Asta Literature Retrieval: Pathophysiology and clinical mechanisms of UNC13A-Related NDD with Seizures and Movement Disorder. Core disease mecha...

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

• Papers retrieved: 18
• Snippets retrieved: 20

Relevant Papers

[1] Shared Disease Mechanisms in Neurodevelopmental Disorders: A Cellular and Molecular Biology Perspective

• Authors: Elizabeth A. Pattie, Philip H. Iffland
• Year: 2025
• Venue: Brain Sciences
• URL: https://www.semanticscholar.org/paper/865dae8982d06d64da4620ccd43bc895dda351f5
• DOI: 10.3390/brainsci16010054
• PMID: 41594775
• PMCID: 12839103
• Summary: Several genes—including CDKL5, TSC1/2, SCN1a, and TANC2—that have been associated with epilepsy, ASD, or other NDD phenotypes that play a critical role in regulating one or more stages of brain development or function but differ widely in their disease-causing mechanisms are described.
• Evidence snippets:
• Snippet 1 (score: 0.526) > However, for genes that are critical for early stages of brain development, there tend to be higher rates of comorbidity. However, even in that context, some genes seem to impact separate downstream processes that serve as distinct etiologies for epilepsy and NDDs, as indicated by the genes where therapeutics improve one but not the other. Alternatively, there may be a causative relationship (e.g., cognitive impairments or developmental regression caused by neurotoxicity of seizure activity). However, many of the molecular and cellular mechanisms behind brain development, epilepsy, ASD, and NDDs still remain unclear. Indeed, there is still much that remains unknown about the molecular function of most of these genes and the sequence of events that connect molecular function to network function to disease phenotype. Further, things like gene dose sensitivity, genetic imprinting, variant-specific changes in protein product and domain functionality, and other factors that impact variable expressivity and penetrance make it challenging to interpret the relationship between gene function and phenotype. Many genes, especially ones that regulate broad cellular functions, such as proliferation, migration, and differentiation, are also likely to have syndromic presentations. Some of them are also linked to cancer development and progression, which further supports the importance of these genes in functional mechanisms of molecular and cellular biology. However, understanding these cellular mechanisms, especially when considering distinct functional outcomes across pathogenic variants, will be invaluable for identifying therapeutic targets and developing new treatment options. > There are several limitations that hinder the ability of investigators to clearly define disease mechanisms and implement novel therapies in NDDs. First, due to the rarity of some of these disorders, it is difficult to establish genotype-phenotype correlations, and the paucity of available samples makes it challenging to elucidate disease mechanism both within, and especially across, variants. Additionally, while the increased accessibility to whole genome sequencing has significantly expanded the number of identified pathogenic variants associated with NDDs, detection of somatic mosaic variants remains challenging in brain-specific disorders. GoF and LoF variants in the same genes can result in similar phenotypes, making understanding disease mechanisms even more challenging and can make large-scale clinical trials of novel therapies difficult.

[2] Role of the UNC13 family in human diseases: A literature review

• Authors: Ubaid Ansari, Vincent Chen, Romteen Sedighi, Burhaan Syed, Zohaer Muttalib et al.
• Year: 2023
• Venue: AIMS Neuroscience
• URL: https://www.semanticscholar.org/paper/8b98aadabb89e217c6b63a9818e1a43df2527e5d
• DOI: 10.3934/Neuroscience.2023029
• PMID: 38188011
• PMCID: 10767061
• Citations: 10
• Summary: This literature review explores the pivotal roles of the Uncoordinated-13 (UNC13) protein family, encompassing UNC13A, UNC13B, UNC 13C, and UNC13D, in the pathogenesis of various human diseases, shedding light on potential therapeutic strategies and avenues for future research.
• Evidence snippets:
• Snippet 1 (score: 0.511) > In recent years, the study of molecular mechanisms underlying various human diseases has garnered significant attention within the scientific community. In particular, neurological and immunological disorders have been the focus of extensive research efforts, aiming to uncover the intricate pathways and molecules that govern disease initiation, progression, and manifestation. Among the key players identified in these contexts, members of the uncoordinated-13 (UNC13) protein family have emerged as pivotal contributors, influencing a range of physiological processes across diverse cell types [1]. Collectively known as the UNC13 family, UNC13A, UNC13B, UNC13C, and UNC13D exhibit distinct functional roles within various cellular contexts and have been implicated in the pathogenesis of multiple diseases. The UNC13 family proteins are evolutionarily conserved members of the priming factor family that play essential roles in synaptic vesicle priming and exocytosis, as well as other cellular processes such as immune responses [2]. The genetic variations and dysregulation of these proteins have been associated with an array of disorders, thus highlighting their indispensable contributions to human health [2]. This review aims to comprehensively examine the role of each UNC13 family member-UNC13A, UNC13B, UNC13C, and UNC13D-in different diseases, thereby shedding light on their distinct molecular functions and their implications in pathological contexts. > UNC13A, which is predominantly expressed in the nervous system, has been implicated in many neurodegenerative disorders and neurological conditions such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) due to its involvement in neurotransmitter release and synaptic plasticity [3]. UNC13B, which is closely related to UNC13A, has shown its significance in autism spectrum disorders (ASD), partial epilepsy, and schizophrenia [4]. Additionally, it has been associated with neurodegenerative disorders and immune-related diseases.

[3] Neurodevelopmental Disorders: From Genetics to Functional Pathways.

