Int. J. Dev. Neurosci. [JOURNAL]
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200 papers
Placental Alterations in Autism Spectrum Disorder: An In Silico Approach to circRNA-miRNA-mRNA Networks.
Braz-Barbosa B, Gottfried C, Santos-Terra J
Int J Dev Neurosci · 2025 Nov · PMID 41218992 · Full text
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication and repetitive behaviours with an aetiology involving genetic and environmental risk factors. Placental a...
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication and repetitive behaviours with an aetiology involving genetic and environmental risk factors. Placental alterations, such as epigenetic DNA methylation and structural abnormalities, have been associated with ASD. Circular RNA (circRNA), covalently closed and highly stable molecules, play an epigenetic role by sequestering microRNA (miRNA) and modulating messenger RNA (mRNA) translation, forming posttranscriptional networks essential for gene expression. However, there is a lack of evidence in the literature regarding the involvement of circRNA, the placenta and ASD. To address this gap, the study aimed to map the interactions among circRNA, miRNA and mRNA, investigating their relevance to ASD and placental development using bioinformatics tools, such as circATLAS and miRTargetLink 2.0. The analysis identified 71 circRNA linked to ASD and 30 highly expressed in the placenta, which regulate pathways such as 'immune response,' 'gene transcription,' and 'replication,' and others previously associated with ASD, such as 'Notch and AKT signalling pathway'. Searches in the SFARI database revealed 11 relevant genes in the ASD group, nine in the placenta group and five shared genes (SRSF11, PSMD11, NOTCH1, CREBBP and TBL1X). Further analysis identified the interaction of the circRNA hsa-MAN1A2_0008 with miRNA associated with these genes. These findings suggest that highly expressed circRNA in the placenta regulate critical pathways for placental development and ASD aetiology, underscoring their role in linking placental alterations to ASD.
The Effects of Anxiety on Social Competence and Behavioural Adjustment in Preschoolers With Developmental Language Disorder.
Kocaman O, Kuru T, Yildiz Özşan O … +3 more , Kara T, Kiliç UM, Aydoğan Avşar P
Int J Dev Neurosci · 2025 Nov · PMID 41218990 · Publisher ↗
This study compared the social competence and emotional-behavioural adjustment of children aged 36-72 months with developmental language disorder (DLD) with those of typically developing peers (TD) and examined the relat...
This study compared the social competence and emotional-behavioural adjustment of children aged 36-72 months with developmental language disorder (DLD) with those of typically developing peers (TD) and examined the relationship between anxiety disorders and these domains in the DLD group. The sample consisted of 229 children (92 DLD, 137 TD). Data were collected using the Social Competence and Behaviour Evaluation Scale-30 and the Preschool Anxiety Scale. Children with DLD exhibited lower social competence and higher anxiety-withdrawal and anger-aggression scores than their TD peers. In the DLD group, generalized anxiety and specific fears were negatively associated with social competence and positively associated with anxiety-withdrawal and anger-aggression. Social anxiety was negatively associated with social competence and positively associated with anxiety-withdrawal. Separation anxiety was positively associated with anxiety-withdrawal and anger-aggression. Regression analyses showed that social anxiety predicted anxiety-withdrawal, and generalized anxiety predicted anger-aggression. Moderation analysis determined that language development levels moderated the relationship between generalized anxiety and anger-aggression in children with DLD, such that generalized anxiety positively predicted anger-aggression, but this effect became weaker as language development levels increased. Children with DLD exhibit social-emotional and behavioural adjustment difficulties, with which anxiety symptoms are significantly associated. Intervention programs should consider anxiety symptoms when supporting the development of social and behavioural skills in children with DLD.
The Effect of Postexposure Sleep Deprivation on Anxiety-Related Behaviours and Hippocampal Neuropathological Changes in a Rat Model of Posttraumatic Stress Disorder.
Karabulut S, Topcu H, Er SN … +4 more , Erozdemir B, Günes H, Yaprak M, Ozkaraca M
Int J Dev Neurosci · 2025 Nov · PMID 41218983 · Publisher ↗
Sleep problems are a hallmark of posttraumatic stress disorder (PTSD). Although the critical role of sleep for memory consolidation is well known, there is no consensus on the effect of sleep interruption or increased sl...
Sleep problems are a hallmark of posttraumatic stress disorder (PTSD). Although the critical role of sleep for memory consolidation is well known, there is no consensus on the effect of sleep interruption or increased sleep duration immediately after a traumatic experience on the development of PTSD. In addition, the effect of the loss of specific sleep stages postexposure on the development of PTSD is not fully elucidated. Using the single prolonged stress (SPS) procedure, we aimed to determine the effect of postexposure REM sleep deprivation (REMSD) or total sleep deprivation (TSD) on memory function, anxiety-related behaviours and related biochemical parameters. Fear and anxiety-like behaviour, hippocampal BDNF and acetylcholinesterase (AChE) levels in animals exposed to SPS alone or to the combination of SPS + REMSD or SPS + TSD were tested against a group of unexposed control animals. In our study, we found that SPS rats had impaired memory formation and performed poorly on anxiety-related behaviours. The effects of REMSD or TSD on anxiety-related behaviours after SPS were similar and did not result in a significant improvement. Furthermore, posttraumatic TSD further reduced the SPS-induced decrease in hippocampal BDNF expression, while it also increased hippocampal AChE levels to a similar extent. These findings underscore the importance of sleep as a focus for ongoing research into the pathogenesis of PTSD, and the fact that eliminating specific REM or total sleep immediately after trauma exposure has limited effects on the development of PTSD.
