Biomedicines

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14 pages, 2008 KiB

Open AccessArticle

Cytomegalovirus-Reactive IgG Correlates with Increased IL-6 and IL-1β Levels, Affecting Eating Behaviours and Tactile Sensitivity in Children with Autism

by Isti Anindya, Rini Sekartini, Ibnu Agus Ariyanto, Tjhin Wiguna, Novika Purnama Sari, Yuni Sri Rahayu and Amin Soebandrio

Biomedicines 2025, 13(2), 338; https://doi.org/10.3390/biomedicines13020338 - 2 Feb 2025

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Abstract

Background/Objectives: Elevated cytokine levels, including IL-6 and IL-1β, can contribute to persistent brain inflammation in children with autism and cytomegalovirus (CMV) infection, exacerbating autism-related behaviours and symptoms. This study evaluates the impact of CMV-induced cytokine increases on the eating behaviours and sensory profiles [...] Read more.

Background/Objectives: Elevated cytokine levels, including IL-6 and IL-1β, can contribute to persistent brain inflammation in children with autism and cytomegalovirus (CMV) infection, exacerbating autism-related behaviours and symptoms. This study evaluates the impact of CMV-induced cytokine increases on the eating behaviours and sensory profiles of children with autism. Methods: A cross-sectional design was employed, involving children aged two to five years (CMV-reactive IgG), with ASD (n= 98) and TD (n = 96). Serological tests using ELISA were conducted to measure IgG CMV, IL-6, and IL-1β biomarkers. Eating behaviours were evaluated using the BAMBI (Brief Autism Mealtime Behaviour Inventory), and sensory profiles were assessed using the SSP (Short Sensory Profile). Statistical analyses were performed using Spearman’s rank and chi-square tests. Results: The results show that autism significantly affects children’s eating behaviours and sensory profiles (p < 0.001), with notable differences found between the groups. Correlation analysis revealed a significant association between IgG CMV and IL-6 (p = 0.026) and IL-1β (p = 0.014) in the ASD group. Additionally, eating behaviours (food refusal and limited variety) in ASD correlated with IL-6 and IL-1β. Sensory characteristics, such as tactile sensitivity, were found to correlate with IL-6 (p = 0.027) and IL-1β (p = 0.002) in the ASD group. Conclusions: These findings suggest that CMV-infected children with autism are at increased risk of IL-6 and IL-1β dysregulation, contributing to sensory processing issues and eating behaviours. Further research is needed to enhance CMV testing protocols and better understand the virus’s role in the development of sensory and behavioural issues in children with autism. Full article

(This article belongs to the Special Issue Diagnostic Biomarkers and Novel Therapeutics Targets for Fragile X Syndrome, Autism Spectrum Disorders and Genetic Neurodevelopmental Diseases: Advances and Challenges)

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15 pages, 2241 KiB

Open AccessArticle

Apocynin, a Selective NADPH Oxidase (Nox2) Inhibitor, Ameliorates Behavioural and Learning Deficits in the Fragile X Syndrome Mouse Model

by Yolanda de Diego-Otero, Rajaa El Bekay, Francisco García-Guirado, Lourdes Sánchez-Salido and Rosa María Giráldez-Pérez

Biomedicines 2024, 12(12), 2887; https://doi.org/10.3390/biomedicines12122887 - 18 Dec 2024

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Abstract

Background/Objectives: Fragile X Syndrome (FXS) is associated with intellectual disability, hyperactivity, social anxiety and signs of autism. Hyperactivation of NADPH oxidase has been previously described in the brain of the male Fmr1-KO mouse. This work aims to demonstrate the efficacy of Apocynin, [...] Read more.

Background/Objectives: Fragile X Syndrome (FXS) is associated with intellectual disability, hyperactivity, social anxiety and signs of autism. Hyperactivation of NADPH oxidase has been previously described in the brain of the male Fmr1-KO mouse. This work aims to demonstrate the efficacy of Apocynin, a specific NADPH oxidase inhibitor, in treating Fragile X mouse hallmarks. Methods: Free radicals, lipid and protein oxidation markers and behavioural and learning paradigms were measured after chronic treatment with orally administered vehicle, 10 mg/kg/day or 30 mg/kg/day of Apocynin. Results: The results revealed a reduction in testis weight, an increase in peritoneal fat, and no variation in body weight after chronic treatment. Furthermore, a reduction in hyperactivity was detected in Apocynin-treated male Fmr1-KO mice. Additionally, the higher dose of 30 mg/kg/day also improves behaviour and learning in the male Fmr1-KO mice, normalising free radical production and oxidative parameters. Moreover, a reduction in phospho-EKR1 and P47-Phox protein signals was observed in specific brain areas. Conclusions: Thus, chronic treatment with Apocynin could lead to a new therapeutic option for the Fragile X Syndrome. Full article

