1. Anderson JT, Roth JD, Rosenau KA, Dwyer PS, Kuo AA, Martinez-Agosto JA. Enhancing multi-site autism research through the development of a collaborative data platform. Autism Res;2024 (May 24)

Data repositories, particularly those storing data on vulnerable populations, increasingly need to carefully consider not only what data is being collected, but how it will be used. As such, the Autism Intervention Research Network on Physical Health (AIR-P) has created the Infrastructure for Collaborative Research (ICR) to establish standards on data collection practices in Autism repositories. The ICR will strive to encourage inter-site collaboration, amplify autistic voices, and widen accessibility to data. The ICR is staged as a three-tiered framework consisting of (1) a request for proposals system, (2) a REDCap-based data repository, and (3) public data dashboards to display aggregate de-identified data. Coupled with a review process including autistic and non-autistic researchers, this framework aims to propel the implementation of equitable autism research, enhance standardization within and between studies, and boost transparency and dissemination of findings. In addition, the inclusion of a contact registry that study participants can opt into creates the base for a robust participant pool. As such, researchers can leverage the platform to identify, reach, and distribute electronic materials to a greater proportion of potential participants who likely fall within their eligibility criteria. By incorporating practices that promote effective communication between researchers and participants, the ICR can facilitate research that is both considerate of and a benefit to autistic people.

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2. Pérez-Cano L, Boccuto L, Sirci F, Hidalgo JM, Valentini S, Bosio M, Liogier D’Ardhuy X, Skinner C, Cascio L, Srikanth S, Jones K, Buchanan CB, Skinner SA, Gomez-Mancilla B, Hyvelin JM, Guney E, Durham L. Characterization of a Clinically and Biologically Defined Subgroup of Patients with Autism Spectrum Disorder and Identification of a Tailored Combination Treatment. Biomedicines;2024 (Apr 30);12(5)

Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental disorders (NDDs) with a high unmet medical need. The diagnosis of ASD is currently based on behavior criteria, which overlooks the diversity of genetic, neurophysiological, and clinical manifestations. Failure to acknowledge such heterogeneity has hindered the development of efficient drug treatments for ASD and other NDDs. DEPI(®) (Databased Endophenotyping Patient Identification) is a systems biology, multi-omics, and machine learning-driven platform enabling the identification of subgroups of patients with NDDs and the development of patient-tailored treatments. In this study, we provide evidence for the validation of a first clinically and biologically defined subgroup of patients with ASD identified by DEPI, ASD Phenotype 1 (ASD-Phen1). Among 313 screened patients with idiopathic ASD, the prevalence of ASD-Phen1 was observed to be ~24% in 84 patients who qualified to be enrolled in the study. Metabolic and transcriptomic alterations differentiating patients with ASD-Phen1 were consistent with an over-activation of NF-κB and NRF2 transcription factors, as predicted by DEPI. Finally, the suitability of STP1 combination treatment to revert such observed molecular alterations in patients with ASD-Phen1 was determined. Overall, our results support the development of precision medicine-based treatments for patients diagnosed with ASD.

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3. Barreto C, Curtin A, Topoglu Y, Day-Watkins J, Garvin B, Foster G, Ormanoglu Z, Sheridan E, Connell J, Bennett D, Heffler K, Ayaz H. Prefrontal Cortex Responses to Social Video Stimuli in Young Children with and without Autism Spectrum Disorder. Brain Sci;2024 (May 16);14(5)

Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting individuals worldwide and characterized by deficits in social interaction along with the presence of restricted interest and repetitive behaviors. Despite decades of behavioral research, little is known about the brain mechanisms that influence social behaviors among children with ASD. This, in part, is due to limitations of traditional imaging techniques specifically targeting pediatric populations. As a portable and scalable optical brain monitoring technology, functional near infrared spectroscopy (fNIRS) provides a measure of cerebral hemodynamics related to sensory, motor, or cognitive function. Here, we utilized fNIRS to investigate the prefrontal cortex (PFC) activity of young children with ASD and with typical development while they watched social and nonsocial video clips. The PFC activity of ASD children was significantly higher for social stimuli at medial PFC, which is implicated in social cognition/processing. Moreover, this activity was also consistently correlated with clinical measures, and higher activation of the same brain area only during social video viewing was associated with more ASD symptoms. This is the first study to implement a neuroergonomics approach to investigate cognitive load in response to realistic, complex, and dynamic audiovisual social stimuli for young children with and without autism. Our results further confirm that new generation of portable fNIRS neuroimaging can be used for ecologically valid measurements of the brain function of toddlers and preschool children with ASD.

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4. Esposito D, Cruciani G, Zaccaro L, Di Carlo E, Spitoni GF, Manti F, Carducci C, Fiori E, Leuzzi V, Pascucci T. A Systematic Review on Autism and Hyperserotonemia: State-of-the-Art, Limitations, and Future Directions. Brain Sci;2024 (May 10);14(5)

Hyperserotonemia is one of the most studied endophenotypes in autism spectrum disorder (ASD), but there are still no unequivocal results about its causes or biological and behavioral outcomes. This systematic review summarizes the studies investigating the relationship between blood serotonin (5-HT) levels and ASD, comparing diagnostic tools, analytical methods, and clinical outcomes. A literature search on peripheral 5-HT levels and ASD was conducted. In total, 1104 publications were screened, of which 113 entered the present systematic review. Of these, 59 articles reported hyperserotonemia in subjects with ASD, and 26 presented correlations between 5-HT levels and ASD-core clinical outcomes. The 5-HT levels are increased in about half, and correlations between hyperserotonemia and clinical outcomes are detected in a quarter of the studies. The present research highlights a large amount of heterogeneity in this field, ranging from the characterization of ASD and control groups to diagnostic and clinical assessments, from blood sampling procedures to analytical methods, allowing us to delineate critical topics for future studies.

