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Frontiers in Neuroscience 2024Fetal alcohol spectrum disorders include a variety of physical and neurocognitive disorders caused by prenatal alcohol exposure. Although their overall prevalence is...
INTRODUCTION
Fetal alcohol spectrum disorders include a variety of physical and neurocognitive disorders caused by prenatal alcohol exposure. Although their overall prevalence is around 0.77%, FASD remains underdiagnosed and little known, partly due to the complexity of their diagnosis, which shares some symptoms with other pathologies such as autism spectrum, depression or hyperactivity disorders.
METHODS
This study included 73 control and 158 patients diagnosed with FASD. Variables selected were based on IOM classification from 2016, including sociodemographic, clinical, and psychological characteristics. Statistical analysis included Kruskal-Wallis test for quantitative factors, Chi-square test for qualitative variables, and Machine Learning (ML) algorithms for predictions.
RESULTS
This study explores the application ML in diagnosing FASD and its subtypes: Fetal Alcohol Syndrome (FAS), partial FAS (pFAS), and Alcohol-Related Neurodevelopmental Disorder (ARND). ML constructed a profile for FASD based on socio-demographic, clinical, and psychological data from children with FASD compared to a control group. Random Forest (RF) model was the most efficient for predicting FASD, achieving the highest metrics in accuracy (0.92), precision (0.96), sensitivity (0.92), F1 Score (0.94), specificity (0.92), and AUC (0.92). For FAS, XGBoost model obtained the highest accuracy (0.94), precision (0.91), sensitivity (0.91), F1 Score (0.91), specificity (0.96), and AUC (0.93). In the case of pFAS, RF model showed its effectiveness, with high levels of accuracy (0.90), precision (0.86), sensitivity (0.96), F1 Score (0.91), specificity (0.83), and AUC (0.90). For ARND, RF model obtained the best levels of accuracy (0.87), precision (0.76), sensitivity (0.93), F1 Score (0.84), specificity (0.83), and AUC (0.88). Our study identified key variables for efficient FASD screening, including traditional clinical characteristics like maternal alcohol consumption, lip-philtrum, microcephaly, height and weight impairment, as well as neuropsychological variables such as the Working Memory Index (WMI), aggressive behavior, IQ, somatic complaints, and depressive problems.
DISCUSSION
Our findings emphasize the importance of ML analyses for early diagnoses of FASD, allowing a better understanding of FASD subtypes to potentially improve clinical practice and avoid misdiagnosis.
PubMed: 38808031
DOI: 10.3389/fnins.2024.1400933 -
Pathogens (Basel, Switzerland) May 2024A common infection, human cytomegalovirus (HCMV) has been associated with a variety of human diseases, including cardiovascular disease and possibly certain cancers.... (Review)
Review
A common infection, human cytomegalovirus (HCMV) has been associated with a variety of human diseases, including cardiovascular disease and possibly certain cancers. HCMV has also been associated with cognitive, psychiatric, and neurological conditions. Children with congenital or early-life HCMV are at risk for microcephaly, cerebral palsy, and sensorineural hearing loss, although in many cases sensorineural loss may resolve. In addition, HCMV can be associated with neurodevelopmental impairment, which may improve with time. In young, middle-aged, and older adults, HCMV has been adversely associated with cognitive function in some but not in all studies. Research has linked HCMV to Alzheimer's and vascular dementia, but again not all findings consistently support these associations. In addition, HCMV has been associated with depressive disorder, bipolar disorder, anxiety, and autism-spectrum disorder, although the available findings are likewise inconsistent. Given associations between HCMV and a variety of neurocognitive and neuropsychiatric disorders, additional research investigating reasons for the considerable inconsistencies in the currently available findings is needed. Additional meta-analyses and more longitudinal studies are needed as well. Research into the effects of antiviral medication on cognitive and neurological outcomes and continued efforts in vaccine development have potential to lower the neurocognitive, neuropsychiatric, and neurological burden of HCMV infection.
