Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Ferguson-Bonni neurodevelopmental syndrome. Core disease mechanisms, molec...

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

• Papers retrieved: 20
• 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: 0.430) > 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] 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: 0.412) > 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

[3] 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: 0.411) > 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.

[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: 0.410) > 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] Patient-Derived Induced Pluripotent Stem Cell Models for Phenotypic Screening in the Neuronal Ceroid Lipofuscinoses

• Authors: A. Morsy, Angelica V Carmona, P. Trippier
• Year: 2021
• Venue: Molecules
• URL: https://www.semanticscholar.org/paper/d510bd31c2c0312641423e0a06892605943439bc
• DOI: 10.3390/molecules26206235
• PMID: 34684815
• PMCID: 8538546
• Citations: 10
• Influential citations: 2
• Summary: An overview of available iPSC models for a number of different NCLs is provided and findings in these models that may spur target identification and drug development are highlighted.
• Evidence snippets:
• Snippet 1 (score: 0.406) > The NCLs encompasses a group of rare, fatal, pediatric neurodegenerative lysosomal storage disorders.Several gene mutations (CLN1-CLN8, CLN10-CLN14) can lead to NCL; however, a partial understanding of the function of the disease-associated proteins has hindered therapy development.Current treatment options are only symptomatic and focus on delaying progression.To date, there are only two clinically approved drugs, Brineuria, for the treatment of CLN2 disease, and Neurogene's recently approved gene therapy to treat CLN5 disease.Different organism models have become available for NCL disease research which have provided a myriad of important information about the protein function or dysfunction for each of the associated genes, possible disease mechanisms, and have enabled detailed preclinical studies and in a small number of cases, clinical trials. > Herein, we have highlighted the contributions of different disease models to NCL research, focusing on the established patient-derived iPSC phenotypic screening models.The ability of iPSCs to encompass the precise pattern of genetic variants, along with acquiring disease pathogenesis and phenotype makes them a more translational model compared to mice and eliminates the problem of species difference.However, compared to animal models, fewer iPSC models currently exist. > The brain is a complex network of many different cellular phenotypes and screening compounds in just one phenotype, i.e., neurons, is not a complete representation of the environment in the brain.While most studies in NCL patient-derived iPSCs employ either NPCs or neurons there are emerging studies looking at biochemical and pathophysiology effects of NCL on other cell phenotypes, one such example is the use of BMECs to model the blood-brain barrier that identified an impaired barrier phenotype in CLN3.Differentiation of iPSCs into other phenotypes including oligodendrocytes, astrocytes, microglia etc. is ongoing and results are expected in due course.These cell types will allow the construction of increasingly complex co-culture models that more readily represent the human brain and thus allow a greater understanding of the disease.

[6] Prominent and Regressive Brain Developmental Disorders Associated with Nance-Horan Syndrome

• Authors: C. Casto, V. Dipasquale, I. Ceravolo, A. Gambadauro, Emanuela Aliberto et al.
• Year: 2021
• Venue: Brain Sciences
• URL: https://www.semanticscholar.org/paper/d2d8619c882943bdd94ddc65f420190f03bf28b6
• DOI: 10.3390/brainsci11091150
• PMID: 34573171
• PMCID: 8465299
• Citations: 11
• Summary: A Sicilian family affected with congenital cataracts and dental anomalies and diagnosed with NHS by whole-exome sequencing is described and the affected boy from this family presented a late regression of cognitive, motor, language, and adaptive skills, as well as broad behavioral anomalies.
• Evidence snippets:
• Snippet 1 (score: 0.404) > Genetic brain developmental disorders with associated psychomotor regression include a broad variety of monogenic conditions with expanding clinical differential diagnosis, genetic heterogeneity, and associated disease mechanisms [1][2][3].Despite being in the era of next-generation sequencing (NGS), the etiology and disease mechanisms underlying regressive neurodevelopmental impairment remain undetermined in a certain proportion of cases [4,5].Defining the full spectrum of disease-causing molecular pathways underlying neurodevelopmental disorders will help to diagnose and monitor developmental trajectories in children affected with these conditions [6][7][8][9][10][11] The neurodevelopmental condition known as 'Nance-Horan syndrome' (NHS) (OMIM 302350) is characterized by frequent intellectual disability and autistic features against a background of broad congenital anomalies, including congenital cataracts and dental abnormalities; distinctive facial features such as long and narrow face, anteverted pinnae, broad nose, and brachymetacarpia may also frequently occur in these patients [12][13][14][15][16][17][18].Heterozygous females may present mild and variable clinical signs [19].Various mutations in NHS and minor variations of the phenotypical features have been described [18][19][20].NHS is caused by mutations in the NHS gene located on Xp22.13 [21], which is expressed in the midbrain, retina, lens, and tooth [22,23].To date, the most frequently reported pathogenic mutations are either nonsense or frameshift mutations, which result in either nonsense mediated decay (NMD) of the respective mRNA or truncation of the respective protein [18,21].In addition, a few microdeletions at Xp22. 13, involving the NHS gene, have been also identified [17,22], some of which encompass also other genes, such as the CDKL5 gene [24,25].