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5. Guner N, Hayton JA. Parental and Child Sleep: Children with Vision Impairment, Autistic Children, and Children with Comorbid Vision Impairment and Autism. Brain Sci;2024 (May 10);14(5)

BACKGROUND: Parents report associations between children’s sleep disturbances and behaviors. Children with neurodevelopmental conditions (e.g., Williams Syndrome and autism) are consistently reported to experience increased sleeping problems. Sleep in children with vision impairment and children with a dual diagnosis of vision impairment and autism remains understudied. METHODS: Our exploratory study compared sleep profiles in 52 children (aged 4-12 years) and their parents (n = 37), across four groups: children with vision impairment (VI; n = 9), autism (n = 10), comorbid vision impairment + autism (n = 6), and typically developing children (n = 27). Childhood sleep was measured using the parental report Childhood Sleep Habits Questionnaire and sleep diaries. Children’s cognitive functioning was measured using digit span, semantic, and phonemic verbal fluency measures. Parental sleep was measured via the Pittsburgh Sleep Quality Index and Epworth Sleepiness Scale. RESULTS: Clinically disordered sleep was reported in all child groups (p ≤ 0.001), particularly children with VI + autism. Age, not sleep quality/quantity, predicted cognitive task performance in TD and autistic groups, but not in VI and VI + autism groups. The child’s diagnosis affected parental sleep, particularly in children with a dual diagnosis of VI + autism. CONCLUSIONS: All participants experienced problematic sleep to varying degrees. Those most affected were children and parents in the VI + autism group, suggesting that autism may be the main driver of sleep problems in our sample.

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6. Pall ML. Central Causation of Autism/ASDs via Excessive [Ca(2+)]i Impacting Six Mechanisms Controlling Synaptogenesis during the Perinatal Period: The Role of Electromagnetic Fields and Chemicals and the NO/ONOO(-) Cycle, as Well as Specific Mutations. Brain Sci;2024 (Apr 30);14(5)

The roles of perinatal development, intracellular calcium [Ca(2+)]i, and synaptogenesis disruption are not novel in the autism/ASD literature. The focus on six mechanisms controlling synaptogenesis, each regulated by [Ca(2+)]i, and each aberrant in ASDs is novel. The model presented here predicts that autism epidemic causation involves central roles of both electromagnetic fields (EMFs) and chemicals. EMFs act via voltage-gated calcium channel (VGCC) activation and [Ca(2+)]i elevation. A total of 15 autism-implicated chemical classes each act to produce [Ca(2+)]i elevation, 12 acting via NMDA receptor activation, and three acting via other mechanisms. The chronic nature of ASDs is explained via NO/ONOO(-) vicious cycle elevation and MeCP2 epigenetic dysfunction. Genetic causation often also involves [Ca(2+)]i elevation or other impacts on synaptogenesis. The literature examining each of these steps is systematically examined and found to be consistent with predictions. Approaches that may be sed for ASD prevention or treatment are discussed in connection with this special issue: The current situation and prospects for children with ASDs. Such approaches include EMF, chemical avoidance, and using nutrients and other agents to raise the levels of Nrf2. An enriched environment, vitamin D, magnesium, and omega-3s in fish oil may also be helpful.

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7. Qian S, Yang Q, Cai C, Dong J, Cai S. Spatial-Temporal Characteristics of Brain Activity in Autism Spectrum Disorder Based on Hidden Markov Model and Dynamic Graph Theory: A Resting-State fMRI Study. Brain Sci;2024 (May 17);14(5)

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder. Functional magnetic resonance imaging (fMRI) can be used to measure the temporal correlation of blood-oxygen-level-dependent (BOLD) signals in the brain to assess the brain’s intrinsic connectivity and capture dynamic changes in the brain. In this study, the hidden Markov model (HMM) and dynamic graph (DG) theory are used to study the spatial-temporal characteristics and dynamics of brain networks based on dynamic functional connectivity (DFC). By using HMM, we identified three typical brain states for ASD and healthy control (HC). Furthermore, we explored the correlation between HMM time-varying properties and clinical autism scale scores. Differences in brain topological characteristics and dynamics between ASD and HC were compared by DG analysis. The experimental results indicate that ASD is more inclined to enter a strongly connected HMM brain state, leading to the isolation of brain networks and alterations in the topological characteristics of brain networks, such as default mode network (DMN), ventral attention network (VAN), and visual network (VN). This work suggests that using different data-driven methods based on DFC to study brain network dynamics would have better information complementarity, which can provide a new direction for the extraction of neuro-biomarkers in the early diagnosis of ASD.

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8. Chu CL, Su WS, Iao LS, Wu CC, Hou YM. Comparison between the Clancy Behavior Scale and the Modified Checklist for Autism in Toddlers in Taiwan. Children (Basel);2024 (May 6);11(5)

(1) Background: Precise diagnosis and early intervention are crucial for toddlers with autism spectrum disorder (ASD) to achieve a better prognosis. This study investigated the efficacy of the Clancy Behavior Scale (CBS) and Modified Checklist for Autism in Toddlers (M-CHAT) in detecting ASD among toddlers under 30 months of age. (2) Methods: A total of 215 toddlers (117 with ASD and 98 with development delays) aged between 18 and 29 months participated in this study. All the primary caregivers of these toddlers were recruited to complete the CBS and M-CHAT. (3) Results: The findings indicated that the accuracy of the CBS and M-CHAT was promising, and the short forms of these two instruments performed better than their full versions. The CBS:9 critical items presented a sensitivity of 0.75 and a specificity of 0.74, while the M-CHAT:14 brief items showed a sensitivity of 0.72 and a specificity of 0.85. (4) Conclusions: The diagnostic accuracy of high-risk ASD toddlers improved via the combination of CBS and M-CHAT, particularly when the information gathered from these two instruments were consistent. The findings may provide implications for enhancing the early detection of ASD.

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9. Menteşe Babayiğit T, Gümüş-Akay G, Uytun M, Doğan Ö, Serdar MA, Efendi GY, Erman AG, Yürümez E, Öztop DB. Investigation of Liver X Receptor Gene Variants and Oxysterol Dysregulation in Autism Spectrum Disorder. Children (Basel);2024 (May 5);11(5)

