Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Dentici-Novelli neurodevelopmental syndrome. Core disease mechanisms, mole...

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

• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] Novel Compound Heterozygous Variants in ZNF526 Causing Dentici‐Novelli Neurodevelopmental Syndrome: A Case Report and Literature Review

• Authors: Shao-Ling Li, Hui Fang, Hong Li, Min Peng, Jinsong Bao et al.
• Year: 2025
• Venue: Molecular Genetics & Genomic Medicine
• URL: https://www.semanticscholar.org/paper/e41f61ba1d9471fef4b455fe945094f6cda9374c
• DOI: 10.1002/mgg3.70089
• PMID: 40197775
• PMCID: 11976872
• Summary: The ZNF526 gene encodes a ubiquitously expressed Kruppel‐type zinc finger protein crucial in transcriptional regulation. Recent studies suggest that biallelic pathogenic variants in ZNF526 may lead to Dentici‐Novelli neurodevelopmental syndrome, characterized by microcephaly, developmental delay, epilepsy, and ocular anomalies. To date, phenotypic details have been reported for only six patients with ZNF526 variants.
• Evidence snippets:
• Snippet 1 (score: 0.486) > pediatric primary care, especially among chronically ill children. The pathogenesis of severe or syndromic NDDs is largely genetic, with over 1500 genes linked to intellectual disability (Maia et al. 2021). Many of these genes play roles in metabolism, transport, neurological development, and transcription. Advanced genetic testing technologies, such as whole exome sequencing (WES), whole genome sequencing (WGS), and RNA sequencing, have become invaluable for the rapid, accurate diagnosis of NDDs (Stefanski et al. 2021). These tools help address the diagnostic challenges posed by the complexity and clinical variability of NDDs 4 . Elucidating the molecular basis of NDDs is essential for diagnosing developmental delays or degeneration and devising tailored management strategies for affected children. > The ZNF526 gene (OMIM* 614387) encodes a widely expressed Kruppel-type zinc finger protein that plays a crucial role in transcriptional regulation. Dentici-Novelli neurodevelopmental syndrome (DENNED, OMIM#619877) is a rare autosomal recessive disorder caused by pathogenic variants in the ZNF526 gene, first described by Dentici in 2022 (Dentici et al. 2022). This syndrome exhibits a highly heterogeneous clinical phenotype, with key features including early-onset severe global developmental delay and microcephaly. Affected individuals often present with various neurologic symptoms, such as axial hypotonia, spastic hypertonia, dystonic quadriplegia, profound intellectual disability, and seizures. Brain imaging commonly reveals abnormalities, often accompanied by ocular defects, such as bilateral cataracts. Due to its rarity, DENNED remains under-characterized, and detailed phenotypic and genetic information is still limited. > In this study, we identified novel compound heterozygous pathogenic variants in the ZNF526 gene in a patient with DENNED using WES. We also reviewed the clinical features and genetic mechanisms of DENNED associated with ZNF526 variants.

[2] 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: 0.477) > 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.

[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: 0.474) > 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] 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: 0.463) > 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

[5] 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: 0.456) > 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.

[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: 0.448) > 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] Precision Therapeutics in Lennox–Gastaut Syndrome: Targeting Molecular Pathophysiology in a Developmental and Epileptic Encephalopathy

• Authors: Debopam Samanta
• Year: 2025
• Venue: Children
• URL: https://www.semanticscholar.org/paper/455479c1bfbea7b90b73c109228f67c813d13888
• DOI: 10.3390/children12040481
• PMID: 40310132
• PMCID: 12025602
• Citations: 19
• Influential citations: 1
• Summary: A narrative review explores precision therapeutic strategies for LGS based on molecular pathophysiology, including channelopathies, receptor and ligand dysfunction, receptor and ligand dysfunction, cell signaling abnormalities, cell signaling abnormalities, synaptopathies, and the repurposing of existing medications with mechanism-specific effects.
• Evidence snippets:
• Snippet 1 (score: 0.446) > A key advantage of disease-modifying therapies is their potential to target pathogenic mechanisms early in the disease course, potentially preventing the progression of some infantile epileptic encephalopathies to LGS. > This narrative review explores precision therapeutic strategies based on specific monogenic causes and disease mechanisms relevant to LGS. A comprehensive literature search (PubMed, MEDLINE, ClinicalTrials.gov, conference abstracts from the American Academy of Neurology and American Epilepsy Society, and gray literature) was conducted through 19 February 2025 to identify established ASMs, repurposed and novel drugs, as well as various gene therapy approaches with potential relevance to LGS. Given that over 900 monogenic causes of DEEs have been identified-implicating diverse cellular components such as ion channels, receptors, synaptic proteins, signaling pathways, metabolic processes, and epigenetic regulators-this review discusses current and emerging precision therapeutics based on shared molecular mechanisms and the pathophysiology of select genes associated with LGS [17] (Table 1).

