Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Parenti-Mignot Neurodevelopmental Syndrome. Core disease mechanisms, molec...

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

• Papers retrieved: 19
• Snippets retrieved: 20

Relevant Papers

[1] 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: 0.446) > 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.

[2] 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).
• Snippet 2 (score: 0.438) > 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.

[3] 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: 0.443) > 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

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

• Authors: C. Torres, Z. Wassouf, Z. Wassouf, Faria Zafar, D. Sastre et al.
• Year: 2020
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/aedea7861a666c1aa7570fc071cccc377ad33d96
• DOI: 10.3390/ijms21165724
• PMID: 32785033
• PMCID: 7460874
• Citations: 56
• Influential citations: 1
• Summary: Clinico-genetic studies of causal variants and overlapping clinical and cellular features of ASD and PD are focused on to re-conceptualize how these disorders are understood and provide a new angle into disease targets and mechanisms linking neurodevelopmental disorders and neurodegeneration.
• Evidence snippets:
• Snippet 1 (score: 0.439) > Neurodevelopmental and late-onset neurodegenerative disorders present as separate entities that are clinically and neuropathologically quite distinct. However, recent evidence has highlighted surprising commonalities and converging features at the clinical, genomic, and molecular level between these two disease spectra. This is particularly striking in the context of autism spectrum disorder (ASD) and Parkinson’s disease (PD). Genetic causes and risk factors play a central role in disease pathophysiology and enable the identification of overlapping mechanisms and pathways. Here, we focus on clinico-genetic studies of causal variants and overlapping clinical and cellular features of ASD and PD. Several genes and genomic regions were selected for our review, including SNCA (alpha-synuclein), PARK2 (parkin RBR E3 ubiquitin protein ligase), chromosome 22q11 deletion/DiGeorge region, and FMR1 (fragile X mental retardation 1) repeat expansion, which influence the development of both ASD and PD, with converging features related to synaptic function and neurogenesis. Both PD and ASD display alterations and impairments at the synaptic level, representing early and key disease phenotypes, which support the hypothesis of converging mechanisms between the two types of diseases. Therefore, understanding the underlying molecular mechanisms might inform on common targets and therapeutic approaches. We propose to re-conceptualize how we understand these disorders and provide a new angle into disease targets and mechanisms linking neurodevelopmental disorders and neurodegeneration.

[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: 0.436) > 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] Neurologic and neurodevelopmental complications in cardiofaciocutaneous syndrome are associated with genotype: A multinational cohort study.

• Authors: E. I. Pierpont, Daniel L Kenney-Jung, R. Shanley, Abigail L Zatkalik, Ashley E Whitmarsh et al.
• Year: 2022
• Venue: Genetics in medicine : official journal of the American College of Medical Genetics
• URL: https://www.semanticscholar.org/paper/c6d0d79ac400996e77a33d21c2fada51bc3d570e
• DOI: 10.1016/j.gim.2022.04.004
• PMID: 35524774
• Citations: 26
• Influential citations: 3
• Summary: Molecular genetic testing can aid in prediction of epilepsy and neurodevelopmental phenotypes in CFC syndrome and study results identified potential CFC Syndrome-associated variants in the development of relevant animal models for neurologic, neurocognitive, and motor function impairment.
• Evidence snippets:
• Snippet 1 (score: 0.436) > PURPOSE > Dysregulation of RAS or its major effector pathway is the molecular mechanism of RASopathies, a group of multisystemic congenital disorders. Neurologic complications are especially challenging in the management of the rare RASopathy cardiofaciocutaneous (CFC) syndrome. This study evaluated clinical neurologic and neurodevelopmental features and their associations with CFC syndrome gene variants. > METHODS > A multinational cohort of 138 individuals with CFC syndrome (BRAF = 90, MAP2K1 = 36, MAP2K2 = 10, KRAS = 2) was recruited. Neurologic presentation was captured via clinician review of medical records and caregiver-completed electronic surveys. Validated measures of seizure severity, adaptive function, and gross motor function were obtained. > RESULTS > The overall frequency of intellectual disability and seizures was 82% and 55%, respectively. The frequency and severity of seizures was higher among individuals with BRAF or MAP2K1 variants than in those with MAP2K2 variants. A disproportionate incidence of severe, treatment-resistant seizures was observed in patients with variants in the catalytic protein kinase domain of BRAF and at the common p.Y130 site of MAP2K1. Neurodevelopmental outcomes were associated with genotype as well as seizure severity. > CONCLUSION > Molecular genetic testing can aid in prediction of epilepsy and neurodevelopmental phenotypes in CFC syndrome. Study results identified potential CFC syndrome-associated variants in the development of relevant animal models for neurologic, neurocognitive, and motor function impairment.

