Autism: Molecular Bases, Diagnosis and Therapies, 2nd Volume

Topic Information

Dear Colleagues,

The causes of autism are still unknown today. More recent studies suggest that autism spectrum disorders may occur following the birth of abnormal neurons (neurobiological causes) that fail to create correct connections with the other nerve cells of the brain, to the point of causing incorrect the functioning of the entire organ. Neuronal networks are formed, above all, during the foetal development phase, allowing one to hypothesize that the cause of this disorder is due to a combination of genetic factors, congenital alterations, and environmental risk factors. There is evidence of familiarity, but also of individuals with autism as carriers of certain genetic diseases (Rett syndrome, Angelman syndrome, etc.), as well as learning disabilities such as dyslexia and dyscalculia, ADHD, Tourette's syndrome, etc. It is therefore necessary to gather more information on the possible causes of the onset of autism in order to better understand it, intervene, and propose targeted therapies. Unfortunately, the diagnosis is often made around the age of 6, when children begin to experience the first difficulties of the condition, with extremely variable symptoms both in extent and in severity. Diagnosis must not be based on psychological tests only, but also on genetic, biochemical and microbiological analysis. A list of possible biomarkers in the urine and blood to allow an early (from the first years of life) and accurate diagnosis is of fundamental importance in order to define the most appropriate therapy. Therapy must be multimodal, i.e., psychological but also pharmacological, especially when some symptoms are particularly debilitating, or present with particular associated pathologies. The outcome of this Special Issue will represent a further step in understanding the molecular mechanisms underlying autism spectrum disorder in order to achieve early diagnosis and provide researchers and clinicians with the most up-to-date information on possible biomarkers to help them understand how to implement therapeutic strategies for patients.

Prof. Dr. Lello Zolla
Prof. Dr. Kunio Yui
Topic Editors

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Participating Journals

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Biomedicines biomedicines	3.9	5.2	2013	14.6 Days	CHF 2600	Submit
Brain Sciences brainsci	2.7	4.8	2011	15.6 Days	CHF 2200	Submit
Current Issues in Molecular Biology cimb	2.8	2.9	1999	15.8 Days	CHF 2200	Submit
Diagnostics diagnostics	3.0	4.7	2011	20.3 Days	CHF 2600	Submit
International Journal of Molecular Sciences ijms	4.9	8.1	2000	16.8 Days	CHF 2900	Submit
International Journal of Translational Medicine ijtm	-	-	2021	24.2 Days	CHF 1000	Submit

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Published Papers (8 papers)

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15 pages, 1157 KiB  

Open AccessReview

Prostaglandins: Biological Action, Therapeutic Aspects, and Pathophysiology of Autism Spectrum Disorders

by Kunio Yui, George Imataka and Mariko Ichihashi

Curr. Issues Mol. Biol. 2025, 47(2), 71; https://doi.org/10.3390/cimb47020071 - 21 Jan 2025

Viewed by 587

Abstract

Esterified ARA on the inner surface of the cell membrane is hydrolyzed to its free form by phospholipase A2 (PLA2), which is further metabolized by COXs and lipoxygenases (LOXs) and cytochrome P450 (CYP) enzymes. PGs produce detrimental effects due to their proinflammatory properties. [...] Read more.

Esterified ARA on the inner surface of the cell membrane is hydrolyzed to its free form by phospholipase A2 (PLA2), which is further metabolized by COXs and lipoxygenases (LOXs) and cytochrome P450 (CYP) enzymes. PGs produce detrimental effects due to their proinflammatory properties. The generation of prostaglandin (PG)G₂ and PGH₂ is triggered by cyclooxygenase (COX) isozymes such as COX-1 and COX-2. Prostaglandin E2 (PGE2) is significantly elevated in ASD. Considerable data indicate that COX enzymes and their metabolites of ARA play important roles in the initiation and development of human neurodevelopmental diseases. The involvement of disrupted COX2/PGE2 signaling in ASD pathology in changing neuronal cell behavior and the expression of ASD-related genes and proteins is due to disrupted COX2/PGE2 signaling. Prostacyclin (PGI2) is synthesized from arachidonic acid by metabolic-pathway-dependent cyclooxygenase (COX) and synthesized in a primary step of ARA transformation (PGG2, PGH2), by degradation of the abovementioned prostaglandins. Full article

(This article belongs to the Topic Autism: Molecular Bases, Diagnosis and Therapies, 2nd Volume)