Adaptive Prototype-Based Subtle Transient Pattern Transformers for Enhanced Neonatal Seizure Classification and Severity Assessment.
Priyanga PT, Kumar RPA
Int J Dev Neurosci · 2025 Nov · PMID 41188060 · Publisher ↗
Neonatal seizures are important neurological episodes that need to be identified and managed early to prevent adverse effects. Cohort comparison and rule-based models do not account for the nuances of electroencephalogra...
Neonatal seizures are important neurological episodes that need to be identified and managed early to prevent adverse effects. Cohort comparison and rule-based models do not account for the nuances of electroencephalography (EEG) signals and require much time to analyse and interpret raw neonatal EEG signals. The latest advancements in AI-based methods demonstrate the possibility of such tasks, but they still possess some drawbacks, such as a requirement for big labelled datasets, inefficiency in computation processes and noise sensitivity, which hinder clinical use. In this regard, to overcome these limitations, the new multi-component framework named Adaptive Prototype-Based Subtle Transient Pattern Aware Transformer (APSTPT) is introduced for neonate seizure detection, classification and its severity quantification. Pre-processing is the first stage, where noise and artefacts are removed, and only relevant brain signals are amplified. This is succeeded by feature extraction, where power spectral density and phase locking value components are used to identify important spectral and phase-synchronisation characteristics. These aspects are fine-tuned using cross-channel covariance attention to handle inter-channel dependencies. Real-time adaptation of the prototype with the use of prototype learning makes the classification of seizure types better and more dynamic because the finer details of the signal are captured. Moreover, multiscale entropy analysis measures the signal complexity across different temporal scales and properly differentiates the severity of the seizure into mild, moderate and severe cases, respectively. This structured approach allows for accurate separation of seizure events on the time-series and also flexibility according to the characteristics of different datasets. Experiments conducted using the TUH EEG Corpus and Zenodo dataset prove the effectiveness of the proposed framework, with a classification accuracy of 99.74% and a severity assessment accuracy of 98.87%, which is higher than previous approaches. Therefore, the APSTPT framework presents stable performance irrespective of window lengths and the condition of different datasets, showing its flexibility for real-time implementation in the clinical setting.
Examining the Associations Among Self-Control, Parental Self-Efficacy and Child Adjustment in Preschool Children With ADHD Compared to Typically Developing Controls.
Gürbüz AA, Kopuz HY, Çelebi SB
Int J Dev Neurosci · 2025 Nov · PMID 41168887 · Publisher ↗
BACKGROUND: While self-control and child adjustment in children with attention-deficit/hyperactivity disorder (ADHD) have been extensively investigated, their association with parental self-efficacy remains underexplored...
BACKGROUND: While self-control and child adjustment in children with attention-deficit/hyperactivity disorder (ADHD) have been extensively investigated, their association with parental self-efficacy remains underexplored. AIM: This study aimed to examine the relationship between self-control and child adjustment in preschool-aged children diagnosed with ADHD and parental self-efficacy, in comparison with a healthy control group. METHODS: The study included 58 children diagnosed with ADHD and 60 healthy children matched for sociodemographic characteristics. All parents completed the study scales during face-to-face interviews. RESULTS: Children with ADHD had significantly higher scores on the ADHD-RS-PV and the CAPES-TR: emotional and CAPES-TR: behavioural subscales, while scoring lower on the SCRS and the CAPES-TR: parental self-efficacy scale. Furthermore, children's self-control skills were found to significantly influence behavioural and emotional problems via parental self-efficacy. CONCLUSION: Deficits in self-control among children with ADHD may contribute to elevated emotional and behavioural difficulties, which in turn may diminish parental self-efficacy. Supporting the development of self-control skills in children with ADHD may not only alleviate behavioural and emotional challenges but also enhance parents' confidence in their caregiving roles.
Whole-Exome Sequencing Revealed a Novel De Novo Pathogenic EFTUD2 Variant in Mandibulofacial Dysostosis, Guion-Almeida Type: Reinforcing Links to Choanal and Oesophageal Atresia.
Jazayeri O, Gorjizadeh N, Salehiomran MR … +2 more , van Dijk-Bos KK, Sinke RJ
Int J Dev Neurosci · 2025 Oct · PMID 41147426 · Publisher ↗
Mandibulofacial dysostosis type Guion-Almeida (MFDGA) is a rare autosomal dominant disorder characterized by malar and mandibular hypoplasia, microcephaly and diverse craniofacial and extracranial malformations, caused b...
