Asta Literature Retrieval: Pathophysiology and clinical mechanisms of BLOC1S1-related complex neurodevelopmental disorder with leukodystrophy. C...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 19
• Snippets retrieved: 20

Relevant Papers

[1] The Role of Alpha-Synuclein and Other Parkinson’s Genes in Neurodevelopmental and Neurodegenerative Disorders

• Authors: C. Torres, Z. Wassouf, Z. Wassouf, Faria Zafar, D. Sastre et al.
• Year: 2020
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/aedea7861a666c1aa7570fc071cccc377ad33d96
• DOI: 10.3390/ijms21165724
• PMID: 32785033
• PMCID: 7460874
• Citations: 56
• Influential citations: 1
• Summary: Clinico-genetic studies of causal variants and overlapping clinical and cellular features of ASD and PD are focused on to re-conceptualize how these disorders are understood and provide a new angle into disease targets and mechanisms linking neurodevelopmental disorders and neurodegeneration.
• Evidence snippets:
• Snippet 1 (score: 0.542) > Neurodevelopmental and late-onset neurodegenerative disorders present as separate entities that are clinically and neuropathologically quite distinct. However, recent evidence has highlighted surprising commonalities and converging features at the clinical, genomic, and molecular level between these two disease spectra. This is particularly striking in the context of autism spectrum disorder (ASD) and Parkinson’s disease (PD). Genetic causes and risk factors play a central role in disease pathophysiology and enable the identification of overlapping mechanisms and pathways. Here, we focus on clinico-genetic studies of causal variants and overlapping clinical and cellular features of ASD and PD. Several genes and genomic regions were selected for our review, including SNCA (alpha-synuclein), PARK2 (parkin RBR E3 ubiquitin protein ligase), chromosome 22q11 deletion/DiGeorge region, and FMR1 (fragile X mental retardation 1) repeat expansion, which influence the development of both ASD and PD, with converging features related to synaptic function and neurogenesis. Both PD and ASD display alterations and impairments at the synaptic level, representing early and key disease phenotypes, which support the hypothesis of converging mechanisms between the two types of diseases. Therefore, understanding the underlying molecular mechanisms might inform on common targets and therapeutic approaches. We propose to re-conceptualize how we understand these disorders and provide a new angle into disease targets and mechanisms linking neurodevelopmental disorders and neurodegeneration.

[2] Gene therapy for the leukodystrophies: From preclinical animal studies to clinical trials

• Authors: J. Metovic, Yedda Li, Yi Gong, Florian S. Eichler
• Year: 2024
• Venue: Neurotherapeutics
• URL: https://www.semanticscholar.org/paper/e55a15b0ccdbd7c57a7518ec748e36720e8b59e9
• DOI: 10.1016/j.neurot.2024.e00443
• PMID: 39276676
• PMCID: 11418141
• Citations: 10
• Summary: The data presented in this review show that gene therapy, while promising, requires systematic monitoring to account for the precarious disease biology and the adverse events associated with new technology.
• Evidence snippets:
• Snippet 1 (score: 0.533) > Leukodystrophies are heritable, progressive disorders that predominantly affect the white matter of the central nervous system (CNS). As a group, the overall incidence is one in approximately 7600 live births [1]. All leukodystrophies affect myelin, the insulation around nerves that enables rapid communication between neurons. Pathologic processes destroy existing myelin (demyelination), trigger abnormal myelin deposition (dysmyelination), or prevent myelin deposition (hypomyelination) in the CNS and/or peripheral nervous system (PNS) during development [2]. Currently, more than 50 disorders are classified as leukodystrophies, and this number continues to grow. Mortality is 34% with an average age at death of 8.2 years [1]. While clinical manifestations can be highly variable even for patients with the same leukodystrophy, disease severity is often inversely correlated with age at disease onset. The most severe forms present in infancy with rapid progression to neurologic devastation and death. > Treatment approaches vary based on pathogenesis, but most fall into one of four categories: 1) enzyme replacement therapies replace the missing or defective enzyme; 2) substrate reduction therapies reduce the buildup of the (often toxic) compound that cannot be adequately metabolized; 3) cell therapies replace diseased cells with healthy allogeneic cells or corrected autologous cells; 4) gene therapies functionally replace the missing or defective gene. In this review, we focus on gene therapies that have reached clinical trials as we aim to understand studies needed to enable leukodystrophy trial readiness. Prior leukodystrophy reviews focus on cellular mechanisms [3] and available clinical trials [4]. Here, we present an updated and comprehensive review of all gene therapy clinical trials for leukodystrophy patients in the context of disease-specific pathophysiology and preclinical studies.
• Snippet 2 (score: 0.477) > The definition of leukodystrophies has evolved significantly with advances in next generation sequencing, magnetic resonance imaging (MRI), and molecular biology techniques that together have informed a more nuanced understanding of pathophysiology [3,5,6]. In 2017, van der Knaap and Bugiani [2] proposed a new classification system that grouped leukodystrophies into five categories related to pathologic changes and pathogenic mechanisms (Fig. 1, Table 1). Myelinopathies arise from defects in oligodendrocytes or myelin structure. They are further subcategorized as disorders of hypomyelination, demyelination, and myelin vacuolization which disrupts myelin integrity. Leuko-axonopathies stem from defects in neurons and their axonal processes. Astrocytopathies and microgliopathies disrupt neuroinflammation and CNS repair. Leuko-vasculopathies develop from pathologic processes within the small blood vessels of the brain [2]. Some pathologically relevant CNS cell types, such as microglia, can derive from hematopoietic stem cell precursors with important implications for therapeutic development. > Pathogenic mutations in leukodystrophy genes affect integral cellular functions involved in recycling (peroxisomal and lysosomal metabolism), energy production (mitochondrial electron transport), structural integrity (of myelin, cytoskeleton, extracellular matrix, blood brain barrier (BBB), etc.), and protein synthesis (messenger ribonucleic acid (mRNA) transcription and translation), among others. Understanding these pathogenic mechanisms (Fig. 2) is critical in designing successful gene therapies.

