Neurodevelopmental Abnormalities Research Articles

Medication Usage Record-Based Predictive Modeling of Neurodevelopmental Abnormality in Infants under One Year: A Prospective Birth Cohort Study.

Early identification of children with neurodevelopmental abnormality is a major challenge, which is crucial for improving symptoms and preventing further decline in children with neurodevelopmental abnormality. This study focuses on developing a predictive model with maternal sociodemographic, behavioral, and medication-usage information during pregnancy to identify infants with abnormal neurodevelopment before the age of one. In addition, an interpretable machine-learning approach was utilized to assess the importance of the variables in the model. In this study, artificial neural network models were developed for the neurodevelopment of five areas of infants during the first year of life and achieved good predictive efficacy in the areas of fine motor and problem solving, with median AUC = 0.670 (IQR: 0.594, 0.764) and median AUC = 0.643 (IQR: 0.550, 0.731), respectively. The final model for neurodevelopmental abnormalities in any energy region of one-year-old children also achieved good prediction performance. The sensitivity is 0.700 (IQR: 0.597, 0.797), the AUC is 0.821 (IQR: 0.716, 0.833), the accuracy is 0.721 (IQR: 0.696, 0.739), and the specificity is 0.742 (IQR: 0.680, 0.748). In addition, interpretable machine-learning methods suggest that maternal exposure to drugs such as acetaminophen, ferrous succinate, and midazolam during pregnancy affects the development of specific areas of the offspring during the first year of life. This study established predictive models of neurodevelopmental abnormality in infants under one year and underscored the prediction value of medication exposure during pregnancy for the neurodevelopmental outcomes of the offspring.

Comparative Assessment of the Effectiveness of HSP70 / HIF-1α System Modulators after Prenatal Hypoxia

Prenatal hypoxia (PH) poses a significant threat to fetal development and may be responsible for neonatal mortality or neurodevelopmental abnormalities. The proteins HSP70 and HIF-1, which hold a distinct significance in the cellular reaction to PH, can be regarded as potential targets for pharmaceutical interventions aimed at mitigating the repercussions of chronic PH. This study aimed to identify a possible correlation between offspring survival and stages of expression of endogenous neuroprotective factors (HSP70 and HIF-1) after chronic prenatal hypoxia with course administration of potential HSP70 modulators (angiolin, piracetam, thiotriazoline, nicomex, cerebrocurin, tamoxifen, L-arginine, glutoredoxin, HSF-1, and mildronate). In the rat offspring after PH we determined the plasma concentrations of HSP70 and HIF-1 by solid-phase ELISA immunoassay, and the expression of HIF-1 mRNA and HSP70 mRNA by real-time PCR. For the first time, we found a positive correlation between offspring survival after PH and the expression of HIF-1 and HSP70, both in groups without experimental therapy and in groups receiving pharmacological agents. The course administration of HSP70/HIF-1α modulators, especially angiolin (50 mg/kg), cerebrocurin (150 mg/kg), and HSF-1 (50 mg/kg), to rats that underwent PH reduces postnatal lethality, increases blood plasma concentrations of HSP70 and HIF-1α, and positively affects the expression level of HIF-1α mRNA in the rat brain. These drugs can be considered as the most promising drug candidates for new therapeutic strategies of pharmacological correction of the consequences of chronic PH.

Assessment of brain structure and volume reveals neurodevelopmental abnormalities in preterm infants with low-grade intraventricular hemorrhage

There is increasing evidence of abnormal neurodevelopmental outcomes in preterm infants with low-grade intraventricular hemorrhage (IVH). The purpose of the study was to explore whether brain microstructure and volume are associated with neuro-behavioral outcomes at 40 weeks corrected gestational age in preterm infants with low-grade IVH. MR imaging at term-equivalent age (TEA) was performed in 25 preterm infants with mild IVH (Papile grading I/II) and 40 control subjects without IVH. These subjects all had neonatal behavioral neurological assessment (NBNA) at 40 weeks’ corrected age. Microstructure and volume evaluation of the brain were performed by using diffusion kurtosis imaging (DKI) and Synthetic MRI. Correlations among microstructure parameters, volume, and developmental outcomes were explored by using Spearman's correlation. In preterm infants with low-grade IVH, the volume of brain parenchymal fraction (BPF) was reduced. In addition, mean kurtosis (MK), fractional anisotropy (FA), radial kurtosis (RK), axial kurtosis (AK) in several major brain regions were reduced, while mean diffusivity (MD) was increased (P < 0.05). BPF, RK in the cerebellum, MK in the genu of the corpus callosum, and MK in the thalamus of preterm infants with low-grade IVH were associated with lower NBNA scores (r = 0.831, 0.836, 0.728, 0.772, P < 0.05). DKI and Synthetic MRI can quantitatively evaluate the microstructure alterations and brain volumes in preterm infants with low-grade IVH, which provides clinicians with a more comprehensive and accurate neurobehavioral assessment of preterm infants with low-grade IVH.