The NR1H2 gene produces the Liver X Receptor Beta (LXRB) protein, which is crucial for brain cholesterol metabolism and neuronal development. However, its involvement in autism spectrum disorder (ASD) remains largely unexplored, aside from animal studies. This study is the first to explore the potential link between autism and rs2695121/rs17373080 single nucleotide polymorphisms (SNPs) in the regulatory regions of NR1H2, known for their association with neuropsychiatric functions. Additionally, we assessed levels of oxysterols (24-Hydroxycholesterol, 25-Hydroxycholesterol, 27-Hydroxycholesterol), crucial ligands of LXR, and lipid profiles. Our cohort comprised 107 children with ASD and 103 healthy children aged 2-18 years. Clinical assessment tools included the Childhood Autism Rating Scale, Autistic Behavior Checklist, and Repetitive Behavior Scale-Revised. Genotyping for SNPs was conducted using PCR-RFLP. Lipid profiles were analyzed with Beckman Coulter kits, while oxysterol levels were determined through liquid chromatography-tandem mass spectrometry. Significantly higher total cholesterol (p = 0.003), LDL (p = 0.008), and triglyceride (p < 0.001) levels were observed in the ASD group. 27-Hydroxycholesterol levels were markedly lower in the ASD group (p ≤ 0.001). ROC analysis indicated the potential of 27-Hydroxycholesterol to discriminate ASD diagnosis. The SNP genotype and allele frequencies were similar in both groups (p > 0.05). Our findings suggest that disturbances in oxysterol metabolism, previously linked to neurodegeneration, may constitute a risk factor for ASD and contribute to its heterogeneous phenotype.

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10. Orhan BE, Uzunçayır D, Canlı U, Karaçam A, Özdemir AS, Popa C, Iconomescu TM, Talaghir LG. Finding Stability-A Case Report on the Benefits of Adapted Kata Training for Children with Autism Spectrum Disorder. Children (Basel);2024 (Apr 26);11(5)

This study investigated the efficacy of an Adapted Kata Training Program (AKTP) in enhancing balance for a 10-year-old child with Autism Spectrum Disorder (ASD), employing a mixed-model approach for data collection. Over 12 weeks, the AKTP demonstrated significant improvements in the child’s balance abilities, with an 11% increase in static balance, 8% in proprioceptive, 12% in horizontal, and 14% in vertical balance performance. These improvements persisted in a follow-up assessment after four weeks. Observations by the child’s mother corroborated the above findings. Consequently, this research suggests the AKTP as a valuable non-pharmacological intervention to improve balance in children with ASD. However, further studies are necessary to validate these results and explore the impact on additional developmental domains, such as cognitive and motor skills.

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11. Xie Q, Yong C, Xiang C, Xi Y, Huo J, Liang J, Zou H, Pan Y, Wu M, Lin Q. The Impact of Caregiver Pressure to Eat on Food Neophobia in Children with Autism Spectrum Disorder: A Cross-Sectional Study. Children (Basel);2024 (Apr 28);11(5)

(1) Background: With autistic children’s high pervasiveness of eating problems and inappropriate feeding behaviors by their caregivers, this study wanted to inspect the connection between caregivers’ pressure to eat and food neophobia in these children. (2) Methods: Cross-sectional overview of 160 guardians of kids aged 2 to 7 years. After one-on-one questioning by the researcher, the collected information on the socio-demographic characteristics of the children with autism, caregiver feeding behavior, and new food neophobia (FN) scores was entered into the Questionnaire Star system. (3) Results: The mean FN score was 25.56 ± 6.46. The caregiver’s pressure to eat positively related to children’s FN (β = 0.164 95% CI, 0.078, 2.163). In these children, we found a negative correlation between FN score and the frequency of vegetable intake (p ≤ 0.001), fruit intake (p ≤ 0.05), aquatic product intake (p ≤ 0.05), and dietary diversity score (p ≤ 0.01), and positively correlated with the frequency of snack intake (p ≤ 0.05). (4) Conclusions: Caregiver pressure to eat was positively associated with high levels of FN in Chinese kids with ASD, which in turn negatively impacted dietary quality. To improve eating habits, caregivers should reconsider their feeding strategies and avoid using forceful methods to ease food neophobia in these children.

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12. Shinsato RN, Correa CG, Herai RH. Genetic network analysis indicate that individuals affected by neurodevelopmental conditions have genetic variations associated with ophthalmologic alterations: A critical review of literature. Gene;2024 (May 25);908:148246.

Changes in the nervous system are related to a wide range of mental disorders, which include neurodevelopmental disorders (NDD) that are characterized by early onset mental conditions, such as schizophrenia and autism spectrum disorders and correlated conditions (ASD). Previous studies have shown distinct genetic components associated with diverse schizophrenia and ASD phenotypes, with mostly focused on rescuing neural phenotypes and brain activity, but alterations related to vision are overlooked. Thus, as the vision is composed by the eyes that itself represents a part of the brain, with the retina being formed by neurons and cells originating from the glia, genetic variations affecting the brain can also affect the vision. Here, we performed a critical systematic literature review to screen for all genetic variations in individuals presenting NDD with reported alterations in vision. Using these restricting criteria, we found 20 genes with distinct types of genetic variations, inherited or de novo, that includes SNP, SNV, deletion, insertion, duplication or indel. The variations occurring within protein coding regions have different impact on protein formation, such as missense, nonsense or frameshift. Moreover, a molecular analysis of the 20 genes found revealed that 17 shared a common protein-protein or genetic interaction network. Moreover, gene expression analysis in samples from the brain and other tissues indicates that 18 of the genes found are highly expressed in the brain and retina, indicating their potential role in adult vision phenotype. Finally, we only found 3 genes from our study described in standard public databanks of ophthalmogenetics, suggesting that the other 17 genes could be novel target for vision diseases.

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13. Merritt JK, Fang X, Caylor RC, Skinner SA, Friez MJ, Percy AK, Neul JL. Normalized Clinical Severity Scores Reveal a Correlation between X Chromosome Inactivation and Disease Severity in Rett Syndrome. Genes (Basel);2024 (May 8);15(5)

Rett Syndrome (RTT) is a severe neurodevelopmental disorder predominately diagnosed in females and primarily caused by pathogenic variants in the X-linked gene Methyl-CpG Binding Protein 2 (MECP2). Most often, the disease causing the MECP2 allele resides on the paternal X chromosome while a healthy copy is maintained on the maternal X chromosome with inactivation (XCI), resulting in mosaic expression of one allele in each cell. Preferential inactivation of the paternal X chromosome is theorized to result in reduced disease severity; however, establishing such a correlation is complicated by known MECP2 genotype effects and an age-dependent increase in severity. To mitigate these confounding factors, we developed an age- and genotype-normalized measure of RTT severity by modeling longitudinal data collected in the US Rett Syndrome Natural History Study. This model accurately reflected individual increase in severity with age and preserved group-level genotype specific differences in severity, allowing for the creation of a normalized clinical severity score. Applying this normalized score to a RTT XCI dataset revealed that XCI influence on disease severity depends on MECP2 genotype with a correlation between XCI and severity observed only in individuals with MECP2 variants associated with increased clinical severity. This normalized measure of RTT severity provides the opportunity for future discovery of additional factors contributing to disease severity that may be masked by age and genotype effects.