[7] Microcephaly in Neurometabolic Diseases

• Authors: Wiktoria Kempińska, Karolina Korta, Magdalena Marchaj, J. Paprocka
• Year: 2022
• Venue: Children
• URL: https://www.semanticscholar.org/paper/63d9574ab9178fa1f4b12a48b9c9d350dc6baaa0
• DOI: 10.3390/children9010097
• PMID: 35053723
• PMCID: 8774396
• Citations: 6
• Summary: The authors review the diseases with microcephaly, which may be one of the most visible signs of neurometabolic disorders, and investigates the mechanisms behind the progressive deterioration of mental, motor, and perceptual functions.
• Evidence snippets:
• Snippet 1 (score: 0.434) > Microcephaly is one of the significant clinical manifestations in pediatric neurology, which can be a difficult diagnostic problem due to its different etiology [93]. Microcephaly occurs in various types of metabolic diseases such as inborn glycosylation disorders, mitochondrial diseases, peroxisomal disorders, glucose transporter defects, congenital amino acid metabolism disorders (enzymatic and receptor defects), organic acidosis, or lipid metabolism disorders. Such a wide variety of disorders that lead to the occurrence of microcephaly result in the fact that microcephaly, as a symptom accompanying neurometabolic diseases, is part of a complex clinical picture that requires a complete multidisciplinary approach by neurologists, psychiatrists, cardiologists, orthopedists, or gastroenterologists. Neurometabolic disorders are mostly diagnosed in neonates and infants. Neurological symptoms are very common in this group of diseases. The onset of symptoms of neurometabolic disorders often occurs after initially relatively normal or near-normal growth and development. In addition, affected children may have metabolic crises that have particularly adverse effects on the developing nervous system. During metabolic decompensation, patients with neurometabolic disorders present with severe clinical symptoms, including eating disorders, vomiting, seizures, lethargy, and loss of consciousness. Progression of CNS damage and regression in neurodevelopmental milestones are reported [1]. Therefore, it would be crucial to find a way to effectively restore damaged nerve cells. Medical advances over the past decades have made it possible to diagnose metabolic disorders much earlier than in the past, which contributes to faster treatment. As a result, complications of the disease can be prevented more successfully. The development of molecular medicine and genetics gives hope for a better understanding of the disease mechanism of individual syndromes, which creates a new field for research into new treatment methods. Neurometabolic disorders could be treated at three levels typical of a given disease. First option is enzyme replacement therapy. Second, interventions could be applied at the metabolite level whose aim is to reduce flux through the pathway or to replenish substrates. Third, gene therapy would replace the mutated DNA [94].

[8] 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: 0.433) > 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.

[9] 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: 0.431) > 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].