• Authors: I. Parenti, Luis G. Rabaneda, Hanna Schoen, G. Novarino
• Year: 2020
• Venue: Trends in neurosciences
• URL: https://www.semanticscholar.org/paper/67a29e485ecef803bfe85217288593b0ce86f89e
• DOI: 10.1016/j.tins.2020.05.004
• PMID: 32507511
• Citations: 478
• Influential citations: 13
• Summary: The multiple factors that influence the clinical presentation of NDDs are discussed, with particular attention to gene vulnerability, mutational load, and the two-hit model.
• Evidence snippets:
• Snippet 1 (score: 0.503) > disease risk. Examples of highly vulnerable genes include DEPDC5, CACNA1A, and SCN8A, which are discussed later in this section. Disruption of one of these genes has a high probability of inducing the onset of a disease phenotype also Glossary BRG1/BRM-associated factor (BAF) chromatin remodeling complex: a chromatin modifier family that uses ATP energy to alter nucleosomal units in chromatin structures. CLIP cells: human-specific caudal late interneuron progenitors characterized in organoids by a late midgestational origin and expression of genes associated with the caudal ganglionic eminence (i.e., COUP-TFII, PROX1, and EGFR). Comorbidity: presence of one or more conditions together with a primary medical condition. In the context of NDDs, this refers to the occurrence of two or more NDD phenotypes in individual patients. Epistasis: physical and/or functional interaction between gene products responsible for the onset of a given phenotype. Gene vulnerability: capability of a given gene to tolerate potentially disruptive mutations. Genetic counseling: process aimed at advising families with one or more individuals affected by a genetic condition. It helps to understand the genetic contributions to the disease and to calculate the risk of recurrence of the disease in the offspring. Molecular diagnosis: identification of the mutational event responsible for the onset of a disease phenotype. To be distinguished from clinical diagnosis, which represents instead the recognition of a specific disease affecting a patient based on the interpretation of the observed clinical signs. mTORopathies: spectrum of dysfunctional cortical development characterized by altered cortical architecture, abnormal neuronal/glial morphology, and intractable seizures as a consequence of deregulation of mTOR signaling. Multifactorial/polygenic disorder: disorder characterized by a combination of genetic and nongenetic factors or by the combination of different mutational events. Multipathway loop: in neurons, changes in synaptic or neuronal physiology are subserved by alterations in dendritic and nuclear events, operating via cellular feedback mechanisms. Mutations affecting one pathway may alter the correct functionality of different pathways, thus pertur

[4] Following Excitation/Inhibition Ratio Homeostasis from Synapse to EEG in Monogenetic Neurodevelopmental Disorders

• Authors: L. Geertjens, T. V. van Voorst, A. Bouman, Maaike A. van Boven, T. Kleefstra et al.
• Year: 2022
• Venue: Genes
• URL: https://www.semanticscholar.org/paper/0c819e29f81200e9d4d410524c5cd7ba413ff1c3
• DOI: 10.3390/genes13020390
• PMID: 35205434
• PMCID: 8872324
• Citations: 11
• Influential citations: 2
• Summary: A concerted multi-level strategy ‘BRAINMODEL’ is presented, focusing on excitation/inhibition ratio homeostasis across different levels of neuroscientific interrogation, to develop personalized treatment strategies for severe genetic neurodevelopmental disorders.
• Evidence snippets:
• Snippet 1 (score: 0.499) > Even though almost all cases present with ID, the mechanisms through which mutations in SNARE genes lead to neurodevelopmental impairments remain unexplained. Additional genetic and/or environmental factors might contribute substantially to disease presentation and should be considered when studying disease mechanisms [55]. Based on mouse models, mutations in SNAREopathy genes also create a disturbed E/I ratio setpoints [55]. However, it is unknown to which extent the different components in the E/I microcircuits in the brain are susceptible to gene mutations [55]. > disorders, caused by mutations that disturb SNARE function, are a subset of the previously defined synaptopathies. The neuronal SNARE complex (soluble NSF attachment protein receptor complex) is an important molecular machine driving synaptic vesicle exocytosis and secretion of neuropeptides and neuromodulators from dense core vesicles [55]. We focus on four of these genes that are associated with NDDs (STXBP1, SYT1, SNAP25, RIMS1) (Figure 3). Although the pathogenic starting point of these disorders is well defined, clinical phenotype and disease severity is very diverse. Moreover, high clinical variety is found in the same amino acid changes between different individuals [55]. Most common clinical aspects found in SNAREopathies are ID and/or DD, seizures, ASD, and neurological motor problems. Even though almost all cases present with ID, the mechanisms through which mutations in SNARE genes lead to neurodevelopmental impairments remain unexplained. Additional genetic and/or environmental factors might contribute substantially to disease presentation and should be considered when studying disease mechanisms [55]. Based on mouse models, mutations in SNAREopathy genes also create a disturbed E/I ratio setpoints [55]. However, it is unknown to which extent the different components in the E/I microcircuits in the brain are susceptible to gene mutations [55].
• Snippet 2 (score: 0.490) > Although mNDDs caused by mutations in these genes have the same neurobiological etiology (altered chromatin remodeling), there is a high variability in clinical presentation. Apart from intellectual disability (ID) and/or developmental delay (DD) presenting in almost 100% of cases, core symptoms are childhood hypotonia, psychiatric disorders (including autism-spectrum disorder (ASD), attention-deficit disorder (ADHD), and anxiety), epilepsy, and sleep disorders. In addition, facial dysmorphisms are present, and anomalies are found in several organ systems [48][49][50][51]. As for the E/I ratio homeostasis, previous studies showed that the Loss of function (LoF) of EHMT1 results in delayed GA-BAergic maturation, reduced inhibition, and hence increased E/I ratio [52][53][54]. SNAREopathies are another group of pathobiological well-defined mNDDs. These disorders, caused by mutations that disturb SNARE function, are a subset of the previously defined synaptopathies. The neuronal SNARE complex (soluble NSF attachment protein receptor complex) is an important molecular machine driving synaptic vesicle exocytosis and secretion of neuropeptides and neuromodulators from dense core vesicles [55]. We focus on four of these genes that are associated with NDDs (STXBP1, SYT1, SNAP25, RIMS1) (Figure 3). Although the pathogenic starting point of these disorders is well defined, clinical Genes 2022, 13, 390 5 of 10 phenotype and disease severity is very diverse. Moreover, high clinical variety is found in the same amino acid changes between different individuals [55]. Most common clinical aspects found in SNAREopathies are ID and/or DD, seizures, ASD, and neurological motor problems. Even though almost all cases present with ID, the mechanisms through which mutations in SNARE genes lead to neurodevelopmental impairments remain unexplained.