[7] Developmental Neuropathology and Neurodegeneration of Down Syndrome: Current Knowledge in Humans

• Authors: Zinnat Hasina, Nicole Wang, Chi-Chiu Wang
• Year: 2022
• Venue: Frontiers in Cell and Developmental Biology
• URL: https://www.semanticscholar.org/paper/449cb787c6a9e6f60c35d84c11a78bd08c0a7c9f
• DOI: 10.3389/fcell.2022.877711
• PMID: 35676933
• PMCID: 9168127
• Citations: 17
• Influential citations: 1
• Summary: This work summarizes current information about the neuropathology and neurodegeneration of the brain from conception to adulthood of foetuses and individuals with DS at anatomical, cellular, and molecular levels in humans.
• Evidence snippets:
• Snippet 1 (score: 0.391) > Individuals with Down syndrome (DS) suffer from developmental delay, intellectual disability, and an early-onset of neurodegeneration, Alzheimer’s-like disease, or precocious dementia due to an extra chromosome 21. Studying the changes in anatomical, cellular, and molecular levels involved may help to understand the pathogenesis and develop target treatments, not just medical, but also surgical, cell and gene therapy, etc., for individuals with DS. Here we aim to identify key neurodevelopmental manifestations, locate knowledge gaps, and try to build molecular networks to better understand the mechanisms and clinical importance. We summarize current information about the neuropathology and neurodegeneration of the brain from conception to adulthood of foetuses and individuals with DS at anatomical, cellular, and molecular levels in humans. Understanding the alterations and characteristics of developing Down syndrome will help target treatment to improve the clinical outcomes. Early targeted intervention/therapy for the manifestations associated with DS in either the prenatal or postnatal period may be useful to rescue the neuropathology and neurodegeneration in DS.

[8] Treatment of Neurodevelopmental Disorders in Adulthood

• Authors: E. Castrén, Y. Elgersma, L. Maffei, R. Hagerman
• Year: 2012
• Venue: The Journal of Neuroscience
• URL: https://www.semanticscholar.org/paper/2c1e2c2eed4cb2efe39fe8658cbd629540207bba
• DOI: 10.1523/JNEUROSCI.3287-12.2012
• PMID: 23055475
• Citations: 66
• Influential citations: 2
• Summary: Findings in mouse models of neurodevelopmental disorders suggest that it is possible to reverse certain molecular, electrophysiological, and behavioral deficits associated with these disorders in adults by genetic or pharmacological manipulations or by pharmacotherapy.
• Evidence snippets:
• Snippet 1 (score: 0.391) > Neurodevelopmental disorders first appear during the course of development and maturation, and they are caused by a variety of genetic and environmental conditions (Ehninger et al., 2008). Down syndrome, fragile X syndrome (FXS), Rett syndrome, neurofibromatosis, and tuberous sclerosis are major developmental syndromes leading to intellectual disability (Ehninger et al., 2008;Auerbach et al., 2011;Zoghbi and Bear, 2012), but in the majority of cases, the molecular and neuronal mechanisms underlying the clinical phenotype remain unknown. Neurodevelopmental disorders affect ϳ1-2% of the population, and because of their typically life-long course they are very costly. Therefore, even a minor improvement in the performance of these patients would be of great significance to the patients themselves, to families, and to society. > The molecular background of many genetic syndromes leading to neurodevelopmental disorders has been elucidated during the last few years (West and Greenberg, 2011). These findings have paved a way for the discovery of pathways affected in neurodevelopmental disorders and the development of mouse models of these disorders. It has turned out that many of the genes associated with neurodevelopmental disorders play a role in synaptic function (West and Greenberg, 2011;Zoghbi and Bear, 2012), in particular in the regulation of protein synthesis in synapses (Bhakar et al., 2012). These studies have also revealed that in several genes associated with neurodevelopmental disorders, both reduced and enhanced expression bring about phenotypes, often with strikingly similar clinical features (Ramocki and Zoghbi, 2008), emphasizing the need for precise maintenance of optimal levels of synaptic regulatory proteins. The elucidation of neuronal pathways that are dysfunctional in different neurodevelopmental disorders has inspired a search of drug treatments that may alleviate the cognitive problems (Ehninger et al., 2008;Wetmore and Garner, 2010). It has turned out that enhanced expression of the dysfunctional gene or increased/decreased signaling in the affected pathways at least in some cases partially reversed the symptoms even when the treatment was started