Mandibulofacial dysostosis type Guion-Almeida (MFDGA) is a rare autosomal dominant disorder characterized by malar and mandibular hypoplasia, microcephaly and diverse craniofacial and extracranial malformations, caused by pathogenic variants in the EFTUD2 gene. This study investigates a 12-year-old boy presenting with congenital microcephaly, choanal atresia, recurrent respiratory infections, moderate hearing loss and typical MFDGA features, born to healthy non-consanguineous Iranian parents. Whole-exome sequencing (WES) was employed, with variants filtered and prioritized using the Phenomizer algorithm based on Human Phenotype Ontology terms. A novel de novo frameshift variant in EFTUD2 (c.1237delC; p.Arg413Alafs*53) was identified and validated by Sanger sequencing. This variant was absent in the parents and healthy brother but detected in an aborted sibling with oesophageal atresia, reinforcing a genotype-phenotype correlation. Paternity and segregation analyses confirmed the biological relationships and de novo nature of the variant, likely arising from germline mosaicism. This finding links the variant to choanal atresia and oesophageal atresia and supports the use of Phenomizer as supplementary aids in validating gene-phenotype correlations during WES analysis, particularly in disorders with variable clinical presentations.
Probiotic Intervention Mitigates Behavioural Effects of Maternal Morphine Exposure in Offspring.
Sadeghi-Adl M, Tarashi S, Zamani MS … +3 more , Soltani H, Siadat SD, Zarrindast MR
Int J Dev Neurosci · 2025 Oct · PMID 41146420 · Publisher ↗
Recent research has highlighted the significant influence of the parental environment on offspring behaviour. Evidence suggests that parental exposure to morphine, even before conception, can have long-lasting adverse ef...
Recent research has highlighted the significant influence of the parental environment on offspring behaviour. Evidence suggests that parental exposure to morphine, even before conception, can have long-lasting adverse effects on offspring phenotypes. Finding noninvasive ways to mitigate these effects is crucial, as the mental health of offspring is of great importance. This study explored the impact of maternal administration of Bifidobacterium longum and Bacteroides fragilis during morphine exposure on male and female offspring. Adult female Wistar rats were exposed to morphine (n = 24) or saline (n = 24) for 10 days. Within each group, the rats were treated with oral saline (n = 8), B. longum (n = 8) or B. fragilis (n = 8) during the morphine or saline treatments. Ten days after the last treatment, the females mated with drug-naïve males, and their adult male and female offspring underwent behavioural assessments for depressive-like behaviour, nociception, memory and compulsive-like behaviour. The findings revealed that both B. longum and B. fragilis restored memory impairment and changes in nociception induced by maternal morphine exposure in male and female offspring. However, B. fragilis did not affect the enhancement of compulsive-like behaviour caused by maternal morphine exposure. In saline-treated female offspring, administration of these probiotics increased the number of buried marbles, which serve as an index for compulsive behaviour. Regarding depressive-like behaviour, maternal morphine exposure increased depressive-like behaviour in the offspring. B. longum was ineffective in reducing depressive-like behaviour in female offspring but significantly alleviated it in male offspring of morphine-exposed dams. In conclusion, the beneficial effects of administering B. longum and B. fragilis to dams during morphine exposure may be due to the direct impact of these probiotics on the mothers, reducing the side effects of morphine or potentially through other mechanisms. Further investigation is needed to clarify these mechanisms.
Evaluation of Nucleated Red Blood Cell Levels in Children With Autism Spectrum Disorder: Relationship With Disorder Severity.
Ateş BÖ, Ayaroğlu P, Cöngöloğlu MA
Int J Dev Neurosci · 2025 Oct · PMID 41116606 · Publisher ↗
OBJECTIVES: Autism spectrum disorder (ASD) has a complex aetiology and a heterogeneous clinical presentation. Having easily accessible and interpretable parameters that can be correlated with disorder severity will provi...
OBJECTIVES: Autism spectrum disorder (ASD) has a complex aetiology and a heterogeneous clinical presentation. Having easily accessible and interpretable parameters that can be correlated with disorder severity will provide important contributions to clinicians. This study aimed to investigate nucleated red blood cell (nRBC) count and other complete blood count parameters and their relationship with ASD severity in preschool children. METHODS: In this retrospective study, 68 ASD cases were included. The severity of the disorder was determined using the Childhood Autism Rating Scale. Regression history and intellectual disability data were obtained from the medical records. RESULTS: The nRBC count was positive in 11.5% of the participants. The nRBC count in male ASD cases was found to be statistically higher in mild/moderate cases than in severe cases. The nRBC count, the platelet count and intellectual disability were found to be predictors of ASD severity. CONCLUSIONS: Differences in some complete blood count parameters, especially nRBC, were found in the study's ASD cases. The platelet count and the nRBC count may be predictive of ASD severity.
Epigenetics, Resilience, Protective Factors and Factors Promoting Positive Outcomes: A Scoping Review.