The association of cumulative vasoactive drugs and neurodevelopmental outcomes in preterm Infants

To assess the effect of cardiovascular medications on the neurodevelopment of preterm infants, as measured by calculated cumulative time of vasoactive-inotropic score (VISct). A retrospective study was conducted on preterm infants who developed significant hypotension defined as a mean BP more than 2SDs below the mean for GA and received treatment with duration > 6 hours for each hypotensive episode, we calculated the vasoactive inotropic score (VIS) and cumulative exposure to cardiovascular medications over time (VISct). The composite Bayley III was reported from the high-risk follow-up clinic for the surviving infants between 18 to 21 months corrected age. VISct was significantly higher in infants with abnormal neurodevelopment. Cognitive Bayley was the most affected component with median (IQR) VISct 882.5(249,2047) versus 309(143,471) (p-value 0.012), followed by language function with VISct 786(261,1563.5), versus 343(106.75,473.75) (p-value 0.016) when those with Bayley III <85 were compared with those with normal Bayley IIIs. High VISct scores may have negative effect on cognitive and language neurodevelopmental outcomes.

Effects of prenatal environmental exposure to pesticides on the neurodevelopment of children in the department of Alto Paraná Paraguay at 34-36 months of age

ABSTRACT Prenatal exposure to pesticides of different chemical groups is associated with an increased risk of anthropometric, neurological, and neurodevelopmental alterations in children. The paper reports an evaluation of the neurodevelopmental, nutritional, and sensory status of a group of children belonging to birth cohorts with and without prenatal environmental exposure to pesticides, in the department of Alto Paraná, from a previously published study. A prospective observational study was conducted. The neurodevelopmental status was evaluated with the Battelle Developmental Inventory Screening test (BDIST). The sensory status was assessed through an ophthalmological examination and an otoacoustic emissions test. A total of 100 children aged 34 to 36 months, of whom only 50 were exposed to pesticides during the prenatal period, were included in the study. Results showed that 45% of the children studied had neurodevelopmental impairments. The cognitive area was the most affected (56%) and the risk of abnormal neurodevelopment was 5.6 times higher in children who had been prenatally exposed to pesticides than in the unexposed. Malnourished children were 4 times more likely to have an abnormal BDIST result. Results suggest that prenatal pesticide exposure is an important risk factor for lower neurodevelopment in children at 34 to 36 months of age, adjusted for socioeconomic factors.

New Therapeutic Targets and Drugs for Schizophrenia Beyond Dopamine D2 Receptor Antagonists.

