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The Lancet. Global Health Jul 2024Data on long-term neurodevelopmental outcomes of normocephalic children (born with normal head circumference) exposed to Zika virus in utero are scarce. We aimed to...
BACKGROUND
Data on long-term neurodevelopmental outcomes of normocephalic children (born with normal head circumference) exposed to Zika virus in utero are scarce. We aimed to compare neurodevelopmental outcomes in normocephalic children up to age 48 months with and without Zika virus exposure in utero.
METHODS
In this prospective cohort study, we included infants from two cohorts of normocephalic children born in León and Managua, Nicaragua during the 2016 Zika epidemic. In León, all women pregnant during the two enrolment periods were eligible. In Managua, mother-child pairs were included from three districts in the municipality of Managua: all women who became pregnant before June 15, 2016, and had a due date of Sept 15, 2016 or later were eligible. Infants were serologically classified as Zika virus-exposed or Zika virus-unexposed in utero and were followed up prospectively until age 48 months. At 36 months and 48 months of age, the Mullen Scales of Early Learning (MSEL) assessment was administered. Primary outcomes were MSEL early learning composite (ELC) scores at 30-48 months in León and 36-48 months in Managua. We used an inverse probability weighting generalised estimating equations model to assess the effect of Zika virus exposure on individual MSEL cognitive domain scores and ELC scores, adjusted for maternal education and age, poverty status, and infant sex.
FINDINGS
The initial enrolment period for the León cohort was between Jan 31 and April 5, 2017 and the second was between Aug 30, 2017, and Feb 22, 2018. The enrolment period for the Managua cohort was between Oct 24, 2019, and May 5, 2020. 478 mothers (482 infants) from the León cohort and 615 mothers (609 infants) from the Managua cohort were enrolled, of whom 622 children (303 from the León cohort; 319 from the Managua cohort) were included in the final analysis; four children had microcephaly at birth and thus were excluded from analyses, two from each cohort. 33 (11%) of 303 children enrolled in León and 219 (69%) of 319 children enrolled in Managua were exposed to Zika virus in utero. In both cohorts, no significant differences were identified in adjusted mean ELC scores between Zika virus-exposed and unexposed infants at 36 months (between-group difference 1·2 points [95% CI -4·2 to 6·5] in the León cohort; 2·8 [-2·4 to 8·1] in the Managua cohort) or at 48 months (-0·9 [-10·8 to 8·8] in the León cohort; 0·1 [-5·1 to 5·2] in the Managua cohort). No differences in ELC scores between Zika virus-exposed and unexposed infants exceeded 6 points at any time between 30 months and 48 months in León or between 36 months and 48 months in Managua, which was considered clinically significant in other settings.
INTERPRETATION
We found no significant differences in neurodevelopmental scores between normocephalic children with in-utero Zika virus exposure and Zika virus-unexposed children at age 36 months or 48 months. These findings are promising, supporting typical neurodevelopment in Zika virus-exposed normocephalic children, although additional follow-up and research is warranted.
FUNDING
National Institute of Child Health and Development, National Institute of Allergy and Infectious Diseases, and Fogarty International Center.
TRANSLATION
For the Spanish translation of the abstract see Supplementary Materials section.