[3] The neurovascular unit in leukodystrophies: towards solving the puzzle

• Authors: Parand Zarekiani, H. Nogueira Pinto, E. Hol, M. Bugiani, H. D. de Vries
• Year: 2022
• Venue: Fluids and Barriers of the CNS
• URL: https://www.semanticscholar.org/paper/73916d3407fc52aa787155c18f02f8c5f521211d
• DOI: 10.1186/s12987-022-00316-0
• PMID: 35227276
• PMCID: 8887016
• Citations: 8
• Summary: This review aims to provide further insights into the NVU functioning in leukodystrophies, with a special focus on iPSC-derived models that can be used to dissect neurovascular pathophysiology in these diseases.
• Evidence snippets:
• Snippet 1 (score: 0.521) > hies are characterized by primarily affected WM regardless of the molecular processes involved and the disease course [41]. Before this new definition, leukodystrophies were seen as progressive WM disorders caused by a genetic defect, where myelin was the primary affected structure. The myelin defect observed was either a direct effect on myelin or indirect on oligodendrocytes, the myelin forming cells [42]. Later, magnetic resonance imaging (MRI) pattern recognition paved the way for stratifying patients and subsequent genetic explorations [43]. In the following decades, sequencing techniques also evolved, pathological data became more available and new disease models emerged. These scientific developments have given an enormous boost to the field of leukodystrophies. Usually, the clinical course of leukodystrophies is progressive, and often eventually fatal. So far only symptomatic treatments are available. Therefore, unravelling the underlying mechanisms of these diseases is a priority. As mentioned, the WM comprises different cell types that create a complex network of signalling in synergy, yet each leukodystrophy is caused by a different genetic deficit that results in a distinct WM pathology. Notably, the genetic deficits underlying these diseases are not restricted to myelin-or oligodendrocyte-specific genes. Recent next-generation sequencing studies combined with MRI pattern recognition have shown that a predominant dysfunction of cell types other than oligodendrocytes may drive the WM pathology in leukodystrophies. To distinguish the underlying mechanisms, it is essential to identify distinct pathological hallmarks and the specific cell types affected in this heterogeneous group of diseases. Therefore, a new classification system for leukodystrophies has recently been proposed based on cellular pathology and pathogenic mechanisms [44]. > Strikingly, some cellular components that are primarily affected, such as astrocytes, are part of the NVU. The function of the NVU, however, has been overlooked in these diseases. The problem in the diagnosis of leukodystrophies is that MRI with contrast agents is not always common practice in the clinic. Additionally, leakage of contrast agents in MR imaging only highlights gross abnormalities of the BBB. Especially when looking at heterogeneous diseases, such as

[4] Uncovering True Cellular Phenotypes: Using Induced Pluripotent Stem Cell-Derived Neurons to Study Early Insults in Neurodevelopmental Disorders

• Authors: James J. Fink, E. Levine
• Year: 2018
• Venue: Frontiers in Neurology
• URL: https://www.semanticscholar.org/paper/25fb8e8d9f748ef2664990bbdf42e80cf103c000
• DOI: 10.3389/fneur.2018.00237
• PMID: 29713304
• PMCID: 5911479
• Citations: 23
• Summary: Electrophysiological analysis at the earliest stages of neuronal development is critical for identifying changes in activity and excitability that can contribute to synaptic dysfunction and identify targets for disease-modifying therapies.
• Evidence snippets:
• Snippet 1 (score: 0.516) > Animal models of neurodevelopmental disorders have provided invaluable insights into the molecular-, cellular-, and circuit-level defects associated with a plethora of genetic disruptions. In many cases, these deficits have been linked to changes in disease-relevant behaviors, but very few of these findings have been translated to treatments for human disease. This may be due to significant species differences and the difficulty in modeling disorders that involve deletion or duplication of multiple genes. The identification of primary underlying pathophysiology in these models is confounded by the accumulation of secondary disease phenotypes in the mature nervous system, as well as potential compensatory mechanisms. The discovery of induced pluripotent stem cell technology now provides a tool to accurately model complex genetic neurogenetic disorders. Using this technique, patient-specific cell lines can be generated and differentiated into specific subtypes of neurons that can be used to identify primary cellular and molecular phenotypes. It is clear that impairments in synaptic structure and function are a common pathophysiology across neurodevelopmental disorders, and electrophysiological analysis at the earliest stages of neuronal development is critical for identifying changes in activity and excitability that can contribute to synaptic dysfunction and identify targets for disease-modifying therapies.

[5] Insights Into Cockayne Syndrome Type B: What Underlies Its Pathogenesis?

