found that the reduced cell growth upon knockdown of DYRK1A can be rescued by overexpression of RHEB, an activator of mTORC1. Our findings suggest that DYRK1A inhibits TSC complex activity through inhibitory phosphorylation on TSC2, thereby promoting mTORC1 activity. Furthermore, using the Drosophila neuromuscular junction as a model, we show that the mnb, the fly homologs of DYRK1A, is rescued by RHEB overexpression, suggesting a conserved role of DYRK1A in TORC1 regulation.

Zika virus (ZIKV), a mosquito-borne flavivirus, is prominently associated with microcephaly in babies born to infected mothers as well as Guillain-Barré Syndrome in adults. Each cell type infected by ZIKV—neuronal cells (radial glial cells, neuronal progenitor cells, astrocytes, microglia cells, and glioblastoma stem cells) and non-neuronal cells (primary fibroblasts, epidermal keratinocytes, dendritic cells, monocytes, macrophages, and Sertoli cells)—displays its own characteristic changes to their cell physiology and has various impacts on disease. Here, we provide an in-depth review of the ZIKV life cycle and its cellular targets, and discuss the current knowledge of how infections cause neuropathologies, as well as what approaches researchers are currently taking to further advance such knowledge. A key aspect of ZIKV neuropathogenesis is virus-induced neuronal apoptosis via numerous mechanisms including cell cycle dysregulation, mitochondrial fragmentation, ER stress, and the unfolded protein response. These, in turn, result in the activation of p53-mediated intrinsic cell death pathways. A full spectrum of infection models including stem cells and co-cultures, transwells to simulate blood–tissue barriers, brain-region-specific organoids, and animal models have been developed for ZIKV research.

The estimated prevalence of intellectual disability (ID) is 10.37/1000 population. One of the major causes of ID is a chromosomal abnormality. SRY-related HMG-box 5 (SOX5) gene encodes a member of the SOX family of transcription factors, which may act as a transcriptional regulator involved in the regulation of chondrogenesis and the development of the nervous system by regulation of the production of subcortical projection neurons. Array-comparative genomic hybridization (array-CGH) is a molecular-cytogenetic method used to detect submicroscopic copy number variants within the genome, which is not visible by conventional karyotyping. We describe the extensive application of array-CGH in a 4-year-old male child who presented with global developmental delay (DD), behavioral abnormality, microcephaly, mild dysmorphic facial features, and constriction ring around prepuce with 12p12.1 microdeletion (166 kb deletion) involving SOX5 gene. The patient is under follow-up with a pediatrician, geneticist, speech therapist, and physiotherapist. A high index of suspicion for cytogenetic abnormalities should be present in a pediatric patient presenting with DD, genitourinary abnormalities, and associated with or without facial dysmorphism.

Abstract Background Zika virus (ZIKV), first discovered in Uganda in 1947, re-emerged globally in 2013 and was later associated with microcephaly and other birth defects. We determined the incidence of ZIKV infection and its association with adverse pregnancy and fetal outcomes in a pregnancy cohort in Kenya. Methods From October 2017 to July 2019, we recruited and followed up women aged ≥ 15 years and ≤ 28 weeks pregnant in three hospitals in coastal Mombasa. Monthly follow-up included risk factor questions and a blood sample collected for ZIKV serology. We collected anthropometric measures (including head circumference), cord blood, venous blood from newborns, and any evidence of birth defects. Microcephaly was defined as a head circumference (HC)

Abstract We present a 10‐year follow‐up and describe our experience in managing a case of neonatal severe primary hyperparathyroidism (NSHPT) for the first time in Iran. Microcephaly, mental retardation, and epilepsy may be long time sequels of NSHPT. The brain MRI findings are compatible with an old hypoxic–ischemic event.

Background: The 2015 – 2016 Zika epidemic highlighted gaps in health and social care services for parents of children with developmental disabilities. In response, we developed the ‘Juntos’ intervention, a 10 week community-based early intervention support group for parents of children with congenital Zika syndrome (CZS). The intervention's components include participatory learning sessions, practical skill acquisition, peer support, and psychological support, aiming to improve caregiver’s knowledge and confidence in caring for their children. This study aimed to evaluate the feasibility of implementing ‘Juntos’ in Colombia. Methods: Two facilitators delivered ‘Juntos’ to four groups of 8-10 caregivers between 2017 and 2018. One researcher observed each group. Data were collected from: observation notes from 40 sessions, focus group discussions held after each session, pre- post intervention questionnaires with 34 caregivers, and semi-structured interviews conducted with four facilitators, 12 caregivers and three stakeholders. We used the Bowen framework in data analysis. Results: The feasibility evaluation revealed that 'Juntos' was highly acceptable and in demand among the target population. The intervention was predominantly delivered with fidelity. Practicality was facilitated by providing transport costs and selecting convenient locations. Additional organisational and social media support was required for successful implementation. Community health worker training may support integration and the established groups could facilitate programme expansion. However, participants perceived lack of prioritisation as a limitation within existing health systems. Participants’ knowledge and confidence to care for their child improved after programme enrolment. Conclusion: The 'Juntos' intervention demonstrated high acceptability, demand, and practicality in supporting parents of children with CZS in Colombia. However, its implementation faces challenges due to existing gaps in health system support for children with CZS.

WDR62 is a spindle pole-associated scaffold protein with pleiotropic functions. Recessive mutations in WDR62 cause structural brain abnormalities and account for the second most common cause of autosomal recessive primary microcephaly (MCPH), indicating WDR62 as a critical hub for human brain development. Here, we investigated WDR62 function in corticogenesis through the analysis of a C-terminal truncating mutation (D955AfsX112). Using induced Pluripotent Stem Cells (iPSCs) obtained from a patient and his unaffected parent, as well as isogenic corrected lines, we generated 2D and 3D models of human neurodevelopment, including neuroepithelial stem cells, cerebro-cortical progenitors, terminally differentiated neurons, and cerebral organoids. We report that WDR62 localizes to the Golgi apparatus during interphase in cultured cells and human fetal brain tissue, and translocates to the mitotic spindle poles in a microtubule-dependent manner. Moreover, we demonstrate that WDR62 dysfunction impairs mitotic progression and results in alterations of the neurogenic trajectories of iPSC neuroderivatives. In summary, impairment of WDR62 localization and function results in severe neurodevelopmental abnormalities, thus delineating new mechanisms in the etiology of MCPH.