[9] 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: 0.390) > 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).

[10] Clinical features and genetic analysis of a family with t(5;9) (p15;p24) balanced translocation leading to Cri-du-chat syndrome in offspring

• Authors: Jing Zhao, Ping Chen, Yijia Ren, Shurong Li, Weiyi Zhang et al.
• Year: 2025
• Venue: Frontiers in Genetics
• URL: https://www.semanticscholar.org/paper/5caf88001c66b473b6565f9e75eb6a4f1a8c4a0a
• DOI: 10.3389/fgene.2025.1550937
• PMID: 40406061
• PMCID: 12094932
• Citations: 1
• Summary: This study reports a rare familial balanced translocation pedigree, particularly noting that the offspring can suffer from Cri-du-chat syndrome, which suggests a potential new genetic model for this syndrome.
• Evidence snippets:
• Snippet 1 (score: 0.386) > Using the Metascape database for GO enrichment analysis of the region containing 60 OMIM genes from 5p15.33p14.1 revealed the potential molecular mechanisms of the disease. The results showed that OMIM genes in the 5p15.33p14.1 region are mainly enriched in Na+/Cl-dependent neurotransmitter transporters, cell-cell adhesion mediated by cadherin, nephron epithelium development, and other signaling pathways (Figure 5A). Disease enrichment analysis showed that genes in this region are mainly associated with Cri-du-chat syndrome (Figure 5B) . Cri-du-chat syndrome is closely related to developmental abnormalities, neurological defects, and craniofacial malformations. Enrichment analysis supports the involvement of molecular mechanisms related to Wnt signaling, neurotransmitter transport, ubiquitination pathways, particularly through diseasegene associations from DisGeNET and GO functional enrichment. These results provide clues for revealing the molecular network of the disease and guide future research. > Using the Metascape database, GO enrichment analysis of 45 OMIM genes located in the 9p24.3-p22.3 region was performed. The results showed that OMIM genes in the 9p24.3-p22.3 region are mainly enriched in signaling pathways such as positive regulation of leukocyte activation, response to amine, cell population proliferation, positive regulation of cell development, etc. (Figure 5C). Disease enrichment analysis revealed that genes in this region are mainly associated with Chromosome 9p deletion syndrome (Figure 5D). This study, through multidimensional bioinformatics analysis, not only clarified the core biological functions of genes in the 9p24.3-p22.3 region, but also revealed their potential association mechanisms with major diseases, providing important theoretical basis and directional guidance for subsequent gene function validation, molecular mechanism research, and clinical translation. Balanced translocation carriers have the opportunity to produce phenotypically normal offspring, but they are at a higher risk of recurrent miscarriages and offspring with chromosomal abnormalities.

[11] Further delineation of EBF3-related syndromic neurodevelopmental disorder in twelve Chinese patients