[5] Toward a new nosology of neurodegenerative diseases

• Authors: M. Menéndez-González
• Year: 2023
• Venue: Alzheimer's & Dementia
• URL: https://www.semanticscholar.org/paper/4407f839d31ee6cbf707ee1aab7b9b0e613cc09a
• DOI: 10.1002/alz.13041
• PMID: 36960767
• Citations: 10
• Summary: This article aims to prompt a change in how NDD is diagnosed and classify, drafting a general scheme for a new nosology based on a tridimensional classification based on three axes: etiology or pathogenic mechanism, pathology markers and molecular biomarkers, anatomic–clinical; and three hierarchical levels of etiology.
• Evidence snippets:
• Snippet 1 (score: 0.498) > In spite of these shared alterations, the eight cellular dysfunctions were more or less associated with the identifiable pathologies in the brain characteristic of each disease. 36 Thus, changes in cellular pathways and cellular processes may be shared by multiple NDDs (and even by some diseases today considered psychiatric 37 ) driving distinctive anatomic-clinical features. Though more studies will be needed to better understand the processes involved, these common factors may be the initial seeds that later develop into each of the distinct CNS disorders, while the mechanisms responsible for them germinate into diverse diseases and symptomologies, attacking different regions of the brain. 38 e characteristic clinical picture for each NDD consists of a variable combination of cognitive, motor, and neuropsychiatric symptoms at the core, with a long list of other potentially associated symptoms. > These phenotypes are the "classic" forms of the disease, that is, as originally described (eponyms). Thus, traditional methods of describing and classifying NDDs are based on the original clinicopathological concept; that is, a distinct clinical profile in combination with "signature" pathological lesions. This system was used to describe the first cases of AD, 39 Pick's disease (PiD), 40 dementia with Lewy bodies TA B L E 1 On the left, the main hallmarks describe cellular health, in cellular aging and in neurodegeneration. On the right, relevant cellular pathways, cellular processes, and pathogenic mechanisms in neurodegeneration.
• Snippet 2 (score: 0.464) > Pathologically, besides cellular loss, most NDDs exhibit molecular hallmarks that are deposits of disease-specific proteins. Because some extent of protein deposits is normal during physiological aging, precise neuropathological criteria are needed to differentiate normal brain aging from NDD. 4 In medicine, good classifications of diseases can help us better understand their symptoms and their evolution to develop better diagnostic methods and potential treatments. NDDs can be classified in various ways, including by the specific type of nerve cells affected, the part of the nervous system affected, and the underlying cause of the disease. Both in research and in clinical practice, one common way to classify NDDs is by the proteins that are deposited; in this way, NDDs can be understood as "proteinopathies." From this perspective, the central event in the pathophysiology of an NDD is a proteostasis imbalance leading to protein aggregation overwhelming the capacity of brain cells to re-establish homeostasis (e.g., via ubiquitin-proteasome and autophagy-lysosome systems), functional proteinopenia, 5 and interfering with the ability of neurons to cope with the pathogenic proteins. 6,7 Autophagy encompasses pathways that route cytoplasmic material to lysosomes for degradation. Because these pathways are crucial for degrading aggregate-prone proteins and dysfunctional organelles such as mitochondria, they help maintain cellular homeostasis. As post-mitotic neurons cannot dilute unwanted protein and organelle accumulation by cell division, the nervous system is particularly dependent on autophagic pathways. This dependence may be a vulnerability as people age and these processes become less effective in the brain. Hence, aging is a prominent risk factor for genetic and sporadic NDDs, and the molecular mechanisms that render the aged brain particularly susceptible to sporadic NDD seem to be linked to proteostasis capacity. 8,9 e origin of proteostasis imbalance may be genetic and/or the result of acquired causes. Today, the etiologies for most genetic NDDs are generally known, yet we do not have a precise understanding of the etiologies of sporadic NDDs.

[6] In Silico Studies in Drug Research Against Neurodegenerative Diseases

• Authors: F. R. Makhouri, Jahan B. Ghasemi
• Year: 2017
• Venue: Current Neuropharmacology
• URL: https://www.semanticscholar.org/paper/37530a95d437cbcf42f801faf79e53e2fab0d22e
• DOI: 10.2174/1570159X15666170823095628
• PMID: 28831921
• PMCID: 6080098
• Citations: 48
• Influential citations: 1
• Summary: Neurodegenerative diseases have a multifactorial pathoetiological origin, so scientists have become persuaded that a multi-target therapeutic strategy aimed at the simultaneous targeting of multiple proteins involved in the development of a disease is recommended in future.
• Evidence snippets:
• Snippet 1 (score: 0.492) > Neurodegenerative diseases (NDDs), termed 'proteinmisfolding disorders', are a heterogeneous group of disorders that are described by profound loss of neurons and distinct involvement of functional systems defining clinical presentations. Comprehensive neuropathological, molecular genetic and biochemical assessments suggested that proteins with modified physical and chemical properties are deposited in the human brain but also in peripheral organs as a fundamental phenomenon in many forms of NDDs [1]. According to this, a physiological protein triggers structural conformational changes, which can result in the loss of function or altered function, aggregation and intra-or extra-neuronal accumulation of amyloid fibrils. The ubiquitin-*Address correspondence to this author at the Chemistry Department, Faculty of Sciences, University of Tehran, Tehran, Iran; Tel: +982161112726; Fax: +98 21 66495291; E-mail: jahan.ghasemi@ut.ac.ir proteasome pathway and the autophagy-lysosome system, oxidative stress response proteins and chaperone network are protein elimination pathways that contribute to controling the quality of cellular components and serve to maintain proteostasis of the cell. These pathways have high impact on the pathogenesis of NDDs. Impaired mitochondrial function and oxidative damage, dysregulated bioenergetics and DNA oxidation, neuroinflammation, dysregulation of ion homeostasis and cellular/axonal transport defects are related to the formation of toxic forms of NDD-related proteins [2]. Classification of NDDs is based on the correlation of clinical symptoms with neuropathology, anatomical distribution of neuronal loss and cell types affected, conformationally changed proteins, and etiology. Clinical-anatomical classification of neurodegenerative disorders, which is useful mostly when clinical symptoms and signs are early diagnosed, is as follows: (1) Cognitive dysfunction as early symptom, dementia and alteration in high-order brain functions that are closely related to involvement of the hippocampus, entorhinal cor-tex, limbic system (amygdala, olfactory cortices, anterior cingulate cortex, subcortical structures) and neocor