Assis SG, Tavares PH, Oliveira N … +2 more , Serpeloni F, Avanci JQ
Int J Dev Neurosci · 2025 Oct · PMID 41114472 · Full text
INTRODUCTION: While several studies have examined the relationship between adverse social exposures and epigenetic mechanisms, the association between DNA methylation, resilience, protective factors and factors that prom...
INTRODUCTION: While several studies have examined the relationship between adverse social exposures and epigenetic mechanisms, the association between DNA methylation, resilience, protective factors and factors that promote positive outcomes remains underexplored. GOALS: This study aims to analyse scientific publications on epigenetics, specifically focusing on DNA methylation in relation to resilience and individual/social protective/positive factors. METHOD: A scoping review was conducted using the descriptors DNA methylation, resilience, self-esteem, emotional regulation, social support and social and emotional functioning, covering the years 2008-2019. The databases used included Web of Science, PubMed and Embase. The analysis included 110 articles, reviewed for identification and profile, article focus, objectives, epidemiological and epigenetic methods, protective/positive factors and impacts on physical and mental health. RESULTS: There has been a significant, gradual increase in publications over the years, particularly regarding epidemiological studies involving human participants. Most studies utilized a candidate gene approach to assess DNA methylation, while broader genome-wide methylation profiles were less frequently examined. Histone modifications and noncoding RNAs were also discussed, especially in review articles. Resilience was identified as the most studied topic, with analyses focusing on (1) mental disorders, (2) parental mental health, (3) early life stress, (4) biological age and development, (5) clinical and physiological conditions and (6) environmental/socioeconomic factors. A wide variety of genes associating resilience and epigenetics were pointed out, for example, NR3C1, SLC6A4, BDNF, and FKBP5. Additionally, individual and social bonds and competencies such as social and emotional functioning, maternal care and social interaction among others were grouped as protective factors or that promote positive outcomes and were linked to genes such as OXTR, followed by FKBP5 and NR3C1. DISCUSSION: The significance of epigenetics in neuroscience and its potential public health applications is still emerging. This field invites reflection on prevention and health promotion strategies and highlights growing evidence that social inequalities, adversities and early-life experiences may have lasting effects on gene expression throughout the lifespan.
Valproic Acid Exposure During the Brain Growth Spurt Leads to Autistic-Like Behaviours in Mice.
Lotufo-Denucci B, de Sousa MC, de Paula Aguiar NA … +9 more , Paes-Branco D, Pinheiro VHSD, Araújo UC, Braga FU, de Souza CA, Ribeiro-Carvalho A, Abreu-Villaça Y, Manhães AC, Filgueiras CC
Int J Dev Neurosci · 2025 · PMID 41036810 · Publisher ↗
Prenatal exposure to valproic acid (VPA) has been associated with an increased risk of autism spectrum disorder (ASD). Studies in rodents have demonstrated that VPA exposure during the first trimester-equivalent period o...
Prenatal exposure to valproic acid (VPA) has been associated with an increased risk of autism spectrum disorder (ASD). Studies in rodents have demonstrated that VPA exposure during the first trimester-equivalent period of gestation results in a lifelong autistic-like phenotype. A growing body of evidence suggests that VPA exposure may be a risk factor for ASD beyond the first trimester of pregnancy. Here, we investigated in adolescent Swiss mice the neurobehavioural effects of exposure to VPA during the brain growth spurt, a period that encompasses the third trimester of human gestation. Offspring received ip injections of VPA (200 mg/kg) or saline solution (NaCl 0.9%) on alternate days, from Postnatal Day 2 (PN2) to PN8. Animals were behaviourally tested either as juveniles (PN12: sociability [aggregation]) or adolescents (PN30: anxiety-like behaviour [elevated plus maze], locomotor activity [open field], repetitive behaviour [marble burying] and sociability [reciprocal social interaction and three-chamber test]). At PN33, serotonin serum levels and frontal cortical norepinephrine, dopamine and DOPAC were evaluated by HPLC. No differences were observed at PN12. Adolescent VPA mice showed increased anxiety-like behaviour, hyperactivity and reduced repetitive behaviour. Lower sociability was identified in the reciprocal social interaction. However, in the three-chamber test, social behaviour was higher in the VPA group. It also showed higher serotonin, but no other neurotransmitter level effects were observed. The results support the idea that the period of brain growth spurt may be relevant for the manifestation of neurobehavioural deficits associated with ASD induced by VPA.
Clinical, Genetic and Molecular Divergences Between Full Mutation and Premutation in Fragile X Syndrome: A Systematic Review.
Souski H, Benmakhlouf Y, Mechita MB
Int J Dev Neurosci · 2025 Oct · PMID 40985503 · Publisher ↗
BACKGROUND: Fragile X syndrome (FXS) is the most prevalent inherited form of intellectual disability (ID) and the primary monogenic cause of autism spectrum disorder (ASD) worldwide. The disorder arises from a CGG trinuc...