PubMed: 38787269
DOI: 10.3390/pathogens13050417 -
Tropical Medicine and Infectious Disease May 2024Brazil reported 18,282 suspected congenital Zika syndrome (CZS) cases up to 2018 and accounts for 61.4% of the total reported Zika cases in the Americas in the period....
Brazil reported 18,282 suspected congenital Zika syndrome (CZS) cases up to 2018 and accounts for 61.4% of the total reported Zika cases in the Americas in the period. To detect high-risk areas for children with CZS in the city of Rio de Janeiro, we used cluster detection and thematic maps. We analyzed data using a Poisson model in Satscan 10.1.3 software. We also analyzed the records of children with CZS from 2015 to 2016 to describe the clinical and epidemiological maternal and child profile, as well as live births in 2016 and the social development index (SDI) by neighborhood. In 2015 and 2016, the incidence rates of CZS were 8.84 and 46.96 per 100,000 live births in the city, respectively. Severe congenital findings such as microcephaly and brain damage, osteoarticular impairment, ocular abnormalities, and hearing loss were observed in 47 children. The spatial distribution of CZS was concentrated in the north and west zones in heterogeneous neighborhoods. The neighborhoods with the highest occurrence of CZS cases were found to have the worst SDIs. Stascan detected three spatial clusters in the north zone, where the SDI is lower. The clusters presented high relative risks for CZS (7.86, 1.46, and 2.08), although they were not statistically significant. Our findings highlight a higher occurrence of CZS in areas with less favorable socioeconomic conditions.
PubMed: 38787038
DOI: 10.3390/tropicalmed9050105 -
Neurology. Genetics Jun 2024The endoplasmic reticulum (ER) membrane protein complex is a conserved multisubunit transmembrane complex that enables energy-independent insertion of newly synthesized...
BACKGROUND AND OBJECTIVES
The endoplasmic reticulum (ER) membrane protein complex is a conserved multisubunit transmembrane complex that enables energy-independent insertion of newly synthesized membrane proteins into ER membranes, mediating protein folding, phospholipid transfer from ER to mitochondria, and elimination of misfolded proteins. The first subunit of EMC (EMC1) is encoded by . Both monoallelic de novo and biallelic variants have been identified to cause cerebellar atrophy, visual impairment, and psychomotor retardation (CAVIPMR) [OMIM #616875]. Eight families with biallelic variants and CAVIPMR have been reported. Here, we describe 8 individuals from 5 Kuwaiti families from the same tribe, with the previously reported homozygous pathogenic missense variant [c.245C>T:p.(Thr82Met)] and CAVIPMR.
METHODS
Proband exome sequencing was performed in 3 families, while targeted molecular testing for [c.245C>T:p.(Thr82Met)] variant was performed in the other 2 families based on strong clinical suspicion and tribal origin. Sanger sequencing confirmed variant segregation with disease in all families.
RESULTS
We identified 8 individuals from 5 Kuwaiti families with the homozygous pathogenic variant [c.245C>T:p.(Thr82Met)] previously reported in a Turkish family with CAVIPMR. The variant was absent from Kuwait Medical Genetic Center database, thus unlikely to represent a population founder allelic variant. The average age at symptom onset was 11 weeks, with all families reporting either visual abnormalities, hypotonia, and/or global developmental delay (GDD) as the presenting features. Shared clinical features included GDD (8/8), microcephaly (8/8), truncal hypotonia (8/8), visual impairment (7/7), and failure to thrive (7/7). Other common features included hyperreflexia (5/6; 83%), peripheral hypertonia (3/5; 60%), dysmorphism (3/6; 50%), epilepsy (4/8; 50%), and chorea (3/8; 36%). Brain imaging showed cerebellar atrophy in 4/7 (57%) and cerebral atrophy in 3/6 (50%) individuals.