[7] Exploring the Landscape of Pre- and Post-Synaptic Pediatric Disorders with Epilepsy: A Narrative Review on Molecular Mechanisms Involved

• Authors: Giovanna Scorrano, Ludovica Di Francesco, Armando Di Ludovico, Francesco Chiarelli, S. Matricardi
• Year: 2024
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/d194d701009fe8f817e4719aa1fcea9d399e1829
• DOI: 10.3390/ijms252211982
• PMID: 39596051
• PMCID: 11593774
• Citations: 6
• Summary: A narrative review of emerged molecular mechanisms related to NDDs and epilepsy due to defects in pre- and post-synaptic transmission focused on the most recently discovered SNAREopathies and AMPA-related synaptopathies.
• Evidence snippets:
• Snippet 1 (score: 0.485) > The association between synaptic dysfunction and epilepsy underscores the importance of understanding the molecular underpinnings of these disorders. Many NDDs with epileptic manifestations involve variants in genes that regulate the formation, maintenance, and plasticity of synapses. proteins such as STXBP1 and TBC1D24 are essential for proper synaptic vesicle dynamics, and their disruption can lead to abnormal neurotransmitter release and epileptic seizures. Likewise, postsynaptic proteins like PSD-95, Shank, and Neuroligins, which play pivotal roles in organizing the postsynaptic density and ensuring effective receptor signaling, are frequently implicated in NDDs associated with seizures. > A prompt and accurate diagnosis of these conditions is crucial for optimizing patient care and improving patients' and their families' quality of life. Genetic testing should be routinely performed in all patients displaying NDDs associated with epilepsy or extraneurological comorbidities, as identifying the underlying genetic cause can guide personalized treatment strategies. This is particularly important given that many synaptic disorders can present with developmental and epileptic encephalopathy, where early intervention can modify the clinical trajectory and improve outcomes. > Concurrently, functional animal model studies and clinical trials on patients with synaptopathies and associated epilepsy should be carried out to enhance our understanding of the pathogenesis of these disorders. By deepening our knowledge of the molecular mechanisms involved in pre-and post-synaptic transmission, we can develop targeted therapies to restore synaptic function and potentially modify the natural history of these complex conditions. > Further understanding of the specific pathways affected in presynaptic versus postsynaptic synaptopathies will be crucial in developing more precise and effective treatments. > As for many other monogenic diseases with epilepsy, the variability in phenotypic expression could arise from several factors, including the possibility that a single variant may lead to multiple phenotypes, reflecting these genes' broad roles in neural development, synaptic function, and brain connectivity. In other cases, different variants within the same gene may result in distinct phenotypes.

[8] The power of human stem cell-based systems in the study of neurodevelopmental disorders.

• Authors: Megha Jhanji, E. York, Sofia B. Lizarraga
• Year: 2024
• Venue: Current opinion in neurobiology
• URL: https://www.semanticscholar.org/paper/e3993562007ed170c8501a1bd854d35f54c628f2
• DOI: 10.1016/j.conb.2024.102916
• PMID: 39293245
• Citations: 5
• Summary: A comprehensive overview of the latest research on two and three-dimensional human stem cell-based models for NDDs is provided and the potential of stem cell systems to draw mechanistic insight for the study of sex dimorphism within NDDs is explored.
• Evidence snippets:
• Snippet 1 (score: 0.479) > During development of the nervous system, careful orchestration of multiple cellular processes takes place to ensure that the proper architecture and wiring of the brain is established. These cellular processes include neuronal progenitor cell (NPC) division, neuronal migration, neuronal/glial differentiation and maturation, as well as synapse development and function. Mutations in genes that modulate any of these processes could alter neuronal population characteristics or connectivity, leading to neurodevelopmental disorders (NDDs) that affect cognition, motor function, behavior, and in some instances, present with seizure activity [1]. Among the most prevalent NDDs are Down syndrome (w1:4000), Angelman syndrome (w1:10000), Rett syndrome (w1:10000), Tuberous sclerosis (w1:20000) and Fragile X (w1:4000 in males) which have been extensively reviewed elsewhere [2e6]. Some of the clinical phenotypes broadly shared across these syndromes and other NDDs include: intellectual disability (ID), autistic behaviors, seizures, alterations in brain size, hypoplasia of the corpus callosum, sleep disturbances, and gastrointestinal problems [2e7]. These overlapping clinical presentations suggest common underlying cellular and physiological phenotypes (Figure 1). However, there is widespread genetic heterogeneity among NDDs. In fact, a comparative analysis of multiple databases of high-risk genes associated with autism spectrum disorders (ASD), ID, and developmental brain disorders discovered over 1500 high confidence risk genes associated with NDDs [8]. Gene ontology analysis of NDDs' high confidence risk genes showed an enrichment of pathways involved in synaptic function, neuronal development, chromatin/transcriptional regulation, cell cycle regulation, transport processes, and mitochondrial function, which points to nodes of functional convergence. > The combination of human genetics, postmortem tissue, and animal studies has advanced the understanding of several underlying mechanisms associated with different NDDs [1].

