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Molecular Investigations in Neurodevelopmental Disorders
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Molecular Investigations in Neurodevelopmental Disorders

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: 30 December 2025 | Viewed by 4652

Special Issue Editor

Dr. Giorgio Medici

E-Mail Website
Guest Editor
Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy
Interests: neuromotor; neurodevelopmental disorders

Special Issue Information

Dear Colleagues,

Neurodevelopmental disorders (NDDs) encompass a group of conditions characterized by impairments in brain function and development, affecting various aspects of cognition, behavior, and social interaction. Research is shedding light on the intricate genetic and biochemical mechanisms underlying these disorders. Dysregulation of gene expression, disruptions in synaptic connectivity, and abnormalities in neurotransmitter signaling pathways are among the key molecular mechanisms implicated in NDDs such as autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and intellectual disability (ID). Understanding the molecular basis of NDDs is crucial for understanding brain functioning and identifying reliable molecular biomarkers in order to develop effective diagnostic tools and personalized treatment strategies aimed at ameliorating symptoms and improving outcomes for individuals affected by these disorders.

We invite researchers to contribute to this Special Issue focusing on “Molecular Investigations in Neurodevelopmental Disorders”. This Special Issue aims to showcase cutting-edge studies elucidating the genetic, epigenetic, and molecular mechanisms underlying neurodevelopmental conditions.

We welcome original research articles, reviews, and perspectives that contribute to advancing our understanding of the molecular basis of NDDs. Topics of interest include but are not limited to, the identification of novel genetic variants associated with NDDs, the elucidation of gene expression patterns and regulatory networks, the characterization of the molecular pathways involved in neuronal development and synaptic function, the identification of biomarkers, and the development of therapeutic strategies.

Dr. Giorgio Medici
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • neurodevelopmental disorders
  • brain
  • neurons
  • synapses
  • molecular research
  • regulatory networks
  • molecular pathways
  • biomarkers
  • therapies

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Published Papers (6 papers)

