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BioRxiv : the Preprint Server For... Jun 2024ECHS1 Deficiency (ECHS1D) is a rare and devastating pediatric disease that currently has no defined treatments. This disorder results from missense loss-of-function...
ECHS1 Deficiency (ECHS1D) is a rare and devastating pediatric disease that currently has no defined treatments. This disorder results from missense loss-of-function mutations in the gene that result in severe developmental delays, encephalopathy, hypotonia, and early death. ECHS1 enzymatic activity is necessary for the beta-oxidation of fatty acids and the oxidation of branched-chain amino acids within the inner mitochondrial matrix. The pathogenesis of disease remains unknown, however it is hypothesized that disease is driven by an accumulation of toxic metabolites from impaired valine oxidation. To expand our knowledge on disease mechanisms, a novel mouse model of ECHS1D was generated that possesses a disease-associated knock-in (KI) allele and a knock-out (KO) allele. To investigate the behavioral phenotype, a battery of testing was performed at multiple time points, which included assessments of learning, motor function, endurance, sensory responses, and anxiety. Neurological abnormalities were assessed using wireless telemetry EEG recordings, pentylenetetrazol (PTZ) seizure induction, and immunohistochemistry. Metabolic perturbations were measured within the liver, serum, and brain using mass spectrometry and magnetic resonance spectroscopy. To test disease mechanisms, mice were subjected to disease pathway stressors and then survival, body weight gain, and epilepsy were assessed. Mice containing KI/KI or KI/KO alleles were viable with normal development and survival, and the presence of KI and KO alleles resulted in a significant reduction in ECHS1 protein. ECHS1D mice displayed reduced exercise capacity and pain sensation. EEG analysis revealed increased slow wave power that was associated with perturbations in sleep. ECHS1D mice had significantly increased epileptiform EEG discharges, and were sensitive to seizure induction, which resulted in death of 60% of ECHS1D mice. Under basal conditions, brain structure was grossly normal, although histological analysis revealed increased microglial activation in aged ECHS1D mice. Increased dietary valine only affected ECHS1D mice, which significantly exacerbated seizure susceptibility and resulted in death. Lastly, acute inflammatory challenge drove regression and early lethality in ECHS1D mice. In conclusion, we developed a novel model of ECHS1D that may be used to further knowledge on disease mechanisms and to develop therapeutics. Our data suggests altered metabolic signaling and inflammation may contribute to epilepsy in ECHS1D, and these alterations may be attributed to impaired valine metabolism.
PubMed: 38915588
DOI: 10.1101/2024.06.13.598697 -
JAMA Pediatrics Jun 2024Health professionals routinely recommend intensive interventions (ie, 20-40 hours per week) for autistic children. However, primary research backing this recommendation...
IMPORTANCE
Health professionals routinely recommend intensive interventions (ie, 20-40 hours per week) for autistic children. However, primary research backing this recommendation is sparse and plagued by methodological flaws.
OBJECTIVE
To examine whether different metrics of intervention amount are associated with intervention effects on any developmental domain for young autistic children.
DATA SOURCES
A large corpus of studies taken from a recent meta-analysis (with a search date of November 2021) of early interventions for autistic children.
STUDY SELECTION
Studies were eligible if they reported a quasi-experimental or randomized clinical trial testing the effects of a nonpharmacological intervention on any outcome in participant samples comprising more than 50% autistic children 8 years or younger.
DATA EXTRACTION AND SYNTHESIS
Data were independently extracted by multiple coders. Meta-regression models were constructed to determine whether each index of intervention amount was associated with effect sizes for each intervention type, while controlling for outcome domain, outcome proximity, age of participants, study design, and risk of detection bias. Data were analyzed from June 2023 to February 2024. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
MAIN OUTCOMES AND MEASURES
The primary predictor of interest was intervention amount, quantified using 3 different metrics (daily intensity, duration, and cumulative intensity). The primary outcomes of interest were gains in any developmental domain, quantified by Hedges g effect sizes.
RESULTS
A total of 144 studies including 9038 children (mean [SD] age, 49.3 [17.2] months; mean [SD] percent males, 82.6% [12.7%]) were included in this analysis. None of the meta-regression models evidenced a significant, positive association between any index of intervention amount and intervention effect size when considered within intervention type.
CONCLUSIONS AND RELEVANCE
Findings of this meta-analysis do not support the assertion that intervention effects increase with increasing amounts of intervention. Health professionals recommending interventions should be advised that there is little robust evidence supporting the provision of intensive intervention.
PubMed: 38913359
DOI: 10.1001/jamapediatrics.2024.1832 -
Epidemiology (Cambridge, Mass.) Jul 2024Maternal folic acid intake has been associated with decreased risk for neurodevelopmental disorders including autism spectrum disorder (ASD). Genetic differences in...