[9] Biomarker-guided classification scheme of neurodegenerative diseases

• Authors: F. Baldacci, S. Lista, F. Garaci, U. Bonuccelli, N. Toschi et al.
• Year: 2016
• Venue: Journal of Sport and Health Science
• URL: https://www.semanticscholar.org/paper/163f1c94ec488108888d3e050a667a0d2ece0ce3
• DOI: 10.1016/j.jshs.2016.08.007
• PMID: 30356557
• PMCID: 6188916
• Citations: 22
• Influential citations: 1
• Summary: A biomarker-guided classification scheme of neurodegenerative diseases and its applications in medicine and physiology are presented.
• Evidence snippets:
• Snippet 1 (score: 0.470) > Among emerging theories, it has been postulated that a specific misfolded protein characteristic of the pathobiochemistry in a particular NDD can spread from one cell to another (both transcellularly and synaptically) in a prionlike manner, thus potentially inducing complex neural network alterations, which are structural and functional system substrates of clinical symptomatic progression at advanced stages of NDDs. 4,5 Notably, these aberrantly altered proteins represent candidate targets for therapy development and/or may be utilized as specific diagnostic and prognostic biomarkers of disease. The neurodegenerative process is hypothesized to initiate focally and then propagate strategically across wider brain regions through complex networks, in line with specific dynamic progression patterns likely defined by genetic drivers and triggers during the initiation stages of the proteinopathy. 4,6 ence, as a consequence, the emerging pathophysiological mechanisms, the subsequent neuropathology, and both the time of onset and dynamics of progression through time and space and the emergence of the late-stage clinical phenotype of NDDs can vary substantially between postulated clinical disease groups, subsets of disease, and individuals grouped into those operationalized categories. For instance, "typical AD"-that is, the hippocampal variant of AD according to the International Working Group-2 diagnostic criteria 7 -shows, at the preclinical asymptomatic stage, a marked alteration and subsequent disruption of the default mode network, 6 whereas primary progressive aphasia displays a pattern of network dysfunction mainly localized in language brain areas. 4 However, several cases of amyloid beta (Aβ) pathophysiology may also exhibit atypical patterns of network change leading to disconnection and disintegration. 7 The atypical variants-namely, frontal, posterior, and logopenic-present behavioral, visual, or language symptoms, which from a clinical point of view overlap those involved in other NDDs.

[10] Editorial: In vitro and in vivo models for neurodevelopmental disorders

• Authors: Angelica D’Amore, Maria Marchese, Wardiya Afshar-Saber, M. Hameed
• Year: 2023
• Venue: Frontiers in Neuroscience
• URL: https://www.semanticscholar.org/paper/363a97d218672cdde3cc7a46abc26b7506313422
• DOI: 10.3389/fnins.2023.1239577
• PMID: 37502680
• PMCID: 10368529
• Citations: 3
• Summary: In vitro and in vivo models for neurodevelopmental disorders and how these models change over time are studied are studied.
• Evidence snippets:
• Snippet 1 (score: 0.468) > In vitro and in vivo models for neurodevelopmental disorders Neurodevelopmental disorders (NDDs) are a group of disorders affecting brain development and function. Each disorder within this heterogenous group (i.e., intellectual disability/ID, autism spectrum disorder/ASD, attention-deficit/hyperactivity disorder etc.) has distinct clinical characteristics and phenotypical variability. While each disorder is indeed defined by a set of symptoms, individual symptoms are not necessarily restricted to one disorder. Comorbidity of two or more NDDs is frequently observed: for instance, a combination of ID, ASD, and epilepsy is commonly reported in patients (Parenti et al., 2020). Many NDDs have strong genetic bases and several hundred genes have been implicated in such NDDs either through genetic association studies, rare mutations, copy number variation etc. However, there is a significant proportion of NDDs with an unknown genetic cause (i.e., idiopathic) and, in those instances, the diagnosis is based only on interviews and medical examination. To date, several pathways have been associated with NDDs (mTOR, WNT, pathways associated with chromatin remodeling and synaptic function etc.) and understanding the molecular mechanism behind NDDs has the potential to define druggable targets, making in-vitro and in-vivo disease models fundamental tools for advancing the field (Thapar et al., 2017;Cardoso et al., 2019;Bozzi and Fagiolini, 2020;Nussinov et al., 2023). > In the last decades, the scientific community has been focusing on investigating the cellular and molecular mechanisms behind NDDs, trying to develop effective tools, using both in-vitro and in-vivo models. These complex disorders can be modeled using either animal models, such as rodents and zebrafish, or cellular models like iPSCs, enabling behavioral and functional analyses in the presence of disease-causing mutations.

[11] Network biology: A promising approach for drug target identification against neurodevelopmental disorders