Topics: Humans; Nicaragua; Zika Virus Infection; Female; Prospective Studies; Child, Preschool; Pregnancy; Male; Prenatal Exposure Delayed Effects; Infant; Pregnancy Complications, Infectious; Child Development; Zika Virus; Adult; Neurodevelopmental Disorders
PubMed: 38876760
DOI: 10.1016/S2214-109X(24)00176-1 -
Medicine Jun 2024Gastric cancer typically originates from the abnormal proliferation of normal cells within the gastric mucosa, eventually forming tumors. The roles of sperm-associated... (Observational Study)
Observational Study
Gastric cancer typically originates from the abnormal proliferation of normal cells within the gastric mucosa, eventually forming tumors. The roles of sperm-associated antigen 5 (SPAG5) and abnormal spindle-like microcephaly (ASPM) associated genes in gastric cancer are not yet clear. Gastric cancer datasets GSE51575 and GSE36076 profiles were downloaded from the GPL13607 and GPL570-generated gene expression omnibus database. The analysis included filtering for differentially expressed genes, weighted gene co-expression network analysis, functional enrichment analysis, gene set enrichment analysis, immune infiltration analysis, construction and analysis of the protein-protein interaction network, survival analysis, and Comparative Toxicogenomics Database analysis. Heatmaps of gene expression were also created. A total of 1457 differentially expressed genes were identified. According to gene ontology analysis, they are primarily enriched in the metabolic processes of organic acids, condensed chromosome centromere regions, and oxidoreductase activity. Kyoto Encyclopedia of Gene and Genome analysis showed they are mainly involved in metabolic pathways, P53 signaling pathway, and PPAR signaling pathway. The soft threshold power for weighted gene co-expression network analysis was set to 8. Three core genes (CENPE, SPAG5, and ASPM) were identified. Heatmaps of core gene expression revealed that SPAG5 and ASPM are highly expressed in gastric cancer samples and low in normal samples. Comparative Toxicogenomics Database analysis indicated that the core genes (CENPE, SPAG5, and ASPM) are associated with gastric tumors, gastric diseases, gastritis, gastric ulcers, tumors, inflammation, and necrosis. The SPAG5 and ASPM genes are overexpressed in gastric cancer tissues, and higher expression levels are associated with worse prognosis, may serve as potential prognostic markers.
Topics: Stomach Neoplasms; Humans; Cell Cycle Proteins; Gene Expression Regulation, Neoplastic; Protein Interaction Maps; Adaptor Proteins, Signal Transducing; Biomarkers, Tumor; Gene Expression Profiling; Nerve Tissue Proteins
PubMed: 38875410
DOI: 10.1097/MD.0000000000038499 -
Cureus May 2024Trisomy 13, also known as Patau syndrome, is a widely congenital anomaly syndrome characterized by microphthalmia, cleft lip, and palate, microcephaly with a sloping...
Trisomy 13, also known as Patau syndrome, is a widely congenital anomaly syndrome characterized by microphthalmia, cleft lip, and palate, microcephaly with a sloping forehead, congenital heart disease, and polydactyly of the limbs. Patau syndrome is identified either prenatally or postnatally. Its survival rate is low, and most of the patients die even before their first year of life. The risk of trisomy 13 is higher in women of advanced maternal age. Brain and cardiovascular abnormalities are typically the primary factors contributing to the syndrome's poor prognosis. We report a case of a male newborn born at full term from a first-degree consanguineous marriage. Upon initial inspection, the patient had classic dysmorphic features, including low-set ears, a cleft lip and palate, a short neck, bilateral anophthalmia, and polydactyly of the limbs. After chromosomal analysis, the diagnosis was made, and a trisomy 13 was discovered.
PubMed: 38872687
DOI: 10.7759/cureus.60264 -
IScience Jun 2024The Tousled-like kinases 1 and 2 (TLK1/TLK2) regulate DNA replication, repair and chromatin maintenance. TLK2 variants underlie the neurodevelopmental disorder (NDD)...
The Tousled-like kinases 1 and 2 (TLK1/TLK2) regulate DNA replication, repair and chromatin maintenance. TLK2 variants underlie the neurodevelopmental disorder (NDD) 'Intellectual Disability, Autosomal Dominant 57' (MRD57), characterized by intellectual disability and microcephaly. Several TLK1 variants have been reported in NDDs but their functional significance is unknown. A male patient presenting with ID, seizures, global developmental delay, hypothyroidism, and primary immunodeficiency was determined to have a heterozygous TLK1 variant (c.1435C>G, p.Q479E), as well as a mutation in MDM1 (c.1197dupT, p.K400∗). Cells expressing TLK1 p.Q479E exhibited reduced cytokine responses and elevated DNA damage, but not increased radiation sensitivity or DNA repair defects. The TLK1 p.Q479E variant impaired kinase activity but not proximal protein interactions. Our study provides the first functional characterization of NDD-associated TLK1 variants and suggests that, such as TLK2, TLK1 variants may impact development in multiple tissues and should be considered in the diagnosis of rare NDDs.