DISCUSSION
The presence of exact biallelic homozygous variant in 5 Kuwaiti families from the same tribe suggests a tribal founder allelic variant. The clinical features in this study are consistent with the phenotypic spectrum of -associated CAVIPMR in previous reports. The presence of chorea, first noted in this study, further expands the phenotypic spectrum. Our findings emphasize the importance of targeted variant [c.245C>T:p.(Thr82Met)] testing for infants from affected tribe who present with visual impairment, GDD, and hypotonia.
PubMed: 38784058
DOI: 10.1212/NXG.0000000000200156 -
BMC Pediatrics May 2024Donohue syndrome (DS), also referred to as leprechaunism, is a remarkably uncommon autosomal recessive disorder that primarily affects the endocrine system. Its...
INTRODUCTION
Donohue syndrome (DS), also referred to as leprechaunism, is a remarkably uncommon autosomal recessive disorder that primarily affects the endocrine system. Its incidence rate is exceedingly low, with only 1 case reported per 4 million live births. The syndrome is distinguished by a series of characteristic clinical features.
CASE PRESENTATION
We present a case of a twenty-month-old male with DS who experienced a range of dysmorphic and clinical features with the involvement of multiple systems. These features include skin hyperpigmentation, hypertrichosis, distinct facial features, abdominal distension, and microcephaly, with the involvement of the endocrine, renal, respiratory, and cardiac systems.
CONCLUSION
The primary features of DS involve severe insulin resistance and growth abnormalities, the association with pulmonary hypertension (PHTN) has not been reported before. This finding adds more complexity to the condition. To the best of the author's knowledge, this is the first report for a patient with DS who has PHTN. Further investigation is required since the mechanisms behind the development of PHTN in DS are not entirely understood. Shedding light on this association will contribute to better management strategies and outcomes for affected patients.
Topics: Humans; Male; Hypertension, Pulmonary; Infant; Donohue Syndrome
PubMed: 38773407
DOI: 10.1186/s12887-024-04714-1 -
Scientific Data May 2024Brain organoids represent a useful tool for modeling of neurodevelopmental disorders and can recapitulate brain volume alterations such as microcephaly. To monitor...
Brain organoids represent a useful tool for modeling of neurodevelopmental disorders and can recapitulate brain volume alterations such as microcephaly. To monitor organoid growth, brightfield microscopy images are frequently used and evaluated manually which is time-consuming and prone to observer-bias. Recent software applications for organoid evaluation address this issue using classical or AI-based methods. These pipelines have distinct strengths and weaknesses that are not evident to external observers. We provide a dataset of more than 1,400 images of 64 trackable brain organoids from four clones differentiated from healthy and diseased patients. This dataset is especially powerful to test and compare organoid analysis pipelines because of (1) trackable organoids (2) frequent imaging during development (3) clone diversity (4) distinct clone development (5) cross sample imaging by two different labs (6) common imaging distractors, and (6) pixel-level ground truth organoid annotations. Therefore, this dataset allows to perform differentiated analyses to delineate strengths, weaknesses, and generalizability of automated organoid analysis pipelines as well as analysis of clone diversity and similarity.
Topics: Organoids; Brain; Humans
PubMed: 38769371
DOI: 10.1038/s41597-024-03330-z -
BioRxiv : the Preprint Server For... May 2024The human dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) is implicated in the pathology of Down syndrome, microcephaly, and cancer, however the...