• Authors: Jitao Zhu, Wenhui Li, Sha Yu, Wei Lu, Qiong Xu et al.
• Year: 2023
• Venue: Frontiers in Pediatrics
• URL: https://www.semanticscholar.org/paper/a102a60d4a7104dbfc9de63bba735fb74a2594bd
• DOI: 10.3389/fped.2023.1091532
• PMID: 36937983
• PMCID: 10020332
• Citations: 4
• Summary: This study further expanded the gene mutation spectrum of EBF3-related NDD by identifying five missense variants (four novel variants and one known variant) and seven copy number variations (CNVs) of E BF3 gene using next-generation sequencing.
• Evidence snippets:
• Snippet 1 (score: 0.385) > Neurodevelopmental disorders (NDDs) account for a significant proportion of congenital disorders, which impose an enormous financial burden on families and society. Researches have suggested that hundreds of genes are involved in the pathogenesis of NDDs, but the underlying mechanisms remain unclear (1). Affected individuals present with various neurological symptoms, including developmental delay (DD), intellectual disability (ID), autism spectrum disorder (ASD), epilepsy and other minor symptoms such as decreased pain sensitivity or hyperactivity (2,3). In addition, patients may also present with phenotypes in other systems, such as congenital heart defects, skeletal or muscular abnormalities, metabolic disorders, gastrointestinal problems, distinctive facial features or strabismus, etc. Despite the high heterogeneity of pathogenic genes and the diverse clinical features of NDDs, advances in next-generation sequencing technology have facilitated the diagnosis of such diseases (4,5). > EBF3 is one of the causative genes that lead to syndromic NDDs. The earliest reports of EBF3-related NDD dated back to 2017, in which a total of 21 cases were summarized and analyzed (6)(7)(8). In their description, multiple systems were involved, including central nervous system (CNS), genitourinary system, skeletal system, etc. Major phenotypes included DD/ID, ataxia, hypotonia, structural CNS malformations, genitourinary abnormalities, subtle facial features, and strabismus. Other less common phenotypes included dysarthria, constipation, decreased pain sensitivity during development, and behavioral deficits such as attention deficit and ASD or ASD-like symptoms. Since then, more than 30 additional cases of EBF3-related NDDs have been reported (9)(10)(11)(12)(13)(14)(15)(16). A recent meta-analysis integrated previously published 42 cases with detailed patient information and their 41 new cases, and quantified the risk and severity of patient phenotypes based on these 83 patients (17).

[12] New therapeutic targets in rare genetic skeletal diseases

• Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
• Year: 2015
• Venue: Expert Opinion on Orphan Drugs
• URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
• DOI: 10.1517/21678707.2015.1083853
• PMID: 26635999
• PMCID: 4643203
• Citations: 38
• Influential citations: 1
• Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
• Evidence snippets:
• Snippet 1 (score: 0.381) > proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.

[13] Hao‐Fountain syndrome: 32 novel patients reveal new insights into the clinical spectrum

• Authors: Moritz Claudius Wimmer, H. Brennenstuhl, Steffen Hirsch, Laura Dötsch, Samy Unser et al.
• Year: 2023
• Venue: Clinical Genetics
• URL: https://www.semanticscholar.org/paper/b1ea56aec4ea458d4d273fc69b330c3dbe7f8750
• DOI: 10.1111/cge.14480
• PMID: 38221796
• Citations: 14
• Summary: A questionnaire‐based study was performed to characterize the phenotype of Hao‐Fountain syndrome more clearly, to highlight new traits, and to better distinguish the disease from related neurodevelopmental disorders.
• Evidence snippets:
• Snippet 1 (score: 0.379) > Hao‐Fountain syndrome (HAFOUS, OMIM: #616863) is a neurodevelopmental disorder caused by pathogenic variants in the gene USP7 coding for USP7, a protein involved in several crucial cellular homeostatic mechanisms and the recently described MUST complex. The phenotype of HAFOUS is insufficiently understood, yet there is a great need to better understand the spectrum of disease, genotype–phenotype correlations, and disease trajectories. We now present a larger cohort of 32 additional individuals and provide further clinical information about six previously reported individuals. A questionnaire‐based study was performed to characterize the phenotype of Hao‐Fountain syndrome more clearly, to highlight new traits, and to better distinguish the disease from related neurodevelopmental disorders. In addition to confirming previously described features, we report hyperphagia and increased body weight in a subset of individuals. HAFOUS patients present an increased rate of birth complications, congenital anomalies, and abnormal pain thresholds. Speech impairment emerges as a potential hallmark of Hao‐Fountain syndrome. Cognitive testing reports reveal borderline intellectual functioning on average, although some individuals score in the range of intellectual disability. Finally, we created a syndrome‐specific severity score. This score neither indicates a sex‐ nor age‐specific difference of clinical severity, yet highlights a more severe outcome when amino acid changes colocalize to the catalytic domain of the USP7 protein.