BACKGROUND: Fragile X syndrome (FXS) is the most prevalent inherited form of intellectual disability (ID) and the primary monogenic cause of autism spectrum disorder (ASD) worldwide. The disorder arises from a CGG trinucleotide expansion of more than 200 repeats, known as a full mutation (FM) that occurs in the fragile X messenger ribonucleoprotein 1 (FMR1) gene locus at Xq27.3. This expansion induces hypermethylation of the gene's promoter region, leading to epigenetic silencing and a consequent reduction in the expression of the FMR1 (FMRP)-a protein critical for synaptic plasticity and maturation. While the genetic basis of FXS is well established, further clarification is needed to understand how variations in the FMR1 gene lead to divergent clinical outcomes. This systematic review explores the differences in clinical features, genetic variations and molecular mechanisms between individuals with a FM, clinically diagnosed with FXS and premutation (PM) carriers with fragile X premutation-associated conditions (FXPAC), with a focus on implications for improving support for individuals with ID and their families. METHODS: Three databases (PubMed, Web of Science and Scopus) were systematically searched, guided by a variety of keywords, to identify qualitative, empirical research about clinical, genetic and molecular differences between FM and PM carriers. A total of 62 articles were examined, and 44 were included in the review. RESULTS: The information is presented in the following categories: clinical features, genetic variations, molecular mechanisms, diagnostics and treatments. Three primary themes are discussed: (1) variability in clinical manifestations, (2) genetic insights and diagnostic advancements and (3) current and emerging management strategies. Research gaps are also highlighted along with perspectives and implications for further research. CONCLUSION: The identification and treatment of FXS and FXPAC remains a major public health and clinical concern. This systematic literature review provides a more robust understanding of FXS and the clinical, genetic and molecular distinctions between FM and PM carriers. Despite growing knowledge of the condition, significant efforts are still required to refine diagnostic tools, develop targeted interventions and support individuals and families affected by FXS.
Therapeutic Effect of LEV in a Propionic Acid-Induced Autism Model via AMPK/SIRT1 Pathway.
Mecit T, Altuntaş İ, Erdoğan MA … +2 more , Uyanıkgil Y, Erbaş O
Int J Dev Neurosci · 2025 Oct · PMID 40968986 · Publisher ↗
OBJECTIVES: In this study, we aimed to evaluate the therapeutic effect of levetiracetam (LEV), an antiepileptic drug used in the treatment of both focal and generalized epilepsy, in a propionic acid (PPA)-induced autism...
OBJECTIVES: In this study, we aimed to evaluate the therapeutic effect of levetiracetam (LEV), an antiepileptic drug used in the treatment of both focal and generalized epilepsy, in a propionic acid (PPA)-induced autism model by assessing social deficits, learning and memory impairments, and their neurochemical correlates. We further examined the involvement of the AMPK/SIRT1 signalling pathway as a potential molecular mechanism. MATERIAL AND METHODS: Thirty male Wistar albino rats were allocated into three groups: normal control (n = 10), PPA + saline (n = 10) and PPA + LEV (n = 10). Autism-like features were induced by intraperitoneal PPA administration (250 mg/kg/day, 5 days). LEV was administered orally (100 mg/kg/day) for 15 days. Behavioural performance (three-chamber sociability test, open-field test, passive avoidance learning), biochemical markers (malondialdehyde [MDA], tumour necrosis factor-alpha [TNF-α], brain-derived neurotrophic factor [BDNF], AMPK, and SIRT1) and histopathological changes (neuronal counts in CA1, CA3, Purkinje cells; GFAP immunostaining) were evaluated. RESULTS: In the sociability test, social interaction time decreased by 51.6% in the PPA + saline group compared to controls (67.2% ± 2.4% vs. 32.5% ± 2.1%), while LEV increased it by 121.8% vs. PPA + saline (72.1% ± 4.5%). Open-field ambulation decreased by 83% in PPA + saline (17.3 ± 3.2 vs. 2.9 ± 0.8) and increased by 158% with LEV (7.5 ± 2.16). Passive avoidance latency decreased by 76% in PPA + saline (245.9 ± 17.5 s vs. 59.2 ± 20.8 s) and increased by 180% with LEV (165.7 ± 18.3 s). MDA levels increased by 187% in PPA + saline vs. controls (49.9 ± 1.4 vs. 143.5 ± 4.7 nmol/g protein) and decreased by 31% with LEV (98.6 ± 5.4). TNF-α increased by 1012% in PPA + saline (13.1 ± 0.9 vs. 145.8 ± 10.6 pg/mg protein) and decreased by 39% with LEV (88.4 ± 3.9). BDNF decreased by 52% in PPA + saline (5.21 ± 0.9 vs. 2.48 ± 0.3 pg/mg protein) and increased by 88% with LEV (4.66 ± 0.5). AMPK decreased by 62% in PPA + saline (113.5 ± 6.3 vs. 43.2 ± 7.5 pg/mg protein) and increased by 73% with LEV (74.8 ± 2.1). SIRT1 decreased by 75% in PPA + saline (4.65 ± 0.5 vs. 1.17 ± 1.1 pg/mg protein) and increased by 132% with LEV (2.72 ± 0.8). Histologically, CA1 neuronal counts decreased by 35% in PPA + saline (67.2 ± 2.04 vs. 43.8 ± 1.1) and increased by 38% with LEV (60.5 ± 1.3). CA3 neuronal counts decreased by 31% in PPA + saline (48.5 ± 3.2 vs. 33.7 ± 1.9) and increased by 31% with LEV (44.2 ± 0.8). Purkinje cells decreased by 53% in PPA + saline (26.2 ± 0.5 vs. 12.2 ± 0.8) and increased by 68% with LEV (20.5 ± 1.1). GFAP indices in CA1, CA3 and cerebellum were elevated in PPA + saline (31.6 ± 2.4 vs. 47.5 ± 1.2; 33.4 ± 1.1 vs. 48.2 ± 0.7; 21.2 ± 1.6 vs. 32.3 ± 0.9) and reduced with LEV (40.3 ± 0.6; 39.5 ± 0.8; 28.5 ± 1.4, respectively). These therapeutic effects were accompanied by marked upregulation of the AMPK/SIRT1 pathway, which was suppressed in the PPA + saline group. CONCLUSION: LEV treatment ameliorated PPA-induced behavioural, biochemical and histological impairments, likely via anti-inflammatory, antioxidant and neuroprotective mechanisms involving activation of the AMPK/SIRT1 pathway. These findings support LEV as a potential therapeutic candidate for autism spectrum disorder.