Schizophrenia is a disease with a complex pathological mechanism that is influenced by multiple genes. The study of its pathogenesis is dominated by the dopamine hypothesis, as well as other hypotheses such as the 5-hydroxytryptamine hypothesis, glutamate hypothesis, immune-inflammatory hypothesis, gene expression abnormality hypothesis, and neurodevelopmental abnormality hypothesis. The first generation of antipsychotics was developed based on dopaminergic receptor antagonism, which blocks dopamine D2 receptors in the brain to exert antipsychotic effects. The second generation of antipsychotics acts by dual blockade of 5-hydroxytryptamine and dopamine receptors. From the third generation of antipsychotics onwards, the therapeutic targets for antipsychotic schizophrenia expanded beyond D2 receptor blockade to explore D2 receptor partial agonism and the antipsychotic effects of new targets such as D3, 5-HT1A, 5-HT7, and mGlu2/3 receptors. The main advantages of the second and third generation antipsychotics over first-generation antipsychotics are the reduction of side effects and the improvement of negative symptoms, and even though third-generation antipsychotics do not directly block D2 receptors, the modulation of the dopamine transmitter system is still an important part of their antipsychotic process. According to recent research, several receptors, including 5-hydroxytryptamine, glutamate, γ-aminobutyric acid, acetylcholine receptors and norepinephrine, play a role in the development of schizophrenia. Therefore, the focus of developing new antipsychotic drugs has shifted towards agonism or inhibition of these receptors. Specifically, the development of NMDARs stimulants, GABA receptor agonists, mGlu receptor modulators, cholinergic receptor modulators, 5-HT2C receptor agonists and alpha-2 receptor modulators has become the main direction. Animal experiments have confirmed the antipsychotic effects of these drugs, but their pharmacokinetics and clinical applicability still require further exploration. Research on alternative targets for antipsychotic drugs, beyond the dopamine D2 receptor, has expanded the potential treatment options for schizophrenia and gives an important way to address the challenge of refractory schizophrenia. This article aims to provide a comprehensive overview of the research on therapeutic targets and medications for schizophrenia, offering valuable insights for both treatment and further research in this field.

TBC1D23 mediates Golgi-specific LKB1 signaling

Liver kinase B1 (LKB1), an evolutionarily conserved serine/threonine kinase, is a master regulator of the AMPK subfamily and controls cellular events such as polarity, proliferation, and energy homeostasis. Functions and mechanisms of the LKB1-AMPK axis at specific subcellular compartments, such as lysosome and mitochondria, have been established. AMPK is known to be activated at the Golgi; however, functions and regulatory mechanisms of the LKB1-AMPK axis at the Golgi apparatus remain elusive. Here, we show that TBC1D23, a Golgi-localized protein that is frequently mutated in the neurodevelopment disorder pontocerebellar hypoplasia (PCH), is specifically required for the LKB1 signaling at the Golgi. TBC1D23 directly interacts with LKB1 and recruits LKB1 to Golgi, promoting Golgi-specific activation of AMPK upon energy stress. Notably, Golgi-targeted expression of LKB1 rescues TBC1D23 deficiency in zebrafish models. Furthermore, the loss of LKB1 causes neurodevelopmental abnormalities in zebrafish, which partially recapitulates defects in TBC1D23-deficient zebrafish, and LKB1 sustains normal neuronal development via TBC1D23 interaction. Our study uncovers a regulatory mechanism of the LKB1 signaling, and reveals that a disrupted Golgi-LKB1 signaling underlies the pathogenesis of PCH.

Heterozygous CAPZA2 mutations cause global developmental delay, hypotonia with epilepsy: a case report and the literature review.

CAPZA2 encodes the α2 subunit of CAPZA, which is vital for actin polymerization and depolymerization in humans. However, understanding of diseases associated with CAPZA2 remains limited. To date, only three cases have been documented with neurodevelopmental abnormalities such as delayed motor development, speech delay, intellectual disability, hypotonia, and a history of seizures. In this study, we document a patient who exhibited seizures, mild intellectual disability, and impaired motor development yet did not demonstrate speech delay or hypotonia. The patient also suffered from recurrent instances of respiratory infections, gastrointestinal and allergic diseases. A novel de novo splicing variant c.219+1 G > A was detected in the CAPZA2 gene through whole-exome sequencing. This variant led to exon 4 skipping in mRNA splicing, confirmed by RT-PCR and Sanger sequencing. To our knowledge, this is the third study on human CAPZA2 defects, documenting the fourth unambiguously diagnosed case. Furthermore, this splicing mutation type is reported here for the first time. Our research offers additional support for the existence of a CAPZA2-related non-syndromic neurodevelopmental disorder. Our findings augment our understanding of the phenotypic range associated with CAPZA2 deficiency and enrich the knowledge of the mutational spectrum of the CAPZA2 gene.

Differences in Motor Development between Preterm Infants and Full-Term Preschool Children.