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16 pages, 3526 KiB  

Open AccessArticle

Mice with 16p11.2 Deletion and Duplication Show Alterations in Biological Processes Associated with White Matter

by Tianqi Wang, Megan Sharp, Ilaria Morella, Francesco Bedogni, Vladimir Trajkovski, Riccardo Brambilla and Yasir Ahmed Syed

Int. J. Mol. Sci. 2025, 26(2), 573; https://doi.org/10.3390/ijms26020573 - 11 Jan 2025

Viewed by 772

Abstract

Deletion and duplication in the human 16p11.2 chromosomal region are closely linked to neurodevelopmental disorders, specifically autism spectrum disorder. Data from neuroimaging studies suggest white matter microstructure aberrations across these conditions. In 16p11.2 deletion and duplication carriers, potential gene dosage effects may impact [...] Read more.

Deletion and duplication in the human 16p11.2 chromosomal region are closely linked to neurodevelopmental disorders, specifically autism spectrum disorder. Data from neuroimaging studies suggest white matter microstructure aberrations across these conditions. In 16p11.2 deletion and duplication carriers, potential gene dosage effects may impact white matter organisation, contributing to phenotypes including impaired cognition. However, the biological mechanisms underlying this white matter pathology remain unclear. To bridge this knowledge gap, we utilised mouse models of 16p11.2 deletion and duplication to explore changes in corpus callosum oligodendrocytes, myelination, axon caliber, and astrocytes. Immunofluorescence staining was employed to measure lineage and mature oligodendrocyte numbers, as well as myelin basic protein and glial fibrillary acidic protein fluorescence intensity. Transmission electron microscopy was utilised to evaluate axonal structural alterations related to myelin, such as myelinated axon percentage, diameter, myelin thickness, and g-ratio. Our findings reveal changes in the number of mature oligodendrocytes, myelination levels, axon diameter, and astrocytes in the corpus callosum of mice with 16p11.2 deletion and duplication. Deletion mice displayed a tendency toward reduced counts of mature oligodendrocytes and myelination levels, while duplication mice exhibited a notable increase. Axon diameter variations included a significant increase in axon diameter and myelin thickness in both deletion and duplication mice, but with irregular structure in duplication mice. Variances in astrocytes between genotypes showed significant early increases in development for both deletion and duplication mice compared to wild-type mice, with this rise sustained in duplication mice but significantly diminished in deletion mice at a later stage. Our research reveals changes in the biological mechanisms impacting white matter. Comparison of reciprocal trends in 16p11.2 deletion and duplication mice with wild-type mice suggests the possibility of gene dosage effects. Identification of these mechanisms offers an initial step in unveiling therapeutic targets for associated neurodevelopmental disorder phenotypes. Full article

(This article belongs to the Topic Autism: Molecular Bases, Diagnosis and Therapies, 2nd Volume)

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13 pages, 543 KiB  

Open AccessReview

The Development of Methods of BLOTCHIP^®-MS for Peptidome: Small Samples in Tuberous Sclerosis

by Kunio Yui, George Imataka, Kotaro Yuge, Hitomi Sasaki, Tadashi Shiohama, Kyoichi Asada and Hidehisa Tachiki

Curr. Issues Mol. Biol. 2025, 47(1), 34; https://doi.org/10.3390/cimb47010034 - 7 Jan 2025

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Abstract

Mutations in TSC1 or TSC2 in axons induce tuberous sclerosis complex. Neurological manifestations mainly include epilepsy and autism spectrum disorder (ASD). ASD is the presenting symptom (25–50% of patients). ASD was observed at significantly higher frequencies in participants with TSC2 than those with [...] Read more.

Mutations in TSC1 or TSC2 in axons induce tuberous sclerosis complex. Neurological manifestations mainly include epilepsy and autism spectrum disorder (ASD). ASD is the presenting symptom (25–50% of patients). ASD was observed at significantly higher frequencies in participants with TSC2 than those with TSC1 mutations. The occurrence of TSC2 mutations is about 50% larger than TSC1. Therefore, ASD may develop due to TSC2 deficiency. TSC2 regulates microRNA biogenesis and Microprocessor activity via GSK3β. Of reference, everolimus has the best treatment target because of the higher potency of interactions with mTORC2 rather than rapamycin. Mutations in the TSC1 and TSC2 genes result in the constitutive hyperactivation of the mammalian target of the rapamycin (mTOR) pathway, contributing to the growth of benign tumors or hamartomas in various organs. TSC2 mutations were associated with a more severe phenotypic spectrum than TSC1 mutations because of the inhibition of the mTOR cascade. There are few studies on the peptide analysis of this disorder in relation to everolimus. Only one study reported that, in ten plasma samples, pre-melanosome protein (PMEL) and S-adenosylmethionine (SAM) were significantly changed as diagnostic prognostic effects. Our study on peptide analysis in Protosera Inc (Osaka, Japan) revealed that three peptides that were related to inflammation in two patients with tuberous sclerosis, who showed a 30% decrease in ASD symptoms following everolimus treatment. TSC2 mutations were associated with a more severe phenotypic spectrum due to the inhibition of the mTOR cascade. PMEL and SAM were significantly changed as diagnostic effects. Full article