(This article belongs to the Special Issue Diagnostic Biomarkers and Novel Therapeutics Targets for Fragile X Syndrome, Autism Spectrum Disorders and Genetic Neurodevelopmental Diseases: Advances and Challenges)

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13 pages, 598 KiB

Open AccessArticle

Examining Erythrocytes as Potential Blood Biomarkers for Autism Spectrum Disorder: Their Relationship to Symptom Severity and Adaptive Behavior

by Tomas Jasenovec, Dominika Radosinska, Ivan Belica, Barbara Raskova, Angelika Puzserova, Norbert Vrbjar and Jana Radosinska

Biomedicines 2024, 12(11), 2619; https://doi.org/10.3390/biomedicines12112619 - 15 Nov 2024

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Abstract

Background: Multiple research teams have documented various abnormalities in erythrocyte properties in children with autism spectrum disorder (ASD) compared with neurotypical individuals. Reduced erythrocyte deformability, a crucial factor for microcirculation and oxygen delivery, may affect brain function. Other key factors like nitric oxide [...] Read more.

Background: Multiple research teams have documented various abnormalities in erythrocyte properties in children with autism spectrum disorder (ASD) compared with neurotypical individuals. Reduced erythrocyte deformability, a crucial factor for microcirculation and oxygen delivery, may affect brain function. Other key factors like nitric oxide (NO) and Na,K-ATPase-regulated cation transport also play roles in both erythrocyte deformability and ASD, suggesting a possible relationship between erythrocyte parameters and autism severity. Thus, this study aims to describe these associations, exploring erythrocyte properties as potential biomarkers in ASD. Methods: A total of 179 ASD children were enrolled in this study. Diagnosis was confirmed by the Autism Diagnostic Observation Schedule—Second Edition (ADOS-2) and Autism Diagnostic Interview-Revised. The Vineland Adaptive Behavior Scales, Third Edition (VABS-3), was used to assess adaptive behavior. RBC deformability was measured using a filtration technique, while NO production by RBCs was assessed via DAF-2DA fluorescence. Na,K-ATPase kinetics and RBC osmotic resistance were evaluated spectrophotometrically. Results: Children with more severe ASD symptoms had more impaired deformability and osmotic resistance than children with mild symptoms. Higher RBC NO production was linked to better scores in some VABS-3 subdomains, and in the social affect domain of ADOS-2. Higher affinity of Na,K-ATPase for sodium negatively correlated with the occurrence of repetitive and restricted behavior—one of the core ASD symptoms. Conclusions: This study identified potential links between ASD severity and RBC properties. While erythrocyte quality can influence ASD symptomatology, the observed relationships—such as those involving RBC deformability, NO production, Na,K-ATPase kinetics, and osmotic resistance—were not strong or consistent enough to be considered reliable diagnostic or prognostic biomarkers. Full article

(This article belongs to the Special Issue Diagnostic Biomarkers and Novel Therapeutics Targets for Fragile X Syndrome, Autism Spectrum Disorders and Genetic Neurodevelopmental Diseases: Advances and Challenges)

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15 pages, 2280 KiB

Open AccessArticle

Comprehensive High-Depth Proteomic Analysis of Plasma Extracellular Vesicles Containing Preparations in Rett Syndrome

by Sho Hagiwara, Tadashi Shiohama, Satoru Takahashi, Masaki Ishikawa, Yusuke Kawashima, Hironori Sato, Daisuke Sawada, Tomoko Uchida, Hideki Uchikawa, Hironobu Kobayashi, Megumi Shiota, Shin Nabatame, Keita Tsujimura, Hiromichi Hamada and Keiichiro Suzuki

Biomedicines 2024, 12(10), 2172; https://doi.org/10.3390/biomedicines12102172 - 24 Sep 2024

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Abstract

Backgroud: Rett syndrome is a neurodevelopmental disorder that affects 1 in 10,000 females. Various treatments have been explored; however, no effective treatments have been reported to date, except for trofinetide, a synthetic analog of glycine-proline-glutamic acid, which was approved by the FDA in [...] Read more.