Although advances in obstetric and neonatal care have improved the survival of preterm infants, many studies document the increased risk of motor and sensory neurodevelopmental abnormalities that can hinder school progress. The aim of this study was to analyze the differences in gross and fine motor development in children born preterm and full term aged 3 to 6 years using the Peabody Developmental Motor Scales 2 (PDMS-II). Fifteen preterm and fifteen term children, matched for age and sex, participated in this study. They were evaluated with the PDMS-II scale. The scores obtained in the PDMS-II scale showed statistically significant differences (p < 0.05) in all subscales except for the "grasping" subscale. No dissimilarities were found between children who attended an early intervention program and those who did not participate, nor was there any correlation between week of gestation and birth weight and motor development in preschool. The results obtained show that differences are found with respect to motor development, with lower scores for those born preterm compared to children born at term. No statistically significant difference was found between preterm children who attended early intervention and those who did not. No correlation was found between motor development at preschool age and birth weight and gestational age.

A Homozygous PTRHD1 Missense Variant (p.Arg122Gln) in an Individual with Intellectual Disability, Generalized Epilepsy, and Juvenile Parkinsonism.

Biallelic variants in PTRHD1 have been associated with autosomal recessive intellectual disability, spasticity, and juvenile parkinsonism, with few reported cases. Here, we present the clinical and genetic findings of a female of Austrian origin exhibiting infantile neurodevelopmental abnormalities, intellectual disability, and childhood-onset parkinsonian features, consistent with the established phenotypic spectrum. Notably, she developed genetic generalized epilepsy at age 4, persisting into adulthood. Using diagnostic exome sequencing, we identified a homozygous missense variant (c.365G > A, p.(Arg122Gln)) in PTRHD1 (NM_001013663). In summary, our findings not only support the existing link between biallelic PTRHD1 variants and parkinsonism with neurodevelopmental abnormalities but also suggest a potential extension of the phenotypic spectrum to include generalized epilepsy.

Neurobehavioral Abnormalities in Offspring of Young Adult Male Rats With a History of Traumatic Brain Injury.

Children of parents with traumatic brain injury (TBI) are more likely to develop psychiatric disorders. This association is usually attributed to TBI-induced changes in parents' personality and families' social environment. We tested the hypothesis that offspring of young adult male rats with TBI develop neurodevelopmental abnormalities in the absence of direct social contact with sires. Male Sprague-Dawley rats (F0 generation) in the TBI group underwent moderate TBI via a midline fluid percussion injury that involved craniectomy under sevoflurane (SEVO) anesthesia for 40 min on post-natal Day 60 (P60), while F0 rats in the control group were placed in a new cage, one per cage, for the equivalent time duration. A subset of F0 rats was sacrificed on P66 to assess acute changes in hypothalamic-pituitary-adrenal (HPA) axis and inflammation markers. The remaining F0 males were mated with naive females on P90 to generate offspring (F1 generation). The F0 males and F1 males and females were sequentially evaluated in the elevated plus maze, for pre-pulse inhibition of acoustic startle, in the Morris water maze, and for resting and stress levels of serum corticosterone starting on ∼P105 (F0) and ∼P60 (F1), followed by tissue collection for further analyses. Acutely, the F0 TBI males had messenger RNA (mRNA) transcripts altered to support an increased hypothalamic and hippocampal Na+-K+-Cl- (Slc12a2) Cl- importer / K+-2Cl- (Slc12a5) Cl- exporter ratio and decreased hippocampal glucocorticoid receptors (Nr3c1), as well as increased serum levels of corticosterone, interleukin-1β (IL-1β), and biomarkers of activated hippocampal microglia and astrocytes. Long-term, F0 TBI rats exhibited increased corticosterone concentrations at rest and under stress, anxiety-like behavior, impaired sensory-motor gating, and impaired spatial memory. These abnormalities were underpinned by reduced mRNA levels of hypothalamic and hippocampal mineralocorticoid receptors (Nr3c2), hippocampal Nr3c1, and hypothalamic brain-derived neurotrophic factor (Bdnf), as well as elevated serum levels of IL-1β, and biomarkers of activated hippocampal microglia and astrocytes. F1 male offspring of TBI sires exhibited abnormalities in all behavioral tests, while their F1 female counterparts had abnormal pre-pulse inhibition responses only. F1 male offspring of TBI sires also had reduced mRNA levels of hippocampal Nr3c1 and Nr3c2, as well as hypothalamic and hippocampal Bdnf, whereas increases in inflammatory markers were more profound in F1 females. These findings suggest that offspring of sires with a history of a moderate TBI that involved craniectomy under SEVO anesthesia for 40 min, develop sex-dependent neurobehavioral abnormalities in the absence of direct social interaction between the sire and the offspring.