[14] Identification of a novel NSD1 pathogenic variant in a Senegalese child with Sotos syndrome

• Authors: J. Diop, Aminata Mbaye, Karamba Diallo, É. Pasmant, Seydi Abdoul Ba et al.
• Year: 2025
• Venue: Journal of Genetic Engineering & Biotechnology
• URL: https://www.semanticscholar.org/paper/c368f6595e3c28511e3628c4a4f26439d29da666
• DOI: 10.1016/j.jgeb.2025.100642
• PMID: 41839667
• PMCID: 12797062
• Summary: The first case of Sotos syndrome from Senegal is reported, confirmed by genetic testing, and a novel heterozygous mutation in exon 5 of the NSD1 gene in the index case is detected, resulting in a frameshift and a premature stop codon.
• Evidence snippets:
• Snippet 1 (score: 0.379) > Sotos syndrome is a rare genetic disorder characterized by a broad spectrum of clinical features, primarily documented in adult population, with limited reports in pediatric cohorts 7 . We reported here the first genetically confirmed case of Sotos syndrome in Senegal. The patient exhibited the hallmark clinical features of Sotos syndrome, including the characteristic facial phenotype; overgrowth mainly involving height and /or head circumference; frontal bossing; temporal baldness and receding frontal hairline. 7,21 Furthermore, the patient exhibited markedly large hands and feet and excessive body growth (size > Z3DS) also in concordance with clinical features of Sotos syndrome. Sotos syndrome is often linked to developmental and neurological issues, as well as heart disease, and ophthalmological disorders 22 . Unfortunately, we were not able to investigate these organ systems in our patient, which limits our understanding of any related complications. > The mutation of the NSD1 gene NM_022455: c.2306dup, p. Gly771Trpfs*38) identified in the index case is a nucleotide duplication at position 2306, causing a shift in the reading frame. The consequence is the introduction of a premature termination codon 38 amino acids downstream, leading to truncated protein synthesis. The variant is expected to lead to a loss of function of NSD1, primarily via nonsensemediated mRNA decay (NMD), a cellular surveillance mechanism that targets transcripts harboring premature termination codons. > The major clinical features of Sotos syndrome were observed in our patient, supporting the pathogenic role of frameshift mutation in the NSD1 gene that led to a haploinsufficiency. However, in some cases, the 5q35 microduplication was confirmed and the patients manifest "reversed Sotos Syndrome as short stature and microcephaly without facial feature. > The de novo nature of the variant, confirmed by its absence in the non-affected parents, strongly suggests a pathogenic role in the index case. De novo variants in NSD1 are well-documented as the major molecular mechanism underlying Sotos syndrome. The identified variant has not been previously reported in major population databases such as gnomAD or ClinVar, but similar truncating mutations in NSD1 have been frequently associated with Sotos syndrome.

[15] Novel BRAT1 variant associated with neurodevelopmental disorder with cerebellar atrophy and seizure: Case report and a literature review

• Authors: M. Ghasemi, Sahand Tehrani Fateh, Farzad Hashemi-Gorji, Morteza Sheikhi Nooshabadi, S. Alijanpour et al.
• Year: 2024
• Venue: Epilepsy & Behavior Reports
• URL: https://www.semanticscholar.org/paper/4017120f59d4696de48a080ad50f80c8f1b23bbb
• DOI: 10.1016/j.ebr.2024.100702
• PMID: 39188779
• PMCID: 11345683
• Citations: 1
• Summary: Highlights • Identification of a novel variant of the BRAT1 gene (c.398A>G;p.His133Arg).• WES is useful for identifying causative variant in rare neurodevelopmental disorders.• BRAT1-related disorders have variability in the clinical presentation.
• Evidence snippets:
• Snippet 1 (score: 0.379) > Neurodevelopmental disorders encompass a diverse range of conditions characterized by impaired cognitive, motor, and social functioning. Genetic factors play a significant role in the etiology of these disorders, and the identification of disease-causing genes is crucial for understanding their underlying mechanisms and improving diagnostic accuracy [1]. One such gene of interest is BRAT1, which has been implicated in various neurodevelopmental disorders [2]. > BRAT1 (BRCA1-associated protein required for ATM activation-1) is a critical gene involved in DNA repair and the maintenance of genomic stability. Mutations in BRAT1 have been associated with a spectrum of neurodevelopmental disorders, including intellectual disability, epilepsy, speech delay, and motor impairments. Biallelic mutations in this gene have been linked to two phenotypes including, neurodevelopmental disorder with cerebellar atrophy and with or without seizures (NEDCAS #MIM 618056) [20], as well as lethal neonatal rigidity and multifocal seizure syndrome (RMFSL#MIM 614498) [21,22]. The RMFSL phenotype is the severe form of disease, and the NEDCAS phenotype is the milder form of BRAT1-related disease. The RMFSL phenotype is presented with severe encephalopathy, drug-resistant epilepsy, cerebral atrophy, and early death. In contrast, the NEDCAS phenotype is presented with intellectual disability, cerebellar atrophy, ataxia, nystagmus, and a higher life expectancy. However, the full extent of BRAT1 genotype-phenotype correlations and the underlying disease mechanisms remain to be fully elucidated [2]. > The goal of this study is to identify a causative variant through whole exome sequencing (WES) in a patient with neurodevelopmental disorders. Furthermore, we conducted a literature review to compare the clinical features observed in individuals with BRAT1 mutations, which can help to improve our understanding of the relationship between genotype and phenotype in BRAT1-related disorders.