• Authors: Wayez Naqvi, Ananya Singh, Prekshi Garg, P. Srivastava
• Year: 2023
• Venue: BIOCELL
• URL: https://www.semanticscholar.org/paper/82eca3c6c2521e79970ccff09d549b692cb259be
• DOI: 10.32604/biocell.2023.029624
• Citations: 4
• Summary: The role and application of network biology is summarized for not only unfolding the mechanism of complex neurodevelopmental disorders but also identifying important drug targets for diseases like ADHD, Autism, Epilepsy, and Intellectual Disability.
• Evidence snippets:
• Snippet 1 (score: 0.464) > The study of the molecular and genetic basis of diseases has been revolutionized in the past decade by the application of next-generation sequencing technologies and computational approaches. One of the biggest challenges these days is the identification of clinically relevant data from the plethora of data available. The functionality of biomolecules is widely known to be interdependent, forming a complex biomolecular network including protein-protein interaction (PPI), metabolic, signaling and transcription-regulatory networks. For instance, a disease is rarely an outcome of the dysfunction of a single gene; rather, it is a consequence of the malfunction of complex networks that regulate genes, tissues and organ systems (Liu et al., 2020). Network biology has emerged as an important approach to understand and integrate these complex networks and gain knowledge of clinically actionable data for understanding the molecular mechanism of diseases, which can provide biological insights for the diagnosis and treatment of these diseases. PPI network has turned out to be an asset in this context (Furlong, 2013). Based on the results of experimental methods, the human interactome was estimated to contain~65000 protein interactions (Stumpf et al., 2008). Biological networks have been used to interpret disease mechanisms to study comorbidities, drug-target interactions and discover network-based biomarkers. Thus, network biology can be used to understand complex genotype-phenotype relations of human diseases (Furlong, 2013). In the present paper, we review the literature on network analysis related to neurodevelopmental disorders (NDDs). > NDDs are a class of disorders that affect brain development and functions characterized by the inability to reach cognitive, emotional, and motor developmental milestones; they pose a serious health problem affecting >3% of children worldwide (Parenti et al., 2020). NDDs include attention-deficit/hyperactivity disorder (ADHD), intellectual disability (ID), autism spectrum disorder (ASD) and epilepsy. Studies provide compelling evidence that many disease genes map to a much smaller number of biological subnetworks (Hormozdiari et al., 2015), suggesting the involved genes share a common molecular pathway, resulting in comorbidity of two or more of these disorders. For instance, a combination of

[12] Copathology in Progressive Supranuclear Palsy: Does It Matter?

• Authors: Milica Jecmenica Lukic, C. Kurz, G. Respondek, O. Grau‐Rivera, Y. Compta et al.
• Year: 2020
• Venue: Movement Disorders
• URL: https://www.semanticscholar.org/paper/7f63154771f33a4b08a57a7888237eb6c7ad5aaf
• DOI: 10.1002/mds.28011
• PMID: 32125724
• Citations: 74
• Summary: The influence of concomitant brain pathologies on the progression rate in PSP is unclear.
• Evidence snippets:
• Snippet 1 (score: 0.464) > Conclusions: In PSP, concomitant neurodegenerative proteinopathies or cerebrovascular diseases are frequent, but generally mild in severity. Our data confirmed that four repeat tau is still the most relevant target for PSP, whereas the impact of copathologies on progression rate appears to be of less importance. This is relevant information for the development of disease-modifying therapies. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. > Key Words: clinical phenotype; clinic-pathological correlation; copathology; progressive supranuclear palsy Understanding the mechanism underlying disease progression, as well as measuring the progression rate of neurodegenerative disorders (NDDs), is central to defining the effects of therapeutic intervention. Progression of NDDs, including PSP, is thought to be largely driven by specific protein aggregations and their cellular and regional transmission within the central nervous system. However, given that NDDs typically manifest later in life, it is not surprising that additional proteinopathies and vascular copathologies may coexist and may also contribute to the progression rate of such diseases. In line with this view, copathologies, such as Alzheimer;s disease (AD)-related pathology in synucleinopathies, as well as transactive response DNA-binding protein 43 (TDP-43) copathology in AD, were found to shape the clinical presentations of these NDDs. [1][2][3][4] PSP is a primary tauopathy, defined by accumulation of the four repeat (4R) isoforms of the microtubuleassociated protein tau in neurons and glial cells, with tufted astrocytes as the diagnostic hallmark lesion of this disease. 5,6 A recent study indicated that, among tauopathies, PSP has the highest prevalence of additional NDD-related proteins. 3 However, no data exist about the influence of such findings on the disease course in PSP. > Given that the tempo of disease progression is mainly highlighted through the latency to reach major clinical milestones of PSP, we aimed to analyze the possible influence of concomitant brain pathology on occurrence of such milestones, in a well

[13] A bibliometric analysis of acupuncture for neurodevelopmental disorders: A Call for increased output and future research priorities

• Authors: Juexuan Chen, Huanjie Li, Dayuan Zhong, Fangwei Xu, Lu Ding et al.
• Year: 2023
• Venue: Heliyon
• URL: https://www.semanticscholar.org/paper/b2fd22c0c156830aa1887d0b4591560e77289f26
• DOI: 10.1016/j.heliyon.2023.e22799
• PMID: 38213582
• PMCID: 10782164
• Citations: 3
• Summary: A bibliometric analysis of published research on acupuncture for neurodevelopmental disorders in children to provide new insights for future studies found research intensity and recognition within the field of acupuncture for treating neurodevelopmental disorders in children has increased.
• Evidence snippets:
• Snippet 1 (score: 0.462) > Neurodevelopmental disorders (NDDs) arise from changes in early brain development, resulting in behavioral and cognitive alterations in sensory and motor systems, speech, and language [1]. NDDs lead to a series of health problems in our society, affecting >3 % of children worldwide [2]. Children with NDDs have a higher prevalence of sleep disturbances [3] and their families experience significant psychological burdens, which have been particularly problematic during prolonged home isolation during the COVID-19 pandemic [4]. NDDs are a major public health concern, as they have a heterogeneous etiology and lead to impaired cognition, communication, adaptive behavior, and psychomotor skills. NDDs include intellectual disorder, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), tic disorder (TD), speech or language disorder, learning disorder, motor coordination disorder, stereotyped movement disorder, and other specific types. Important, typical characteristics of NDDs that lead to their grouping include childhood manifestation and early-onset neurocognitive abnormalities. In addition, these diseases often have multiple etiologies, which gives us reason to consider them together [1]. Many studies have suggested that shared molecular pathways could account for the multiple clinical symptoms of NDDs [2]. Accordingly, comorbidity of two or more of these disorders is frequently observed. For instance, a comorbid ADHD, TD, and learning disorder is common. Genetic studies indicate that different NDDs are associated with a channelopathy with similar underlying transcriptional mechanisms [5]. Thus, understanding the shared pathogenic mechanisms among NDDs may help explain their comorbidity and aid development of more effective treatments. > NDD treatment options are currently limited, largely because of their heterogeneous etiology [6]. Currently, only symptomatic treatments are available to manage the behavior problems common among patients with NDDs [7]. The available evidence-based treatment options for NDDs mainly aim to reduce basic behavioral symptoms [8]. The outlook for autism is even more concerning as there are currently no United States (USA) Food and Drug Association-approved medications to address the core symptoms of this disorder [9].