Identification of a Novel TRIT1 Mutation in a Consanguineous Iranian-Azeri-Turkish Family With Global Developmental Delay.
Beyad F, Bonyadi M, Barzegar M
Int J Dev Neurosci · 2025 Oct · PMID 40908562 · Publisher ↗
Global developmental delay (GDD) and intellectual disability (ID) affect up to 3% of the paediatric population, with a multifactorial aetiology that complicates genetic identification. To date, over 400 genes have been i...
Global developmental delay (GDD) and intellectual disability (ID) affect up to 3% of the paediatric population, with a multifactorial aetiology that complicates genetic identification. To date, over 400 genes have been implicated in GDD. Here, we report a novel homozygous splice acceptor variant, NC_000001.11(NM_017646.6):c.1235-3C>G, in the TRIT1 gene, classified as 'likely pathogenic' through bioinformatics analysis. The proband, a 5-year-old male from a consanguineous family, presented with severe GDD, microcephaly, progressive spasticity, contractures, dysmorphic features (low-set ears, high-arched palate, simian creases and hypospadias), and refractory seizures (focal motor clonic, generalized myoclonic, and tonic) since 6 months of age. Brain MRI revealed nonspecific atrophy, while metabolic, laboratory and electrophysiological evaluations were unremarkable. To further assess the variant's frequency, we screened 430 healthy individuals from the same ethnic group and found no occurrences of the variant. Notably, this variant has not been documented in any published population databases, including gnomAD, the 1000 Genomes Project, Genome Asia, GME Variome and Iranome, despite coverage of the locus in these databases. Taken together, these findings strongly support the potential pathogenicity of the variant. In addition, the prenatal diagnosis results from the subsequent pregnancy in this family showed that the embryo was heterozygous for the mutation. The baby was born, and follow-up studies indicated that she was healthy, with no clinical manifestations observed in her affected brother. This further supports the classification of the variant as 'likely pathogenic.' This study expands the phenotypic spectrum of TRIT1-related disorders.
Integrative Analysis of Key Signalling Pathways in Neural Tube Defects: From Molecular Mechanisms to Therapeutic Strategies.
Zheng J, Huo D, Wang K … +1 more , Zhao H
Int J Dev Neurosci · 2025 · PMID 40898587 · Full text
Neural tube defects (NTDs), such as anencephaly and spina bifida, are prevalent congenital anomalies of the central nervous system. These defects can give rise to severe lifelong disabilities and incur substantial health...
Neural tube defects (NTDs), such as anencephaly and spina bifida, are prevalent congenital anomalies of the central nervous system. These defects can give rise to severe lifelong disabilities and incur substantial healthcare expenses for the affected individuals. The occurrence of NTDs is caused by multiple factors, including molecular regulatory mechanisms and environmental factors. This article comprehensively reviews the underlying mechanisms of three crucial signalling pathways associated with neural tube development: the Wnt/Planar Cell Polarity (PCP) signalling pathway, the Sonic Hedgehog signalling pathway and the Notch signalling pathway, and, on this basis, delves into the potential molecular therapeutic strategies for NTDs. This review is of great significance for comprehensively elucidating the molecular causes of NTDs and expanding prevention and treatment strategies for related congenital anomalies.
Ketogenic Diet in Niemann-Pick Type C: Insights From a Case Report.
Kulu B, Kısa PT, Er E … +4 more , Pekuz S, Akisin Z, Ceylaner S, Arslan N
Int J Dev Neurosci · 2025 Oct · PMID 40898442 · Publisher ↗
Niemann-Pick disease type C (NPC) is a lysosomal storage disorder characterized by progressive neurological deterioration. Although there is no curative treatment, early initiation of miglustat, prior to significant neur...