BACKGROUND
Maternal folic acid intake has been associated with decreased risk for neurodevelopmental disorders including autism spectrum disorder (ASD). Genetic differences in folate metabolism could explain some inconsistencies. To our knowledge, newborn folate concentrations remain unexamined.
METHODS
We measured folate in archived newborn dried blood spots of children from the CHARGE (Childhood Autism Risks from Genetics and the Environment) case-control study who were clinically confirmed at 24-60 months to have ASD (n = 380), developmental delay (n = 128), or typical development (n = 247). We quantified monthly folic acid intake from maternally-reported supplements and cereals consumed during pregnancy and 3 months prior. We assessed associations of newborn folate with maternal folic acid intake and with ASD or developmental delay using regression. We stratified estimates across maternal and child MTHFR genotypes.
RESULTS
Among typically developing children, maternal folic acid intake in prepregnancy and each pregnancy month and prepregnancy prenatal vitamin intake were positively associated with newborn folate. Among children with ASD, prenatal vitamin intake in pregnancy months 2-9 was positively associated with newborn folate. Among children with developmental delay, maternal folic acid and prenatal vitamins during the first pregnancy month were positively associated with neonatal folate. Associations differed by MTHFR genotype. Overall, neonatal folate was not associated with ASD or developmental delay, though we observed associations with ASD in children with the MTHFR 677 TT genotype (odds ratio: 1.76, 95% CI = 1.19, 2.62; P for interaction = 0.08).
CONCLUSION
Maternal prenatal folic acid intake was associated with neonatal folate at different times across neurodevelopmental groups. Neonatal folate was not associated with reduced ASD risk. MTHFR genotypes modulated these relationships.
Topics: Humans; Folic Acid; Autism Spectrum Disorder; Female; Case-Control Studies; Infant, Newborn; Male; Pregnancy; Developmental Disabilities; Methylenetetrahydrofolate Reductase (NADPH2); Child, Preschool; Self Report; Dried Blood Spot Testing; Adult; Dietary Supplements; Genotype
PubMed: 38912713
DOI: 10.1097/EDE.0000000000001750 -
Environment International Jun 2024Childhood exposure to polycyclic aromatic hydrocarbons (PAHs) or lead (Pb) is associated with epigenetic modifications. However, the effects of their co-exposures on...
Associations of co-exposure to polycyclic aromatic hydrocarbons and lead (Pb) with IGF1 methylation in peripheral blood of preschool children from an e-waste recycling area.
BACKGROUND
Childhood exposure to polycyclic aromatic hydrocarbons (PAHs) or lead (Pb) is associated with epigenetic modifications. However, the effects of their co-exposures on IGF1 (Insulin-like growth factor 1) methylation and the potential role in child physical growth are unclear.
METHODS
From our previous children study (N = 238, ages of 3-6), 75 children with higher total concentrations of urinary ten hydroxyl PAH metabolites (∑OH-PAHs) from an e-waste recycling area, Guiyu, and 75 with lower ∑OH-PAHs from Haojiang (reference area) were included. Pb and IGF1 P2 promoter methylation in peripheral blood were also measured. Multivariable linear regression analyses were performed to estimate individual associations, overall effects and interactions of co-exposure to OH-PAHs and Pb on IGF1 methylation were further explored using Bayesian kernel machine regression.
RESULTS
Methylation of IGF1 (CG-232) was lower (38.00 vs. 39.74 %, P < 0.001), but of CG-207 and CG-137 were higher (59.94 vs. 58.41 %; 57.60 vs. 56.28 %, both P < 0.05) in exposed children than the reference. The elevated urinary 2-OHPhe was associated with reduced methylation of CG-232 (B = -0.051, 95 % CI: -0.096, -0.005, P < 0.05), whereas blood Pb was positively associated with methylation of CG-108 (B = 0.106, 95 %CI: 0.013, 0.199, P < 0.05), even after full adjustment. Methylations of CG-224 and 218 significantly decreased when all OH-PAHs and Pb mixtures were set at 35th - 40th and 45th - 55th percentile compared to when all fixed at 50th percentile. There were bivariate interactions of co-exposure to the mixtures on methylations of CG-232, 224, 218, and 108. Methylations correlated with height, weight, were observed in the exposed children.
CONCLUSIONS
Childhood co-exposure to high PAHs and Pb from the e-waste may be associated with IGF1 promoter methylation alterations in peripheral blood. This, in turn, may interrupt the physical growth of preschool children.
PubMed: 38908275
DOI: 10.1016/j.envint.2024.108833 -
Journal of Autism and Developmental... Jun 2024Co-occurring intellectual/developmental disability (IDD) and overweight/obesity (OW/OB) is an important consideration of IDD psychiatric care. The relationship between...