PubMed: 38868186
DOI: 10.1016/j.isci.2024.109984 -
Cureus May 2024Background Cerebral palsy (CP) is a major cause of childhood motor impairment worldwide. The prevalence of CP related to preterm births has increased consistently....
Background Cerebral palsy (CP) is a major cause of childhood motor impairment worldwide. The prevalence of CP related to preterm births has increased consistently. Perinatal hypoxic-ischemic encephalopathy, intra- or periventricular haemorrhage, cerebral dysgenesis and intracranial infections are among the factors contributing to CP onset. Several studies have explored epilepsy-related morbidity among children with CP, finding notable correlations between the two conditions. Worldwide, there are multiple studies highlighting the high prevalence of epilepsy among children with CP and its association with specific CP subtypes and neurologic insults. However, research on the risk factors for epilepsy in CP children is limited, particularly in the Middle East and Saudi Arabia. Aim This study aims to address this gap by analysing potential prenatal, antenatal, and postnatal risk factors associated with epilepsy development in children with CP. Methods A retrospective cohort analysis of 152 children aged 1-14 years diagnosed with CP at King Abdulaziz University Hospital, Jeddah, Saudi Arabia, was conducted. Results The study showed a significant prevalence of epilepsy (68.4%), with generalised seizures being the most common type. Quadriplegia was notably common among CP children with epilepsy, indicating a potential correlation between motor impairment severity and epilepsy risk. Furthermore, CP children with epilepsy exhibited a higher prevalence of co-morbidities, emphasising the multifaceted nature of this condition. Perinatal and neonatal factors, such as hypoxic events, mechanical ventilation, perinatal asphyxia, neonatal convulsions, and microcephaly, were identified as significant risk factors for epilepsy in children with CP. While speech and hearing disorders were present in CP children with and without epilepsy, a slightly higher prevalence of impaired speech was observed in those with epilepsy. However, the difference between the two groups was not significant. Conclusion This study provides valuable insights into the epidemiology, clinical characteristics and potential risk factors associated with epilepsy among children diagnosed with CP in Saudi Arabia. The findings underscore the complexity of managing epilepsy in this population and highlight the need for further research to elucidate the underlying mechanisms and support the development of targeted interventions to improve patient outcomes.
PubMed: 38854260
DOI: 10.7759/cureus.59980 -
Neurobiology of Disease Jun 2024Bioenergetics describe the biochemical processes responsible for energy supply in organisms. When these changes become dysregulated in brain development, multiple... (Review)
Review
Bioenergetics describe the biochemical processes responsible for energy supply in organisms. When these changes become dysregulated in brain development, multiple neurodevelopmental diseases can occur, implicating bioenergetics as key regulators of neural development. Historically, the discovery of disease processes affecting individual stages of brain development has revealed critical roles that bioenergetics play in generating the nervous system. Bioenergetic-dependent neurodevelopmental disorders include neural tube closure defects, microcephaly, intellectual disability, autism spectrum disorders, epilepsy, mTORopathies, and oncogenic processes. Developmental timing and cell-type specificity of these changes determine the long-term effects of bioenergetic disease mechanisms on brain form and function. Here, we discuss key metabolic regulators of neural progenitor specification, neuronal differentiation (neurogenesis), and gliogenesis. In general, transitions between glycolysis and oxidative phosphorylation are regulated in early brain development and in oncogenesis, and reactive oxygen species (ROS) and mitochondrial maturity play key roles later in differentiation. We also discuss how bioenergetics interface with the developmental regulation of other key neural elements, including the cerebrospinal fluid brain environment. While questions remain about the interplay between bioenergetics and brain development, this review integrates the current state of known key intersections between these processes in health and disease.
PubMed: 38849103
DOI: 10.1016/j.nbd.2024.106550 -
Dialogues in Clinical Neuroscience 2024Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder with a multifaceted etiology. This case report explores the ischemic cryptogenic vascular... (Review)
Review
INTRODUCTION
Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder with a multifaceted etiology. This case report explores the ischemic cryptogenic vascular dissection as a potential underlying cause of ASD.