• Authors: Ricardo Afonso-Reis, Cristiana R Madeira, D. Brito, C. Nóbrega
• Year: 2025
• Venue: Aging Cell
• URL: https://www.semanticscholar.org/paper/1b86ba09359d5e2f0ff083dd037d872b4faec812
• DOI: 10.1111/acel.70136
• PMID: 40536083
• PMCID: 12266758
• Citations: 3
• Summary: It is proposed that CS‐B pathogenesis arises from a combination of DNA damage accumulation, transcriptional dysregulation, and mitochondrial dysfunction, and it is argued that these molecular features influence each other, rather than acting as isolated mechanisms.
• Evidence snippets:
• Snippet 1 (score: 0.498) > This interplay has the potential to exacerbate dysfunction of affected features or induce dysfunction of an otherwise functional feature. Furthermore, in a therapeutic standpoint, exploring CS-B pathogenesis and potential synergies between pathological mechanism is essential to determine effective therapeutic targets. In line with this, here we propose some interactions that may improve the understanding of the complexity underlying CS-B pathophysiology. In the future, the interplay between CS-B-affected mechanisms should be assessed. This may be done by inducing the impairment of individual mechanisms and evaluating the function of other potentially related cellular processes. > Given that CS-B presumably arises from a combination of interconnected mechanisms, a therapeutic approach targeting a singular pathological mechanism will be constrained within the broader context of the disorder. Additionally, CS-B is an autosomal recessive disorder resulting from monogenic mutations in ERCC6. These characteristics of CS-B render ERCC6 supplementation a straightforward gene therapy approach that would address the underlying cause of this complex disorder and theoretically mitigate all associated disease mechanisms. > The lack of reliable biomarkers for CS-B, make it challenging to assess CS-B at a molecular level. Recent efforts have revealed several potential CS biomarkers that will facilitate more precise tracking of disease progression and evaluate the impact of potential therapies at a molecular level. Hyperactivation of NDN has been associated with neuropathological features of CS-B, especially for neurodevelopmental defects (Liang et al. 2023). In contrast, the downregulation of ATF-3 responsive gene following genotoxic stress serves as also been proposed to serve biomarker for CS specific phenotype (Epanchintsev et al. 2017). Interestingly, the CS-specific epigenetic signature may be used to assess the accelerated aging phenotype of CS-cells (Crochemore et al. 2019). > Relevant advances have been made in the field, however some crucial question that will prove foundational for the mechanisms behind CS-B to remain to be unveiled.

[6] Chromatin modifiers in neurodevelopment

• Authors: Sarallah Rezazadeh, H. Ji, Cecilia Giulivi
• Year: 2025
• Venue: Frontiers in Molecular Neuroscience
• URL: https://www.semanticscholar.org/paper/7a4d8c063c2b3a908a65bcb637cd818edad8db92
• DOI: 10.3389/fnmol.2025.1551107
• PMID: 40469903
• PMCID: 12133960
• Citations: 2
• Summary: This mini review delves into key chromatin modifiers, including the histone methyl transferases NSD1 and ASH1L, the methyl-CpG-binding repressor MeCP2, and the enzymatic repressor EZH2, and spotlight their pivotal roles in early brain development and neurological disorders.
• Evidence snippets:
• Snippet 1 (score: 0.497) > Therefore, while epigenetic changes are essential for understanding specific aspects of neurodevelopmental disorders, it is crucial to view these mechanisms as part of a larger, more complex system that encompasses genetic, proteomic, and metabolic factors. Few examples underscore that while epigenetic mechanisms-such as DNA methylation and histone modificationsare essential in regulating gene expression and contribute to neurodevelopmental disorders, they do not fully explain the complex pathophysiology of these diseases. In many cases, the genetic mutations, absence of or dysfunction of protein, or toxic protein aggregation (e.g., Fragile X syndrome, HD) that occur in these disorders play a central role in the clinical phenotypes. Therefore, a comprehensive understanding of neurodevelopmental disorders must integrate epigenetic mechanisms and the broader genetic, proteomic, and cellular pathways that contribute to disease. An integrative approach that considers not only the regulation of gene expression but also the functional consequences of these changes at the protein, metabolic and cellular pathway levels will be essential for advancing our understanding of these intricate disorders and developing effective interventions and treatments. . B., Villate, O., Llano, I., Ocio, I., Martí, I., et al. (2020). Targeted next-generation sequencing in patients with suggestive X-linked intellectual disability. Genes 11:51. doi: 10.3390/genes11010051

[7] HiPSC-derived 3D neural models reveal neurodevelopmental pathomechanisms of the Cockayne Syndrome B

• Authors: J. Kapr, I. Scharkin, Haribaskar Ramachandran, Philipp Westhoff, M. Pollet et al.
• Year: 2024
• Venue: Cellular and Molecular Life Sciences: CMLS
• URL: https://www.semanticscholar.org/paper/2529c1071851fe7dff72513bcee090354dd893fe
• DOI: 10.1007/s00018-024-05406-w
• PMID: 39179905
• PMCID: 11343962
• Citations: 9
• Summary: Using human induced pluripotent stem cell (hiPSC)-derived neural 3D models generated from CSB patient-derived and isogenic control lines, explanations for CSB deficiency are provided and the impaired migration and oligodendrocyte maturation could both be partially rescued by pharmacological HDAC inhibition.
• Evidence snippets:
• Snippet 1 (score: 0.495) > Mimicking human disease and identifying treatments with animal models often undermines expectations. Especially for diseases involving the brain, translation from animals to humans is challenging. Species differences in brain physiology and kinetic properties are key here, with high dropout rates in drug development pointing to this [54]. Drugs developed for CNS diseases display the second highest attrition rates right after cancer drugs with causes of drug failure allocating to lack of efficacy and second most frequently to toxicity [55]. As an example, drug development for treating Alzheimer's disease alone produced over 99% failure rates [56]. Similarly, treatments for neurodevelopmental disorders like autism spectrum disorders [57] are sparse. This is mainly due to the lack of pathophysiological understanding of the disease and a consecutive lack of known drug targets. In this study we aim at setting an example for unraveling molecular and cellular causes of a severe neurodevelopmental disease, the Cockayne Syndrome B (CSB), using 3D neural models like hiPSC-derived neurospheres and Brain-Spheres. We identified in vitro phenotypes that we relate to the children's pathophysiology and based on that propose novel treatment strategies for this devastating disease. > CSB is a heterogeneous hereditary disease with a spectrum of clinical phenotypes highly depending on the associated mutant genotype. However, common pathophysiological brain features of CSB patients include microcephaly, intellectual disability and demyelination [1,2,7,14]. In this work, we provide for the first time mechanistic explanations for the cardinal brain phenotypes observed in CSB patients. We here use two 3D hiPSC-derived neural CSB models and their isogenic controls, a CSB patient-derived line and a genome-edited healthy donor hiPSC line carrying a truncating CSB mutation, both of which result in CSB protein deficiency. Specifically, our results suggest that CSB deficiency inhibits migration through defective autophagy, which is consistent with the clinical microcephaly observed in CSB patients.