Background: Microcephaly is a condition that causes a reduction in brain volume as well as cognitive and motor impairments. It can be seen alone or in conjunction with a variety of genetic disorders and environmental factors. Microcephaly is still a poorly defined condition, identifying the etiological causes is critical for providing genetic counseling, and preventing potential consequences. Objective: The aim of this study was to assess the etiology, diagnosis, and management of the childhood microcephaly. Methods: We conducted a retrospective analysis on 50 children with microcephaly (25 males, 25 females) who presented to University of Health Sciences, Ankara Keçiören Training and Research Hospital between 2017-2021.The demographic features of the patients, neuroimaging, clinical and laboratory findings were examined. Results: The etiology of microcephaly was documented in 76% of all patients. Genetic causes were identified in 16 % of the patients; including Aicardi Goutieres Syndrome,Williams Syndrome , Wolfram Syndrome, Rett Syndrome and Asparagine Synthetase Deficiency. Syndactyly, scoliosis, Poland syndrome, dysmorphic face, alopecia, auricular ear deformities, hearing loss, strabismus, nystagmus, hydronephrosis, single umbilical artery, and cardiac septal defect were detected systemic malformations associated with microcephaly. In sixty percent of the patients, a neuroimaging was performed; results were abnormal in 24% of the patients. The mean follow-up period of the patients was 1.88± 0.6 years. Cognitive impairment was associated with microcephaly in 38% of the cases, and epilepsy in 20%. Of those 28% of the children required special education. One patient was operated by neurosurgeon due to craniosynostosis. Conclusion: Microcephaly is still a poorly defined condition, identifying the etiological causes is critical for providing genetic counseling, and preventing potential consequences.

ABSTRACT Objective To analyze the relationship between microcephaly and social inequality indicators in the state of Paraíba during the biennium January 2015 and December 2016. Methods Ecological study with data from newborn microcephaly records and municipal socioeconomic, environmental, and demographic indicators was conducted using two health information systems from the Brazilian Ministry of Health (SINASC and SINAN) and the Brazilian Institute of Geography and Statistics. A Poisson multiple regression model was applied with a significance level of 5%. Results Among 223 municipalities in Paraíba, 74 registered new cases of microcephaly. The number of Zika virus cases, number of inhabitants, number of households without adequate water supply, and household income were predictor variables of the number of new cases of microcephaly in Paraíba. Conclusion Microcephaly is associated with indicators of social inequality in Paraíba. Zika virus cases, water supply, and family income are the indicators that best explain the increase in microcephaly cases. Therefore, these variables must be monitored by health professionals and authorities.

With the increase in cases of microcephaly caused by the Zika virus, the demand for special care and a better quality of life for the child and caregiver increased proportionally. Objective This study aimed to analyze the burden on caregivers of children with congenital Zika syndrome associated with viral infections in the state of Pernambuco, Brazil using the Zarit Burden interview scale. Method A quantitative study was conducted at the Oswaldo Cruz University Hospital, Recife City, State of Pernambuco, Brazil. By convenience sampling, 56 mothers, two grandmothers, and two caregivers were enrolled, all are female. Data were collected from July 2019 to January 2020. In the analysis, the percentage frequencies were calculated. The normality was identified using the Kolmogorov–Smirnov test, and participant profiles were compared using Student’s t-test and analysis of variance. In descriptive statistics, quantitative variables are described by the median and interquartile range and categorical variables by proportions using the Chi-square test. Results In the comparative analysis, all factors evaluated were significant, except for the “gestational period in which the disease occurred” (p

Abstract Fanconi anemia, FA, is a rare, multi‐system disease caused by pathogenic variants in DNA repair genes. We report a novel RAD51 variant in an infant with FA whose tracheobronchomalacia has not been described in FA. His severe presentation expands the phenotype of RAD51‐associated FA, reported only in three patients previously.

Introduction Prenatal exposure to the Zika virus can impair neurodevelopment and cause auditory damage. Objective To analyze the frequency-following response (FFR) and the auditory behavior (with the LittlEars ® questionnaire) of children with and without prenatal exposure to Zika virus infection. Methods A total of 30 children participated in the present study, divided into 3 groups: 10 children with microcephaly and prenatal exposure to the Zika virus; 10 normocephalic children with prenatal exposure to the Zika virus; and 10 children with no evidence of prenatal exposure to the virus. The FFR test was performed with the /da/ syllable. The LittlEars ® questionnaire was used with parents/guardians. Results For the FFR measurements, there was no difference between the groups. The children with exposure to the Zika virus presented a final score in the questionnaire below what is expected from children with normal hearing. A significant difference was observed for the final, semantic, and expressive scores between the group with microcephaly and the other groups. A strong negative correlation was seen between the LittlEars ® questionnaire final score and the FFR measurements for the group with microcephaly when compared with the other groups. Conclusion Children exposed to the Zika virus, with and without microcephaly, presented FFR patterns similar to what was seen in children with no evidence of virus exposure. However, they showed signs of immature auditory behavior, suggesting auditory development delay.

Abstract Feingold syndrome 1 (FS1) is a rare disorder that is inherited in autosomal dominant manner with full penetrance but with variable expressivity. The most common phenotypical features described are finger and toe anomalies, microcephaly, short stature, and intestinal atresia. Dysmorphic features, intellectual disability and other organ anomalies are less frequently described. Here, we present a 7‐year‐old boy with severe intellectual disability who is diagnosed with FS1 syndrome caused by a new heterozygous variant of MYCN gene

Abstract A novel splice site mutation in the GTPBP2 gene was identified by whole‐exome sequencing in two siblings with microcephaly and progressive generalized muscular atrophy associated with hypotrichosis.