[10] Zika Virus Neuropathogenesis: The Different Brain Cells, Host Factors and Mechanisms Involved

• Authors: Thamil Vaani Komarasamy, N. Adnan, W. James, V. Balasubramaniam
• Year: 2022
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/8c068778627f693fa4bd4bf49a1e5e72044c056c
• DOI: 10.3389/fimmu.2022.773191
• PMID: 35371036
• PMCID: 8966389
• Citations: 37
• Summary: This review provides a comprehensive and up-to-date overview of ZIKV-induced neuroimmunopathogenesis by dissecting its main target cells in the brain, and the underlying cellular and molecular mechanisms.
• Evidence snippets:
• Snippet 1 (score: 0.429) > Zika virus (ZIKV) has evolved to induce new clinical syndromes, particularly in newborns. Accumulating evidence support that ZIKV interacts with key host proteins to induce neuropathogenesis through various molecular mechanisms, including neuronal apoptosis, cell cycle dysregulation, exploitation of host immune response and activation of inflammatory response. These mechanisms were shown to be dependent on the types of cells, strains and infection rate. It is also evident that the ZIKV-induced anomalies are also the result of indirect effects of modulation of host immune response and inflammatory process, rather than just the virus itself. These findings suggest that a combination of different mechanisms may be responsible for the neuropathogenesis of ZIKV. However, more indepth studies are required to fully understand the distinct molecular pathways involved in ZIKV induced infection in different brain cells and to further validate the differences observed in different strains of the virus. > In addition to brain proteins, it is also crucial to identify other host factors that drive inflammation and immune response during ZIKV infection. Identification of host proteins is important for developing effective host-directed antivirals and for drug repurposing for the treatment of ZIKV infection, particularly to prevent neurological complications in newborns and of the possible long-term effects. In addition, the combination of the host-factors-targeting agents with drugs that directly target viral enzymes could lead to a more effective therapeutic regimen to fight ZIKV as well as other flaviviruses. Importantly, given the ability of ZIKV to alter genes in the brain cells associated with CNS development, it is crucial for long-term neurodevelopmental follow-up of ZIKV-exposed infants. Notably, the absence of microcephaly at birth with prenatal exposure to ZIKV does not preclude the presence of ZIKVassociated brain abnormalities. Hence, it is crucial for long-term neurodevelopmental follow-up of ZIKV-exposed infants.

[11] 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: 0.427) > 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

[12] Induced pluripotent stem cells from patients with focal cortical dysplasia and refractory epilepsy

• Authors: D. Marinowic, F. Majolo, A. Sebben, Vinícius da Silva, T. G. Lopes et al.
• Year: 2017
• Venue: Molecular Medicine Reports
• URL: https://www.semanticscholar.org/paper/e62c2509f437018a91e2c2b5054f715407d65c22
• DOI: 10.3892/mmr.2017.6264
• PMID: 28260047
• PMCID: 5364982
• Citations: 14
• Summary: The positive staining characteristics of the embryonic cells confirmed the successful generation of iPSCs derived from the patients' fibroblasts, which may help to understand embryonic brain development associated with FCD.
• Evidence snippets:
• Snippet 1 (score: 0.425) > Several neural diseases remain poorly understood, in particular those that affect the central nervous system, from the course of embryonic development up to the onset of clinical signs. These diseases represent a huge physical and social burden to patients and families, with high financial costs to public health systems. Although significant advances have been made in understanding the genetic basis of these diseases, clinical classification, patient care and effective treatments remain scarce (14). > Fortunately, the unquestionable advance of methods for iPSC generation and their subsequent differentiation into several tissue types have rendered these cells a standout cellular model for diverse diseases, including those affecting the central nervous system. This strategy allows for the investigation and development of novel approaches to study the mechanisms of embryonic neurodevelopment and pathological contexts specific for each patient, considering their unique genetic backgrounds (14). To the best of our knowledge, the present study is the first to present a method for the generation of a cell model to study the embryonic neurogenesis of epilepsy refractory to drug treatment in the context of FCD. > Previous studies have demonstrated a link between genetic alterations and various types of cortical malformation, which may be specifically associated with the main stages of central nervous system development (8). More than 100 genes have been associated with various types of cortical malformation (50). The major genes identified, including those that are involved in signaling pathways associated with cerebral cortex malformation, are associated with apoptosis, cell proliferation, cytoskeletal structure, cell migration and neurodifferentiation. Alterations in signaling and/or other regulatory pathways may have a variable impact on not only the pattern of brain cortical malformation but also on the site affected (8). > The diagnoses of certain cortical defects, including megalencephaly, polymicrogyria, hemimegalencephaly and cortical dysplasia, are generated following the observation of typical features in clinical imaging. Pathological alterations associated with these disorders include a wide range of abnormalities, including those typically associated with FCD. A growing number of gene alterations have been associated with polymicrogyria and hemimegalencephaly, in particular in cases with more severe phenotypes.