[8] Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders

• Authors: R. Kaiyrzhanov, Aboulfazl Rad, Sheng-Jia Lin, A. Bertoli-Avella, Wouter W. Kallemeijn et al.
• Year: 2023
• Venue: Brain
• URL: https://www.semanticscholar.org/paper/1ecbe69033fec410707a0ce9122e14afdd2108f9
• DOI: 10.1093/brain/awad380
• PMID: 37951597
• PMCID: 10994533
• Citations: 15
• Summary: Evidence is provided that bi-allelic pathogenic variants in ACBD6 lead to a distinct neurodevelopmental syndrome accompanied by complex and progressive cognitive and movement disorders and altered peroxisomal parameters in patient fibroblasts.
• Evidence snippets:
• Snippet 1 (score: 0.490) > 8][39][40] Thus, several forms of complicated hereditary spastic paraplegia, spastic ataxia, and young-onset dystonia-parkinsonism syndromes may overlap with ACBD6 phenotypes. A suggested differential diagnosis with the disease pathways involved is given in Supplementary Table 7. > It has been suggested that neurodevelopmental abnormalities and neurodegeneration could share several molecular and cellular mechanisms. For instance, proteins, such as Aβ, MAPT/ tau, Rac1, progranulin, huntingtin, PINK and parkin, frequently implicated in Alzheimer's disease, Parkinson's disease and Huntington's diseases are important for nervous system development. 41 A wide range of multisystem genetic disorders could present with a biphasic course where a complex neurological phenotype gradually evolves on the background of a pre-existing neurodevelopmental disorder. 42,43 Therefore, we propose a likely clinical continuum associated with ACBD6-related disease, characterized by a combination of neurodevelopmental abnormalities and neurodegeneration.

[9] Towards a Treatment for Leukodystrophy Using Cell-Based Interception and Precision Medicine

• Authors: B. Coulombe, Alexandra Chapleau, J. Macintosh, T. Durcan, Christian Poitras et al.
• Year: 2024
• Venue: Biomolecules
• URL: https://www.semanticscholar.org/paper/3b5baaf7cd1b2db3d00377fb8cc8a091540962a6
• DOI: 10.3390/biom14070857
• PMID: 39062571
• PMCID: 11274857
• Summary: Recent progress is described towards developing cell-based interception and precision medicine to detect, understand, and advance the development of novel therapeutic approaches through a single-cell omics and drug screening platform, as part of a multi-laboratory collaborative effort, for a group of neurodegenerative disorders named leukodystrophies.
• Evidence snippets:
• Snippet 1 (score: 0.488) > Once affected cells are detected, disease mechanisms can be elucidated using experimental cell models and predictive computational cell trajectory modeling [7]. This approach can identify proteins (including posttranslational modifications, PTMs), protein complexes, and intra-or extra-cellular networks that participate in the disease process and provides the necessary knowledge for the development of disease-modifying therapies. This procedure can be briefly summarized into four steps: detection, understanding, therapy development, and lastly, the implementation of collaborative work to form a multidisciplinary team of experts (Figure 1). As a prototype of step 4, we have initiated the development of a procedure applied to hypomyelinating leukodystrophies. Leukodystrophies are a group of hereditary white matter disorders that predominantly affect children, causing a gradual decline in abilities and often resulting in early mortality within months to years after onset [8]. These conditions selectively affect the brain's white matter, which serves as the protective covering for nerve cells within the brain and spinal cord. Ultimately, this results in abnormalities in myelin formation (classified as hypomyelinating) or disruptions in myelin maintenance (non-hypomyelinating) which compromises the proper functioning of the central nervous system (CNS) leading to neurodegeneration and ensuing sequalae [9][10][11]. To date, there are over 50 different well-defined leukodystrophies with diverse clinical and genetic characteristics and varied Mendelian inheritance patterns. A myriad of genes involved in disparate cellular processes are known to cause leukodystrophies, including those involved in brain development and functioning, metabolism, and housekeeping functions to name a few. Most leukodystrophies remain without a cure or disease-modifying therapy, and interventions are primarily focused on symptomatic treatment [12,13]. Here, we examine the benefits of cell-based interception and precision medicine procedures to hypomyelinating leukodystrophies, with a focus on RNA polymerase III-related leukodystrophy.

[10] Neuroimaging Findings in Neurodevelopmental Copy Number Variants: Identifying Molecular Pathways to Convergent Phenotypes.