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14. Thompson MD, Knaus A. Rare Genetic Developmental Disabilities: Mabry Syndrome (MIM 239300) Index Cases and Glycophosphatidylinositol (GPI) Disorders. Genes (Basel);2024 (May 14);15(5)

The case report by Mabry et al. (1970) of a family with four children with elevated tissue non-specific alkaline phosphatase, seizures and profound developmental disability, became the basis for phenotyping children with the features that became known as Mabry syndrome. Aside from improvements in the services available to patients and families, however, the diagnosis and treatment of this, and many other developmental disabilities, did not change significantly until the advent of massively parallel sequencing. As more patients with features of the Mabry syndrome were identified, exome and genome sequencing were used to identify the glycophosphatidylinositol (GPI) biosynthesis disorders (GPIBDs) as a group of congenital disorders of glycosylation (CDG). Biallelic variants of the phosphatidylinositol glycan (PIG) biosynthesis, type V (PIGV) gene identified in Mabry syndrome became evidence of the first in a phenotypic series that is numbered HPMRS1-6 in the order of discovery. HPMRS1 [MIM: 239300] is the phenotype resulting from inheritance of biallelic PIGV variants. Similarly, HPMRS2 (MIM 614749), HPMRS5 (MIM 616025) and HPMRS6 (MIM 616809) result from disruption of the PIGO, PIGW and PIGY genes expressed in the endoplasmic reticulum. By contrast, HPMRS3 (MIM 614207) and HPMRS4 (MIM 615716) result from disruption of post attachment to proteins PGAP2 (HPMRS3) and PGAP3 (HPMRS4). The GPI biosynthesis disorders (GPIBDs) are currently numbered GPIBD1-21. Working with Dr. Mabry, in 2020, we were able to use improved laboratory diagnostics to complete the molecular diagnosis of patients he had originally described in 1970. We identified biallelic variants of the PGAP2 gene in the first reported HPMRS patients. We discuss the longevity of the Mabry syndrome index patients in the context of the utility of pyridoxine treatment of seizures and evidence for putative glycolipid storage in patients with HPMRS3. From the perspective of the laboratory innovations made that enabled the identification of the HPMRS phenotype in Dr. Mabry’s patients, the need for treatment innovations that will benefit patients and families affected by developmental disabilities is clear.

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15. da Silva RV, de Lima Carvalhal MM, Gomes DL. The Relationship between Anxiety Symptoms and Perceived Quality of Life among Caregivers of Children with Autism Spectrum Disorder in the Amazon. Int J Environ Res Public Health;2024 (Apr 26);21(5)

The relationship between anxiety symptoms and perceived quality of life among caregivers of children with autism was verified. To assess perceived quality of life, the Short Form Healthy Survey Item was used; perception of anxiety symptoms was assessed using the Beck Anxiety Inventory. Eighty caregivers of children with autism participated, with 68.7% of caregivers being mothers. Of the total number of caregivers, 68.8% had a severe level of anxiety. Regarding perceived quality of life, they demonstrated greater impairment in limitation due to physical aspects, limitation due to emotional aspects, vitality, and pain. Caregivers with severe anxiety levels had a worse quality of life in the domains of pain (p = 0.012), social aspects (p < 0.001), limitation due to emotional aspects (p = 0.001), and mental health (p < 0.001). However, in the functional capacity domain, caregivers with a moderate level of anxiety had a better physical capacity score (p = 0.001). There was a negative correlation between the general anxiety score and the general physical (p = 0.029) and general emotional components of perceived quality of life (p < 0.001). It was found that caregivers of children with ASD have a high level of anxiety, which is a predictor of the perception of a worse quality of life.

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16. Jesus-Filho E, Barros SG, Vianna MIP, Cangussu MCT. Public Dental Service Access Policies for People with Autism Spectrum Disorder (ASD) in Salvador, Bahia, Brazil: A Pre-Evaluation Study. Int J Environ Res Public Health;2024 (Apr 27);21(5)

This study sought to carry out a systematic and preliminary evaluation of the policies on access to public dental services for people with ASD in a Brazilian city. The study, conducted between November/2019 and February/2020, was developed through document analysis, the design of the theoretical logical model of the policies, and seven semi-structured interviews with key informants. The sample was intentionally selected. We also considered the answers to 108 questionnaires from a pilot study on the access of people with ASD to dental services applied to caregivers, dentists, and non-dental professionals. No refusals were recorded. The availability study showed that the policies’ objectives were not being achieved in terms of care network organization: there were no institutional flows, personal contacts were used between professionals to guarantee access to secondary attention, there was no specific training for the dentists about ASD, and the oral health care network was unknown to non-dentist professionals and caregivers. Most people with ASD have visited the dentist at least once in their lives, but a large percentage of those within this study did not do so in the last year. This study identified difficulties in implementing policies and suggested possible strategies for overcoming them as dimensions and subdimensions for evaluation.

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17. Chien WH, Chen CH, Cheng MC, Wu YY, Gau SS. Neuregulin 2 Is a Candidate Gene for Autism Spectrum Disorder. Int J Mol Sci;2024 (May 19);25(10)

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with heterogeneous and complex genetic underpinnings. Our previous microarray gene expression profiling identified significantly different neuregulin-2 gene (NRG2) expression between ASD patients and controls. Thus, we aimed to clarify whether NRG2 is a candidate gene associated with ASD. The study consisted of two stages. First, we used real-time quantitative PCR in 20 ASDs and 20 controls to confirm the microarray gene expression profiling results. The average NRG2 gene expression level in patients with ASD (3.23 ± 2.80) was significantly lower than that in the controls (9.27 ± 4.78, p < 0.001). Next, we conducted resequencing of all the exons of NRG2 in a sample of 349 individuals with ASD, aiming to identify variants of the NRG2 associated with ASD. We identified three variants, including two single nucleotide variants (SNVs), IVS3 + 13A > G (rs889022) and IVS10 + 32T > A (rs182642591), and one small deletion at exon 11 of NRG2 (delGCCCGG, rs933769137). Using data from the Taiwan Biobank as the controls, we found no significant differences in allele frequencies of rs889022 and rs182642591 between two groups. However, there is a significant difference in the genotype and allele frequency distribution of rs933769137 between ASDs and controls (p < 0.0001). The small deletion is located in the EGF-like domain at the C-terminal of the NRG2 precursor protein. Our findings suggest that NRG2 might be a susceptibility gene for ASD.