Abstract Background Coat protein complex 1 (COPI) is integral in the sorting and retrograde trafficking of proteins and lipids from the Golgi apparatus to the endoplasmic reticulum (ER). In recent years, coat proteins have been implicated in human diseases known collectively as “coatopathies”. Methods Whole exome or genome sequencing of two families with a neuro-developmental syndrome, variable microcephaly and cataracts revealed biallelic variants in COPB1, which encodes the beta-subunit of COPI (β-COP). To investigate Family 1’s splice donor site variant, we undertook patient blood RNA studies and CRISPR/Cas9 modelling of this variant in a homologous region of the Xenopus tropicalis genome. To investigate Family 2’s missense variant, we studied cellular phenotypes of human retinal epithelium and embryonic kidney cell lines transfected with a COPB1 expression vector into which we had introduced Family 2’s mutation. Results We present a new recessive coatopathy typified by severe developmental delay and cataracts and variable microcephaly. A homozygous splice donor site variant in Family 1 results in two aberrant transcripts, one of which causes skipping of exon 8 in COPB1 pre-mRNA, and a 36 amino acid in-frame deletion, resulting in the loss of a motif at a small interaction interface between β-COP and β’-COP. Xenopus tropicalis animals with a homologous mutation, introduced by CRISPR/Cas9 genome editing, recapitulate features of the human syndrome including microcephaly and cataracts. In vitro modelling of the COPB1 c.1651T>G p.Phe551Val variant in Family 2 identifies defective Golgi to ER recycling of this mutant β-COP, with the mutant protein being retarded in the Golgi. Conclusions This adds to the growing body of evidence that COPI subunits are essential in brain development and human health and underlines the utility of exome and genome sequencing coupled with Xenopus tropicalis CRISPR/Cas modelling for the identification and characterisation of novel rare disease genes.

We examined pregnant women’s use of personal protective measures to prevent mosquito bites during the 2016–2017 Zika outbreak in Puerto Rico. Healthcare provider counseling on recommended measures was associated with increased use of insect repellent among pregnant women but not with wearing protective clothing.

Background: The 2015-16 Zika epidemic resulted in thousands of children born with congenital Zika syndrome (CZS). In Brazil, gaps in the health system often caused parents to be left with insufficient information and support. Consequently, we developed and piloted Juntos - a participatory support programme which aims to improve knowledge, capacities and build support networks for caregivers of children with CZS. Methods: Six caregiver groups received the programme between August 2017 and June 2018: three in Rio de Janeiro and three in Bahia. We assessed the feasibility of Juntos against six of the eight areas of a feasibility framework described by Bowen et al. to consider whether Juntos ‘could work’. These areas were: acceptability, demand, implementation, practicality, adaptation and limited efficacy. We used mixed methods including: 1) baseline and end-line questionnaires completed by all group participants; 2) in-depth interviews with 18 participants, seven facilitators and three key stakeholders; 3) participant focus group discussions after each session; 4) researchers session observation; and 5) recording programme costs. Results: 37/48 (77%) enrolled families completed both questionnaires. Acceptability and demand were noted as high, based on participant responses to interview questions, focus group feedback and satisfaction scores. Potential for implementation and practicality were also demonstrated through interviews with facilitators and key stakeholders and analysis of project documents. Two groups included caregivers of children with non-Zika related developmental disabilities, showing potential for adaptability. Self-reported quality of life scores increased in caregivers between baseline and end-line, as did the dimensions of family relationships and daily activities in the Pediatric Quality of Life Inventory (PEDS QL) Family Impact Module, showing limited efficacy. Conclusions: The programme showed feasibility according to Bowen’s framework. However, further research of scale up, particularly in the areas of integration, expansion and limited efficacy are needed to ascertain if the programme is effective.

Cyclin-dependent kinase-like-5 (CDKL5) deficiency disorder (CDD) is a severe X-linked neurodegenerative disease characterised by early-onset epileptic seizures, low muscle tone, progressive intellectual disability and severe motor function. CDD affects ∼1 in 60,000 live births, with many patients experiencing a reduced quality of life due to the severity of their neurological symptoms and functional impairment. There are no effective therapies for CDD, with current treatments focusing on improving symptoms rather than addressing the underlying causes of the disorder. Zebrafish offer many unique advantages for high-throughput preclinical evaluation of potential therapies for neurological diseases, including CDD. In particular, the large number of offspring produced, together with the possibilities for in vivo imaging and genetic manipulation, allows for the detailed assessment of disease pathogenesis and therapeutic discovery. We have characterised a loss-of-function zebrafish model for CDD, containing a nonsense mutation in cdkl5. cdkl5 mutant zebrafish display defects in neuronal patterning, seizures, microcephaly, and reduced muscle function caused by impaired muscle innervation. This study provides a powerful vertebrate model for investigating CDD disease pathophysiology and allowing high-throughput screening for effective therapies. This article has an associated First Person interview with the first author of the paper.

Introduction: The risk of Iron Deficiency (ID) is a major concern associated with exclusively breastfed infants of age 4-6 months. According to World Health Organisation (WHO) iron should be universally supplemented from six months onwards instead of four months as recommended by American Academy of Paediatrics (AAP). Aim: To determine ID and Iron Deficiency Anaemia (IDA) among infants of age 4-6 months and relation of same to various socioeconomic and maternal parameters. Materials and Methods: This was a hospital-based, prospective, cross-sectional study conducted in the Department of Paediatrics of a tertiary care hospital in India. It included a sample population of 200 exclusively breastfed term infants, of age 4-6 months. Iron status was determined by studying the haemoglobin and serum ferritin levels and their associations to demographic, socio-economic and maternal parameters. Qualitative variables were analysed using the Chi-square test/Fisher’s-exact test. Univariate and multivariate logistic regression was used to find out significant risk factors of ID and IDA. Results: Age wise distribution of infants was 91 (45.5%), 62 (31%), and 47 (23.5%) at 4, 5, and 6 months. Male-to-female ratio was 1.7:1. Mean±SD value of haemoglobin and serum ferritin was 10.82±0.60 g/dL and 44.60±25.02 μg/L, respectively. Prevalence of ID was 11 (12.09%), 16 (25.81%), and 16 (34.04%) at ages 4, 5, and 6 months, respectively. On multivariate regression analysis, age of mother