METHODS
A 9-year-old child presented with symptoms of ASD, including social interaction difficulties, repetitive behaviors, and cognitive challenges. Despite conventional ASD treatments, significant improvement was only observed after addressing an underlying ischemic cryptogenic vascular dissection identified through DCE-CT.
RESULTS
Following a reconstructive treatment approach to the vascular dissection, the patient showed marked improvement in cognitive functions, social abilities, and a reduction in ASD-related symptoms whether during the perioperative period or during approximately 5-month follow-up.
CONCLUSION
This case suggests that ischemic cryptogenic vascular dissection may contribute to the symptoms of ASD. Identifying and treating underlying vascular anomalies may offer a new avenue for mitigating ASD symptoms, emphasizing the need for comprehensive diagnostic estimations in ASD management.
Topics: Humans; Autism Spectrum Disorder; Child; Male; Microcephaly
PubMed: 38829782
DOI: 10.1080/19585969.2024.2359918 -
Heliyon May 2024Autosomal Recurrent Primary Microscopic (MCPH, OMIM: 251200) is a neurodevelopmental disorder that is characterized by a noticeable decrease in brain size, particularly...
Autosomal Recurrent Primary Microscopic (MCPH, OMIM: 251200) is a neurodevelopmental disorder that is characterized by a noticeable decrease in brain size, particularly in the cerebral cortex, but with a normal brain structure and a non-progressive intellectual disability. has been identified as the gene that triggers primary microcephaly (MCPH1,OMIM: 607117). Here we report a case of autosomal recessive primary microcephaly as caused by a novel variant in the gene. Head circumference was measured by Magnetic Resonance Imaging (MRI), while the Wechsler Intelligence Scale was used to evaluate the intelligence of the individual being tested. B-ultrasound was used to assess gonadal development, and semen routine was used to assess sperm status. The whole-exome sequencing (WES) was performed on the proband. Sanger sequencing was conducted on the parents of the proband to determine if the novel variant in the MCPH1 gene was present. The effect of the mutation on the splicing of was verified by minigene approach. It was observed that the proband had autosomal recessive primary microcephaly and azoospermatism. A novel splice-site homozygous mutation (c.233+2T > G) of the gene was identified, which inherited from his parents. Minigene approach confirmed that c.233+2T > G could affect the splicing of . Therefore, our findings contributed to the mutation spectrum of the gene and may be useful in the diagnosis and gene therapy of MCPH.
PubMed: 38818167
DOI: 10.1016/j.heliyon.2024.e30285 -
Cell Death & Disease May 2024CSMD1 (Cub and Sushi Multiple Domains 1) is a well-recognized regulator of the complement cascade, an important component of the innate immune response. CSMD1 is highly...
CSMD1 (Cub and Sushi Multiple Domains 1) is a well-recognized regulator of the complement cascade, an important component of the innate immune response. CSMD1 is highly expressed in the central nervous system (CNS) where emergent functions of the complement pathway modulate neural development and synaptic activity. While a genetic risk factor for neuropsychiatric disorders, the role of CSMD1 in neurodevelopmental disorders is unclear. Through international variant sharing, we identified inherited biallelic CSMD1 variants in eight individuals from six families of diverse ancestry who present with global developmental delay, intellectual disability, microcephaly, and polymicrogyria. We modeled CSMD1 loss-of-function (LOF) pathogenesis in early-stage forebrain organoids differentiated from CSMD1 knockout human embryonic stem cells (hESCs). We show that CSMD1 is necessary for neuroepithelial cytoarchitecture and synchronous differentiation. In summary, we identified a critical role for CSMD1 in brain development and biallelic CSMD1 variants as the molecular basis of a previously undefined neurodevelopmental disorder.
Topics: Humans; Intellectual Disability; Membrane Proteins; Female; Male; Neurodevelopmental Disorders; Alleles; Malformations of Cortical Development; Child; Child, Preschool; Cell Differentiation; Tumor Suppressor Proteins
PubMed: 38816421
DOI: 10.1038/s41419-024-06768-6