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18. Didiasova M, Cesaro S, Feldhoff S, Bettin I, Tiegel N, Füssgen V, Bertoldi M, Tikkanen R. Functional Characterization of a Spectrum of Genetic Variants in a Family with Succinic Semialdehyde Dehydrogenase Deficiency. Int J Mol Sci;2024 (May 11);25(10)

Succinic semialdehyde dehydrogenase (SSADH) is a mitochondrial enzyme involved in the catabolism of the neurotransmitter γ-amino butyric acid. Pathogenic variants in the gene encoding this enzyme cause SSADH deficiency, a developmental disease that manifests as hypotonia, autism, and epilepsy. SSADH deficiency patients usually have family-specific gene variants. Here, we describe a family exhibiting four different SSADH variants: Val90Ala, Cys93Phe, and His180Tyr/Asn255Asp (a double variant). We provide a structural and functional characterization of these variants and show that Cys93Phe and Asn255Asp are pathogenic variants that affect the stability of the SSADH protein. Due to the impairment of the cofactor NAD(+) binding, these variants show a highly reduced enzyme activity. However, Val90Ala and His180Tyr exhibit normal activity and expression. The His180Tyr/Asn255Asp variant exhibits a highly reduced activity as a recombinant species, is inactive, and shows a very low expression in eukaryotic cells. A treatment with substances that support protein folding by either increasing chaperone protein expression or by chemical means did not increase the expression of the pathogenic variants of the SSADH deficiency patient. However, stabilization of the folding of pathogenic SSADH variants by other substances may provide a treatment option for this disease.

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19. Gabaldon-Albero A, Mayo S, Martinez F. NR4A2 as a Novel Target Gene for Developmental and Epileptic Encephalopathy: A Systematic Review of Related Disorders and Therapeutic Strategies. Int J Mol Sci;2024 (May 10);25(10)

The NR4A2 gene encodes an orphan transcription factor of the steroid-thyroid hormone-retinoid receptor superfamily. This review focuses on the clinical findings associated with the pathogenic variants so far reported, including three unreported cases. Also, its role in neurodegenerative diseases, such as Parkinson’s or Alzheimer’s disease, is examined, as well as a brief exploration on recent proposals to develop novel therapies for these neurological diseases based on small molecules that could modulate NR4A2 transcriptional activity. The main characteristic shared by all patients is mild to severe developmental delay/intellectual disability. Moderate to severe disorder of the expressive and receptive language is present in at least 42%, while neuro-psychiatric issues were reported in 53% of patients. Movement disorders, including dystonia, chorea or ataxia, are described in 37% patients, although probably underestimated because of its frequent onset in late adolescence-young adulthood. Finally, epilepsy was surprisingly present in 42% of patients, being drug-resistant in three of them. The age at onset varied widely, from five months to twenty-six years, as did the classification of epilepsy, which ranged from focal epilepsy to infantile spasms or Lennox-Gastaut syndrome. Accordingly, we propose that NR4A2 should be considered as a first-tier target gene for the genetic diagnosis of developmental and epileptic encephalopathy.

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20. Jang EH, Kim SA. Long-Term Epigenetic Regulation of Foxo3 Expression in Neonatal Valproate-Exposed Rat Hippocampus with Sex-Related Differences. Int J Mol Sci;2024 (May 13);25(10)

Perinatal exposure to valproic acid is commonly used for autism spectrum disorder (ASD) animal model development. The inhibition of histone deacetylases by VPA has been proposed to induce epigenetic changes during neurodevelopment, but the specific alterations in genetic expression underlying ASD-like behavioral changes remain unclear. We used qPCR-based gene expression and epigenetics tools and Western blotting in the hippocampi of neonatal valproic acid-exposed animals at 4 weeks of age and conducted the social interaction test to detect behavioral changes. Significant alterations in gene expression were observed in males, particularly concerning mRNA expression of Foxo3, which was significantly associated with behavioral changes. Moreover, notable differences were observed in H3K27ac chromatin immunoprecipitation, quantitative PCR (ChIP-qPCR), and methylation-sensitive restriction enzyme-based qPCR targeting the Foxo3 gene promoter region. These findings provide evidence that epigenetically regulated hippocampal Foxo3 expression may influence social interaction-related behavioral changes. Furthermore, identifying sex-specific gene expression and epigenetic changes in this model may elucidate the sex disparity observed in autism spectrum disorder prevalence.

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21. Galán-Olleros M, González-Alguacil E, Soto-Insuga V, Vara-Arias MT, Ortiz-Cabrera NV, Serrano JI, Egea-Gámez RM, García-Peñas JJ, Martínez-Caballero I. Orthopedic Conditions and Interplay with Functional Abilities and MECP2 Variant Subtype in Rett Syndrome Patients. J Autism Dev Disord;2024 (May 25)

PURPOSE: Rett syndrome (RTT) is a rare multi-systemic disorder primarily linked to mutations in MECP2 gene. This study aims to describe the prevalence of orthopedic conditions in RTT patients, and examine their intricate interplay with functional capabilities, and MECP2 variant subtypes. METHODS: Conducted as a cross-sectional retrospective observational study, the research encompassed 55 patients meeting clinical RTT criteria and holding MECP2 mutations. A review of clinical records was performed to gather demographic data, mutation subtypes, orthopedic conditions, management strategies, and assessments of function. RESULTS: Mean age of the participants was 10.22 ± 4.64 years (range, 2.9-19.41). Prevalence rates of orthopedic conditions were as follows: kyphoscoliosis 63.6%, hip displacement 14.6%, knee problems 40%, and foot deformities 75.5%. Significant relationship emerged between spinal (p < 0.01) and knee deformities (p < 0.01) with reduced motor function across various domains. Hip displacement significantly affected sitting ability (p = 0.002), and foot deformities impacted standing and walking capabilities (p = 0.049). Mutation clusters analysis revealed significant correlations with spinal (p = 0.022) and knee deformities (p = 0.002). Linear models highlighted the critical importance of mutation clusters, spine deformities, age, and hip management concerning functional variables. CONCLUSIONS: In this study, foot deformities were the most frequent orthopedic manifestation, followed by spinal, knee, and hip deformities; and unveiled their relationships with functional status and groups of mutations in RTT patients. LEVEL OF EVIDENCE: Level IV, Case series.