A Homozygous PTRHD1 Missense Variant (p.Arg122Gln) in an Individual with Intellectual Disability, Generalized Epilepsy, and Juvenile Parkinsonism.

Biallelic variants in PTRHD1 have been associated with autosomal recessive intellectual disability, spasticity, and juvenile Parkinsonism, with few reported cases. Here, we present the clinical and genetic findings of a female of Austrian origin exhibiting infantile neurodevelopmental abnormalities, intellectual disability, and childhood-onset parkinsonian features, consistent with the established phenotypic spectrum. Notably, she developed genetic generalized epilepsy at age 4, persisting into adulthood. Using diagnostic exome sequencing, we identified a homozygous missense variant (c.365G > A, p.(Arg122Gln)) in PTRHD1 (NM_001013663). In summary, our findings not only support the existing link between biallelic PTRHD1 variants and Parkinsonism with neurodevelopmental abnormalities but also suggest a potential extension of the phenotypic spectrum to include generalized epilepsy.

Postnatal Zika virus infection leads to morphological and cellular alterations within the neurogenic niche.

The Zika virus received significant attention in 2016, following a declaration by the World Health Organization of an epidemic in the Americas, in which infections were associated with microcephaly. Indeed, prenatal Zika virus infection is detrimental to fetal neural stem cells and can cause premature cell loss and neurodevelopmental abnormalities in newborn infants, collectively described as congenital Zika syndrome. Contrastingly, much less is known about how neonatal infection affects the development of the newborn nervous system. Here, we investigated the development of the dentate gyrus of wild-type mice following intracranial injection of the virus at birth (postnatal day 0). Through this approach, we found that Zika virus infection affected the development of neurogenic regions within the dentate gyrus and caused reactive gliosis, cell death and a decrease in cell proliferation. Such infection also altered volumetric features of the postnatal dentate gyrus. Thus, we found that Zika virus exposure to newborn mice is detrimental to the subgranular zone of the dentate gyrus. These observations offer insight into the cellular mechanisms that underlie the neurological features of congenital Zika syndrome in children.

Italian Guidelines for the diagnosis and treatment of Fetal Alcohol Spectrum Disorders: diagnostic criteria

Fetal Alcohol Spectrum Disorders (FASD) encompass a spectrum of clinical manifestations resulting from maternal alcohol consumption during pregnancy. This condition presents with diverse anomalies including intrauterine and extrauterine growth retardation, phenotypic abnormalities, cerebral structural anomalies, cognitive delays, and behavioral abnormalities. Regrettably, FASD remains an irreversible and epigenetic condition, with total abstention from alcohol during pregnancy being the sole effective preventive measure due to the absence of a viable therapy. Diagnosis typically occurs postnatally, based on a combination of alcohol exposure history and the presence of aforementioned physical or behavioral abnormalities. The diagnosis is not always easy to make even in the post-natal period due to the different subtypes of existing FASD. Indeed, only some of these subtypes cause behavioral or neurodevelopmental abnormalities in the absence of pathognomic physical anomalies. Although the diagnostic criteria are useful, unfortunately, there is a heterogeneity resulting from the different guidelines that are used in different countries. The aim of our review, based on a literature search of online databases including Medline, Medline Complete, PubMed, and Google Scholar, is therefore to provide an overview of the diagnostic criteria used in Italy.

The Impact of Microglia on Neurodevelopment and Brain Function in Autism.

Microglia, as one of the main types of glial cells in the central nervous system (CNS), are widely distributed throughout the brain and spinal cord. The normal number and function of microglia are very important for maintaining homeostasis in the CNS. In recent years, scientists have paid widespread attention to the role of microglia in the CNS. Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder, and patients with ASD have severe deficits in behavior, social skills, and communication. Most previous studies on ASD have focused on neuronal pathological changes, such as increased cell proliferation, accelerated neuronal differentiation, impaired synaptic development, and reduced neuronal spontaneous and synchronous activity. Currently, more and more research has found that microglia, as immune cells, can promote neurogenesis and synaptic pruning to maintain CNS homeostasis. They can usually reduce unnecessary synaptic connections early in life. Some researchers have proposed that many pathological phenotypes of ASD may be caused by microglial abnormalities. Based on this, we summarize recent research on microglia in ASD, focusing on the function of microglia and neurodevelopmental abnormalities. We aim to clarify the essential factors influenced by microglia in ASD and explore the possibility of microglia-related pathways as potential research targets for ASD.