(This article belongs to the Topic Autism: Molecular Bases, Diagnosis and Therapies, 2nd Volume)

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23 pages, 2201 KiB  

Open AccessArticle

Effects of Extremely Low-Frequency Electromagnetic Field Treatment on ASD Symptoms in Children: A Pilot Study

by Kierra Pietramala, Alessandro Greco, Alberto Garoli and Danielle Roblin

Brain Sci. 2024, 14(12), 1293; https://doi.org/10.3390/brainsci14121293 - 22 Dec 2024

Viewed by 1318

Abstract

Background/Objectives: Autism Spectrum Disorder (ASD) are neurodevelopmental disorders marked by challenges in social interaction, communication, and repetitive behaviors. People with ASD may exhibit repetitive behaviors, unique ways of learning, and different ways of interacting with the world. The term “spectrum” reflects the wide [...] Read more.

Background/Objectives: Autism Spectrum Disorder (ASD) are neurodevelopmental disorders marked by challenges in social interaction, communication, and repetitive behaviors. People with ASD may exhibit repetitive behaviors, unique ways of learning, and different ways of interacting with the world. The term “spectrum” reflects the wide variability in how ASD manifests in individuals, including differences in abilities, symptoms, and support needs, and conditions characterized by difficulties in social interactions, communication, restricted interests, and repetitive behaviors. Inflammation plays a crucial role in the pathophysiology, with increased pro-inflammatory cytokines in cerebrospinal fluid. Previous studies with transcranial magnetic stimulation have shown promising results, suggesting nervous system susceptibility to electromagnetic fields, with evidence indicating that extremely low-frequency electromagnetic field (ELF-EMF) treatment may modulate inflammatory responses through multiple pathways, including the reduction of pro-inflammatory cytokines like IL-6 and TNF-α, and the enhancement of anti-inflammatory mediators. Methods: This pilot study included 20 children (ages 2–13) with a confirmed diagnosis of ASD. A 15-week protocol involved ELF-EMF treatments using the SEQEX device, with specific day and night programs. Assessment was conducted through standardized pre- and post-treatment tests: Achenbach Child Behavior Checklist, Peabody Picture Vocabulary Test-4, Expressive One Word Picture Vocabulary Test-4, and Conner’s 3GI. Results: Statistically significant improvements were observed in receptive language (PPVT-4: from 74.07 to 90.40, p = 0.002) and expressive language (EOWPVT-4: from 84.17 to 90.50, p = 0.041). Notable reductions, with statistical significance, were found in externalizing problems across both age groups (1.5–5 years: p = 0.028; 6–18 years: p = 0.027), with particular improvement in attention and behavioral problems. The results were observed over a short period of 15 weeks, therefore excluding the possibility of coincidental age-related gains, that would typically occur during a normal developmental timeframe. Parent evaluations showed significant reduction in ASD symptoms, particularly in the 1.5–5 years group (p = 0.046). Conclusions: ELF-EMF treatment demonstrated a high safety profile and efficacy in mitigating ASD-related symptoms. The observed improvements suggest both direct effects on central and autonomic nervous systems and indirect effects through inflammatory response modulation. Further studies are needed to confirm these promising results through broader demographics and randomized control designs. Full article

(This article belongs to the Topic Autism: Molecular Bases, Diagnosis and Therapies, 2nd Volume)

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19 pages, 1132 KiB  

Open AccessArticle

Understanding Emotional Outbursts: A Cross-Cultural Study in Latin American Children with Autism Spectrum Disorder

by Maria Cristina Triguero Veloz Teixeira, Rosane Lowenthal, Alexia Rattazzi, Sebastian Cukier, Daniel Valdez, Ricardo Garcia, Gabriela Garrido Candela, Analia Rosoli Murillo, Francislene Pereira da Silva Leite, Giuliana Pinheiro, Kate Woodcock, Justin Cheuk Yin Chung, Carmel Mevorach, Cecilia Montiel-Nava and Cristiane Silvestre Paula

Brain Sci. 2024, 14(10), 1010; https://doi.org/10.3390/brainsci14101010 - 8 Oct 2024

Viewed by 1823

Abstract

Objectives: One of the behavioral problems strongly associated with emotional dysregulation (ED) in ASD is emotional outbursts (EOs) characterized by a pattern of challenging behavior that varies across individuals and across time. Cultural factors can modulate the expression of EOs. This study aimed [...] Read more.