[13] Copy number variants in absence epilepsy

• Authors: C. Depondt
• Year: 2016
• Venue: Neurology: Genetics
• URL: https://www.semanticscholar.org/paper/48796dea401fab2a2d9594997bf36e014f04f750
• DOI: 10.1212/NXG.0000000000000067
• PMID: 27123485
• PMCID: 4830202
• Citations: 3
• Summary: Genetic generalized epilepsy (GGE), either associated or not associated with intellectual disability, is the most commonly reported phenotype in patients carrying these CNVs, which constitute the single largest risk factor for sporadic epilepsies known to date.
• Evidence snippets:
• Snippet 1 (score: 0.423) > CNVs across the 3 types of absence epilepsy, lending support to the hypothesis that these different subtypes of epilepsy share common genetic mechanisms. > The present study is the first to systematically address the identification of CNVs in patients with absence epilepsy specifically. Many previous studies have reported the presence of recurrent and novel CNVs in a variety of GGE syndromes, including absence epilepsies, but because of the heterogeneity of phenotypes included in these studies, the distribution of CNVs in this specific subtype of GGE is presently unclear. GGE, and epilepsy in general, is not a single disease, and the large variety of syndromes and inherent difficulties in classifying the epilepsies constitute a unique challenge to the elucidation of the underlying genetic and molecular pathways. Deep phenotyping and careful patient classification can help refine genotype-phenotype correlations and improve our insight into the underlying disease pathophysiology. As pointed out by the authors, the retrospective nature of the current study represents a major limitation in this respect. Detailed clinical information was lacking for several patients, and the availability of prospective clinical information could have helped to refine the diagnosis, particularly in those patients with unclassified absence epilepsy, some of whom were reported to also have febrile seizures and developmental delay. > The results further confirm the involvement of some of the known recurrent CNVs in GGEs. The identification of CNVs previously reported in neurodevelopmental disorders, including often ill-defined seizures, in 4 patients with absence epilepsy further widens the phenotypic spectrum associated with these variants. Despite the well-known association of some of these recurrent CNVs with epilepsy and other neuropsychiatric disorders, the exact pathophysiologic mechanisms remain largely unknown. It is also important to point out that most of these CNVs act as susceptibility factors for epilepsy, rather than providing the sole explanation for the phenotype. This is illustrated by the wide phenotypic variability and by the fact that these CNVs may also be detected in asymptomatic relatives, complicating genetic counseling. Interpretation of the significance of the novel gene-disrupting CNVs is even more problematic.

[14] 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: 0.423) > 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).

[15] Next Generation Sequencing Mitochondrial DNA Analysis in Autism Spectrum Disorder