UNLABELLED
The human dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) is implicated in the pathology of Down syndrome, microcephaly, and cancer, however the exact mechanism through which it functions is unknown. Here, we have studied the role of the ortholog of DYRK1A, Minibrain (Mnb), in brain development. The neuroblasts (neural stem cells) that eventually give rise to differentiated neurons in the adult brain are formed from a specialized tissue in the larval optic lobe called the neuroepithelium, in a tightly regulated process. Molecular marker analysis of mutants revealed alterations in the neuroepithelium and neuroblast regions of developing larval brains. Using affinity purification-mass spectrometry (AP-MS), we identified the novel Mnb binding partners Ral interacting protein (Rlip) and RALBP1 associated Eps domain containing (Reps). Rlip and Reps physically and genetically interact with Mnb, and the three proteins may form a ternary complex. Mnb phosphorylates Reps, and human DYRK1A binds to the Reps orthologs REPS1 and REPS2. Furthermore, Mnb engages the small GTPase Ras-like protein A (Rala) to regulate brain and wing development. This work uncovers a previously unrecognized early role of Mnb in the neuroepithelium and defines the functions of the Mnb/Reps/Rlip/Rala signaling network in brain development.
SIGNIFICANCE STATEMENT
The kinase Minibrain(Mnb)/DYRK1A regulates the development of the brain and other tissues across many organisms. Here we show the critical importance of Mnb within the developing neuroepithelium. Advancing our understanding of Mnb function, we identified novel protein interactors of Mnb, Reps and Rlip, which function together with Mnb to regulate growth in . We also identify and characterize a role for the small GTPase Rala in Mnb-regulated growth and nervous system development. This work reveals an early role of Mnb in brain development and identifies a new Mnb/Reps/Rlip/Rala signaling axis.
PubMed: 38766038
DOI: 10.1101/2024.05.10.593605 -
BMC Pediatrics May 2024Prenatal exposure to the Zika virus can lead to microcephaly and adverse developmental outcomes, even in children without evident birth defects. The social environment...
Associations between the social environment and early childhood developmental outcomes of Puerto Rican children with prenatal Zika virus exposure: a cross-sectional study.
BACKGROUND
Prenatal exposure to the Zika virus can lead to microcephaly and adverse developmental outcomes, even in children without evident birth defects. The social environment plays a crucial role in infant health and developmental trajectories, especially during periods of heightened brain plasticity. The study aimed to assess socioenvironmental factors as predictors of developmental outcomes of 36-month-old children exposed to Zika virus prenatally.
STUDY DESIGN
This cross-sectional study included 53 mothers and 55 children enrolled in the Pediatric Outcomes of Prenatal Zika Exposure cohort study in Puerto Rico. The study performs follow-up developmental assessments of children born to mothers with confirmed and probable Zika virus infection during pregnancy. Mothers completed socioenvironmental questionnaires (e.g., Perceived Neighborhood Scale and US Household Food Insecurity Survey). Children's developmental outcomes were assessed with the Bayley Scales of Infant and Toddler Development: Third Edition, the Ages and Stages Questionnaires: Third Edition, the Ages and Stages Questionnaire-Socioemotional: Second Edition, and the Child Adjustment and Parent Efficacy Scale.
RESULTS
Linear regression models, adjusting for a child's sex and age and maternal education, revealed that early life exposure to food insecurity and maternal pregnancy stressors were significantly associated with poorer developmental outcomes in Zika virus-exposed children at 36 months of age. Maternal resilience representation of adaptive ability was associated with the preservation of adequate developmental outcomes in children.
CONCLUSIONS
Pregnancy and early childhood are critical life periods for ensuring optimal brain development in children. While the mechanisms in the interaction of children with their environment are complex, the risk and protective factors identified in the study are modifiable through public policy and preventive initiatives. Implementation of comprehensive strategies that improve access to social support programs, educational and nutritional interventions, and mental health services during pregnancy and early childhood can enhance the developmental potential of vulnerable children.
Topics: Humans; Female; Pregnancy; Cross-Sectional Studies; Zika Virus Infection; Puerto Rico; Child, Preschool; Prenatal Exposure Delayed Effects; Male; Child Development; Social Environment; Pregnancy Complications, Infectious; Adult; Infant
PubMed: 38755525
DOI: 10.1186/s12887-024-04806-y -
Annals of Clinical and Translational... May 2024COASY, the gene encoding the bifunctional enzyme CoA synthase, which catalyzes the last two reactions of cellular de novo coenzyme A (CoA) biosynthesis, has been linked...