Objectives: One of the behavioral problems strongly associated with emotional dysregulation (ED) in ASD is emotional outbursts (EOs) characterized by a pattern of challenging behavior that varies across individuals and across time. Cultural factors can modulate the expression of EOs. This study aimed to characterize the profile of emotional outbursts (EOs) in children with autism spectrum disorder (ASD) across various countries in Latin America and to identify clinical, emotional, and contextual factors that contribute to the onset and frequency of EOs within this diverse sample. Methods: A cross-sectional and cross-cultural study was conducted between 2023 and 2024 comprising samples from five countries in the Latin American Network for Autism-REAL: Argentina, Brazil, Chile, Uruguay, and the Dominican Republic. We studied 689 children with ASD (age x = 8.7 ± 2.6 years) using the Emotional Outburst Questionnaire (EOQ). Results: We identified different types of EO among children with ASD in our sample. The most frequent was the ‘behavioral indicators of emotion’ (52.0%) followed by ‘increased motor activity’ (28.3%), ‘non-speech vocalizations’, (27.6%), ‘mild verbal aggression’ (23.8%), and ‘avoidance’ (21.5%). Children in a bad mood or having a bad day or experiencing irritability were the most significant factors that increased the likelihood of EOs. Conclusions: Our results revealed that irritability is an important trigger for EOs and should not be disregarded or underestimated when monitoring the mental health of children with ASD. Full article

(This article belongs to the Topic Autism: Molecular Bases, Diagnosis and Therapies, 2nd Volume)

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15 pages, 2102 KiB  

Open AccessArticle

Intranasal Insulin Eases Autism in Rats via GDF-15 and Anti-Inflammatory Pathways

by Duygu Burcu Arda, Kerem Can Tunç, Mehmet Fatih Bozkurt, Ejder Saylav Bora, Ayşe Çiğel and Oytun Erbaş

Curr. Issues Mol. Biol. 2024, 46(9), 10530-10544; https://doi.org/10.3390/cimb46090624 - 20 Sep 2024

Viewed by 1330

Abstract

In rat models, it is well-documented that chronic administration of propionic acid (PPA) leads to autism-like behaviors. Although the intranasal (IN) insulin approach is predominantly recognized for its effects on food restriction, it has also been shown to enhance cognitive memory by influencing [...] Read more.

In rat models, it is well-documented that chronic administration of propionic acid (PPA) leads to autism-like behaviors. Although the intranasal (IN) insulin approach is predominantly recognized for its effects on food restriction, it has also been shown to enhance cognitive memory by influencing various proteins, modulating anti-inflammatory pathways in the brain, and reducing signaling molecules such as interleukins. This study seeks to explore the potential therapeutic benefits of IN insulin in a rat model of autism induced by PPA. Thirty male Wistar albino rats were categorized into three cohorts: the control group, the PPA-induced autism (250 mg/kg/day intraperitoneal PPA dosage for five days) group, treated with saline via IN, and the PPA-induced autism group, treated with 25 U/kg/day (250 µL/kg/day) insulin via IN. All treatments were administered for 15 days. After behavioral testing, all animals were euthanized, and brain tissue and blood samples were collected for histopathological and biochemical assessments. Following insulin administration, a substantial reduction in autism symptoms was observed in all three social behavior tests conducted on the rats. Moreover, insulin exhibited noteworthy capabilities in decreasing brain MDA, IL-2, IL-17, and TNF-α levels within autism models. Additionally, there is a notable elevation in the brain nerve growth factor level (p < 0.05) and GDF-15 (p < 0.05). The assessment of cell counts within the hippocampal region and cerebellum revealed that insulin displayed effects in decreasing glial cells and inducing a significant augmentation in cell types such as the Purkinje and Pyramidal cells. The administration of insulin via IN exhibits alleviating effects on autism-like behavioral, biochemical, and histopathological alterations induced by PPA in rats. Insulin-dependent protective effects show anti-inflammatory, anti-oxidative, and neuroprotective roles of insulin admitted nasally. Full article

(This article belongs to the Topic Autism: Molecular Bases, Diagnosis and Therapies, 2nd Volume)