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22. Herrero R, Díaz A, Zueco J. The Burden and Psychological Distress of Family Caregivers of Individuals with Autism Spectrum Disorder: A Gender Approach. J Clin Med;2024 (May 13);13(10)

Background/Objectives: Relatives play the main role as caregivers of autism spectrum disorder (ASD) individuals. Women, specifically mothers, are the majority of caregivers of ASD relatives. In addition, the literature on caregivers has shown that women have worse mental health and higher perceived burdens than men. Therefore, the aim of this work was to evaluate the relationships between psychological distress and burden using a gender approach in caregivers of ASD relatives. Methods: A cross-sectional design was applied in this study with a convenience sample of 250 caregivers of ASD relatives. Most of them were mothers caring for a child who ranged in age from 1 to 31 years. Sociodemographic variables considered were age, education level, marital status, and relation to the care recipient. Additionally, psychological distress and objective burden, in the form of hours/day caring, and subjective burden, in the form of perceived burden, were analyzed. Results: Significant gender differences were found in psychological distress and objective and subjective burden, with women showing higher scores than men. Both types of burden played a serial mediating role between gender and psychological distress. Conclusions: The results highlight the important role of gender, with women bearing the high cost of caring for their children with ASD in the form of high objective burden, caring for more hours, and subjective burden, perceiving more burden and showing poorer mental health than men. These results show the need for specific support and intervention programs targeted to women caregivers to reduce burden and improve their mental health.

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23. Gallion T, Williams ZJ, Niarchou M, Duncan L, Hooker G, Taylor KA. Attitudes of autistic adults toward genetic testing for autism. J Genet Couns;2024 (May 25)

Genetic testing for autism has been a controversial topic within the autistic community. Opinions regarding the benefits, risks, and limitations of genetic testing often differ between autistic people, researchers, and healthcare providers. The present study sought to understand the beliefs, attitudes, and intentions to pursue genetic testing of autistic adults and compare perspectives of autistic people who have had genetic testing with those who have not. An international sample of 173 autistic adults (19 [11%] who had previously undergone autism-related genetic testing) completed an online survey with questions assessing beliefs, attitudes, and intentions to pursue genetic testing. Beliefs and attitudes about genetic testing varied widely across the sample. Autistic individuals who had received prior genetic testing had much more positive beliefs about autism-related genetic testing (d = 0.87, 95% CI [0.37, 1.36]) and attitudes toward genetic testing (d = 1.14, 95% CI [0.66, 1.61]) compared to those who had not received such testing, although there were no meaningful differences between those same groups regarding beliefs about genetic testing unrelated to autism (d = 0.02, 95% CI [-0.45, 0.49], p = 0.93). Intention to genetically test oneself or one’s (hypothetical) children was also significantly predicted by autism-specific beliefs, attitudes, and prior genetic testing status. A large majority of the sample (78.6%) also agreed that autistic individuals would benefit from contact with a genetic counselor in certain situations. These findings suggest that the autistic community does not have a singular view of genetic testing, and for those Autistic individuals who are interested in pursuing genetic testing for themselves or a family member, genetic counselors have the potential to play a key role in clinical care.

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24. Anastasescu CM, Gheorman V, Popescu F, Stepan MD, Stoicănescu EC, Gheorman V, Udriștoiu I. A Clinical Study of Urine Amino Acids in Children with Autism Spectrum Disorder. Life (Basel);2024 (May 15);14(5)

Amino acids are organic compounds that enter the protein structure, being involved in the proper functioning of the body. The role of amino acids in the onset of autism spectrum disorder (ASD) is yet to be established. Our aim was to identify correlations between urine amino acids and their derivatives and ASD. METHODS: We designed a case-control study that consisted of 75 boys and girls, aged between 2 and 12 years. For amino acid profile, we used urine samples that were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: Descriptive analysis showed higher values for glutamine, hydroxyproline, tyrosine, aspartic acid, and tryptophan and lower values for serine in the autism group than in the control group. Also, we found that boys with autism had higher values than the boys in the control group for serine, threonine, and aspartic acid. For girls from both groups, we did not find statistically significant values. In terms of age groups, we found significantly higher values for histidine, threonine, valine, methionine, aspartic acid, glutamic acid, alpha amino-adipic acid, sarcosine, alanine, and beta-alanine and significantly lower values for proline for both the autism and control groups under 5 years. CONCLUSIONS: The findings of this study support the assumption that amino acids may have a role in the expression of ASD.

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25. Courchesne E, Taluja V, Nazari S, Aamodt CM, Pierce K, Duan K, Stophaeros S, Lopez L, Barnes CC, Troxel J, Campbell K, Wang T, Hoekzema K, Eichler EE, Nani JV, Pontes W, Sanchez SS, Lombardo MV, de Souza JS, Hayashi MAF, Muotri AR. Embryonic origin of two ASD subtypes of social symptom severity: the larger the brain cortical organoid size, the more severe the social symptoms. Mol Autism;2024 (May 25);15(1):22.