• Authors: A. Patowary, Ryan R Nesbitt, Marilyn Archer, R. Bernier, Z. Brkanac
• Year: 2017
• Venue: Autism Research
• URL: https://www.semanticscholar.org/paper/a4bb1d55039cf435f59303680bedf243e693ba8b
• DOI: 10.1002/aur.1792
• PMID: 28419775
• PMCID: 5573912
• Citations: 44
• Influential citations: 4
• Summary: This work has analyzed the mtDNA sequence derived from whole‐exome sequencing in 10 multiplex families and identified two variants of interest in MT‐ND5 gene that were previously determined to impair mitochondrial function, providing further support for the role of mitochondria in ASD.
• Evidence snippets:
• Snippet 1 (score: 0.422) > An additional limitation of our study is that our samples were derived from lymphoblastoid cell lines. Although no differences in mtDNA mutation profile between lymphoblastoid cell lines and whole blood DNA were reported [Diroma et al., 2014]; such a difference might be present. However, although brain tissues could be more informative for evaluating mtDNA in ASD, our focus on shared VOIs assumes that the variants we have identified are inherited and present in all tissues including brain tissues. > Our work further highlights difficulties in interpreting genetic findings and establishing genotype phenotype correlation for RCC variants. The MD are clinically and genetically heterogeneous and frequently caused by RCC mutations. MD manifestations are broad with age at onset ranging from the prenatal period to adulthood and severity ranging from prenatal lethality and severe multisystemic neurodevelopmental disorders such as MELAS to milder single organ phenotypes such as non-syndromic hearing loss and LHON. The MD spectrum of phenotypes, such as developmental delay, loss of skills, seizures and abnormalities in musculoskeletal, endocrine and gastrointestinal systems overlaps with ASD [Frye & Rossignol, 2011]. This makes it plausible that in a subset of ASD subjects mitochondrial dysfunction is a pathogenic mechanism leading to the clinical phenotype. Further analyses of mtDNA and nDNA RCC and other genes involved in mitochondrial function in adequately powered samples are needed to evaluate the role of mitochondria in ASD. Such analysis should also take into account the combined effects of mitochondrial variation and gene interactions. The genes encoding mitochondrial proteins are excellent candidates for a "synergistic heterozygosity" genetic mechanism that postulates that combined effects in multiple steps of a pathway or process may lead to disease [Vockley, Rinaldo, Bennett, Matern, & Vladutiu, 2000]. Such a mechanism was experimentally demonstrated in mice with genes involved in mitochondrial fatty acid b-oxidation [Schuler et al., 2005]. However, to strengthen the evidence linking variants that are thought to result from synergistic heterozygosity, functional data will be needed for large number of variants and their combinations.

[16] 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: 0.414) > 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.

[17] Molecular Systems Biology of Neurodevelopmental Disorders, Rett Syndrome as an Archetype

• Authors: V. Faundez, Meghan E. Wynne, A. Crocker, D. Tarquinio
• Year: 2019
• Venue: Frontiers in Integrative Neuroscience
• URL: https://www.semanticscholar.org/paper/2360989d80e21136f1bc3eb3c5c196d5a6a5a6be
• DOI: 10.3389/fnint.2019.00030
• PMID: 31379529
• PMCID: 6650571
• Citations: 16
• Summary: It is proposed that an approach to testing the potential of systems biology to identify mechanisms and biomarkers of disease in the example of Rett syndrome can not only aid in monitoring clinical disease severity but also provide a measure of target engagement in clinical trials.
• Evidence snippets:
• Snippet 1 (score: 0.414) > Defining molecular biomarkers for autism spectrum disorder, or any neurodevelopmental disorder, could be best materialized by considering the following heuristic criteria: > 1. Disorder definition should ideally be founded on unequivocal genetic diagnosis, as is the case with Rett syndrome, or any other monogenic neurodevelopmental disorder. Rett syndrome is caused by mutations in methyl-CpG-binding protein 2 (MECP2) in >95% of patients meeting consensus clinical diagnostic criteria (Neul et al., 2010(Neul et al., , 2014Cuddapah et al., 2014). 2. If the disorder is well-defined genetically, then the gene affected should ideally have loss-and gain-of-function mutations in humans with a certain degree of phenotypic overlap. MECP2 mutations are ideal in this regard, as Rett syndrome is the result of loss-of-function mutations in MECP2, while duplication of the MECP2 gene causes a distinctive syndrome, the MECP2 duplication syndrome, that shares autism symptoms with Rett (OMIM: 300005 3 ; Ramocki et al., 2009;Lombardi et al., 2015;Leonard et al., 2017). > 3. High phenotypic penetrance of the mutation and consistency should exist in the clinical phenotype. Rett syndrome manifests mostly with autism and intellectual disability symptoms (Percy, 2011). This is in contrast with other neurodevelopmental disorders that can present themselves as multiple psychopathologies, even though the genetic defects are well defined, as is the case with copy number variations (Girirajan et al., 2011;Rutkowski et al., 2017). 4. There should be some knowledge about mechanisms of disease at any biological complexity level. Mechanisms of disease exist in a pathogenesis continuum along increasing levels of biological complexity. This continuum spans from the mechanisms most proximal to the mutation, such as is the role of MECP2 as a transcriptional regulator, to mesoscale processes affected by the mutation, like cell and tissue mechanisms, to macroscale phenotypes at the level of circuit or anatomical brain dysfunction. 5. Animal and cellular models of disease should genetically and phenotypically reproduce disease