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30 pages, 1375 KiB  

Open AccessReview

Mesenchymal Stem Cells and Purinergic Signaling in Autism Spectrum Disorder: Bridging the Gap between Cell-Based Strategies and Neuro-Immune Modulation

by Agata Wikarska, Kacper Roszak and Katarzyna Roszek

Biomedicines 2024, 12(6), 1310; https://doi.org/10.3390/biomedicines12061310 - 13 Jun 2024

Viewed by 1932

Abstract

The prevalence of autism spectrum disorder (ASD) is still increasing, which means that this neurodevelopmental lifelong pathology requires special scientific attention and efforts focused on developing novel therapeutic approaches. It has become increasingly evident that neuroinflammation and dysregulation of neuro-immune cross-talk are specific [...] Read more.

The prevalence of autism spectrum disorder (ASD) is still increasing, which means that this neurodevelopmental lifelong pathology requires special scientific attention and efforts focused on developing novel therapeutic approaches. It has become increasingly evident that neuroinflammation and dysregulation of neuro-immune cross-talk are specific hallmarks of ASD, offering the possibility to treat these disorders by factors modulating neuro-immunological interactions. Mesenchymal stem cell-based therapy has already been postulated as one of the therapeutic approaches for ASD; however, less is known about the molecular mechanisms of stem cell influence. One of the possibilities, although still underestimated, is the paracrine purinergic activity of MSCs, by which stem cells ameliorate inflammatory reactions. Modulation of adenosine signaling may help restore neurotransmitter balance, reduce neuroinflammation, and improve overall brain function in individuals with ASD. In our review article, we present a novel insight into purinergic signaling, including but not limited to the adenosinergic pathway and its role in neuroinflammation and neuro-immune cross-talk modulation. We anticipate that by achieving a greater understanding of the purinergic signaling contribution to ASD and related disorders, novel therapeutic strategies may be devised for patients with autism in the near future. Full article

(This article belongs to the Topic Autism: Molecular Bases, Diagnosis and Therapies, 2nd Volume)

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11 pages, 1038 KiB  

Open AccessArticle

Combining Anti-Mitochondrial Antibodies, Anti-Histone, and PLA2/COX Biomarkers to Increase Their Diagnostic Accuracy for Autism Spectrum Disorders

by Afaf El-Ansary, Hanan A. Alfawaz, Abir Ben Bacha and Laila Y. Al-Ayadhi

Brain Sci. 2024, 14(6), 576; https://doi.org/10.3390/brainsci14060576 - 5 Jun 2024

Viewed by 1551

Abstract

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in social interaction and restricted and repetitive behaviors. Oxidative stress may be a critical link between mitochondrial dysfunction and ASD as reactive oxygen species (ROS) generated from pro-oxidant environmental toxicants and [...] Read more.

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in social interaction and restricted and repetitive behaviors. Oxidative stress may be a critical link between mitochondrial dysfunction and ASD as reactive oxygen species (ROS) generated from pro-oxidant environmental toxicants and activated immune cells can result in mitochondrial failure. Recently, mitochondrial dysfunction, autoimmunity, and abnormal lipid mediators have been identified in multiple investigations as an acknowledged etiological mechanism of ASD that can be targeted for therapeutic intervention. Methods: The relationship between lipid mediator markers linked to inflammation induction, such as phospholipase A2/cyclooxygenase-2 (PLA2/Cox-2), and the mitochondrial dysfunction marker anti-mitochondrial antibodies (AMA-M2), and anti-histone autoantibodies in the etiology of ASD was investigated in this study using combined receiver operating characteristic (ROC) curve analyses. This study also sought to identify the linear combination for a given set of markers that optimizes the partial area under ROC curves. This study included 40 age- and sex-matched controls and 40 ASD youngsters. The plasma of both groups was tested for PLA2/COX-2, AMA-M2, and anti-histone autoantibodies’ levels using ELISA kits. ROC curves and logistic regression models were used in the statistical analysis. Results: Using the integrated ROC curve analysis, a notable rise in the area under the curve was noticed. Additionally, the combined markers had markedly improved specificity and sensitivity. Conclusions: The current study suggested that measuring the predictive value of selected biomarkers related to mitochondrial dysfunction, autoimmunity, and lipid metabolism in children with ASD using a ROC curve analysis could lead to a better understanding of the etiological mechanism of ASD as well as its relationship with metabolism. Full article

(This article belongs to the Topic Autism: Molecular Bases, Diagnosis and Therapies, 2nd Volume)

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