Deficiency of FRMD5 results in neurodevelopmental dysfunction and autistic-like behavior in mice.

The pathophysiology of autism spectrum disorders (ASDs) is causally linked to postsynaptic scaffolding proteins, as evidenced by numerous large-scale genomic studies [1, 2] and in vitro and in vivo neurobiological studies of mutations in animal models [3, 4]. However, due to the distinct phenotypic and genetic heterogeneity observed in ASD patients, individual mutation genes account for only a small proportion (<2%) of cases [1, 5]. Recently, a human genetic study revealed a correlation between de novo variants in FERM domain-containing-5 (FRMD5) and neurodevelopmental abnormalities [6]. In this study, we demonstrate that deficiency of the scaffolding protein FRMD5 leads to neurodevelopmental dysfunction and ASD-like behavior in mice. FRMD5 deficiency results in morphological abnormalities in neurons and synaptic dysfunction in mice. Frmd5-deficient mice display learning and memory dysfunction, impaired social function, and increased repetitive stereotyped behavior. Mechanistically, tandem mass tag (TMT)-labeled quantitative proteomics revealed that FRMD5 deletion affects the distribution of synaptic proteins involved in the pathological process of ASD. Collectively, our findings delineate the critical role of FRMD5 in neurodevelopment and ASD pathophysiology, suggesting potential therapeutic implications for the treatment of ASD.

Prenatal tobacco smoke exposure and risk for cognitive delays in infants born very premature

Prenatal tobacco smoke exposure (TSE) and prematurity are independent risk factors for abnormal neurodevelopment. The objectives were to compare differences in Bayley-III cognitive, language, and motor scores at 2 years corrected age (CA) in 395 infants born very preterm (≤ 32 weeks gestation) with and without prenatal TSE. We performed multivariable linear regression analyses to examine associations between prenatal TSE and neurodevelopmental outcomes and a mediation analysis to estimate direct effects of prenatal TSE on outcomes and indirect effects through preterm birth. In total, 50 (12.6%) infants had prenatal TSE. Infants with prenatal TSE had lower mean [95% CI] Cognitive score (82.8 [78.6, 87.1]) vs. nonexposed infants (91.7 [90.1, 93.4]). In children with and without prenatal TSE, there were significant differences in mean [95% CI] Language scores (81.7 [76.0, 87.4] vs. 92.4 [90.2, 94.6], respectively) and mean [95% CI] Motor scores (86.5 [82.2, 90.7] vs. 93.4 [91.8, 95.0], respectively); scores remained significant after controlling for confounders. Preterm birth indirectly mediated 9.0% of the total effect of prenatal TSE on Cognitive score (P = NS). However, 91% of the remaining total effect was significant and attributable to TSE’s direct harmful effects on cognitive development (β = − 5.17 [95% CI − 9.97, − 0.38]). The significant association is largely due to TSE’s direct effect on cognitive development and not primarily due to TSE’s indirect effect on preterm birth.

GLUT-1DS resistant to ketogenic diet: from clinical feature to in silico analysis. An exemplificative case report with a literature review.

Glucose transporter type 1 deficiency syndrome (GLUT-1DS) is characterized by alterations in glucose translocation through the blood-brain barrier (BBB) due to mutation involving the GLUT-1 transporter. The fundamental therapy is ketogenic diet (KD) that provide an alternative energetic substrate - ketone bodies that across the BBB via MCT-1 - for the brain. Symptoms are various and include intractable seizure, acquired microcephalia, abnormal ocular movement, movement disorder, and neurodevelopment delay secondary to an energetic crisis for persistent neuroglycopenia. KD is extremely effective in controlling epileptic seizures and has a positive impact on movement disorders and cognitive impairment. Cases of KD resistance are rare, and only a few of them are reported in the literature, all regarding seizure. Our study describes a peculiar case of GLUT-1DS due to a new deletion involving the first codon of SLC2A1 gene determining a loss of function with a resistance to KD admitted to hospital due to intractable episodes of dystonia. This patient presented a worsening of symptomatology at higher ketonemia values but without hyperketosis and showed a complete resolution of symptomatology while maintaining low ketonemia values. Our study proposes an in-silico genomic and proteomic analysis aimed at explaining the atypical response to KD exhibited by our patient. In this way, we propose a new clinical and research approach based on precision medicine and molecular modelling to be applied to patients with GLUT-1DS resistant to first-line treatment with ketogenic diet by in silico study of genetic and altered protein product.