Backgroud: Rett syndrome is a neurodevelopmental disorder that affects 1 in 10,000 females. Various treatments have been explored; however, no effective treatments have been reported to date, except for trofinetide, a synthetic analog of glycine-proline-glutamic acid, which was approved by the FDA in 2023. Serological biomarkers that correlate with the disease status of RTT are needed to promote early diagnosis and to develop novel agents. Methods: In this study, we performed a high-depth proteomic analysis of extracellular vesicles containing preparations extracted from patient plasma samples to identify novel biomarkers. Results: We identified 33 upregulated and 17 downregulated candidate proteins among a total of 4273 proteins in RTT compared to the healthy controls. Among these, UBE3B was predominantly increased in patients with Rett syndrome and exhibited a strong correlation with the clinical severity score, indicating the severity of the disease. Conclusions: We demonstrated that the proteomics of high-depth extracellular vesicles containing preparations in rare diseases could be valuable in identifying new disease biomarkers and understanding their pathophysiology. Full article

(This article belongs to the Special Issue Diagnostic Biomarkers and Novel Therapeutics Targets for Fragile X Syndrome, Autism Spectrum Disorders and Genetic Neurodevelopmental Diseases: Advances and Challenges)

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12 pages, 2825 KiB

Open AccessArticle

An Observational Longitudinal Study on Seasonal Variations in Tourette Syndrome: Evidence for a Role of Ambient Temperature in Tic Exacerbation

by Jacopo Lamanna, Riccardo Mazzoleni, Ramona Farina, Mattia Ferro, Roberta Galentino, Mauro Porta and Antonio Malgaroli

Biomedicines 2024, 12(8), 1668; https://doi.org/10.3390/biomedicines12081668 - 26 Jul 2024

Viewed by 1327

Abstract

Tourette syndrome (TS) is a high-incidence neurobehavioral disorder that generally begins in childhood. Several factors play a role in its etiology, including genetic influence and auto-immune activation by streptococcal infections. In general, symptoms subside after the end of adolescence, but, in a significant [...] Read more.

Tourette syndrome (TS) is a high-incidence neurobehavioral disorder that generally begins in childhood. Several factors play a role in its etiology, including genetic influence and auto-immune activation by streptococcal infections. In general, symptoms subside after the end of adolescence, but, in a significant number of patients, they remain in adulthood. In this study, we evaluated temporal variations in the two core clinical features of TS including tics and obsessive–compulsive disorder (OCD) symptoms. An observational longitudinal study lasting 15 months (2017–2019) was conducted on a cohort of 24 people recruited in Milan (Italy) who were diagnosed with a subtype of TS known as obsessive–compulsive tic disorder. Inclusion criteria included a global score of the Yale global tic severity scale (Y-GTSS) > 50, a Yale–Brown obsessive–compulsive scale (Y-BOCS) global score > 15, and TS onset at least one year prior. Y-GTSS and Y-BOCS data were acquired at six time points, together with local environmental data. Tics, but not OCD symptoms, were found to be more severe in spring and summer compared with winter and autumn (p < 0.001). Changes in tics displayed an appreciable oscillation pattern in the same subject and also a clear synchrony among different subjects, indicating an external orchestrating factor. Ambient temperature showed a significant correlation with Y-GTSS measurements (p < 0.001). We argue that the increase in tics observed during hot seasons can be related to increasing ambient temperature. We believe that our results can shed light on the seasonal dynamics of TS symptomatology and provide clues for preventing their worsening over the year. Full article

(This article belongs to the Special Issue Diagnostic Biomarkers and Novel Therapeutics Targets for Fragile X Syndrome, Autism Spectrum Disorders and Genetic Neurodevelopmental Diseases: Advances and Challenges)

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19 pages, 5700 KiB

Open AccessArticle

Safety, Tolerability, and EEG-Based Target Engagement of STP1 (PDE3,4 Inhibitor and NKCC1 Antagonist) in a Randomized Clinical Trial in a Subgroup of Patients with ASD

by Craig A. Erickson, Laura Perez-Cano, Ernest V. Pedapati, Eric Painbeni, Gregory Bonfils, Lauren M. Schmitt, Hannah Sachs, Meredith Nelson, Lisa De Stefano, Grace Westerkamp, Adriano L. S. de Souza, Oliver Pohl, Offir Laufer, Gil Issachar, Thomas Blaettler, Jean-Marc Hyvelin and Lynn A. Durham

Biomedicines 2024, 12(7), 1430; https://doi.org/10.3390/biomedicines12071430 - 27 Jun 2024

Viewed by 2367

Abstract

This study aimed to evaluate the safety and tolerability of STP1, a combination of ibudilast and bumetanide, tailored for the treatment of a clinically and biologically defined subgroup of patients with Autism Spectrum Disorder (ASD), namely ASD Phenotype 1 (ASD-Phen1). We conducted a [...] Read more.