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

• Authors: G. Torres, Mervat Mourad, Saba Iqbal, Emmanuel Moses-Fynn, Ashani Pandita et al.
• Year: 2023
• Venue: Genes
• URL: https://www.semanticscholar.org/paper/bf76f0682a8a1986ce889cee1fef818480abc83b
• DOI: 10.3390/genes14091734
• PMID: 37761876
• PMCID: 10531442
• Citations: 11
• Summary: The present work reviews recent evolutionary, molecular, and epigenetic mechanisms potentially linked to the etiology of autism, and presents a clinical vignette to describe clusters of maladaptive behaviors frequently diagnosed in autistic patients.
• Evidence snippets:
• Snippet 1 (score: 0.413) > Currently, there are hundreds of gene variants associated with the onset of ASD. Thus, the clinical presentation of the disease is highly variable, as one or more behavioral symptoms may be related to other comorbid conditions (e.g., anxiety disorder, seizure disorder) besides autism. In addition, antagonistic pleiotropy and dosage-sensitive genes further fragment the phenotypic characteristics of ASD. Regardless, here, we present a prototypical autism clinical vignette with five behavioral specifiers: cognitive disability; deficits in social-emotional reciprocity; repetitive or stereotyped motor behavior; improper coordinated language communication; and gastrointestinal distress. Underneath this clinical vignette, we microdissected and correlated a particular phenotype of the disease to functionally and anatomically related regions of the brain and bilateral body plan. The structural organization imposed here will not only identify a wide network of cells, but also specific clusters of genes targeting a particular symptom within behaviorally relevant regions. It is expected that such structural organization will help lay a solid foundation in psychiatry and point to more focused approaches to a deeper understanding of ASD and its individualized treatment (Table 2). Autism Spectrum Disorders can be managed with appropriate pharmacotherapy. Selective dopamine (DA) and serotonin (5HT) based drugs are the mainstay of pharmacological treatment [43,44]. Additional neurotransmitter systems (e.g., norepinephrine (NE) and histamine) are also drug targets. It is not known whether the listed drugs regulate epigenetic mechanisms to counteract autistic symptoms. What is broadly known is that atypical, typical and psychoactive drugs act on DA and 5HT signaling pathways within regions of the human brain (e.g., cortex and basal ganglia) that are behaviorally relevant to the pathophysiology of ASD. Attention Deficit Hyperactivity Disorder (ADHD) and Fragile X Syndrome are debilitating neuropsychiatric conditions commonly diagnosed in pediatric populations. Fragile X Syndrome is a monogenic inherited disease leading to cognitive disability and ASD.

[19] New therapeutic targets in rare genetic skeletal diseases

• Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
• Year: 2015
• Venue: Expert Opinion on Orphan Drugs
• URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
• DOI: 10.1517/21678707.2015.1083853
• PMID: 26635999
• PMCID: 4643203
• Citations: 37
• Influential citations: 1
• Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
• Evidence snippets:
• Snippet 1 (score: 0.412) > proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.

Notes

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