Adenylosuccinate lyase (ADSL) functions in de novo purine synthesis (DNPS) and the purine nucleotide cycle. ADSL deficiency (ADSLD) causes numerous neurodevelopmental pathologies, including microcephaly and autism spectrum disorder. ADSLD patients have normal serum purine nucleotide levels but exhibit accumulation of dephosphorylated ADSL substrates, S-Ado, and SAICAr, the latter being implicated in neurotoxic effects through unknown mechanisms. We examined the phenotypic effects of ADSL depletion in human cells and their relation to phenotypic outcomes. Using specific interventions to compensate for reduced purine levels or modulate SAICAr accumulation, we found that diminished AMP levels resulted in increased DNA damage signaling and cell cycle delays, while primary ciliogenesis was impaired specifically by loss of ADSL or administration of SAICAr. ADSL-deficient chicken and zebrafish embryos displayed impaired neurogenesis and microcephaly. Neuroprogenitor attrition in zebrafish embryos was rescued by pharmacological inhibition of DNPS, but not increased nucleotide concentration. Zebrafish also displayed phenotypes commonly linked to ciliopathies. Our results suggest that both reduced purine levels and impaired DNPS contribute to neurodevelopmental pathology in ADSLD and that defective ciliogenesis may influence the ADSLD phenotypic spectrum.

Objective. To establish the risk of microcephaly in neonates born to women infected with ZIKV during pregnancy. Methods. A cohort of laboratory-confirmed ZIKV cases of congenital infections (109 mothers infected during pregnancy and 101 newborns) among 308 suspect cases was followed in Belem, Pará, Brazil, from October 2015 to December 2017. Results. A microcephaly risk of 1.98% (95% CI 0.54-6.93%) was found, or 2 cases among the 101 neonates infected with ZIKV during pregnancy. 72% of the pregnant women had ZIKV infection confirmed by RT-qPCR during gestation. Conclusions. Results showed a low incidence of ZIKV-associated birth defects, stillbirth, and miscarriage, which contrasts with previous studies in other Brazilian regions. Previous exposure to yellow fever vaccine and/or multiserotype DENV infection could be implicated in the protection from ZIKV congenital infection.

Background: Congenital infection is a primary cause of malformations during infancy including hydrocephaly and microcephaly. In addition, cytomegalovirus and toxoplasma are the two prevalent causes of congenital infections. The present research aimed to investigate the prevalence of cytomegalovirus and toxoplasma infections among neonates afflicted with microcephaly and hydrocephaly in a pediatric hospital in 2018. Materials and Methods: The present descriptive, cross-sectional research was conducted on all neonates diagnosed with microcephaly and hydrocephaly hospitalized in the pediatric hospital of Bandar Abbas in 2018. Blood samples were taken from the neonates to be analyzed for cytomegalovirus and toxoplasma serology, followed by statistically analyzing the information describing 11 subjects including 5 hydrocephaly and 6 microcephaly cases. Results: The mean gestational age was estimated at 35.8±4.08 and 37.16±1.32 weeks in hydrocephaly and microcephaly groups, respectively (P=0.507). In both groups, the female population was larger than the males. In addition, blood relations among parents were stronger in the microcephaly group (40%) compared to the microcephaly group (83.3%). Moreover, the anomaly was found to be more in the microcephaly group. This rate was 60% and 16.7% in the hydrocephaly and microcephaly groups, respectively. The serology of cytomegalovirus and toxoplasma in neither groups showed to be positive. One hundred percent of patients with an anomaly were term although 50% of those without any anomaly belonged to the term group. It appears that the presence of an anomaly was positively correlated with term birth. One hundred percent of patients with an anomaly were found to have parents who were close relatives. However, 50% of patients with no anomaly showed to have parents closely related in the family. Finally, heart problems were found to prevail in the group diagnosed with an anomaly. Conclusion: In the present research, the prevalence of cytomegalovirus and toxoplasma infections was reported to be zero in neonates who were afflicted with microcephaly and hydrocephaly.

During 2015–2016, Cape Verde, an island nation off the coast of West Africa, experienced a Zika virus (ZIKV) outbreak involving 7,580 suspected Zika cases and 18 microcephaly cases. Analysis of the complete genomes of 3 ZIKV isolates from the outbreak indicated the strain was of the Asian (not African) lineage. The Cape Verde ZIKV sequences formed a distinct monophylogenetic group and possessed 1–2 (T659A, I756V) unique amino acid changes in the envelope protein. Phylogeographic and serologic evidence support earlier introduction of this lineage into Cape Verde, possibly from northeast Brazil, between June 2014 and August 2015, suggesting cryptic circulation of the virus before the initial wave of cases were detected in October 2015. These findings underscore the utility of genomic-scale epidemiology for outbreak investigations.

Abstract Background DNA Ligase IV (LIG4) syndrome is a rare disease with few reports to date. Patients suffer from a broad spectrum of clinical features, including microcephaly, growth retardation, developmental delay, dysmorphic facial features, combined immunodeficiency, and malignancy predisposition. There may be a potential association between genotypes and phenotypes. We investigated the characteristics of LIG4 syndrome in a Chinese cohort. Results All seven patients had growth restriction. Most patients (6/7) had significant microcephaly (< − 3 SD). Recurrent bacterial infections of the lungs and intestines were the most common symptoms. One patient had myelodysplastic syndromes. One patient presented with an inflammatory bowel disease (IBD)-like phenotype. Patients presented with combined immunodeficiency. The proportions of naïve CD4+ and naïve CD8+ T cells decreased notably in five patients. All patients harbored compound heterozygous mutations in the LIG4 gene, which consisted of a missense mutation (c.833G > T, p.R278L) and a deletion shift mutation, primarily c.1271_1275delAAAGA (p.K424Rfs*20). Two other deletion mutations, c.1144_1145delCT and c.1277_1278delAA, were novel. Patients with p.K424Rfs*20/p.R278 may have milder dysmorphism but more significant IgA/IgM deficiency compared to the frequently reported genotype p.R814X/p.K424Rfs*20. One patient underwent umbilical cord blood stem cell transplantation (UCBSCT) but died. Conclusions The present study reported the clinical and molecular characteristics of a Chinese cohort with LIG4 syndrome, and the results further expand the phenotypic and genotypic spectrum and our understanding of genotype-to-phenotype correlations in LIG4 syndrome.