Niemann-Pick disease type C (NPC) is a lysosomal storage disorder characterized by progressive neurological deterioration. Although there is no curative treatment, early initiation of miglustat, prior to significant neurological decline, may slow disease progression. This case report describes a patient whose initial symptoms emerged around age 9 and who was diagnosed with NPC at age 14 following gradual neurological decline. Despite being treated with miglustat, the patient's neurological symptoms worsened significantly. A high-ratio ketogenic diet (KD), based on fat to protein plus carbohydrate, was initiated as an adjunctive therapy. Following dietary modification, neurological findings stabilized. An initially abnormal electroencephalogram (EEG) normalized during follow-up. Due to significant weight loss, financial constraints and adherence difficulties, the KD ratio was reduced to 1:1 by the sixth month. At the time of the last evaluation, the patient had been maintained on the low-ratio KD for 4 years with continued adherence. The ketogenic diet is known to offer therapeutic benefits in various neurological disorders. In NPC patients treated with miglustat-particularly those experiencing seizures-a ketogenic diet may support neurological stabilization. A lower ratio KD may enhance long-term compliance.
Polyvagal Theory and Neonatal Sleep: A Review of Autonomic Regulation and Implications for Sudden Infant Death Syndrome.
Beyazgül S, Laleh SS
Int J Dev Neurosci · 2025 · PMID 40898438 · Publisher ↗
BACKGROUND: Neonatal sleep is critical for brain maturation and autonomic nervous system regulation. Disruptions in sleep patterns and vagal tone may contribute to the risk of sudden infant death syndrome (SIDS). METHODS...
BACKGROUND: Neonatal sleep is critical for brain maturation and autonomic nervous system regulation. Disruptions in sleep patterns and vagal tone may contribute to the risk of sudden infant death syndrome (SIDS). METHODS: This narrative review summarizes current evidence on the relationship between neonatal sleep states, autonomic nervous system maturation and polyvagal theory. RESULTS: Studies suggest that vagal activity modulates neonatal sleep states, with implications for both emotional and physiological development. Premature infants may display immature vagal pathways, increasing their vulnerability to sleep-related disorders and SIDS. CONCLUSION: The polyvagal framework offers a useful lens for understanding neonatal sleep regulation and guiding strategies for SIDS prevention and healthy neonatal care. Further research is warranted.
Selumetinib Treatment in a Neurofibromatosis Type 1 Child With Second Hit Mutation on the NF1 Gene.
Su S, Bai Y, Lu Y … +5 more , Ren Y, Zhang W, Wang G, Ma K, Zhang H
Int J Dev Neurosci · 2025 Oct · PMID 40891287 · Full text
Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder, with plexiform neurofibromas occurring in approximately 20%-50% of patients. A 12-year-old girl underwent surgery due to unbearable pain caused by...
Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder, with plexiform neurofibromas occurring in approximately 20%-50% of patients. A 12-year-old girl underwent surgery due to unbearable pain caused by diffuse neurofibromas. Postoperatively, the girl exhibited rapid growth and extremely extensive plexiform neurofibromas, with multiple plexiform neurofibromas that were inoperable. Through high-throughput sequencing (HTS), genetic molecular analysis was conducted on the peripheral blood samples of the child, and it was found that there was a splice site mutation c.3113 + 1G > A in the NF1 gene. Additionally, we identified a pathogenic variant c.2033dup (Ile679Aspfs*21), citing ClinVar and PMID: 77655472 to confirm its established pathogenicity in the paraffin-embedded section sample of the diffuse neurofibroma, which was exclusively found in the girl's plexiform neurofibroma. This 'second-hit' mutation could explain the rapid growth of the diffuse neurofibroma. The patient was effectively treated with oral administration of the selective MEK inhibitor selumetinib, resulting in rapid tumour regression. The treatment has shown promising efficacy against the rapid tumour growth induced by the patient's 'second-hit' mutation.
Moyamoya Syndrome, Epilepsy and Hydrocephalus in Neurofibromatosis Type 1.
Zhao F, Yue X, Wang G … +1 more , Zhang H
Int J Dev Neurosci · 2025 Aug · PMID 40879249 · Full text
BACKGROUND: Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous syndrome. NF1-related vasculopathy represents a clinically significant yet underrecognized complication. Moyamoya syndrome, a rare cerebr...