Evaluation of serum interleukin-17 A and interleukin-22 levels in pediatric patients with autism spectrum disorder: a pilot study

BackgroundMany neurodevelopmental abnormalities are connected to autism spectrum disorder (ASD), which can result in inflammation and elevated cytokine levels due to immune system dysregulation. Interleukin (IL)-17 A and IL-22 have been linked to the regulation of host defense against pathogens at the barrier surface, the regeneration of injured tissue, and the integration of the neurological, endocrine, and immune systems. Several studies have investigated the possible connection between IL-17 A and ASD as well as the severity of behavioral symptoms, but few of them included IL-22.ObjectivesTo measure serum levels of interleukin (IL)-17 A and IL-22 in children with ASD and to investigate their association with disease severity.MethodsThis pilot study was performed on 24 children with ASD and 24 matched controls. Childhood Autism Rating Scale (CARS) assessed ASD severity, and serum levels of IL-17 A and IL-22 were assessed by enzyme-linked immunosorbent assay (ELISA).ResultsIn ASD patients, serum levels of IL-17 A and IL-22 showed a significant increase compared to controls (p-values < 0.001). We compared serum levels of IL-17 A and IL-22 according to the severity categories by CARS and could not find any significant differences (p-values > 0.05). Only IL-22 had a significant positive correlation with ASD severity by CARS scores.ConclusionsRaised serum levels of IL-17 A and IL-22 are associated with ASD; only IL-22, not IL-17 A, is correlated with ASD severity. This finding proposes IL-22 as a possible future effective target for ASD treatment. To fully comprehend the significance of these cytokines in ASD and their possible effects on ASD diagnosis and treatment, more research on a wider scale is required.

Language defi cit in boys with autism spectrum disorder in relation to maternal reproductive health, endocrine disruptors, and delivery method.

The presented research aimed to identify prenatal factors involved in abnormal neurodevelopment and postnatal manifestation of an autistic phenotype in 107 boys (average age 4.31 ± 2.24 years). Their biological mothers were asked to fill out a comprehensive questionnaire about their reproductive health, infections during pregnancy, oral contraceptive intake before conception, and potential substance abuse before and during pregnancy as well as delivery and newborn information. The boys were subsequently diagnosed with autism spectrum disorder (ASD) using the combination of Autism Diagnostic Observation Schedule (ADOS-2) and Autism Diagnostic Interview - Revised (ADI-R). Based on the ADOS-2 module chosen during diagnosis, boys diagnosed with Module 1 can be classified as nonverbal or minimally verbal (N = 68), while those diagnosed using Module 3 are fully verbal (N = 39). According to our results, reproductive health related to the length of the menstrual cycle before pregnancy with the autistic child seems to play a role with regards to the severity of the disorder (P = 0.017) as well as the number of previous pregnancies (P = 0.026). Mothers of nonverbal children reported to have had a much shorter menstrual cycle (27.35 ± 6.60 days) than those with verbal children (30.14 ± 4.44 days) and reported more previous pregnancies (0.93 ± 1.07 vs. 0.51 ± 0.91), while not reporting the number of live births before they had the autistic child. Children who were later diagnosed as non-verbal had a longer delivery time (from 2 to 48 hours; on average 11.13 hours, SD = 9.49) than verbal ones (between 1 and 27 hours, which was on average 7.09 hours, SD = 8.91), P = 0.0182. Delivery method didn't play a role in this context, and neither did the type of conception (natural, insemination, etc.). Studying the involvement of prenatal factors in the etiology of autism based on the speech of the child seems to be a promising approach.