• Authors: Ana I. Silva, F. Ehrhart, M. Ulfarsson, H. Stefánsson, K. Stefánsson et al.
• Year: 2022
• Venue: Biological psychiatry
• URL: https://www.semanticscholar.org/paper/c856263af3dabb593698bdd11a313648b05a16c5
• DOI: 10.1016/j.biopsych.2022.03.018
• PMID: 35659384
• Citations: 14
• Influential citations: 1
• Summary: New approaches that integrate human molecular data with neuroimaging, cognitive, and animal model data, while taking into account critical developmental time points are needed to better understand the link between key molecular mechanisms and convergent psychiatric phenotypes.
• Evidence snippets:
• Snippet 1 (score: 0.484) > ISSN: 0006-3223 Biological Psychiatry September 1, 2022; 92:341-361 www.sobp.org/journal molecular pathways have been identified across genetic risk variants and across neurodevelopmental disorders. In recent years, magnetic resonance imaging (MRI) studies on CNV cohorts have led to important discoveries on genetic drivers of altered brain structure and function. However, identifying convergent brain effects and linking cellular mechanisms to these changes has proved more challenging. With growing initiatives of data-sharing and large-scale collaborations across research groups, exciting opportunities are emerging to combine multidimensional data from neuroimaging, cognitive, and bioinformatics studies to identify key pathogenic mechanisms in the path from genome to clinical phenotypes. > In this narrative review, we provide an overview of biological findings on CNVs and neurodevelopmental disorders, placing a special focus on both convergent and locus-specific brain abnormalities across CNVs from human and animal studies. We further discuss the need to develop integrated approaches combining multiomics databases (e.g., transcriptomics, proteomics, and metabolomics) with neuroimaging and clinical data to identify relevant disease mechanisms that can be targeted using novel therapies.

[11] Drug repurposing in Rett and Rett-like syndromes: a promising yet underrated opportunity?

• Authors: Claudia Fuchs, P. A. ‛. ’t Hoen, A. Müller, Friederike Ehrhart, C. V. van Karnebeek
• Year: 2024
• Venue: Frontiers in Medicine
• URL: https://www.semanticscholar.org/paper/b00d0859458647edeebf3cf53f9b39c79311d5ed
• DOI: 10.3389/fmed.2024.1425038
• PMID: 39135718
• PMCID: 11317438
• Citations: 1
• Summary: The potential of drug repurposing (DR) as a promising avenue for addressing the unmet medical needs of individuals with RTT and related disorders is explored and Leveraging existing drugs for new therapeutic purposes presents an attractive strategy.
• Evidence snippets:
• Snippet 1 (score: 0.483) > Rett syndrome (RTT, #312750) and Rett-like syndromes, e.g., CDKL5 deficiency disorder (CDD, #300672) and FOXG1-syndrome (or FOXG1-related encephalopathy, #613454) are rare monogenic neurodevelopmental disorders (NDDs). The relative recent recognition of their distinct clinical entities (1,2) has deepened our understanding of their underlying pathogenic mechanisms and clinical characteristics (Table 1). Although each disorder exhibits unique clinical features, they share common core symptoms and neurological traits (Table 1), suggesting that these disorders share critical molecular etiology. > Identifying shared pathways holds significant implications for targeted therapies development and drug repurposing (DR). DR, which involves using existing drugs for new therapeutic purposes, represents a promising approach in the treatment across multiple diseases especially for neurological disorders (3,4). The complex structure of the central nervous system (CNS), coupled with the challenge of penetrating the blood-brain barrier, poses significant hurdles in the development of new drugs for neuropathological conditions, making DR of particular interest for these disorders. Notable successes of DR in NDDs include e.g., repurposing of fenfluramine in Dravet syndrome (5) or bumetanide (6) and pregnenolone (7) for autism spectrum disorders. These studies validate DR as a valid treatment approach for multiple neuropathological conditions. > We here discuss the current state of art of DR efforts in RTT, CDD and FOXG1-syndrome, with particular emphasis on the shared molecular pathways and the identification of common drug targets across the three conditions. For a more detailed overview on the molecular and circuit mechanisms underlying each syndrome, please refer to (8)(9)(10) for RTT, (11,12) for CDD and (2, 13) for FOXG1-syndrome (2,13).

[12] Neuronal Autophagy and Neurodevelopmental Disorders

• Authors: Kyung-Min Lee, S. Hwang, Jin-A Lee
• Year: 2013
• Venue: Experimental Neurobiology
• URL: https://www.semanticscholar.org/paper/1a459280c89432689a58adcb5fb481781343b4de
• DOI: 10.5607/en.2013.22.3.133
• PMID: 24167408
• PMCID: 3807000
• Citations: 98
• Influential citations: 4
• Summary: The current understanding of neuronal autophagy as well as recent findings on genetics and the roles of autophagic pathway in common neurodevelopmental disorders are focused on.
• Evidence snippets:
• Snippet 1 (score: 0.483) > Neurodevelopmental disorders include a wide range of diseases such as autism spectrum disorders and mental retardation. Mutations in several genes that regulate neural development and synapse function have been identified in neurodevelopmental disorders. Interestingly, some affected genes and pathways in these diseases are associated with the autophagy pathway. Autophagy is a complex, bulky degradative process that involves the sequestration of cellular proteins, RNA, lipids, and cellular organelles into lysosomes. Despite recent progress in elucidating the genetics and molecular pathogenesis of these disorders, little is known about the pathogenic mechanisms and autophagy-related pathways involved in common neurodevelopmental disorders. Therefore, in this review, we focus on the current understanding of neuronal autophagy as well as recent findings on genetics and the roles of autophagy pathway in common neurodevelopmental disorders.