[16] GRIN2B-related neurodevelopmental disorder: current understanding of pathophysiological mechanisms

• Authors: S. Sabo, Jessica M. Lahr, Madelyn Offer, Anika LA Weekes, M. Sceniak
• Year: 2023
• Venue: Frontiers in Synaptic Neuroscience
• URL: https://www.semanticscholar.org/paper/261e9ad3a207becd3d96e20fa3139a66b5318a25
• DOI: 10.3389/fnsyn.2022.1090865
• PMID: 36704660
• PMCID: 9873235
• Citations: 51
• Influential citations: 2
• Summary: Together, the existing data provide insight into the pathophysiological mechanisms that underlie GRIN2B-related neurodevelopmental disorder and emphasize the importance of comparing the effects of individual, disease-associated variants.
• Evidence snippets:
• Snippet 1 (score: 0.378) > The GRIN2B-related neurodevelopmental disorder is a rare disease caused by mutations in the GRIN2B gene, which encodes the GluN2B subunit of NMDA receptors. Most individuals with GRIN2B-related neurodevelopmental disorder present with intellectual disability and developmental delay. Motor impairments, autism spectrum disorder, and epilepsy are also common. A large number of pathogenic de novo mutations have been identified in GRIN2B. However, it is not yet known how these variants lead to the clinical symptoms of the disease. Recent research has begun to address this issue. Here, we describe key experimental approaches that have been used to better understand the pathophysiology of this disease. We discuss the impact of several distinct pathogenic GRIN2B variants on NMDA receptor properties. We then critically review pivotal studies examining the synaptic and neurodevelopmental phenotypes observed when disease-associated GluN2B variants are expressed in neurons. These data provide compelling evidence that various GluN2B mutants interfere with neuronal differentiation, dendrite morphogenesis, synaptogenesis, and synaptic plasticity. Finally, we identify important open questions and considerations for future studies aimed at understanding this complex disease. Together, the existing data provide insight into the pathophysiological mechanisms that underlie GRIN2B-related neurodevelopmental disorder and emphasize the importance of comparing the effects of individual, disease-associated variants. Understanding the molecular, cellular and circuit phenotypes produced by a wide range of GRIN2B variants should lead to the identification of core neurodevelopmental phenotypes that characterize the disease and lead to its symptoms. This information could help guide the development and application of effective therapeutic strategies for treating individuals with GRIN2B-related neurodevelopmental disorder.

[17] Conceptualizing Epigenetics and the Environmental Landscape of Autism Spectrum Disorders