Autosomal recessive primary microcephaly; MCPH is a rare neurologically condition observed in new born at the birth. Most patients suffer from moderate to severe intellectual disability. In this review article, we introduce MCPH disorder; include all of the chromosomal locations, kind of MCPH genes and numbers of mutations, functional efficacy, how to identify the genes separately and diagnostic algorithm of articles and data base such as OMIM, HGMD. 23 locations genes (MCPH1-23) have been recognized causes primary microcephaly in different population, so far. Function of them is to correct orientation of mitosis spindles, duplication of DNA, organization and function of centrosome, transfer of vesicles, transcription regulation, response to DNA lesion, etc. According to investigations, MCPH in Iran and Pakistan population is common because of more consanguinity marriage. MCPH1 and MCPH5 genes are more common in Iran. Recent advances in molecular biological techniques and animal models have helped to identify the genetic cause of microcephaly and open up the horizons for researchers in the field, and also elucidating of the underlying molecular mechanisms will improve our understanding of the structure and function of the brain.

Zika virus remains a major public health concern because of its association with microcephaly and other neurologic disorders in newborns. A prophylactic vaccine has the potential to reduce disease incidence and eliminate birth defects resulting from prenatal Zika virus infection in future outbreaks. We evaluated the cost-effectiveness of a Zika vaccine candidate, assuming a protection efficacy of 60%–90%, for 18 countries in the Americas affected by the 2015–2017 Zika virus outbreaks. Encapsulating the demographics of these countries in an agent-based model, our results show that vaccinating women of reproductive age would be very cost-effective for sufficiently low (75% with vaccination. These findings indicate that targeted vaccination of women of reproductive age is a noteworthy preventive measure for mitigating the effects of Zika virus infection in future outbreaks.

Abstract: 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.

Although Zika virus (ZIKV) circulates in sub-Saharan Africa, no case of ZIKV-associated microcephaly has thus far been reported. Here, we report evidence of a possible association between a 2007 outbreak of febrile illness and an increase in microcephaly and possibly ZIKV infection in Gabon.

Congenital microcephaly is caused by a multitude of drivers affecting maternal–fetal health during pregnancy. It is a rare outcome in high-income industrial countries where microcephaly rates are in the range of 0.3–0.9 per 1000 newborns. Prevalence of microcephaly varies considerably across developing countries and can go as high as 58 cases per 1000 live births in pregnancies exposed to infection by Zika virus (ZIKV). Not only ZIKV-infected pregnancies, but other drivers can modulate the occurrence and severity of this outcome. Here, we sought to test the ZIKV–microcephaly association vs. competing hypotheses using a meta-analysis with 8341 microcephaly cases pooled from 10,250,994 newborns in the Americas, Africa, and Asia. Analysis of risk ratios (RR) showed teratogens the most likely microcephaly-associated risk factor (RR = 3.43; 95%-CI 2.69–4.38; p-value < 0.0001), while the statistical significance of the ZIKV–microcephaly association was marginal (RR = 2.12; 95%-CI 1.01–4.48; p-value = 0.048). Other congenital infections showed strong but variable associations with microcephaly (RR = 15.24; 95%-CI 1.74–133.70; p-value = 0.014). Microcephaly cases were associated with impoverished socioeconomic settings, but this association was statistically non-significant (RR = 2.75; 95%-CI 0.55–13.78; p-value = 0.22). The marginal ZIKV–microcephaly association and statistical significance of the competing hypotheses suggest maternal ZIKV infection might not be a cause of microcephaly alone.

Flaviviruses are small RNA viruses that are mainly transmitted via arthropod vectors and are found in tropic and sub-tropical regions. Most infections are asymptomatic (90–95%), but symptoms can be as severe as hemorrhagic fever and encephalitis. One recently emerged flavivirus is Zika virus (ZIKV), which was originally isolated from rhesus monkeys in Uganda roughly 70 years ago but has recently spread east, reaching S. America in 2015–2016. This outbreak was associated with the development of Guillain–Barré syndrome in adults and microcephaly in infants born to expectant mothers infected early in pregnancy. ZIKV must traverse the placenta to impact the development of the fetus, but the mechanisms responsible are unknown. While flaviviruses are known to disrupt splicing patterns in host cells, little is known about how flaviviruses such as ZIKV impact the alternative polyadenylation (APA) of host transcripts. This is important as APA is well-established as a mechanism in the regulation of mRNA metabolism and translation. Thus, we sought to characterize transcriptomic changes including APA in human placental (JEG3) cells in response to ZIKV infection using Poly(A)-ClickSeq (PAC-Seq). We used our differential Poly(A)-cluster (DPAC) analysis pipeline to characterize changes in differential gene expression, alternative poly-adenylation (APA) and the use of alternative terminal exons. We identified 98 upregulated genes and 28 downregulated genes. Pathway enrichment analysis indicated that many RNA processing and immune pathways were upregulated in ZIKV-infected JEG3 cells. We also updated DPAC to provide additional metrics of APA including the percentage-distal usage index (PDUI), which revealed that APA was extensive and the 3′ UTRs of 229 genes were lengthened while 269 were shortened. We further found that there were 214 upregulated and 59 downregulated poly(A)-clusters (PACs). We extracted the nucleotide sequences surrounding these PACs and found that the canonical signals for poly-adenylation (binding site for poly-A binding protein (PABP) upstream and a GU-rich region down-stream of the PAC) were only enriched in the downregulated PACs. These results indicate that ZIKV infection makes JEG3 cells more permissive to non-canonical poly-adenylation signals.