[13] Vesicular trafficking and cell-cell communication in neurodevelopment and neurodegeneration

• Authors: Salma Amin, Elena Taverna
• Year: 2025
• Venue: Frontiers in Cell and Developmental Biology
• URL: https://www.semanticscholar.org/paper/b8709087adfaa6cf6c66c6e27551cf4ad071c325
• DOI: 10.3389/fcell.2025.1600034
• PMID: 40552310
• PMCID: 12183288
• Citations: 7
• Summary: The role of intracellular and extracellular vesicles in cortical development and neurodegeneration is reviewed, and how trafficking between organelles in specific cell types contributes to brain pathologies is discussed.
• Evidence snippets:
• Snippet 1 (score: 0.479) > The study of vesicle trafficking and its related disorders presents a major challenge but also offers an opportunity to unlock new frontiers by bridging cell biology, biochemistry, metabolism, and genetic medicine. Given the wide variety of diseases and the complexity of the biological processes involved, many key questions remain unanswered. How are transport intermediates, such as synaptic vesicles, secretory vesicles, lysosomes, extracellular vesicles, and peroxisomes, organized at various cellular interfaces and in different cell types? Since most mutations associated with these diseases result in a loss of function, how will this impact and inform potential therapeutic strategies? The pivotal role of vesicle trafficking in the nervous system, alongside the unique vulnerability of neurons to trafficking defects, raises important questions. This is particularly true for neurodegenerative and neurodevelopmental diseases, where disruptions in vesicle trafficking affecting structures like synaptic vesicles or lysosomes have profound effects on brain development and function. > In this context, the identification of biomarkers to detect dysfunctions in these pathways could lead to earlier diagnosis and personalized treatments. Furthermore, patient-derived induced pluripotent stem cells (iPSCs) and organoid models offer valuable platforms for studying these mechanisms in a more physiologically relevant environment, providing powerful tools to deepen our understanding of these complex disorders. The increased understanding of basic cell biological mechanisms underlying neurodevelopmental disorders and neurodegenerative clinical phenotypes may translate into personalized clinical management and improved quality of life for patients and families. > 10.3389/fcell.2025.1600034 organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

[14] Clinical characteristics, molecular mechanisms, and exploration of association with gastrointestinal symptoms in CHAMP1 gene variation-related neurodevelopmental disorders

• Authors: Ziming Xu, Yan Xu, Xiaoyou Tao, Chen Chen, Guojuan Dong
• Year: 2025
• Venue: Frontiers in Neurology
• URL: https://www.semanticscholar.org/paper/6f0e393d50e15cc43082d7a8ac1e01d1f74dd118
• DOI: 10.3389/fneur.2025.1664776
• PMID: 41111978
• PMCID: 12527885
• Summary: This review aims to integrate the latest research progress on the molecular functions of the CHAMP1 gene, the pathogenic mechanisms of its variants, and the clinical phenotype spectrum of related neurodevelopmental disorders to provide valuable references for clinical diagnosis, management, and future research directions for this rare disease.
• Evidence snippets:
• Snippet 1 (score: 0.478) > The CHAMP1 (Chromosome Alignment-Maintaining Phosphoprotein 1) gene encodes a nuclear protein crucial for maintaining proper chromosome alignment and genomic stability during cell mitosis. Heterozygous variants of this gene, particularly de novo truncating mutations, are the primary cause of a rare neurodevelopmental disorder: autosomal dominant intellectual disability Autosomal Dominant Mental Retardation 40 (MRD40) or CHAMP1-related Neurodevelopmental Disorder (CHAND). The core clinical features of this disorder include moderate to severe global developmental delay, intellectual disability, significant language impairment, and distinctive facial features. Additionally, patients may exhibit abnormal muscle tone, behavioral issues (such as autism spectrum disorder traits and attention deficit hyperactivity disorder), epilepsy, microcephaly, and involvement of other multi-systemic complications, including gastrointestinal dysfunction. The pathogenic mechanisms of CHAMP1 truncating mutations remain debated, with main hypotheses including haploinsufficiency and dominant-negative effect or gain-of-function, where the latter better explains the more severe clinical phenotypes observed in some patients. Although neurological manifestations are the research focus of CHAMP1-related disorders, the involvement of other systems such as the digestive system—particularly symptoms like repeated vomiting—has been underreported and lacks systematic research within this disease spectrum. This review aims to integrate the latest research progress on the molecular functions of the CHAMP1 gene, the pathogenic mechanisms of its variants, and the clinical phenotype spectrum of related neurodevelopmental disorders. Based on clinical observations, we also preliminarily explored the potential association between CHAMP1 gene variation and gastrointestinal symptoms (especially recurrent vomiting), with the goal of providing valuable references for clinical diagnosis, management, and future research directions for this rare disease.

[15] The neurovascular unit in leukodystrophies: towards solving the puzzle

• Authors: Parand Zarekiani, H. Nogueira Pinto, Elly M. Hol, M. Bugiani, H. D. de Vries
• Year: 2022
• Venue: Fluids and Barriers of the CNS
• URL: https://www.semanticscholar.org/paper/221ee2c19d3083575da5ef42d55dc9a9b3156d12
• DOI: 10.1186/s12987-022-00316-0
• Citations: 1
• Summary: This review aims to provide further insights into the NVU functioning in leukodystrophies, with a special focus on iPSC-derived models that can be used to dissect neurovascular pathophysiology in these diseases.
• Evidence snippets:
• Snippet 1 (score: 0.478) > Leukodystrophies are classified into several categories depending on the main cellular mechanism of WM injury and other pathological mechanisms that contribute to the disease progression [44]. In this section, we describe the different leukodystrophy classes, and the key components driving the pathology, and we review the knowledge on how the NVU can contribute to disease. The common denominator in leukodystrophies is selectively affected WM, ranging from lack of myelin to complete WM atrophy. Clinically and pathologically, leukodystrophies are highly heterogeneous, therefore the main MRI characteristics, clinical phenotype, and pathological hallmarks are summarized in Table 1. > Hypomyelinating leukodystrophies are characterized by an impaired developmental myelination in the CNS and possibly also the peripheral nervous system (PNS). Leukodystrophies in this category are both clinically and genetically heterogeneous, yet show similarities [46]. The prototypical hypomyelinating leukodystrophy is Pelizaeus-Merzbacher disease (PMD). PMD is an X-linked disorder caused by changes in PLP1, encoding proteolipid protein 1 (PLP1) and the alternative spliced variant DM20 [47]. PLP1 and DM20 are solely expressed by oligodendrocytes in the CNS and Schwann cells in the PNS and are crucial components of the myelin sheath [48]. Therefore, a disruption in PLP1/DM20 has detrimental effects on the structure and functioning of myelin. Depending on the type of PLP1 mutation, histopathology varies, yet some features overlap. There is a significant decrease in the number of mature oligodendrocytes, resulting in a lack of myelin. Altered levels of PLP1 in PMD induce the activation of the unfolded protein response (UPR), which causes apoptosis of oligodendrocytes and neurons [49][50][51]. The UPR in oligodendrocytes, however, may not be the only neurodegenerative mechanism underlying PMD.