This study aimed to evaluate the safety and tolerability of STP1, a combination of ibudilast and bumetanide, tailored for the treatment of a clinically and biologically defined subgroup of patients with Autism Spectrum Disorder (ASD), namely ASD Phenotype 1 (ASD-Phen1). We conducted a randomized, double-blind, placebo-controlled, parallel-group phase 1b study with two 14-day treatment phases (registered at clinicaltrials.gov as NCT04644003). Nine ASD-Phen1 patients were administered STP1, while three received a placebo. We assessed safety and tolerability, along with electrophysiological markers, such as EEG, Auditory Habituation, and Auditory Chirp Synchronization, to better understand STP1’s mechanism of action. Additionally, we used several clinical scales to measure treatment outcomes. The results showed that STP1 was well-tolerated, with electrophysiological markers indicating a significant and dose-related reduction of gamma power in the whole brain and in brain areas associated with executive function and memory. Treatment with STP1 also increased alpha 2 power in frontal and occipital regions and improved habituation and neural synchronization to auditory chirps. Although numerical improvements were observed in several clinical scales, they did not reach statistical significance. Overall, this study suggests that STP1 is well-tolerated in ASD-Phen1 patients and shows indirect target engagement in ASD brain regions of interest. Full article

(This article belongs to the Special Issue Diagnostic Biomarkers and Novel Therapeutics Targets for Fragile X Syndrome, Autism Spectrum Disorders and Genetic Neurodevelopmental Diseases: Advances and Challenges)

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20 pages, 4285 KiB

Open AccessArticle

Characterization of a Clinically and Biologically Defined Subgroup of Patients with Autism Spectrum Disorder and Identification of a Tailored Combination Treatment

by Laura Pérez-Cano, Luigi Boccuto, Francesco Sirci, Jose Manuel Hidalgo, Samuel Valentini, Mattia Bosio, Xavier Liogier D’Ardhuy, Cindy Skinner, Lauren Cascio, Sujata Srikanth, Kelly Jones, Caroline B. Buchanan, Steven A. Skinner, Baltazar Gomez-Mancilla, Jean-Marc Hyvelin, Emre Guney and Lynn Durham

Biomedicines 2024, 12(5), 991; https://doi.org/10.3390/biomedicines12050991 - 30 Apr 2024

Cited by 2 | Viewed by 2482

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Diagnostic Biomarkers and Novel Therapeutics Targets for Fragile X Syndrome, Autism Spectrum Disorders and Genetic Neurodevelopmental Diseases: Advances and Challenges)

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Review

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27 pages, 1365 KiB

Open AccessReview

From Discovery to Innovative Translational Approaches in 80 Years of Fragile X Syndrome Research

by Mathijs B. van der Lei and R. Frank Kooy

Biomedicines 2025, 13(4), 805; https://doi.org/10.3390/biomedicines13040805 - 27 Mar 2025

Viewed by 669

Abstract

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and a major genetic contributor to autism spectrum disorder. It is caused by a CGG trinucleotide repeat expansion in the FMR1 gene, resulting in gene silencing and the loss of [...] Read more.

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and a major genetic contributor to autism spectrum disorder. It is caused by a CGG trinucleotide repeat expansion in the FMR1 gene, resulting in gene silencing and the loss of FMRP, an RNA-binding protein essential for synaptic plasticity. This review covers over 80 years of FXS research, highlighting key milestones, clinical features, genetic and molecular mechanisms, the FXS mouse model, disrupted molecular pathways, and current therapeutic strategies. Additionally, we discuss recent advances including AI-driven combination therapies, CRISPR-based gene editing, and antisense oligonucleotides (ASOs) therapies. Despite these scientific breakthroughs, translating preclinical findings into effective clinical treatments remains challenging. Clinical trials have faced several difficulties, including patient heterogeneity, inconsistent outcome measures, and variable therapeutic responses. Standardized preclinical testing protocols and refined clinical trial designs are required to overcome these challenges. The development of FXS-specific biomarkers could also improve the precision of treatment assessments. Ultimately, future therapies will need to combine pharmacological and behavioral interventions tailored to individual needs. While significant challenges remain, ongoing research continues to offer hope for transformative breakthroughs that could significantly improve the quality of life for individuals with FXS and their families. Full article