Argininemia is an autosomal recessive urea cycle disorder caused by the deficiency of arginase. Our first case presented with psychomotor retardation, difficulty of walking, and progressive tiptoeing. Laboratory investigations revealed mildly elevated hepatic enzymes and elevated plasma arginine concentration. Molecular genetic analysis was performed for suspected argininemia and a novel homozygous mutation c. 231C> A (p. S77R) was detected in the ARG1 gene. The second patient was admitted because of poor head control when he was aged 6 months. Microcephaly was detected in his physical examination, and basic metabolic tests were studied. Elevated levels of plasma arginine and orotic acid in urine organic acid analysis were compatible with argininemia. A homozygous mutation c.703G> C (p. G235R) was detected in the ARG1 gene and the diagnosis was confirmed. Arginineemia is a rare cause of progressive spastic diplegia. Patients may be mistakenly diagnosed as having cerebral palsy. Microcephaly may be the initial clinical finding of the disorder.

Zika virus infection during pregnancy may result in birth defects and pregnancy complications. We describe the Zika virus outbreak in pregnant women in the Dominican Republic during 2016–2017. We conducted multinomial logistic regression to identify factors associated with fetal losses and preterm birth. The Ministry of Health identified 1,282 pregnant women with suspected Zika virus infection, a substantial proportion during their first trimester. Fetal loss was reported for ≈10% of the reported pregnancies, and 3 cases of fetal microcephaly were reported. Women infected during the first trimester were more likely to have early fetal loss (adjusted odds ratio 5.9, 95% CI 3.5–10.0). Experiencing fever during infection was associated with increased odds of premature birth (adjusted odds ratio 1.65, 95% CI 1.03–2.65). There was widespread morbidity during the epidemic. Our findings strengthen the evidence for a broad range of adverse pregnancy outcomes resulting from Zika virus infection.

Abstract Background The TUBA1A-associated tubulinopathy is clinically heterogeneous with brain malformations, microcephaly, developmental delay and epilepsy being the main clinical features. It is an autosomal dominant disorder mostly caused by de novo variants in TUBA1A. Results In three individuals with developmental delay we identified heterozygous de novo missense variants in TUBA1A using exome sequencing. While the c.1307G > A, p.(Gly436Asp) variant was novel, the two variants c.518C > T, p.(Pro173Leu) and c.641G > A, p.(Arg214His) were previously described. We compared the variable phenotype observed in these individuals with a carefully conducted review of the current literature and identified 166 individuals, 146 born and 20 fetuses with a TUBA1A variant. In 107 cases with available clinical information we standardized the reported phenotypes according to the Human Phenotype Ontology. The most commonly reported features were developmental delay (98%), anomalies of the corpus callosum (96%), microcephaly (76%) and lissencephaly (agyria-pachygyria) (70%), although reporting was incomplete in the different studies. We identified a total of 121 specific variants, including 15 recurrent ones. Missense variants cluster in the C-terminal region around the most commonly affected amino acid position Arg402 (13.3%). In a three-dimensional protein model, 38.6% of all disease-causing variants including those in the C-terminal region are predicted to affect the binding of microtubule-associated proteins or motor proteins. Genotype-phenotype analysis for recurrent variants showed an overrepresentation of certain clinical features. However, individuals with these variants are often reported in the same publication. Conclusions With 166 individuals, we present the most comprehensive phenotypic and genotypic standardized synopsis for clinical interpretation of TUBA1A variants. Despite this considerable number, a detailed genotype-phenotype characterization is limited by large inter-study variability in reporting.

Introduction: Zika virus disease (ZVD) is a mosquito-borne arbovirus infection caused by Zika virus, a Flavivirus from the Flaviviridae family spread via a type of mosquito called Aedes mosquito, namely Aedes aegypti and Aedes albopictus which is also responsible for spreading diseases such as dengue, chikungunya, and yellow fever. Outbreaks of ZVD have been recorded in Africa, the Americas, Asia, and the Pacific. Materials and Methods: A cross-sectional study with complete enumeration was carried out among non-PG junior residents (JRs) of a tertiary care hospital of Delhi. Those who agreed to fill the questionnaire were included in the study after written consent. A self-administered, pretested, semistructured questionnaire, consisted of three sections, is used. Results: 125 (72.7%) participants had heard about ZVD, and almost 61% of participants believed A. aegypti to be the vector for transmission of ZVD. More than 80% of participants believed that ZVD outbreak is possible in India. The various reasons they quoted for the outbreak were environmental factors (50%), travel and immigration (16.3%), unawareness and unpreparedness (11.5%), host factors (9.6%), agent factors (6.4%), and easy transmission (4.7%). Approximately 90% of the study participants who have heard of ZVD knew that travel to the endemic area should be postponed. Participants with high level of knowledge according to knowledge score think that ZVD outbreak is possible in India in the future and they tried to gain more knowledge about ZVD. The results were found to be statistically significant. Conclusion: It can be concluded that the low knowledge among JR area is worrisome and a great deal of importance needs to be paid because health-care providers should be able to identify and screen potential patients to prevent further progression of this disease.

Zika virus (ZIKV) was an emergent flavivirus transmitted by Aedes genus mosquitoes and made an explosive outbreak in Latin America in 2015. A few months later, an obvious increase in the number of microcephaly neonates has been observed, which might be related to ZIKV infection during the mothers’ pregnancy. Since then, researchers in many countries and territories have been working on the causal link between ZIKV and microcephaly and have made a number of achievements. To summarize the most recent evidence and the contribution of Chinese researchers on this issue, and to provide perspectives and challenges for future studies, we reviewed the literature of both microcephaly and ZIKV. Based on previous research results, ZIKV has been preliminarily proved to be the direct cause of microcephaly in newborns and Chinese researchers have made many important discoveries in the pathogenesis of microcephaly. Even so, future researches should also further investigate the mechanism of ZIKV-related microcephaly to advance the development of therapeutic and preventive strategies.