[14] Movement Disorders in Multiple Sclerosis: An Update

• Authors: R. Ghosh, D. Roy, Souvik Dubey, Shambaditya Das, J. Benito‐León
• Year: 2022
• Venue: Tremor and Other Hyperkinetic Movements
• URL: https://www.semanticscholar.org/paper/3ec8238232a3cc4f9a19626fe1efc0a587481733
• DOI: 10.5334/tohm.671
• PMID: 35601204
• PMCID: 9075048
• Citations: 33
• Influential citations: 1
• Summary: The most prevalent movement disorders described in MS include restless leg syndrome, tremor, ataxia, parkinsonism, paroxysmal dyskinesias, chorea and ballism, facial myokymia, including hemif facial spasm and spastic paretic hemifacial contracture, tics, and tourettism.
• Evidence snippets:
• Snippet 1 (score: 0.461) > Background: Multiple sclerosis (MS), a subset of chronic primary inflammatory demyelinating disorders of the central nervous system, is closely associated with various movement disorders. These disorders may be due to MS pathophysiology or be coincidental. This review describes the full spectrum of movement disorders in MS with their possible mechanistic pathways and therapeutic modalities. Methods: The authors conducted a narrative literature review by searching for ‘multiple sclerosis’ and the specific movement disorder on PubMed until October 2021. Relevant articles were screened, selected, and included in the review according to groups of movement disorders. Results: The most prevalent movement disorders described in MS include restless leg syndrome, tremor, ataxia, parkinsonism, paroxysmal dyskinesias, chorea and ballism, facial myokymia, including hemifacial spasm and spastic paretic hemifacial contracture, tics, and tourettism. The anatomical basis of some of these disorders is poorly understood; however, the link between them and MS is supported by clinical and neuroimaging evidence. Treatment options are disorder-specific and often multidisciplinary, including pharmacological, surgical, and physical therapies. Discussion: Movements disorders in MS involve multiple pathophysiological processes and anatomical pathways. Since these disorders can be the presenting symptoms, they may aid in early diagnosis and managing the patient, including monitoring disease progression. Treatment of these disorders is a challenge. Further work needs to be done to understand the prevalence and the pathophysiological mechanisms responsible for movement disorders in MS.

[15] 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: 0.460) > Lennox–Gastaut syndrome (LGS) is a severe childhood-onset developmental and epileptic encephalopathy characterized by multiple drug-resistant seizure types, cognitive impairment, and distinctive electroencephalographic patterns. Current treatments primarily focus on symptom management through antiseizure medications (ASMs), dietary therapy, epilepsy surgery, and neuromodulation, but often fail to address the underlying pathophysiology or improve cognitive outcomes. As genetic causes are identified in 30–40% of LGS cases, precision therapeutics targeting specific molecular mechanisms are emerging as promising disease-modifying approaches. This narrative review explores precision therapeutic strategies for LGS based on molecular pathophysiology, including channelopathies (SCN2A, SCN8A, KCNQ2, KCNA2, KCNT1, CACNA1A), receptor and ligand dysfunction (GABA/glutamate systems), cell signaling abnormalities (mTOR pathway), synaptopathies (STXBP1, IQSEC2, DNM1), epigenetic dysregulation (CHD2), and CDKL5 deficiency disorder. Treatment modalities discussed include traditional ASMs, dietary therapy, targeted pharmacotherapy, antisense oligonucleotides, gene therapy, and the repurposing of existing medications with mechanism-specific effects. Early intervention with precision therapeutics may not only improve seizure control but could also potentially prevent progression to LGS in susceptible populations. Future directions include developing computable phenotypes for accurate diagnosis, refining molecular subgrouping, enhancing drug development, advancing gene-based therapies, personalizing neuromodulation, implementing adaptive clinical trial designs, and ensuring equitable access to precision therapeutic approaches. While significant challenges remain, integrating biological insights with innovative clinical strategies offers new hope for transforming LGS treatment from symptomatic management to targeted disease modification.

[16] Emerging Promise of Therapeutic Approaches Targeting Mitochondria in Neurodegenerative Disorders

• Authors: M. Rahman, Mst. Afroza Alam Tumpa, Md. Saidur Rahaman, F. Islam, Popy Rani Sutradhar et al.
• Year: 2023
• Venue: Current Neuropharmacology
• URL: https://www.semanticscholar.org/paper/9158fe888b1b2eefcc7182cef90e7789a176d18b
• DOI: 10.2174/1570159X21666230316150559
• PMCID: 10286587
• Citations: 5
• Summary: The main objective of this review is to highlight the basic mitochondrial problems that occur in NDDs and discuss the use mitochondrial drugs, especially mitochondrial antioxidants, mitochondrial permeability transition blockade, and mitochondrial gene therapy, for the treatment and control of N DDs.
• Evidence snippets:
• Snippet 1 (score: 0.458) > The identification of NDDs as mitochondrial disorders has gained increasing interest in recent years. Several NDDs, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and progressive supranuclear palsy, have been found to involve free radicals, mtDNA mutations, reduced mitochondrial respiration, and mitochondrial calcium dysregulation to varying degrees [10][11][12][13][14]. Considering the widespread mitochondrial pathology, mitochondrial dysfunction is thought to be involved in the pathophysiological mechanism of neurological disorders. It has also been suggested that clinical approaches to treat NDDs that target mitochondrial dysfunction should be developed [15][16][17]. > Recent developments in genetic, biological, biochemical, and animal model studies of hereditary NDDs have shown that mutant proteins-such as amyloid-beta (Aß) in AD, mutant huntingtin in HD, and mutant parkin and a-synuclein in PD-are correlated with mitochondria, leading to increased free radical production, low cellular adenosine triphosphate (ATP) production, and ultimately cell death [18]. > Mitochondrial dysfunction is now recognized as a typical cellular alteration in the progression of many hereditary NDDs. The importance of developing therapeutics to treat mitochondria in age-related NDDs is underscored by the role of mitochondrial dysfunction in both hereditary and lateonset NDDs. In this article, we discuss the physiological and functional changes of mitochondria in the elderly and patients with age-related NDDs. This article also discusses the potential of mitochondrial drugs for the treatment of aging and NDDs. Research that has uncovered mitochondrial characteristics associated with cellular dysfunction NDDs is reviewed in this article. The defects of the mitochondria and potential mitochondrial treatments for NDDs are also covered in this paper. Here, we describe some current applications of mitochondrial medicine in the treatment of NDDs and provide an overview of mitochondrial pathologies in NDDs.