BACKGROUND: Social affective and communication symptoms are central to autism spectrum disorder (ASD), yet their severity differs across toddlers: Some toddlers with ASD display improving abilities across early ages and develop good social and language skills, while others with « profound » autism have persistently low social, language and cognitive skills and require lifelong care. The biological origins of these opposite ASD social severity subtypes and developmental trajectories are not known. METHODS: Because ASD involves early brain overgrowth and excess neurons, we measured size and growth in 4910 embryonic-stage brain cortical organoids (BCOs) from a total of 10 toddlers with ASD and 6 controls (averaging 196 individual BCOs measured/subject). In a 2021 batch, we measured BCOs from 10 ASD and 5 controls. In a 2022 batch, we tested replicability of BCO size and growth effects by generating and measuring an independent batch of BCOs from 6 ASD and 4 control subjects. BCO size was analyzed within the context of our large, one-of-a-kind social symptom, social attention, social brain and social and language psychometric normative datasets ranging from N = 266 to N = 1902 toddlers. BCO growth rates were examined by measuring size changes between 1- and 2-months of organoid development. Neurogenesis markers at 2-months were examined at the cellular level. At the molecular level, we measured activity and expression of Ndel1; Ndel1 is a prime target for cell cycle-activated kinases; known to regulate cell cycle, proliferation, neurogenesis, and growth; and known to be involved in neuropsychiatric conditions. RESULTS: At the BCO level, analyses showed BCO size was significantly enlarged by 39% and 41% in ASD in the 2021 and 2022 batches. The larger the embryonic BCO size, the more severe the ASD social symptoms. Correlations between BCO size and social symptoms were r = 0.719 in the 2021 batch and r = 0. 873 in the replication 2022 batch. ASD BCOs grew at an accelerated rate nearly 3 times faster than controls. At the cell level, the two largest ASD BCOs had accelerated neurogenesis. At the molecular level, Ndel1 activity was highly correlated with the growth rate and size of BCOs. Two BCO subtypes were found in ASD toddlers: Those in one subtype had very enlarged BCO size with accelerated rate of growth and neurogenesis; a profound autism clinical phenotype displaying severe social symptoms, reduced social attention, reduced cognitive, very low language and social IQ; and substantially altered growth in specific cortical social, language and sensory regions. Those in a second subtype had milder BCO enlargement and milder social, attention, cognitive, language and cortical differences. LIMITATIONS: Larger samples of ASD toddler-derived BCO and clinical phenotypes may reveal additional ASD embryonic subtypes. CONCLUSIONS: By embryogenesis, the biological bases of two subtypes of ASD social and brain development-profound autism and mild autism-are already present and measurable and involve dysregulated cell proliferation and accelerated neurogenesis and growth. The larger the embryonic BCO size in ASD, the more severe the toddler’s social symptoms and the more reduced the social attention, language ability, and IQ, and the more atypical the growth of social and language brain regions.

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26. Allan NP, Yamamoto BY, Kunihiro BP, Nunokawa CKL, Rubas NC, Wells RK, Umeda L, Phankitnirundorn K, Torres A, Peres R, Takahashi E, Maunakea AK. Ketogenic Diet Induced Shifts in the Gut Microbiome Associate with Changes to Inflammatory Cytokines and Brain-Related miRNAs in Children with Autism Spectrum Disorder. Nutrients;2024 (May 7);16(10)

In this interventional pilot study, we investigated the effects of a modified ketogenic diet (KD) on children with autism spectrum disorder (ASD). We previously observed improved behavioral symptoms in this cohort following the KD; this trial was registered with Clinicaltrials.gov (NCT02477904). This report details the alterations observed in the microbiota, inflammation markers, and microRNAs of seven children following a KD for a duration of 4 months. Our analysis included blood and stool samples, collected before and after the KD. After 4 months follow up, we found that the KD led to decreased plasma levels of proinflammatory cytokines (IL-12p70 and IL-1b) and brain-derived neurotrophic factor (BDNF). Additionally, we observed changes in the gut microbiome, increased expression of butyrate kinase in the gut, and altered levels of BDNF-associated miRNAs in the plasma. These cohort findings suggest that the KD may positively influence ASD sociability, as previously observed, by reducing inflammation, reversing gut microbial dysbiosis, and impacting the BDNF pathway related to brain activity.

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27. Petropoulos A, Anesiadou S, Michou M, Lymperatou A, Roma E, Chrousos G, Pervanidou P. Functional Gastrointestinal Symptoms in Children with Autism and ADHD: Profiles of Hair and Salivary Cortisol, Serum Leptin Concentrations and Externalizing/Internalizing Problems. Nutrients;2024 (May 20);16(10)

BACKGROUND: Functional Gastrointestinal Disorders (FGIDs) present a higher prevalence in individuals with Neurodevelopmental Disorders (NDDs). The Stress System and the Gut-Brain axis (GBA) may mediate these relations. We aimed to assess the prevalence and profile of FGIDs in a clinical sample of children with Autism Spectrum Disorder (ASD) and Attention Deficit/Hyperactivity Disorder (ADHD) compared to typically developing children (TD) as well as to investigate possible relations between stress-related biomarkers and internalizing/externalizing problems in children with NDDS. METHODS: In total, 120 children, aged between 4 and 12 years old, formed three groups (N = 40, each): ADHD, ASD and TD. Salivary cortisol, hair cortisol and serum leptin were measured. RESULTS: The ASD group had more FGID problems than the TD group (p = 0.001). The ADHD and ASD groups had higher total internalizing/externalizing problems than the TD group (p < 0.0001, p < 0.0001, p = 0.005, respectively). Children with FGIDs showed more total, internalizing and externalizing problems compared to children without FGIDs (p < 0.0001, p < 0.0001, p = 0.041, respectively). The ADHD group showed lower AUCg values (p < 0.0001), while the hair cortisol was higher for the TD group (p < 0.0001). CONCLUSION: In conclusion, children with NDDs had more FGID symptoms and present higher internalizing and externalizing problems. Children with ADHD and FGIDs had more internalizing problems compared to those without FGIDs. No differences in stress-related biomarkers were shown to differentiate children with NDDs with and without FGIDs. Future prospective studies including a greater number of children may elucidate the biological pathways linking these comorbidities.

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28. Campos MG, China M, Cláudio M, Capinha M, Torres R, Oliveira S, Fortuna A. Drug-Cannabinoid Interactions in Selected Therapeutics for Symptoms Associated with Epilepsy, Autism Spectrum Disorder, Cancer, Multiple Sclerosis, and Pain. Pharmaceuticals (Basel);2024 (May 10);17(5)

Clinical practice entails a translation of research that assists in the use of scientific data and therapeutic evidence for the benefit of the patient. This review critically summarizes the potential impact of cannabinoids in conjunction with other drugs when associated with treatments for epilepsy, autism spectrum disorder, cancer, multiple sclerosis, and chronic pain. In these associations, potential drug interactions may occur and alter the predicted clinical results. Therefore, the potential for drug interactions must always be assessed to avoid therapeutic failures and/or increased side effects. Some effects may be additive, synergistic, or antagonistic, but changes in absorption, distribution, metabolism, particularly through cytochrome P450 (CYP) isoenzymes (e.g., CYP2C9 and CYP3A4), and excretion may also occur. For example, the combination of cannabis-derived compounds and the antifungal drug ketoconazole, a CYP3A4 inhibitor, increases the plasma concentration of Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). In contrast, rifampicin, a CYP3A4 inducer, stands out for reducing plasma THC levels by approximately 20-40% and 50% to 60% for CBD. Other CYP3A4 inhibitors and inducers are likely to have a similar effect on plasma concentrations if co-administered. Pharmacokinetic interactions with anticonvulsant medications have also been reported, as have pharmacodynamic interactions between cannabinoids and medications with sympathomimetic effects (e.g., tachycardia, hypertension), central nervous system depressants (e.g., drowsiness, ataxia), and anticholinergics (e.g., tachycardia and somnolence). Although further studies are still pending, there is currently clinical evidence supporting drug interactions with cannabinoids, requiring doctors to evaluate the risk of drug combinations with cannabinoids and vice versa. The tables provided here were designed to facilitate the identification of biorelevant interactions that may compromise therapeutic efficacy and toxicity.