BACKGROUND: Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous syndrome. NF1-related vasculopathy represents a clinically significant yet underrecognized complication. Moyamoya syndrome, a rare cerebrovascular manifestation of NF1, has been rarely reported in the paediatric population. Epilepsy and hydrocephalus are also uncommon neurological manifestations of NF1. However, the co-occurrence of the above three symptoms in NF1 cases is rarely found. METHODS: Here, we report a 2-year-old boy with moyamoya syndrome, epilepsy and hydrocephalus caused by de novo NF1 pathogenetic variants. RESULTS: He experienced a 1-week history of paroxysmal hands weakness and frequent seizures. Physical examination showed macrocephaly (head circumference was 52 cm), reduced distal muscle strength in both upper limbs (grade III) and the presence of 6 or more café-au-lait macules (CALMs). Brain magnetic resonance imaging (MRI) showed moyamoya syndrome and hydrocephalus. Electroencephalographic (EEG) monitored two episodes of electrical persistent seizures and one focal motor seizure. Trio whole exome sequencing (Trio-WES) demonstrated a de novo and heterozygous NF1 missense mutation (c.5488C > G, p. Arg1830Gly). The final diagnoses were 'neurofibromatosis type 1, moyamoya syndrome, epilepsy, and hydrocephalus'. Following surgical intervention and treatment with levetiracetam, the patient achieved normal muscle strength and was seizure-free. CONCLUSION: When articles about complications of NF1 are placed in a separate category, little is written about NF-1-related moyamoya syndrome, hydrocephalus and epilepsy simultaneously. This report describes a case of NF1 with moyamoya syndrome combined with hydrocephalus and epilepsy, which could enhance clinicians' understanding of the neurological manifestations of NF1 and provide reference value for clinical practice.
Rapid Electroclinical Evolution in HECW2-Related Developmental and Epileptic Encephalopathy: Report of a Likely Splicing Variant With Familial Transmission.
Melgarejo S, Reyes Valenzuela G, Juanes M … +9 more , Touzon MS, Suyo C, Alonso C, Gauto A, Princich JP, Loos M, Obregón R, Pérsico A, Caraballo R
Int J Dev Neurosci · 2025 Aug · PMID 40879666 · Publisher ↗
The HECW2 gene, essential for neurodevelopment, plays a critical role in maintaining cellular homeostasis and regulating key pathways in the nervous system. Deleterious variants in the HECW2 gene have been associated wit...
The HECW2 gene, essential for neurodevelopment, plays a critical role in maintaining cellular homeostasis and regulating key pathways in the nervous system. Deleterious variants in the HECW2 gene have been associated with developmental delay, intellectual disability, hypotonia and epilepsy, as well as dysmorphic features. We present the case of an infant with a novel variant in HECW2 with an unusual clinical presentation and a progressive disease course, showing three successive electroclinical patterns, consisting of burst suppression characteristic of early infantile developmental and epileptic encephalopathy, subcontinuous myoclonic seizures and infantile epileptic spasms syndrome without hypsarrhythmia, occurring over a short period of time. This case expands the clinical spectrum associated with this gene and highlights the intrafamilial phenotypic variability. It also underscores the importance of personalized therapeutic strategies, as demonstrated by the use of perampanel in this patient. These findings emphasize the need to include HECW2 as a possible aetiology in the diagnostic evaluation of developmental and epileptic encephalopathies.
Pontocerebellar Hypoplasia and Periventricular Leukomalacia Associated With p.Phe262Val Homozygous Variant in TTC1 Gene: A Report of 4 Cases.
Sarıkaya Uzan G, Yaramış AH, Sönmezler E … +8 more , Hız Kurul S, Yaramış A, Yiş U, Günay Ç, Lochmuller H, Horvath R, Oktay Y, Yaramış A
Int J Dev Neurosci · 2025 Aug · PMID 40879651 · Publisher ↗
OBJECTIVE: Pontocerebellar hypoplasia (PCH) encompasses a heterogeneous group of neurodevelopmental disorders, currently comprising 28 subtypes listed in the Online Mendelian Inheritance in Man (OMIM) database (as of May...
OBJECTIVE: Pontocerebellar hypoplasia (PCH) encompasses a heterogeneous group of neurodevelopmental disorders, currently comprising 28 subtypes listed in the Online Mendelian Inheritance in Man (OMIM) database (as of May 2025). No clinical phenotype has been associated with the TTC1 gene in OMIM. In this report, we present four female patients from two unrelated families exhibiting PCH with cerebral periventricular leukomalacia and additional clinical features potentially linked to TTC1. CASE PRESENTATIONS: All four affected individuals presented with global developmental delay. Physical examination revealed axial hypotonia, microcephaly and esotropia. Neuroimaging (brain MRI) consistently demonstrated PCH, reduced white matter volume and ventriculomegaly secondary to periventricular leukomalacia. Genomic DNA extracted from peripheral blood samples of the affected individuals, their unaffected parents and siblings was analyzed using trio-based whole-exome sequencing. Variant prioritization was performed via the RD-Connect Genome-Phenome Analysis Platform, which identified a homozygous missense variant in TTC1 (NM_003314.3: c.784 T > G, p.Phe262Val) in all affected individuals. The variant was present in the heterozygous state in all parents and unaffected siblings. This variant is classified as likely pathogenic in the ClinVar database. RESULT: Our findings in four patients confirm that this variant in the TTC1 gene may be associated with PCH and cerebral periventricular leukomalacia. To our knowledge, this is the first report implicating TTC1 in congenital brain malformations. We propose that TTC1 should be considered a candidate gene in the genetic evaluation of patients with PCH and related cerebral abnormalities.
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