[8] 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: 0.433) > 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.

[9] 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: 0.431) > 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.

[10] Recent advances in modelling of cerebellar ataxia using induced pluripotent stem cells

• Authors: M. M. Wong, L. Watson, Esther B. E. Becker
• Year: 2017
• Venue: Journal of neurology & neuromedicine
• URL: https://www.semanticscholar.org/paper/0d962652305116e383ab260b9e82d3a5ffe1722f
• DOI: 10.29245/2572.942X/2017/7.1134
• PMID: 28825058
• PMCID: 5558869
• Citations: 9
• Summary: This review focuses on recent breakthroughs in generating human iPSC-derived Purkinje cells and highlights the future challenges that will need to be addressed in order to fully exploit these models for the modelling of the molecular mechanisms underlying cerebellar ataxias and the development of effective therapeutics.
• Evidence snippets:
• Snippet 1 (score: 0.430) > dominant polyglutamine spinocerebellar ataxias (SCAs) are the most studied forms of ataxias. Despite significant clinical and genetic heterogeneity, emerging evidence points to the existence of common pathogenic mechanisms that may be shared by several genetically distinct forms of cerebellar ataxias (reviewed in5-8). However, it is still unclear how the proposed pathological pathways ultimately result in cerebellar dysfunction and degeneration, predominantly affecting Purkinje cells. > Understanding disease mechanisms is key to treating neurodegenerative disorders. The heterogeneous nature of the cerebellar ataxias combined with the unavailability of human brain tissue and the lack of reliable disease models have, however, hampered our understanding of the molecular disease mechanisms underlying cerebellar ataxias and thus, the development of effective therapies. Although mouse models of several cerebellar ataxias, including FRDA and SCAs, have provided valuable insights into the pathophysiology of these disorders (reviewed in9), many questions remain about the observed species differences in disease phenotypes and the effectiveness of potential drugs in clinical trials. > To help translate research from animal models into novel treatments for ataxia patients, it is essential to validate findings in the relevant affected human cell types, particularly in cerebellar Purkinje cells. The current obstacles might be overcome by exploiting recently developed human induced pluripotent stem cell (iPSC) technology and neuronal differentiation protocols.

[11] An overview of inborn errors of metabolism affecting the brain: from neurodevelopment to neurodegenerative disorders

• Authors: J. Saudubray, A. Garcia-Cazorla
• Year: 2018
• Venue: Dialogues in Clinical Neuroscience
• URL: https://www.semanticscholar.org/paper/1026aace2ad9a87f6ff6f0a25593c2f7030b26b4
• DOI: 10.31887/DCNS.2018.20.4/jmsaudubray
• PMID: 30936770
• PMCID: 6436954
• Citations: 90
• Influential citations: 3
• Summary: This paper provides a comprehensive list of IEMs that affect neurodevelopment and may also present with neurodegeneration.
• Evidence snippets:
• Snippet 1 (score: 0.429) > Due to the fact that brain function is still one of the most unknown mysteries of biology, concepts and approaches that could have been well-established in the past, can be seen as a matter of controversy nowadays. This is the case for neurodevelopment and neurodegeneration. Initially considered as opposite ends of the spectrum, an accumulating body of evidence shows significant similarities between cellular processes involved in both of them. 2,3,17 For that matter, an important question includes the extent to which rare neurodevelopmental diseases have progressive pathology across the Figure 1. Main neurological presentations, pathophysiological categories, and neurodevelopmental to neurodegenerative features. Main clinical presentations are presented depending on the severity degree, from antenatal malformations to isolated symptoms. It is not rare that the same disease could have different types of presentation. Severe global encephalopathies include genetic defects that lead to early disruption of fundamental biological processes that are required for a proper brain development and affect motor, cognitive and behavioural aspects. Synaptopathies correspond to diseases impairing synaptic communication and often have epilepsy, intellectual disability, behavioural abnormalities (including autism) and movement disorders in any combination. Synaptic diseases produce connectivity impairments (abnormal brain circuitries' organization). Complex motor presentations correspond to diseases leading to abnormal motor symptoms; these are related to brain structures and circuits that regulate voluntary and passive movements, strength and muscle tone. In pediatrics' IEMs it is not rare to detect combinations of different motor signs (dyskinetic movements, pyramidal signs, hypotonia, ataxia…). Some additional explanations: COG6 plays a major role in Golgi trafficking and positioning of glycosylation enzymes. HCFC1: gene responsible for X-linked cobalamin deficiency. PHARC: Acronym for a neuropathy syndrome due to a phospholipid remodeling defect that mimics Refsum disease. PIGA is one of the 7 proteins require for the 1st step of the GPI synthesis. SERAC1 lifespan into adulthood, and how these potentially neurodegenerative mechanisms may inform more common diseases. For trisomy 21 and Rett syndrome, the existence of both neurodev