Co-occurring intellectual/developmental disability (IDD) and overweight/obesity (OW/OB) is an important consideration of IDD psychiatric care. The relationship between OW/OB and comorbid diagnoses of Autism Spectrum Disorder (ASD) and/or IDD remains inadequately described in existing literature. The purpose of this study is to explore these co-occurring diagnoses. Improved understanding of associated comorbidities can guide clinicians toward interventions to minimize complications associated with OW/OB. We conducted a retrospective review of adult patients of a telepsychiatry clinic with IDD or ASD defined by DSM-5. ICD-10 diagnosis of IDD or ASD, demographics, BMI, comorbidities, and current medications were recorded. Binary logistic regression was used to estimate associations between each predictor and the outcomes overweight (body mass index (BMI) ≥ 25 kg/m) and obesity (BMI ≥ 30 kg/m). Prevalence of obesity in these 412 adults was 52.4% (95% CI 47.5, 57.3). There was a significant inverse relationship between IDD severity and the odds of each outcome (p < .001). 80.3% of patients were being actively treated with an antidepressant. Patients taking an antidepressant had twice the odds of obesity (adjusted OR 2.03, 95% CI 1.23, 3.41, p = .006). These findings provide a sense of urgency for prevention of OW/OB and its associated medical sequelae. Prevalence of obesity was higher in this sample compared to the general population. The inverse relationship between IDD severity and OW/OB warrants further research examining age, caregiver involvement, and access to care as potential modifiers.
PubMed: 38907779
DOI: 10.1007/s10803-024-06432-0 -
PloS One 2024It is well known that maternal diet affects the development of offspring. Herein, the relationship between maternal intake of fermented foods during pregnancy and...
BACKGROUND
It is well known that maternal diet affects the development of offspring. Herein, the relationship between maternal intake of fermented foods during pregnancy and offspring development was investigated.
METHODS
The diet of 103,060 pregnant women at >4 months of gestation who were enrolled in the Japan Environment and Children's Study was analyzed. Their intake levels of fermented soybeans (miso and natto), yogurt, and cheese were investigated. The developmental status of the offspring at 3 years of age was assessed using the Ages and Stages Questionnaires (ASQ-3). Multivariable logistic regression analysis was performed to determine the risk of maternal intake levels of the fermented foods associated with subsequent developmental delay in the offspring.
RESULTS
Intake of cheese was associated with a reduced risk of child developmental delay in all intake level groups from the second quartile onward. Intakes of miso and yogurt were associated with a reduced risk of developmental delay in communication skills in the fourth quartile. There was no association between intake of natto and developmental delay.
CONCLUSION
Maternal consumption of fermented foods during pregnancy may reduce the risk of later developmental delay in offspring. It is therefore important to review the mother's diet for fermented foods during pregnancy. However, further studies are warranted to evaluate the factors influencing the association between diet and offspring development.
Topics: Female; Humans; Japan; Pregnancy; Child, Preschool; Fermented Foods; Adult; Male; Child Development; Diet; Surveys and Questionnaires; Maternal Nutritional Physiological Phenomena
PubMed: 38905296
DOI: 10.1371/journal.pone.0305535 -
Developmental Neuropsychology Jun 2024In the absence of any complaints in early childhood, preterm children remain more at risk of encountering academic difficulties, but their clinical picture remains not...
In the absence of any complaints in early childhood, preterm children remain more at risk of encountering academic difficulties, but their clinical picture remains not well characterized. We screened visuospatial perception in 70 children born preterm consulting for scholar complaints. Developmental Coordination Disorder (with or without comorbidities) was associated with high prevalence (27%) of impaired perception of spatial relationship. Prematurely born children who obtained no diagnosis of Neuro-Developmental Disorder exhibited a high prevalence (31%) of impaired perception of object magnitude. Regression revealed that low gestational age and fetal growth restriction significantly predicted the magnitude but not the spatial relationship perception.
PubMed: 38904205
DOI: 10.1080/87565641.2024.2366217 -
Gut Microbes 2024The gut microbiota, comprising trillions of diverse microorganisms inhabiting the intestines of animals, forms a complex and indispensable ecosystem with profound... (Review)
Review
The gut microbiota, comprising trillions of diverse microorganisms inhabiting the intestines of animals, forms a complex and indispensable ecosystem with profound implications for the host's well-being. Its functions include contributing to developing the host's immune response, aiding in nutrient digestion, synthesizing essential compounds, acting as a barrier against pathogen invasion, and influencing the development or regression of various pathologies. The dietary habits of the host directly impact this intricate community of gut microbes. Diet influences the composition and function of the gut microbiota through alterations in gene expression, enzymatic activity, and metabolome. While the impact of diet on gut ecology is well-established, the investigation into the relationship between dietary consumption and microbial genotypic diversity has been limited. This review provides an overview of the relationship between diet and gut microbiota, emphasizing the impact of host nutrition on both short- and long-term evolution in the mammalian gut. It is evident that the evolution of the gut microbiota occurs even on short timescales through the acquisition of novel mutations, within the gut bacteria of individual hosts. Consequently, we discuss the importance of considering alterations in bacterial genomic diversity when analyzing microbiota-dependent effects on host physiology. Future investigations into the various microbiota-related traits shall greatly benefit from a deeper understanding of commensal bacterial evolutionary adaptation.