(This article belongs to the Special Issue Diagnostic Biomarkers and Novel Therapeutics Targets for Fragile X Syndrome, Autism Spectrum Disorders and Genetic Neurodevelopmental Diseases: Advances and Challenges)

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9 pages, 246 KiB

Open AccessOpinion

Barking Up the Wrong Tree—Motor–Sensory Elements as Prodrome in Autism

by Meir Lotan

Biomedicines 2024, 12(6), 1235; https://doi.org/10.3390/biomedicines12061235 - 2 Jun 2024

Viewed by 992

Abstract

Autism spectrum disorder (ASD) has been intensely investigated since the term was first used over 80 years ago. The prevalence of ASD is constantly rising, and, currently, 1:36 children are diagnosed with this disorder. Despite the intense interest in ASD, the origins of [...] Read more.

Autism spectrum disorder (ASD) has been intensely investigated since the term was first used over 80 years ago. The prevalence of ASD is constantly rising, and, currently, 1:36 children are diagnosed with this disorder. Despite the intense interest in ASD, the origins of this disorder remain obscure. This article explores motor issues and proprioceptive interoception difficulties as the prodrome of ASD. The importance of early intervention in the prognosis of ASD is common knowledge. Yet, since the communicational and social behaviors typical of ASD are observable only after the age of 18 months, diagnosis and early intervention are delayed. Therefore, the quest into the involvement of sensory–motor difficulties as a source of ASD traits, or at least as a potential early indicator, is warranted, with the intention of enabling early diagnosis and early intervention. This article examines the justification for this new avenue of early diagnosis and intervention and may open up a completely different way of viewing ASD. This new point of view may suggest an original path of assessment and intervention in infancy with this group of clients, possibly leading to improved prognosis for children and their families. Full article

(This article belongs to the Special Issue Diagnostic Biomarkers and Novel Therapeutics Targets for Fragile X Syndrome, Autism Spectrum Disorders and Genetic Neurodevelopmental Diseases: Advances and Challenges)

14 pages, 1045 KiB

Open AccessSystematic Review

DDX3X Syndrome Behavioral Manifestations with Particular Emphasis on Psycho-Pathological Symptoms—A Review

by Urszula Stefaniak, Roksana Malak, Ada Kaczmarek, Włodzimierz Samborski and Ewa Mojs

Biomedicines 2023, 11(11), 3046; https://doi.org/10.3390/biomedicines11113046 - 14 Nov 2023

Cited by 1 | Viewed by 3069

Abstract

(1) Background: Identification of typical behavioral manifestations in patients with DEAD-Box Helicase 3 X-linked gene (DDX3X) variants plays a crucial role in accurately diagnosing and managing the syndrome. The objective of this paper was to carry out a review of medical [...] Read more.

(1) Background: Identification of typical behavioral manifestations in patients with DEAD-Box Helicase 3 X-linked gene (DDX3X) variants plays a crucial role in accurately diagnosing and managing the syndrome. The objective of this paper was to carry out a review of medical and public databases and assess the behavioral features of the DDX3X syndrome (DDX3X), with a particular focus on psycho-pathological symptoms. (2) Methods: An extensive computerized search was conducted in various databases, including PubMed, Medline Complete, Science Direct, Scopus, and Web of Science. Specific keywords and Medical Subject Headings were used to ensure the inclusion of relevant studies. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were applied to assess the methodological quality of the manuscripts. (3) Results: Only nine papers out of the 272 assessed met the inclusion criteria. These articles revealed various psycho-pathological manifestations in patients with the DDX3X syndrome. Intellectual disability (ID) or developmental disability (DD), speech delay, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), generalized anxiety disorder (GAD), self-injurious behaviors (SIBs), sensory symptoms and sleep disturbance were demonstrated to be the most common psycho-pathological behavior manifestations. (4) Conclusions: Patients with the DDX3X syndrome manifest a wide spectrum of psycho-pathological symptoms. A comprehensive investigation of these symptoms in patients is essential for early diagnosis and effective therapy. Full article

(This article belongs to the Special Issue Diagnostic Biomarkers and Novel Therapeutics Targets for Fragile X Syndrome, Autism Spectrum Disorders and Genetic Neurodevelopmental Diseases: Advances and Challenges)

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