[12] Quantitative proteomic analysis shows alterations in patient Rett syndrome iPSC cultures at early neuronal progenitor stages

• Authors: S. Varderidou-Minasian, Lisa Hinz, D. Hagemans, D. Posthuma, M. Altelaar et al.
• Year: 2020
• Venue: Unknown venue
• URL: https://www.semanticscholar.org/paper/83e54a16eb8dbb318b5e190c1fbb719547f63f12
• DOI: 10.21203/rs.3.rs-15527/v1
• Summary: The data gives evidence of proteomic alteration at early neurodevelopmental stages, suggesting alterations long before the phase that symptoms of RTT syndrome become apparent, and provides a valuable resource of proteins to study potential targets for early treatment ofRTT symptoms.
• Evidence snippets:
• Snippet 1 (score: 0.428) > BackgroundRett syndrome (RTT) is a progressive neurodevelopmental disease that is characterized by abnormalities in cognitive, social and motor skills. RTT is often caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2). The mechanism by which impaired MeCP2 induces the pathological abnormalities in the brain is not understood. Both patients and mouse models have shown abnormalities at molecular and cellular level before typical RTT-associated symptoms appear. This implies that underlying mechanisms are already affected during neurodevelopmental stages.MethodsTo understand the molecular mechanisms involved in disease onset, we used an RTT patient induced pluripotent stem cell (iPSC)-based model with isogenic controls and performed time-series of proteomic analysis using in-depth high-resolution quantitative mass spectrometry during early stages of neuronal development. ResultsWe provide mass spectrometry-based quantitative proteomic data, depth of about 7000 proteins, at neuronal progenitor developmental stages of RTT patient cells and isogenic controls. Our data gives evidence of proteomic alteration at early neurodevelopmental stages, suggesting alterations long before the phase that symptoms of RTT syndrome become apparent. We found changes in proteins involved in pathway associated with RTT phenotypes, including dendrite morphology and synaptogenesis. Differential expression increased from early to late neural stem cell phases, although proteins involved in immunity, metabolic processes and calcium signaling were affected throughout all stages analyzed. LimitationsThe limitation of our study is the number of biological replicates. As the aim of our study was to investigate a large number of proteins, only a limited amount of biological replicates were suitable for inclusions without reducing the number of target proteins. Therefore, larger sample sizes derived from RTT patients will be needed to validate results. ConclusionsOur results provide a valuable resource of proteins to study potential targets for early treatment of RTT symptoms. We found consistent and time-point specific alterations during early neuronal differentiation in RTT cultures. Insight into altered protein levels can help development of new biomarkers and therapeutic approaches in RTT syndrome. Therefore, we hope that our results give awareness of the early pre-natal onset of RTT, providing new insights to explore early diagnosis and treatment

[13] 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: 0.426) > 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].

[14] A Multi-Label Learning Framework for Drug Repurposing

• Authors: Suyu Mei, Kun Zhang
• Year: 2019
• Venue: Pharmaceutics
• URL: https://www.semanticscholar.org/paper/6025d6668bd544c1f3cbb8e4433c549b4f7eed03
• DOI: 10.3390/pharmaceutics11090466
• PMID: 31505805
• PMCID: 6781509
• Citations: 18
• Influential citations: 1
• Summary: The proposed multi-label learning framework is used to predict new drugs for the known target genes, identify new genes for the old drugs, and infer new associations between old drugs and new disease phenotypes via the OMIM database.
• Evidence snippets:
• Snippet 1 (score: 0.425) > The predicted associations between drugs and diseases show that the disease phenotypes associated with identical drugs share some common molecular mechanisms. For instance, neurodevelopmental disorder with microcephaly (OMIM:192150), lung cancer (OMIM:604050), 3MC syndrome 1 (OMIM:600521), and Fanconi anemia (OMIM:613976) are all associated with dysregulation of cell cycles and DNA repair, the supporting evidences for which have been reported in recent literature [43][44][45][46]. The computational results promise to provide insights into new clinical therapies for new or old disease phenotypes and establish associations between drugs and diseases, which can be further augmented by exploring the drug-gene associations (e.g., search in the open target database (https://www.opentargets.org/)) and the gene-disease associations (e.g., search in the human protein atlas (https://www.proteinatlas.org/).

[15] 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: 0.424) > 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].

[16] 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: 0.422) > 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.