• Authors: G. Torres, Mervat Mourad, Saba Iqbal, Emmanuel Moses-Fynn, Ashani Pandita et al.
• Year: 2023
• Venue: Genes
• URL: https://www.semanticscholar.org/paper/bf76f0682a8a1986ce889cee1fef818480abc83b
• DOI: 10.3390/genes14091734
• PMID: 37761876
• PMCID: 10531442
• Citations: 11
• Summary: The present work reviews recent evolutionary, molecular, and epigenetic mechanisms potentially linked to the etiology of autism, and presents a clinical vignette to describe clusters of maladaptive behaviors frequently diagnosed in autistic patients.
• Evidence snippets:
• Snippet 1 (score: 0.377) > Currently, there are hundreds of gene variants associated with the onset of ASD. Thus, the clinical presentation of the disease is highly variable, as one or more behavioral symptoms may be related to other comorbid conditions (e.g., anxiety disorder, seizure disorder) besides autism. In addition, antagonistic pleiotropy and dosage-sensitive genes further fragment the phenotypic characteristics of ASD. Regardless, here, we present a prototypical autism clinical vignette with five behavioral specifiers: cognitive disability; deficits in social-emotional reciprocity; repetitive or stereotyped motor behavior; improper coordinated language communication; and gastrointestinal distress. Underneath this clinical vignette, we microdissected and correlated a particular phenotype of the disease to functionally and anatomically related regions of the brain and bilateral body plan. The structural organization imposed here will not only identify a wide network of cells, but also specific clusters of genes targeting a particular symptom within behaviorally relevant regions. It is expected that such structural organization will help lay a solid foundation in psychiatry and point to more focused approaches to a deeper understanding of ASD and its individualized treatment (Table 2). Autism Spectrum Disorders can be managed with appropriate pharmacotherapy. Selective dopamine (DA) and serotonin (5HT) based drugs are the mainstay of pharmacological treatment [43,44]. Additional neurotransmitter systems (e.g., norepinephrine (NE) and histamine) are also drug targets. It is not known whether the listed drugs regulate epigenetic mechanisms to counteract autistic symptoms. What is broadly known is that atypical, typical and psychoactive drugs act on DA and 5HT signaling pathways within regions of the human brain (e.g., cortex and basal ganglia) that are behaviorally relevant to the pathophysiology of ASD. Attention Deficit Hyperactivity Disorder (ADHD) and Fragile X Syndrome are debilitating neuropsychiatric conditions commonly diagnosed in pediatric populations. Fragile X Syndrome is a monogenic inherited disease leading to cognitive disability and ASD.

[18] Spatiotemporal 7q11.23 Protein Network Implicates the GTF2I-PRKDC-DDR Pathway During Early-Fetal Brain Development in Psychiatric Diseases

• Authors: G. Lin, Liang Chen, Weidi Wang, Wenxiang Cai, Weichen Song et al.
• Year: 2020
• Venue: Unknown venue
• URL: https://www.semanticscholar.org/paper/6a2df6310ac4d8f7f3f76da6f21f8a221ebf1cce
• DOI: 10.21203/rs.3.rs-93461/v1
• Summary: Striatum, hippocampus, and amygdala are crucial regions for establishing connectivity between 7q11.23 proteins and their partners in early and late fetal periods, and the results suggested that GTF2I-PRKDC-DDR and GTF 2I-BRCA1-dDR pathway is crucial for the 7q 11.23 CNV genes to contribute to the pathogenesis of psychiatric diseases.
• Evidence snippets:
• Snippet 1 (score: 0.376) > A different approach of addressing this issue is based on creating animal or cell models to help identify the related molecular and cellular mechanisms. For instance, mice with a heterozygous deletion of GTF2I or GTF2IRD1 show defects in skeletal and craniofacial. [14]. In addition, the embryos of these mice present with a small head; this is consistent with the clinical phenotype of patients carrying a 7q11. 23 deletion. Nevertheless, the signaling pathways affected by this CNV remain unknown. > Replication factor C subunit 2 (RFC2), another 7q11.23 gene, encodes a subunit of the replication factor C (RFC) complex [15] and is known to play a role in ATR signaling [16,17]. Haploinsufficiency for RFC2 leaded to G2/M checkpoint arrest after DNA damage [18]. However, little is known about how genes with the 7q11.23 deletion/duplication may affect the occurrence of neurodevelopmental disorders because these genes are involved not only in multiple developmental stages but also within different tissues. Hence, genes exhibiting 7q11.23 deletion/duplication play different roles in different developmental stages and different anatomic structures. > CNVs have been reported to modulate gene expression, which, ultimately, might affect disease predisposition or clinical phenotypes [19,20]. Several researches have investigated CNV pathogenesis in psychiatric disorders by constructing a static topological network based on a single developmental stage [21]. Within different developmental periods, protein expression can change, as can protein-protein interactions (PPIs) [22]. Nevertheless, protein expression is a dynamic process that can occur in a different manner across different anatomical areas [23,24]. Analyses of molecular networks can reveal biological modularity and complex signaling pathways [25,26]. Previous studies discovered the pathogenesis of CNVs by constructing dynamic protein-protein interaction (PPI) networks according to alterations of protein expression in different anatomical areas and during different developmental periods [27,28]. > In addition, multiple studies mentioned above focused only on one or two genes and were unable to demonstrate how the 7q11.23 CNV is involved in brain development.