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Research

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25 pages, 3575 KiB  
Article
Assessment of Brain Morphological Abnormalities and Neurodevelopmental Risk Copy Number Variants in Individuals from the UK Biobank
by Sara Azidane, Sandra Eizaguerri, Xavier Gallego, Lynn Durham, Emre Guney and Laura Pérez-Cano
Int. J. Mol. Sci. 2025, 26(15), 7062; https://doi.org/10.3390/ijms26157062 - 22 Jul 2025
Abstract
Brain morphological abnormalities are common in patients with neurodevelopmental disorders (NDDs) and other neuropsychiatric disorders, often reflecting abnormal brain development and function. Genetic studies have found common genetic factors in NDDs and other neuropsychiatric disorders, although the etiology of brain structural changes in [...] Read more.
Brain morphological abnormalities are common in patients with neurodevelopmental disorders (NDDs) and other neuropsychiatric disorders, often reflecting abnormal brain development and function. Genetic studies have found common genetic factors in NDDs and other neuropsychiatric disorders, although the etiology of brain structural changes in these disorders remains poorly understood. In this study, we analyzed magnetic resonance imaging (MRI) and genetic data from more than 30K individuals from the UK Biobank to evaluate whether NDD-risk copy number variants (CNVs) are also associated with neuroanatomical changes in both patients and neurotypical individuals. We found that the size differences in brain regions such as corpus callosum and cerebellum were associated with the deletions of specific areas of the human genome, and that specific neuroanatomical changes confer a risk of neuropsychiatric disorders. Furthermore, we observed that gene sets located in these genomic regions were enriched for pathways crucial for brain development and for phenotypes commonly observed in patients with NDDs. These findings highlight the link between CNVs, brain structure abnormalities, and the shared pathophysiology of NDDs and other neuropsychiatric disorders, providing new insights into the underlying mechanisms of these disorders and the identification of potential biomarkers for better diagnosis. Full article
(This article belongs to the Special Issue Molecular Investigations in Neurodevelopmental Disorders)
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13 pages, 1421 KiB  
Article
The Complex Etiology of Epilepsy: Genetic Analysis and HLA Association in Patients in the Middle East
by Abeer Fadda, Mohamed Alsabbagh, Dhanya Vasudeva, Amira Saeed, Sara Aglan Tarek, Satanay Z. Hubrack, Ruba Benini, Khaled Zamel and Bernice Lo
Int. J. Mol. Sci. 2025, 26(12), 5815; https://doi.org/10.3390/ijms26125815 - 17 Jun 2025
Viewed by 511
Abstract
Epilepsy is one of the most common neurological disorders. Disease etiology and pathogenesis are still not well understood. Genetic mutations are associated with 70% of epilepsies, while 30% are still enigmatic. Attempting to close the knowledge gap, we performed genetic analysis of a [...] Read more.
Epilepsy is one of the most common neurological disorders. Disease etiology and pathogenesis are still not well understood. Genetic mutations are associated with 70% of epilepsies, while 30% are still enigmatic. Attempting to close the knowledge gap, we performed genetic analysis of a cohort of patients from the Middle East and North Africa, both understudied and highly consanguineous populations. Whole exome sequencing (WES) was carried out on 81 patients and their family members at a tertiary center in Qatar. We found damaging mutations in half of the patients: 15 in known epilepsy genes, and 19 in contested or unknown genes. The mutations include single nucleotide polymorphisms (SNVs), frameshifts, copy number variations (CNVs), and loss of homozygosity (LOH). Fifteen of the SNVs are novel, and seventeen are homozygous, reflective of the characteristics of the cohort. In addition, we used the WES data to type HLA alleles for 13 class I and II genes. We show that DRB3*01:01:02G is negatively associated with epilepsy, in contrast to DRB4*01:01:01G, which may be a risk allele. In addition to expanding the knowledge base of genes involved in epilepsy, our findings show that genetic predisposition, inclusive of immune genes, suggests a complex etiology. Full article
(This article belongs to the Special Issue Molecular Investigations in Neurodevelopmental Disorders)
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15 pages, 4185 KiB  
Article
Sex-Specific Behavioral and Molecular Responses to Maternal Lipopolysaccharide-Induced Immune Activation in a Murine Model: Implications for Neurodevelopmental Disorders
by Jing Xu, Rujuan Zhao, Mingyang Yan, Meng Zhou, Huanhuan Liu, Xueying Wang, Chang Lu, Qiang Li, Yan Mo, Paihao Zhang, Xingda Ju and Xianlu Zeng
Int. J. Mol. Sci. 2024, 25(18), 9885; https://doi.org/10.3390/ijms25189885 - 13 Sep 2024
Cited by 1 | Viewed by 1788
Abstract
Maternal immune activation (MIA) during pregnancy has been increasingly recognized as a critical factor in the development of neurodevelopmental disorders, with potential sex-specific impacts that are not yet fully understood. In this study, we utilized a murine model to explore the behavioral and [...] Read more.
Maternal immune activation (MIA) during pregnancy has been increasingly recognized as a critical factor in the development of neurodevelopmental disorders, with potential sex-specific impacts that are not yet fully understood. In this study, we utilized a murine model to explore the behavioral and molecular consequences of MIA induced by lipopolysaccharide (LPS) administration on embryonic day 12.5. Our findings indicate that male offspring exposed to LPS exhibited significant increases in anxiety-like and depression-like behaviors, while female offspring did not show comparable changes. Molecular analyses revealed alterations in pro-inflammatory cytokine levels and synaptic gene expression in male offspring, suggesting that these molecular disruptions may underlie the observed behavioral differences. These results emphasize the importance of considering sex as a biological variable in studies of neurodevelopmental disorders and highlight the need for further molecular investigations to understand the mechanisms driving these sex-specific outcomes. Our study contributes to the growing evidence that prenatal immune challenges play a pivotal role in the etiology of neurodevelopmental disorders and underscores the potential for sex-specific preventative approaches of MIA. Full article
(This article belongs to the Special Issue Molecular Investigations in Neurodevelopmental Disorders)
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Review

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21 pages, 1985 KiB  
Review
Neuroplasticity-Based Approaches to Sensory Processing Alterations in Autism Spectrum Disorder
by Maria Suprunowicz, Julia Bogucka, Natalia Szczerbińska, Stefan Modzelewski, Aleksandra Julia Oracz, Beata Konarzewska and Napoleon Waszkiewicz
Int. J. Mol. Sci. 2025, 26(15), 7102; https://doi.org/10.3390/ijms26157102 - 23 Jul 2025
Abstract
Sensory dysregulation represents a core challenge in autism spectrum disorder (ASD), affecting perception, behavior, and adaptive functioning. The brain’s ability to reorganize, known as neuroplasticity, serves as the basic principle for therapeutic interventions targeting these deficits. Neuroanatomical mechanisms include altered connectivity in the [...] Read more.
Sensory dysregulation represents a core challenge in autism spectrum disorder (ASD), affecting perception, behavior, and adaptive functioning. The brain’s ability to reorganize, known as neuroplasticity, serves as the basic principle for therapeutic interventions targeting these deficits. Neuroanatomical mechanisms include altered connectivity in the sensory and visual cortices, as well as in the limbic system and amygdala, while imbalances of neurotransmitters, in particular glutamate and gamma-aminobutyric acid (GABA), contribute to atypical sensory processing. Traditional therapies used in sensory integration are based on the principles of neuroplasticity. Increasingly, new treatments use this knowledge, and modern therapies such as neurofeedback, transcranial stimulation, and immersive virtual environments are promising in modulating neuronal circuits. However, further research is needed to optimize interventions and confirm long-term effectiveness. This review discusses the role of neuroplasticity in the etiopathogenesis of sensory integration deficits in autism spectrum disorder. The neuroanatomical and neurotransmitter basis of impaired perception of sensory stimuli is considered, and traditional and recent therapies for sensory integration are discussed. Full article
(This article belongs to the Special Issue Molecular Investigations in Neurodevelopmental Disorders)