Abstract Background Galloway-Mowat syndrome (GAMOS) is a rare autosomal recessive disease characterized by the combination of glomerulopathy with early-onset nephrotic syndrome and microcephaly with central nervous system anomalies. Given its clinical heterogeneity, GAMOS is believed to be a genetically heterogenous group of disorders. Recently, it has been reported that mutations in KEOPS-encoding genes, including the OSGEP gene, were responsible for GAMOS. Results Overall, 6 patients from 5 different Taiwanese families were included in our study; the patients had an identical OSGEP gene mutation (c.740G > A transition) and all exhibited a uniform clinical phenotype with early-onset nephrotic syndrome, craniofacial and skeletal dysmorphism, primary microcephaly with pachygyria, and death before 2 years of age. We reviewed their clinical manifestations, the prenatal and postnatal presentations and ultrasound findings, results of imaging studies, associated anomalies, and outcome on follow-up. All individuals were found to have an “aged face” comprising peculiar facial dysmorphisms. Arachnodactyly or camptodactyly were noted in all patients. Neurological findings consisted of microcephaly, hypotonia, developmental delay, and seizures. Brain imaging studies all showed pachygyria and hypomyelination. All patients developed early-onset nephrotic syndrome. The proteinuria was steroid-resistant and eventually resulted in renal function impairment. Prenatal ultrasound findings included microcephaly, intrauterine growth restriction, and oligohydramnios. Fetal MRI in 2 patients confirmed the gyral and myelin abnormalities. Conclusions Our study suggests that a careful review of the facial features can provide useful clues for an early and accurate diagnosis. Prenatal ultrasound findings, fetal MRI, genetic counseling, and mutation analysis may be useful for an early prenatal diagnosis.

Mutations of SMC5/6 components cause developmental defects, including primary microcephaly. To model neurodevelopmental defects, we engineered a mouse wherein Smc5 is conditionally knocked out (cKO) in the developing neocortex. Smc5 cKO mice exhibited neurodevelopmental defects due to neural progenitor cell (NPC) apoptosis, which led to reduction in cortical layer neurons. Smc5 cKO NPCs formed DNA bridges during mitosis and underwent chromosome missegregation. SMC5/6 depletion triggers a CHEK2-p53 DNA damage response, as concomitant deletion of the Trp53 tumor suppressor or Chek2 DNA damage checkpoint kinase rescued Smc5 cKO neurodevelopmental defects. Further assessment using Smc5 cKO and auxin-inducible degron systems demonstrated that absence of SMC5/6 leads to DNA replication stress at late-replicating regions such as pericentromeric heterochromatin. In summary, SMC5/6 is important for completion of DNA replication prior to entering mitosis, which ensures accurate chromosome segregation. Thus, SMC5/6 functions are critical in highly proliferative stem cells during organism development.

Introduction We present temporal and spatial variation of deaths from microcephaly in children under 1 year of age is analyzed at regional, state, and municipal level in the pre-Zika period in Brazil. Materials and Methods Data on births and deaths of infants with microcephaly was obtained from DATASUS from 1996 to 2013. Infant mortality rate from microcephaly (IMR-M) was estimated at Region, Federative Unit (UF), and Municipality level. Secular trend (ST) and risk of death variation were estimated using a Poisson regression model. Satscan software was used to obtain a statistic spatial scan for the Poisson model. Results IMR-M shows a non-significant negative ST in the Southeast, South and Central West Regions of Brazil. A greater IMR-M risk of death variation is found in the North and Northeast Regions. Most UFs in the Southeast, South and Central West Regions showed a negative ST, in contrast to what occurs in the UFs of the North and Northeast Regions showed a positive ST. Six high risk significant clusters were found: 3 in the North-Northeast and 3 in the South-SouthWest-Center-West. Conclusions The North and Northeast Regions showed positive ST for IRM-M and higher death risk, which was not observed in the other regions. Cluster distribution for higher IMR-M and risk resembles the distribution of the microcephaly and Zika cases in the outbreak period.

Introduction: Microcephaly is a clinical finding that can arise from congenital anomalies or emerge after childbirth. Maternal infections acquired during pregnancy can result in characteristic brain damage in the newborn (NB), which may be visible even in the fetal stage. Objective: To describe the epidemiological profile of newborns with reported microcephaly and diagnosed with congenital infections in the state of Rio Grande do Sul between 2015 and 2017. Method: A cross-sectional study was carried out on data collected from the Public Health Event Registry as well as from medical records. The investigation included serologies for toxoplasmosis and rubella; polymerase chain reaction (PCR) for Zika virus (ZIKV) in the blood and cytomegalovirus in the urine; non-treponemal tests for syphilis; and brain imaging tests. Results: Of the 257 reported cases of microcephaly, 39 were diagnosed with congenital infections. Severe microcephaly was identified in 13 patients (33.3%) and 51.3% of the cases showed alterations in brain imaging tests. In relation to the diagnosis of congenital infections, three patients (7.7%) were diagnosed with ZIKV, nine (23.1%) with cytomegalovirus, nine (23.1%) with toxoplasmosis, and 18 (46.1%) with congenital syphilis. The three cases of ZIKV showed calcification in brain imaging tests, signs of arthrogryposis, excess occipital skin and irritability, characterizing the typical phenotype of ZIKV infection. Conclusion: Most cases of congenital infection had severe neurological lesions, particularly the cases of ZIKV, which can cause neurodevelopmental delays and sequelae in these infants throughout early childhood. Keywords: Microcephaly; Congenital Infection; Zika Virus

Occludin (OCLN) mutations cause human microcephaly and cortical malformation. A tight junction component thought absent in neuroepithelium after neural tube closure, OCLN isoform-specific expression extends into corticogenesis. Full-length and truncated isoforms localize to neuroprogenitor centrosomes, but full-length OCLN transiently localizes to plasma membranes while only truncated OCLN continues at centrosomes throughout neurogenesis. Mimicking human mutations, full-length OCLN depletion in mouse and in human CRISPR/Cas9-edited organoids produce early neuronal differentiation, reduced progenitor self-renewal and increased apoptosis. Human neural progenitors were more severely affected, especially outer radial glial cells, which mouse embryonic cortex lacks. Rodent and human mutant progenitors displayed reduced proliferation and prolonged M-phase. OCLN interacted with mitotic spindle regulators, NuMA and RAN, while full-length OCLN loss impaired spindle pole morphology, astral and mitotic microtubule integrity. Thus, early corticogenesis requires full-length OCLN to regulate centrosome organization and dynamics, revealing a novel role for this tight junction protein in early brain development.