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29. Tadesse AW, Ayano G, Dachew BA, Betts K, Alati R. Exposure to maternal cannabis use disorder and risk of autism spectrum disorder in offspring: A data linkage cohort study. Psychiatry Res;2024 (May 20);337:115971.

This study aimed to investigate the association between pre-pregnancy, prenatal and perinatal exposures to cannabis use disorder (CUD) and the risk of autism spectrum disoder (ASD) in offspring. Data were drawn from the New South Wales (NSW) Perinatal Data Collection (PDC), population-based, linked administrative health data encompassing all-live birth cohort from January 2003 to December 2005. This study involved 222 534 mother-offspring pairs. . The exposure variable (CUD) and the outcome of interest (ASD) were identified using the 10th international disease classification criteria, Australian Modified (ICD-10-AM). We found a three-fold increased risk of ASD in the offspring of mothers with maternal CUD compared to non-exposed offspring. In our sensitivity analyses, male offspring have a higher risk of ASD associated with maternal CUD than their female counterparts. In conclusion, exposure to maternal CUD is linked to a higher risk of ASD in offspring, with a stronger risk in male offspring. Further research is needed to understand these gender-specific effects and the relationship between maternal CUD and ASD risk in children.

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30. Fajardo-Martinez V, Ferreira F, Fuller T, Cambou MC, Kerin T, Paiola S, Mok T, Rao R, Mohole J, Paravastu R, Zhang D, Marschik P, Iyer S, Kesavan K, Borges Lopes MDC, Britto JAA, Moreira ME, Brasil P, Nielsen-Saines K. Neurodevelopmental delay in children exposed to maternal SARS-CoV-2 in-utero. Sci Rep;2024 (May 24);14(1):11851.

It is unclear if SARS CoV-2 infection during pregnancy is associated with adverse neurodevelopmental repercussions to infants. We assessed pediatric neurodevelopmental outcomes in children born to mothers with laboratory-confirmed SARS CoV-2 infection during pregnancy. Neurodevelopmental outcomes of in-utero exposed children were compared to that of pre-pandemic control children in Los Angeles (LA), CA, USA and Rio de Janeiro, Brazil. Bayley Scales of Infant and Toddler Development, 3rd edition (Bayley-III), the gold standard tool for evaluating neurodevelopment until 36 months of age and Ages and Stages Questionnaires (ASQ-3), a frequently used screening instrument for evaluating neurodevelopment in this same age group were the assessment tools used. Developmental delay (DD) was defined as having a score < - 2 SD below the norm (< 70) in at least one of three Bayley-III domains, (cognitive, motor or language) or a score below the cut-off (dark zone) in at least one of five ASQ-3 domains (communication, gross motor, fine motor, problem solving, personal-social). Exposed children were born between April 2020 and December 2022 while control children were born between January 2016 to December 2019. Neurodevelopmental testing was performed in 300 children total: 172 COVID-19 exposed children between 5-30 months of age and 128 control children between 6-38 months of age. Bayley-III results demonstrated that 12 of 128 exposed children (9.4%) had DD versus 2 of 128 controls (1.6%), p = 0.0007. Eight of 44 additional exposed children had DD on ASQ-3 testing. Fully, 20 of 172 exposed children (11.6%) and 2 of 128 control children (1.6%), p = 0.0006 had DD. In Rio, 12% of exposed children versus 2.6% of controls, p = 0.02 had DD. In LA, 5.7% of exposed children versus 0 controls, p = 0.12 had DD. Severe/critical maternal COVID-19 predicted below average neurodevelopment in the exposed cohort (OR 2.6, 95% CI 1.1-6.4). Children exposed to antenatal COVID-19 have a tenfold higher frequency of DD as compared to controls and should be offered neurodevelopmental follow-up.

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31. Feng YR, Zhang Q, Miao JK, Yang T, Chen J, Chen HY, Mou QH, Xiang XL, Long D, Wei QH, Wu Y, Li TY. Association of the retinol to all-trans retinoic acid pathway with autism spectrum disorder. World J Pediatr;2024 (May 24)

BACKGROUND: Autism spectrum disorder (ASD) is a complex group of neurodevelopmental disorders. Research has highlighted a close association between the retinoic acid (RA) signaling pathway and ASD. This study investigates alterations in the vitamin A (VA, retinol) to RA metabolic pathway in children with ASD and speculates on the underlying reasons for these changes. We propose a subtype characterized by downregulated RA signaling in ASD, laying the groundwork for precise diagnosis and treatment research. METHODS: We included 489 children with ASD and 280 typically developing (TD) children. Those with ASD underwent evaluations of core symptoms and neuro-developmental levels, which were conducted by professional developmental behavior physicians using assessment scales. Serum VA and all-trans RA (atRA) levels were determined by high-performance liquid chromatography and ultra-high-performance liquid chromatography-tandem mass spectrometry. The expression levels and concentrations of enzyme molecules such as retinol dehydrogenase 10 were assessed using quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. RESULTS: Children with ASD exhibited reduced serum atRA, accompanied by a downregulation of atRA synthesis enzymes. The reduction in serum atRA levels was linked not only to VA levels but also to the aberrant expression of metabolic enzymes responsible for atRA. Furthermore, the serum atRA levels in children with ASD were more strongly correlated with core symptoms and neurodevelopmental levels than VA levels. CONCLUSION: Children with ASD exhibited a dual regulation of reduced serum atRA levels, influenced by both VA levels and abnormal expression of atRA metabolic enzymes.

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