Other

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10 pages, 1282 KiB  
Case Report
Biallelic Loss-of-Function Variant in MINPP1 Causes Pontocerebellar Hypoplasia with Characteristic Severe Neurodevelopmental Disorder
by Aljazi Al-Maraghi, Rulan Shaath, Katherine Ford, Waleed Aamer, Jehan AlRayahi, Sura Hussein, Elbay Aliyev, Nourhen Agrebi, Muhammad Kohailan, Satanay Z. Hubrack, Sasirekha Palaniswamy, Adam D. Kennedy, Karen L. DeBalsi, Sarah H. Elsea, Ruba Benini, Tawfeg Ben-Omran, Bernice Lo, Ammira S. A. Akil and Khalid A. Fakhro
Int. J. Mol. Sci. 2025, 26(11), 5213; https://doi.org/10.3390/ijms26115213 - 29 May 2025
Viewed by 534
Abstract
Pontocerebellar hypoplasia (PCH) encompasses a group of autosomal recessive neurodegenerative disorders marked by cerebellar and pontine atrophy. Multiple subtypes of PCH have been identified, among which the rare subtype PCH type 16 is caused by MINPP1 genetic variants. MINPPI encodes an enzyme essential [...] Read more.
Pontocerebellar hypoplasia (PCH) encompasses a group of autosomal recessive neurodegenerative disorders marked by cerebellar and pontine atrophy. Multiple subtypes of PCH have been identified, among which the rare subtype PCH type 16 is caused by MINPP1 genetic variants. MINPPI encodes an enzyme essential for inositol polyphosphate dephosphorylation, regulating calcium and iron homeostasis. We conducted genome sequencing on a proband from the consanguineous family, who presented with a severe neurodegenerative disorder, to identify the underlying cause of disease. A comprehensive clinical assessment in addition to neuroradiological findings are described. We performed the functional validation of the identified variant and conducted untargeted metabolomic analyses. The clinical and radiological assessment of the patient showed a congenital brain anomaly and neurodegenerative symptoms. Further genetic analysis identified a homozygous loss-of-function variant (c.1401del, p.Ser468Valfs10*) in MINPP1, providing molecular confirmation of a clinical PCH diagnosis. While real-time quantitative PCR (RT-qPCR) showed that MINPP1 gene expression was unaffected in the proband, Western blot analysis demonstrated reduced protein abundance, supporting a pathogenic role of the variant. Metabolomic profiling revealed elevated lipid levels and disrupted inositol metabolism, providing further insights into the disease mechanism. These findings establish the pathogenicity of the p.Ser468Valfs10* variant in MINPP1 and highlight inositol metabolism as a potential pathway involved in PCH16, advancing the understanding of the pathophysiology of the disease. Full article
(This article belongs to the Special Issue Molecular Investigations in Neurodevelopmental Disorders)
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15 pages, 2213 KiB  
Case Report
Novel SCYL2 Mutations and Arthrogryposis Multiplex Congenita 4: Case Report and Review of the Literature
by Khaled Zamel, Abdulrahman Ahmed Al-Subaiey, Mohamed Alsabbagh, Abeer Fadda, Amira Saeed, Bruno Mourao Pacheco, Bernice Lo and Ruba Benini
Int. J. Mol. Sci. 2025, 26(7), 3079; https://doi.org/10.3390/ijms26073079 - 27 Mar 2025
Cited by 1 | Viewed by 647
Abstract
SCY1 Like Pseudokinase 2 (SCYL2) is a protein that regulates secretory protein trafficking and plays a pivotal role in neurodevelopment by attenuating excitotoxicity. Neurogenic arthrogryposis due to SCYL2 mutations, also known as arthrogryposis multiplex congenita 4 (AMC4), is a rare condition that presents [...] Read more.
SCY1 Like Pseudokinase 2 (SCYL2) is a protein that regulates secretory protein trafficking and plays a pivotal role in neurodevelopment by attenuating excitotoxicity. Neurogenic arthrogryposis due to SCYL2 mutations, also known as arthrogryposis multiplex congenita 4 (AMC4), is a rare condition that presents with microcephaly, agenesis of the corpus callosum, optic atrophy, global developmental delay, and early lethality. We used whole-exome sequencing to identify pathogenic variants, DynaMut2 to determine the predicted effect on protein stability, and Western blot to investigate the effect on protein expression. We present two novel missense mutations in SCYL2 resulting in loss of function at the protein level in a pediatric case of AMC4, further highlighting the key role of SCYL2 in neuronal cell survival and healthy brain development. There is diversity in the pathological features among previously published cases of AMC4, most likely due to the nature of each mutation. This report summarizes the clinical data of all known patients with SCYL2 mutations. Full article
(This article belongs to the Special Issue Molecular Investigations in Neurodevelopmental Disorders)
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