[19] Common immunopathogenesis of central nervous system diseases: the protein-homeostasis-system hypothesis

• Authors: Kyung-Yil Lee
• Year: 2022
• Venue: Cell & Bioscience
• URL: https://www.semanticscholar.org/paper/2984270ae67451b93007040848d9694d19714c9f
• DOI: 10.1186/s13578-022-00920-5
• PMID: 36384812
• PMCID: 9668226
• Citations: 9
• Influential citations: 1
• Summary: This article proposes a common immunopathogenesis of CNS diseases, including prion diseases, Alzheimer’s disease, and genetic diseases, through the PHS hypothesis, which proposes that the immune systems in the host control those substances according to the size and biochemical properties of the substances.
• Evidence snippets:
• Snippet 1 (score: 0.374) > There are hundreds of genetic diseases of the CNS. The defective proteins in genetic disorders include structural proteins for neurotransmitter receptors and other receptors or ion channels on CNS cells, and proteins involved in enzymatic process, metabolism (transport), or signal transduction pathways in various communication systems [98]. Because a discussion of each genetic disease is beyond the scope of this review, only crucial points about the pathogenesis of genetic diseases are discussed. Singlegene defect diseases of the CNS can be caused by a defective product from a gene, i.e., a protein deficiency or a malfunctioning protein. In general, autosomal dominant genetic diseases are caused by structural protein defects, and autosomal recessive diseases are caused by defects in enzymatic proteins. However, certain genetic diseases that involve an enzymatic or multifunctional protein defect can induce structural cell injury during the natural course of the illness. > Patients with genetic diseases, including HD, familial JCD, GSS, and the genetic forms of AD and PD, show different clinical manifestations from other affected people in their family, including the time of onset of neurological symptoms, speed of progression of the disease, and prognosis, suggesting that phenotypes can vary even when the genotypes are identical. Likewise, similar phenotypes of CNS symptoms can be found in different genetic diseases. In genetic animal models, the phenotypes of single gene knockout can vary by strain in mice, and the clinical manifestations of a gene defect can differ between mice and humans, and mice null for some genes have also no observable phenotypic abnormalities compared with controls [99]. These findings suggest that default of a protein might be at least partly controlled by individual's control systems and that there might exist a similar immune/repair system against cell injury in genetic diseases. > The pathophysiology of most genetic diseases in the CNS is complex because any affected gene is associated with numerous proteins and their corresponding activations of genes and epigenetic changes that occur during disease processes. Thus, the use of a genetic marker for diagnosing or predicting a prognosis remains impractical in clinical settings [100].

[20] Nasopharyngeal Carcinoma Signaling Pathway: An Update on Molecular Biomarkers

• Authors: W. Tulalamba, T. Janvilisri
• Year: 2012
• Venue: International Journal of Cell Biology
• URL: https://www.semanticscholar.org/paper/307cb9186444d9dad6e2e3b53763be0de76de186
• DOI: 10.1155/2012/594681
• PMID: 22500174
• PMCID: 3303613
• Citations: 93
• Influential citations: 5
• Summary: The molecular signaling pathways in the NPC are discussed for the holistic view of NPC development and progression and the important insights toward NPC pathogenesis may offer strategies for identification of novel biomarkers for diagnosis and prognosis.
• Evidence snippets:
• Snippet 1 (score: 0.374) > In the pregenomic eras, highly integrated and complex circuitry of molecular signaling in NPC pathogenesis was only partially understood. Over the past decade, the knowledge of the molecular mechanisms in NPC carcinogenesis has been rapidly accumulated. Dysregulation and abnormal protein expression of molecules in certain signaling pathways involved in cellular functions including proliferation, adhesion, survival, and apoptosis has been demonstrated in the NPC cells. Detailed information on the complex network in signaling pathway leading to a coordinated pattern of gene expression and regulation in NPC will undoubtedly provide important clues to develop novel prognostic and therapeutic strategies for this cancer. Refining molecular markers into clinically relevant assays may assist in the detection of NPC in asymptomatic patients, as well as stage classification and monitoring disease progression and treatments. Furthermore, selective regulation of particular proteins targeting cancer cell proliferation, invasion, and apoptosis is a hopeful prospect for future anticancer therapy that slow disease progression and improve survival.

Notes

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