[16] Role of Ash1l in Tourette syndrome and other neurodevelopmental disorders

• Authors: Cheng Zhang, Lulu Xu, Xueping Zheng, Shiguo Liu, F. Che
• Year: 2020
• Venue: Developmental Neurobiology
• URL: https://www.semanticscholar.org/paper/ba6592434032acf96c1d63a51a9856d7ed8927d1
• DOI: 10.1002/dneu.22795
• PMID: 33258273
• PMCID: 8048680
• Citations: 19
• Summary: A new perspective is proposed for basic scientific research and clinical interventions for cross‐disorder diseases because of the importance and necessity of transcending a single gene to complicated mechanisms of network convergence underlying these diseases.
• Evidence snippets:
• Snippet 1 (score: 0.478) > Although TS, ADHD, ASD, and SCZ have complicated genetic etiologies, behavioral phenotypes and heterogeneity, a significant overlap in symptoms exists, proposing the idea that these different diseases may share common pathogenic mechanisms. The pathways involved in neural development networks provide a framework for understanding how different genetic disturbances of different diseases interact in a convergent way to disrupt neuronal structure, synaptic function, and neuronal circuit organization and behavior. Disease-related changes rather than causing a wide-spread damage, may not be specific, but may be subtle-affecting only a subset of synapses in a selective neuron group. As a result, different changes in shared cell substrates may be the basis for phenotypic variability and classified as different neurological diseases. > Given the considerable evidence, we propose a reasonable hypothesis that these diseases may have a common network of pathogenesis, and Ash1l may be located at the epicenter hub of neural co-networks that are the center of pathological damage. Mutations in Ash1l interacting with the local environment may result in transcriptional abnormalities, causing physiological, metabolic, and/or structural damage of neurons and synapses in specific networks. The disease process may initially involve a high degree of regional change, thereby exposing areas in the topological neighborhood to alter functional input or communication, resulting in a series of changes throughout the brain and subsequent neural circuit and E/I imbalance reorganization mechanisms. Owing to the high interconnectivity of the networks, the adjacent topological structure nodes quickly respond, causing cascading network reactions, thus, suggesting that these disorders are part of a continuum. > The elucidation of the shared function of newly discovered disease-related genes is a key step in translating genetic discoveries into clinical applications, and discussing how the destruction of these molecules related to TS disrupts shared pathways and contributes to the urgency of these diseases. Therefore, further work is required to determine the specific cell types that play a key role in these circuits and common intercellular signaling pathways connecting different risk genes. Only when we are able to predispose the heterogeneity of neurodevelopmental disorders in a shared landscape can the shared molecular regulatory mechanisms of overlapped symptoms and common developmental and/or genetic mechanisms be unlocked.

[17] Immune Dysregulation in Autism Spectrum Disorder: What Do We Know about It?

• Authors: M. Robinson-Agramonte, Elena Noris García, Jarasca Fraga Guerra, Yamilé Vega Hurtado, Nicola Antonucci et al.
• Year: 2022
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/0d5e761dc4d912894a808ce3353286fc759f2ee5
• DOI: 10.3390/ijms23063033
• PMID: 35328471
• PMCID: 8955336
• Citations: 132
• Influential citations: 1
• Summary: Current insights into immune dysfunction in ASD are summarized, with particular reference to the impact of immunological factors related to the maternal influence of autism development; comorbidities influencing autism disease course and severity; and others factors with particular relevance, including obesity.
• Evidence snippets:
• Snippet 1 (score: 0.477) > Neuropsychiatric and neurodegenerative disorders display a biologically defined expression related to brain dysfunctions and age-related disease onset. The former, considered as a disturbed behavior and emotional state derived from the functional brain impairment, and the latter, viewed as an organic brain disease where the symptoms follow the damage of specific brain regions. Studies from different groups show biological evidence for the presence of common immune-mediated mechanisms overlapping both disease processes, although understandably with some distinctive characteristics. > Clinical and experimental evidence have argued similar mechanisms of innate immunity pathway signaling overlapping immune-pathological events in both neuropsychiatric and neurodegenerative disorders, characterized by the common influence of resident glial cells mediating inflammation via soluble molecules (mainly cytokines, chemokines, and complement proteins), which promote the recruitment of local immune cells and others coming from the peripheral compartment. To show this evidence, we refer to two pathologies occurring in the both extremes of the life: ASD, the main object of this review, and Parkinson disease (PD), following the main aspects of innate immunity relevant to both disorders and where the glial cells are the main cellular element. > In general, both disorders, ASD and PD, are related to brain dysfunctions, and in their particular context, genetic causes and risk factors play a central role in disease pathophysiology, severity, and disease progression besides the overlapping immunopathological mechanisms and molecular pathways. More than 100 candidate genes identified in ASD may converge as causal factors related to neuronal development, plasticity, synaptic structure, and performance [230,231]. Several genes and genomic regions, including alpha-synuclein (SNCA), parkinRBRE3 ubiquitin protein ligase (PARK2), chromosome 22q11deletion/DiGeorge region, and fragile X mental retardation 1 (FMR1) repeats, may be relevant to the development of both ASD and PD, with converging features related to synaptic function and neurogenesis. Both PD and ASD also show alterations and impairments at the synaptic level, representing early main disease phenotypes converging upon mechanisms active in the two diseases [232].