Topics: Gastrointestinal Microbiome; Animals; Diet; Humans; Bacteria; Symbiosis; Biological Evolution; Host Microbial Interactions
PubMed: 38904092
DOI: 10.1080/19490976.2024.2369337 -
Frontiers in Pediatrics 2024West syndrome (WS) is a devastating epileptic encephalopathy with onset in infancy and early childhood. It is characterized by clustered epileptic spasms, developmental...
BACKGROUND
West syndrome (WS) is a devastating epileptic encephalopathy with onset in infancy and early childhood. It is characterized by clustered epileptic spasms, developmental arrest, and interictal hypsarrhythmia on electroencephalogram (EEG). Hypsarrhythmia is considered the hallmark of WS, but its visual assessment is challenging due to its wide variability and lack of a quantifiable definition. This study aims to analyze the EEG patterns in WS and identify computational diagnostic biomarkers of the disease.
METHOD
Linear and non-linear features derived from EEG recordings of 31 WS patients and 20 age-matched controls were compared. Subsequently, the correlation of the identified features with structural and genetic abnormalities was investigated.
RESULTS
WS patients showed significantly elevated alpha-band activity (0.2516 vs. 0.1914, < 0.001) and decreased delta-band activity (0.5117 vs. 0.5479, < 0.001), particularly in the occipital region, as well as globally strengthened theta-band activity (0.2145 vs. 0.1655, < 0.001) in power spectrum analysis. Moreover, wavelet-bicoherence analysis revealed significantly attenuated cross-frequency coupling in WS patients. Additionally, bi-channel coherence analysis indicated minor connectivity alterations in WS patients. Among the four non-linear characteristics of the EEG data (i.e., approximate entropy, sample entropy, permutation entropy, and wavelet entropy), permutation entropy showed the most prominent global reduction in the EEG of WS patients compared to controls (1.4411 vs. 1.5544, < 0.001). Multivariate regression results suggested that genetic etiologies could influence the EEG profiles of WS, whereas structural factors could not.
SIGNIFICANCE
A combined global strengthening of theta activity and global reduction of permutation entropy can serve as computational EEG biomarkers for WS. Implementing these biomarkers in clinical practice may expedite diagnosis and treatment in WS, thereby improving long-term outcomes.
PubMed: 38903771
DOI: 10.3389/fped.2024.1406772 -
Frontiers in Neuroscience 2024Recently a broad range of phenotypic abnormalities related to the neurodevelopmental and neurodegenerative disorder NEDAMSS (Neurodevelopmental Disorder with Regression,... (Review)
Review
Recently a broad range of phenotypic abnormalities related to the neurodevelopmental and neurodegenerative disorder NEDAMSS (Neurodevelopmental Disorder with Regression, Abnormal Movements, Loss of Speech, and Seizures) have been associated with rare single-nucleotide polymorphisms (SNPs) or insertion and deletion variants (Indel) in the intron-less gene IRF2BPL. Up to now, 34 patients have been identified through whole exome sequencing carrying different heterozygous pathogenic variants spanning the intron-less gene from the first polyglutamine tract at the N-terminus to the C3HC4 RING domain of the C-terminus of the protein. As a result, the phenotypic spectrum of the patients is highly heterogeneous and ranges from abnormal neurocognitive development to severe neurodegenerative courses with developmental and seizure-related encephalopathies. While the treatment of IRF2BPL-related disorders has focused on alleviating the patient's symptoms by symptomatic multidisciplinary management, there has been no prospect of entirely relieving the symptoms of the individual patients. Yet, the recent advancement of CRISPR-Cas9-derived gene editing tools, leading to the generation of base editors (BEs) and prime editors (PEs), provide an encouraging new therapeutic avenue for treating NEDAMSS and other neurodevelopmental and neurodegenerative diseases, which contain SNPs or smaller Indels in post-mitotic cell populations of the central nervous system, due to its ability to generate site-specific DNA sequence modifications without creating double-stranded breaks, and recruiting the non-homologous DNA end joining repair mechanism.
PubMed: 38903604
DOI: 10.3389/fnins.2024.1426177