[17] Probing disorders of the nervous system using reprogramming approaches

• Authors: J. Ichida, E. Kiskinis
• Year: 2015
• Venue: The EMBO Journal
• URL: https://www.semanticscholar.org/paper/07c84453351dfc9065d2f4870f5c534a96e63282
• DOI: 10.15252/embj.201591267
• PMID: 25925386
• PMCID: 4474524
• Citations: 4
• Summary: Tables listing the various human neural cell types that can be generated and the neurological disease modeling studies that have been reported are presented, the current state of the field is described, important breakthroughs are highlighted and the next steps and future challenges are discussed.
• Evidence snippets:
• Snippet 1 (score: 0.422) > Neurological disorders including schizophrenia, ALS, PD, FTD and epilepsy are often characterized by a profound clinical and genetic heterogeneity, suggesting that they might represent a syndrome rather than a single nosological entity (Fanous & Kendler, 2005;Tremblay et al, 2013;Jeste & Geschwind, 2014). The variable combination of positive and negative symptoms in schizophrenia, the variable degree of upper and lower motor neuron dysfunction in ALS, the heterogeneity of cognitive symptoms in PD, the variable rate of progression in FTD and the differential response to anti-epileptic treatments in epileptic syndromes are some examples of the clinical diversity in neurological disorders. In addition, genetic studies in ALS, for example, have demonstrated that the disease can be caused by mutations in genes that encode proteins involved in diverse cellular functions ranging from RNA metabolism, vesicle transport, cytoskeletal homeostasis and the processing of unfolded proteins (Cleveland & Rothstein, 2001;Pasinelli & Brown, 2006;Sreedharan & Brown, 2013). While progress has been achieved in terms of genetic taxonomy, pathological stratification and the classification of patients based on their clinical presentation, little is known about how similar or different patients are, in terms of the molecular pathways that mediate their disease processes. Reprogramming technologies can be used to develop in vitro models of genetic and sporadic disease cases and effectively stratify patients, based on (i) the neuronal subtype that exhibits a disease-associated phenotype and (ii) the pathway that leads to this phenotype in each case (Fig 3). This approach may lead to the identification of overlapping disease mechanisms that will be broadly relevant and represent the best therapeutic opportunities, or toward a personalized approach to clinical trials and therapeutic treatments.

[18] Systems-Level Integration of Multi-Omics Identifies Genetic Modifiers of TANGO2 Deficiency Disorder

• Authors: Manuel Airoldi, Heather Bondi, Veronica Remori, Silvia Carestiato, G. B. Ferrero et al.
• Year: 2025
• Venue: Biomolecules
• URL: https://www.semanticscholar.org/paper/843a98899e43b4ade1c22b4dcbdef76801cfa130
• DOI: 10.3390/biom15121742
• PMID: 41463395
• PMCID: 12730736
• Summary: An integrative multi-omics framework provides a valuable strategy for elucidating genotype-phenotype relationships in rare diseases and supports personalized therapeutic approaches and suggest autophagy and mitophagy as additional modifier mechanisms influencing phenotypic variability.
• Evidence snippets:
• Snippet 1 (score: 0.421) > Systems biology is an interdisciplinary approach that seeks to understand biological complexity by integrating diverse layers of molecular information, such as genomics, transcriptomics, proteomics, and metabolomics, within the framework of networks and dynamic systems [1]. Rather than examining single genes or molecules in isolation, it models how genes, proteins, and pathways interact to influence health and disease. This approach has greatly advanced the understanding of disease mechanisms, particularly through the construction of molecular interaction networks and the identification of key drivers of disease phenotypes, even in small or genetically heterogeneous cohorts [2,3]. By mapping protein-protein interactions (PPI) and signaling pathways, Systems biology provides a holistic view of cellular processes that is especially valuable for rare Mendelian disorders, which often remain poorly characterized due to limited patient numbers and scarce functional studies of disease-associated genes. Even when patients carry identical causative mutations, rare diseases frequently show marked phenotypic variability. In such cases, secondary variants may act as genetic modifiers (gene variants able to modify the phenotypic outcome of the primary disease gene) and thereby influence disease severity and contribute to clinical variability [4]. Identifying these genetic modifiers remains a major challenge, especially in the context of rare diseases where traditional association studies lack statistical power [4]. Advanced statistical and multivariate methods are therefore essential to extract mechanistic insight from high-dimensional multi-omics datasets, particularly in neurodevelopmental disorders and other rare conditions where sample sizes are limited but molecular complexity is high [5]. Network-based analyses have proven effective in pinpointing key regulatory nodes and functional modules that drive disease pathogenesis, which may serve as therapeutic targets [6]. Moreover, the integration of omics data with curated phenotype repositories, such as the Human Phenotype Ontology (HPO, a structured vocabulary of phenotypic abnormalities), facilitates mapping molecular signatures to clinical features, providing deeper insights into disease heterogeneity and underlying biological processes [7].

[19] 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: 0.420) > 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

[20] 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: 0.418) > 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).

Notes

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