[18] Modeling psychiatric disorders: from genomic findings to cellular phenotypes

• Authors: Anna Falk, Vivi M. Heine, A. Harwood, Patrick F. Sullivan, M. Peitz et al.
• Year: 2016
• Venue: Molecular Psychiatry
• URL: https://www.semanticscholar.org/paper/235b41240d78140de7ab06a3ad8a7d0b1bdff1a5
• DOI: 10.1038/mp.2016.89
• PMID: 27240529
• PMCID: 4995546
• Citations: 77
• Influential citations: 2
• Summary: The challenges for modeling of psychiatric disorders, potential solutions and how iPSC technology can be used to develop an analytical framework for the evaluation and therapeutic manipulation of fundamental disease processes are critically reviewed.
• Evidence snippets:
• Snippet 1 (score: 0.475) > The key challenge for iPSC-based disease modeling is to identify one or more relevant cellular phenotypes that accurately represent the disease pathophysiology. Increasing numbers of reports have demonstrated that for many diseases specific pathophysiology can be captured in human iPSC-based disease models. These range from cardiovascular disease, 44,45 cancer, 46,47 ocular disease, 48,49 diabetes mellitus 50,51 and neurological disorders of the brain. 52,53 Can the same approach be applied to complex psychiatric disorders? > The problem is that almost all psychiatric disorders are characterized by clinical signs and symptoms, but lack independent verification from objective biomarkers. Thus, how might these clinical phenotypes manifest themselves in terms of cell behavior? The identity of robust cellular 'readouts', which typify any psychiatric disorder, is a crucial unsolved problem and an area of intense study 54 (Table 2). When satisfactorily answered, this will herald a new degree of biological objectivity and quantification for the study of psychiatric disorders. > The aim is to find a single or small number of cell phenotypes or parameters that strongly associate with psychiatric disorders, and establish a cellular profile characteristic of cells derived from the general patient population. Although a consensus set of cellular phenotypes for psychiatric disorder is yet to be established, we can define some of their desired characteristics. First, cellular phenotypes have to relate to the biological pathways identified by genetics. Second, although there are many risk genes in disparate biological pathways, at some level, phenotypes should converge onto a much smaller grouping. Third, phenotypes need to be quantifiable. Finally, to be useful for drug development cellular phenotypes should be reversed by pharmacological treatment, although not necessarily by drugs in current use. > Although human iPSC-based approaches underrepresent the complexity of the human central nervous system, cellular phenotypes are likely to lie more proximal to molecular disease mechanisms than phenotypes seen at the level of a tissue or organism, 55 and thus may bypass compensatory homeostatic (2) Gene expression profiles of SCZ human iPSC neurons identified altered expression of many components of the cyclic AMP and WNT signaling pathways. > (3

[19] Metachromatic Leukodystrophy

• Authors: Marije A B C Asbreuk, Daphne H. Schoenmakers, L. Adang, Shanice Beerepoot, Caroline G. Bergner et al.
• Year: 2025
• Venue: Neurology
• URL: https://www.semanticscholar.org/paper/6c8e1c02d09a6aa062dd4c050995174bda50aef3
• DOI: 10.1212/WNL.0000000000213817
• PMID: 40577679
• PMCID: 12205745
• Citations: 2
• Summary: This review provides a comprehensive overview of the significant progress made in MLD research in the past decade, regarding natural history, disease and treatment mechanisms, and newborn screening (NBS).
• Evidence snippets:
• Snippet 1 (score: 0.474) > Metachromatic leukodystrophy (MLD) is a rare autosomal recessive lysosomal storage disorder caused by disease-causing variants in the gene coding for arylsulfatase A, leading to deficient enzyme activity and subsequent accumulation of sulfatides. MLD is characterized by demyelination and neurodegeneration of the central and peripheral nervous system, manifesting as progressive motor and cognitive defects in affected individuals. This review provides a comprehensive overview of the significant progress made in MLD research in the past decade, regarding natural history, disease and treatment mechanisms, and newborn screening (NBS). Traditionally, MLD has been classified according to age at onset (late-infantile, early-juvenile and late-juvenile, and adult MLD), with earlier forms leading to more rapid neurologic decline. New data show that the type of presenting symptoms further influences the dynamic of disease progression. Patients with a cognitive presentation have a much slower or even no motor decline than patients with a mixed motor and cognitive presentation. Research advancements have enabled improved understanding of the effects of allogeneic hematopoietic stem cell transplantation and the development of novel therapeutic approaches, including hematopoietic stem cell gene therapy, which is now authorized in the EU, United Kingdom, and United States as treatment for selected patients with early-onset forms of MLD. Both hematopoietic stem cell transplantation and hematopoietic stem cell gene therapy are most effective when administered before disease onset. To identify presymptomatic patients, NBS for MLD is becoming available in several countries, resulting in new challenges. Decisions regarding patient eligibility for these treatments in already symptomatic individuals, as well as the timing of treatment for patients identified through NBS, require thorough understanding of disease progression. Biomarkers may be helpful for disease staging and prediction of disease evolution. Moreover, apart from timing, challenges remain regarding optimal treatment strategies across MLD subtypes, especially late-onset MLD, and management of the clinical heterogeneity and course of the disease. Another important issue is ensuring therapy accessibility, which forms a substantial barrier for equitable care. Continued research and international collaboration are essential to address these challenges, with the goal of improving care and outcomes for patients with MLD and

Notes

• This provider combines search_papers_by_relevance with snippet_search.
• No synthesis or second-stage model call is performed.