OBJECTIVE
COASY, the gene encoding the bifunctional enzyme CoA synthase, which catalyzes the last two reactions of cellular de novo coenzyme A (CoA) biosynthesis, has been linked to two exceedingly rare autosomal recessive disorders, such as COASY protein-associated neurodegeneration (CoPAN), a form of neurodegeneration with brain iron accumulation (NBIA), and pontocerebellar hypoplasia type 12 (PCH12). We aimed to expand the phenotypic spectrum and gain insights into the pathogenesis of COASY-related disorders.
METHODS
Patients were identified through targeted or exome sequencing. To unravel the molecular mechanisms of disease, RNA sequencing, bioenergetic analysis, and quantification of critical proteins were performed on fibroblasts.
RESULTS
We identified five new individuals harboring novel COASY variants. While one case exhibited classical CoPAN features, the others displayed atypical symptoms such as deafness, language and autism spectrum disorders, brain atrophy, and microcephaly. All patients experienced epilepsy, highlighting its potential frequency in COASY-related disorders. Fibroblast transcriptomic profiling unveiled dysregulated expression in genes associated with mitochondrial respiration, responses to oxidative stress, transmembrane transport, various cellular signaling pathways, and protein translation, modification, and trafficking. Bioenergetic analysis revealed impaired mitochondrial oxygen consumption in COASY fibroblasts. Despite comparable total CoA levels to control cells, the amounts of mitochondrial 4'-phosphopantetheinylated proteins were significantly reduced in COASY patients.
INTERPRETATION
These results not only extend the clinical phenotype associated with COASY variants but also suggest a continuum between CoPAN and PCH12. The intricate interplay of altered cellular processes and signaling pathways provides valuable insights for further research into the pathogenesis of COASY-associated diseases.
PubMed: 38750253
DOI: 10.1002/acn3.52079 -
MedRxiv : the Preprint Server For... May 2024Retinoblastoma (RB) proteins are highly conserved transcriptional regulators that play important roles during development by regulating cell-cycle gene expression. RBL2...
Retinoblastoma (RB) proteins are highly conserved transcriptional regulators that play important roles during development by regulating cell-cycle gene expression. RBL2 dysfunction has been linked to a severe neurodevelopmental disorder. However, to date, clinical features have only been described in six individuals carrying five biallelic predicted loss of function (pLOF) variants. To define the phenotypic effects of mutations in detail, we identified and clinically characterized a cohort of 28 patients from 18 families carrying LOF variants in , including fourteen new variants that substantially broaden the molecular spectrum. The clinical presentation of affected individuals is characterized by a range of neurological and developmental abnormalities. Global developmental delay and intellectual disability were uniformly observed, ranging from moderate to profound and involving lack of acquisition of key motor and speech milestones in most patients. Frequent features included postnatal microcephaly, infantile hypotonia, aggressive behaviour, stereotypic movements and non-specific dysmorphic features. Common neuroimaging features were cerebral atrophy, white matter volume loss, corpus callosum hypoplasia and cerebellar atrophy. In parallel, we used the fruit fly, , to investigate how disruption of the conserved RBL2 orthologueue Rbf impacts nervous system function and development. We found that LOF mutants recapitulate several features of patients harboring variants, including alterations in the head and brain morphology reminiscent of microcephaly, and perturbed locomotor behaviour. Surprisingly, in addition to its known role in controlling tissue growth during development, we find that continued expression is also required in fully differentiated post-mitotic neurons for normal locomotion in , and that adult-stage neuronal re-expression of is sufficient to rescue mutant locomotor defects. Taken together, this study provides a clinical and experimental basis to understand genotype-phenotype correlations in an -linked neurodevelopmental disorder and suggests that restoring expression through gene therapy approaches may ameliorate aspects of LOF patient symptoms.
PubMed: 38746364
DOI: 10.1101/2024.05.03.24306631