Introduction: Microcephaly is characterized by a smaller than normal head circumference. Recently, Zika virus (ZV) has been associated with microcephaly. Objective: To describe the prevalence of microcephaly in Colombia taking as the baseline the information from the period before the Zika virus infection epidemics. Materials and methods: We reviewed Medline, Scopus, Scielo, Lilacs and annual reports of congenital malformation monitoring systems across Latin America, among others sources, for articles published before April, 2015, reporting the prevalence of microcephaly in Colombia between 1982 and 2013. Results: We identified 32 non-duplicate articles; we selected 25 articles for revision of which 12 met the criteria for inclusion in the systematic review, including 2,808,308 births. Conclusions: The prevalence of microcephaly in Colombia from 1982 to 2013, before the introduction of ZV, ranged from 0.3 to 3.1 per 10,000 births, with an average of 1.8 (95% CI 1.7-1.8) per 10,000 births. These findings are important to determine if the prevalence after the introduction of the Zika virus infection registered significant changes.

Background Autism spectrum disorders (ASD) and intellectual disabilities (ID) are heterogeneous and complex developmental diseases with significant genetic backgrounds and overlaps of genetic susceptibility loci. Copy number variants (CNVs) are known to be frequent causes of these impairments. However, the clinical heterogeneity of both disorders causes the diagnostic efficacy of CNV analysis to be modest. This could be resolved by stratifying patients according to their clinical features. Aim First, we sought to assess the significance of particular clinical features for the detection of pathogenic CNVs in separate groups of ID and ASD patients and determine whether and how these groups differ from each other in the significance of these variables. Second, we aimed to create a statistical model showing how particular clinical features affect the probability of pathogenic CNV findings. Method We tested a cohort of 204 patients with ID (N = 90) and ASD (N = 114) for the presence of pathogenic CNVs. We stratified both groups according to their clinical features. Fisher’s exact test was used to determine the significance of these variables for pathogenic CNV findings. Logistic regression was used to create a statistical model of pathogenic CNV findings. Results The frequency of pathogenic CNV was significantly higher in the ID group than in the ASD group: 18 (19.78%) versus 8 (7%) (p

Abstract Background A number of Zika vaccine platforms are currently being investigated, some of which have entered clinical trials. We sought to evaluate the cost-effectiveness of a potential Zika vaccine candidate under the WHO Vaccine Target Product Profile for outbreak response, prioritizing women of reproductive age to prevent microcephaly and other neurological disorders. Methods Using an agent-based simulation model of ZIKV transmission dynamics in a Colombian population setting, we conducted cost-effectiveness analysis with and without pre-existing herd immunity. The model was parameterized with estimates associated with ZIKV infection, risks of microcephaly in different trimesters, direct medical costs, and vaccination costs. We assumed that a single dose of vaccine provides a protection efficacy in the range 60% to 90% against infection. Cost-effectiveness analysis was conducted from a government perspective. Results Under a favorable scenario when the reproduction number is relatively low (R 0 = 2.2) and the relative transmissibility of asymptomatic infection is 10% compared with symptomatic infection, a vaccine is cost-saving (with negative incremental cost-effective ratio; ICER) for vaccination costs up to US$6 per individual without herd immunity, and up to US$4 per individual with 8% herd immunity. For positive ICER values, vaccination is highly cost-effective for vaccination costs up to US$10 (US$7) in the respective scenarios with the willingness-to-pay of US$6610 per disability-adjusted life-year, corresponding to the average per capita GDP of Colombia between 2013 and 2017. Our results indicate that the effect of other control measures targeted to reduce ZIKV transmission decreases the range of vaccination costs for cost-effectiveness due to reduced returns of vaccine-induced herd immunity. In all scenarios investigated, the median reduction of microcephaly exceeded 64% with vaccination. Conclusions Our study suggests that a Zika vaccine with protection efficacy as low as 60% could significantly reduce the incidence of microcephaly. From a government perspective, Zika vaccination is highly cost-effective, and even cost-saving in Colombia if vaccination costs per individual is sufficiently low. Efficacy data from clinical trials and number of vaccine doses will be important requirements in future studies to refine our estimates, and conduct similar studies in other at-risk populations.

Abstract Background As the number of children with Zika virus-related complications grows, the long-term developmental trajectory and its effects on families are unknown. We present the first known case of congenital Zika syndrome seen at our institution with significant fundus findings. Case presentation A 3-day-old Hispanic baby girl presented with severe microcephaly of 24 cm and temperature instability at birth. Her mother had traveled to Honduras early in pregnancy and testing of amniotic fluid was positive for Zika virus via polymerase chain reaction. A dilated fundus examination was significant for bilateral severe colobomatous chorioretinal atrophy of the macula and pigmentary changes. Neonatal magnetic resonance imaging revealed diffuse lissencephaly with decreased brain volume, atrophic corpus callosum and brainstem, periventricular calcifications, and ventriculomegaly of the lateral ventricles. Conclusions Our patient, who presented with the first known case of congenital Zika syndrome in Northern Florida, demonstrated profound bilateral colobomatous chorioretinal atrophy of the macula. The ophthalmologic findings along with severe microcephaly emphasize the neurotropism of the Zika virus, and ultimately are indicative of poor developmental and visual prognosis for affected infants. With the increased prevalence of Zika virus, ophthalmologists should be aware of the associated findings and the importance of an eye-screening examination with a dilated fundus examination within 1 month of life of infants in which congenital Zika syndrome is suspected. A multidisciplinary care approach is essential for the care of affected infants and their families.