[17] A Heme Oxygenase-1 Transducer Model of Degenerative and Developmental Brain Disorders

• Authors: H. Schipper, Wei Song
• Year: 2015
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/ba6c0992eb8b5f0e69da3d72a74e3aca770ca4b0
• DOI: 10.3390/ijms16035400
• PMID: 25761244
• PMCID: 4394483
• Citations: 56
• Influential citations: 1
• Summary: The glial HO-1 response may represent a pivotal transducer of noxious environmental and endogenous stressors into patterns of neural damage and repair characteristic of many human degenerative and developmental CNS disorders.
• Evidence snippets:
• Snippet 1 (score: 0.456) > Human neurodegenerative and neurodevelopmental disorders vary with respect to risk factors, sex predilections, ages of onset, regions of the neuraxis involved, behavioral and neurological symptoms, hallmark cellular inclusions (if any), neurochemical disturbances, structural and functional neuroimaging, and electrophysiology. The advent of successful therapeutic interventions to prevent, attenuate, arrest or reverse neuronal depletion and clinical decline in these conditions pre-supposes a thorough understanding of intrinsic central nervous system (CNS) responses to stressors and their relationship to cytopathological mechanisms that underlie clinical disease expression. Classically, specific pharmacotherapeutics and non-pharmacological interventions have been implemented to manage these conditions commensurate with the perceived etiopathogenesis or, when the latter is uncertain, the neurobehavioral phenotype (symptomatic treatment). Thiamine replacement in cases of Wernicke encephalopathy would be an example of the former; levo-dopa administration for the amelioration of extrapyramidal symptoms (tremor, rigidity, etc.) in Parkinson disease (PD) patients would exemplify the latter. A second approach, and the focus of our laboratory, is to delineate "core" neuropathological mechanisms operating in many, if not all, chronic CNS disorders and develop therapeutic strategies targeting these shared manifestations. While this approach may not directly address disease "etiology" (which may differ substantially among the diverse entities), it may disrupt salient common pathways that drive disease "pathogenesis" and thereby achieve meaningful clinical outcomes. In this article, we review evidence that (1) iron deposition, oxidative stress (OS), mitochondrial injury and macroautophagy constitute a single neuropathological "lesion" which may foster progression of various degenerative and developmental brain disorders and (2) these ubiquitous neuropathological changes result from the over-expression of astroglial heme oxygenase-1 (HO-1) in the affected neural tissues.

[18] Recent advances in epilepsy genomics and genetic testing

• Authors: M. Hebbar, H. Mefford
• Year: 2020
• Venue: F1000Research
• URL: https://www.semanticscholar.org/paper/fed719aa3e9431d33ff157c61af9c0ef59c15333
• DOI: 10.12688/f1000research.21366.1
• PMID: 32201576
• PMCID: 7076331
• Citations: 75
• Influential citations: 4
• Summary: This review discusses the major advances in epilepsy genomics that have surfaced in recent years and aims to build a better understanding of pathogenesis and genetic testing options in DEE.
• Evidence snippets:
• Snippet 1 (score: 0.453) > Several novel genes and disorders associated with DEE have been identified in the last few years [16][17][18] (Table 1). Many of the genes causing epilepsy encode components of neuronal ion channels leading to neuronal hyperexcitability or depletion of inhibitory mechanisms 19,20 . However, recently, several new genes coding for proteins other than ion channels have been identified, such as chromatin remodelers, intracellular signaling molecules, metabolic enzymes, transcription factors, and mitochondrial complex genes 5,21,22 . The search term "epilepsy" OR "seizure" OR "epileptic syndrome" OR "epileptic encephalopathy" from 2016 to 2019 led to 66 entries in Online Mendelian Inheritance in Man. Although comprehensive discussion of all the discoveries is beyond the scope of this review, selected major advances are highlighted below. > ES trios have revealed the influence of de novo mutations as a genetic cause of severe epilepsies (Table 1). A recent study compared de novo variants identified in individuals with variable NDDs with and without epilepsy 23 . In the subset of 1,942 subjects with NDDs with epilepsy, 33 genes were observed to have significant excess of de novo variants, three of which had limited or no previous evidence of disease association: CACNA1E, SNAP25, and GABRB2. Nine de novo missense and two truncating variants in CACNA1E variants were identified in this cohort 23 . In a subsequent study, de novo variants in CACNA1E were identified in 30 individuals with DEE 16 . Detailed phenotyping revealed refractory infantile-onset seizures, severe hypotonia, and profound developmental delay, often with congenital contractures, hyperkinetic movement disorders, macrocephaly, and early death 16 . Functional analysis revealed consistent gain-of-function effects in R-type calcium channels. Some patients were seizure free on treatment with the anti-epileptic drug topiramate, which blocks R-type calcium channels. The condition is now catalogued as early infantile epileptic encephalopathy type 69 (#MIM 618285).

Notes

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