Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Mowat-Wilson syndrome. Core disease mechanisms, molecular and cellular pat...

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

• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] Mowat-Wilson syndrome: unraveling the complexities of diagnosis, treatment, and symptom management

• Authors: Yalda Zhoulideh, Jamil Joolideh
• Year: 2024
• Venue: Egyptian Journal of Medical Human Genetics
• URL: https://www.semanticscholar.org/paper/909c4ae87c0ea609bf397ee850c448693dfcd8b5
• DOI: 10.1186/s43042-024-00517-2
• Citations: 1
• Summary: This review will examine the gene involved in this disease, phenotype, clinical manifestations, ways of diagnosis, and treatment of this disease.
• Evidence snippets:
• Snippet 1 (score: 0.429) > The altered protein fails to perform its normal regulatory functions in the intricate processes of embryonic development. This disruption has cascading effects on the expression of other genes involved in the development of the nervous system, face, and several internal organs. Individuals with Mowat-Wilson syndrome typically exhibit a distinct set of features, including characteristic facial abnormalities (such as a broad nasal bridge and prominent chin), intellectual disabilities, delayed development, seizures, and congenital heart defects. The severity of symptoms can vary among affected individuals. ZEB2 mutations are mainly of the frameshift type, creating a premature termination codon. The frequency of nonsense mutations is next. Nevertheless, sometimes the whole gene is completely deleted, which causes a very severe phenotype of the disease. On the other hand, the missense mutation causes minor disease severity. Most mutations in this gene affect the nervous system [13][14][15][16][17]. > ZEB2 protein plays a central role in cell function by participating in important pathways, especially the TGF-β/SMAD pathway. Through this interaction, the protein contributes to the regulation of cellular responses and developmental processes. Additionally, an important aspect of ZEB2 protein function is that it may play an important role in the restoration of histone deacetylase in the context of cancer. These features suggest that this protein is involved in epigenetic regulation, influencing gene expression patterns and cell behavior in the biological environment of tumors. Importantly, the relationship between the ZEB2 protein and CtBP further emphasizes its importance. This interaction implies a sophisticated level of coordination in cellular regulatory mechanisms, suggesting that the ZEB2 protein is not merely a passive participant but a key orchestrator in the complex interplay of molecular events governing cellular homeostasis and pathological processes [18,19].

[2] The hyperornithinemia–hyperammonemia-homocitrullinuria syndrome

• Authors: D. Martinelli, D. Diodato, Emanuela Ponzi, M. Monné, S. Boenzi et al.
• Year: 2015
• Venue: Orphanet Journal of Rare Diseases
• URL: https://www.semanticscholar.org/paper/ed033868ee677da141e5c926bc7c93cac242ea06
• DOI: 10.1186/s13023-015-0242-9
• PMID: 25874378
• PMCID: 4358699
• Citations: 92
• Influential citations: 5
• Summary: The clinical phenotype of HHH syndrome is extremely variable and its severity does not correlate with the genotype or with recorded ammonium/ornithine plasma levels, suggesting the need for a better understanding of the still unsolved pathophysiology of the disease.
• Evidence snippets:
• Snippet 1 (score: 0.386) > Although the disease responds well to treatment with low risk of relapse of hyperammonemia [38], slowly progressive pyramidal signs characterize the chronic course, as also seen in argininemia [89]. However, the mechanism(s) of pyramidal dysfunction in HHH syndrome still remains to be elucidated. Creatine deficiency may contribute to the pathogenetic mechanism of the syndrome, as creatine is relevant for mitochondrial energy metabolism, regulation of glycolysis, proteins synthesis, membrane stabilization and neuromodulation [77,78,85]. This could be in line with the finding of abnormally shaped mitochondria at electron microscopy studies in skin fibroblasts, hepatocytes and muscle biopsy from HHH syndrome patients [11,23,82]. Furthermore, a mitochondrial dysfunction has been recently related to the effects of ornithine and homocitrulline in causing oxidative stress and disturbed mitochondrial homeostasis [79,80]. > A further mechanism that can be involved in the pathophysiology of HHH syndrome is related to polyamines metabolism. Shimizu and colleagues reported increased total and fractional (putrescine, cadaverine, spermine, spermidine) polyamines in one HHH syndrome patient [30]. Indeed, the clinical similarities between HHH syndrome and argininemia, which has been associated to an abnormal polyamine metabolism [91,92], may suggest a common pathogenetic mechanism causing pyramidal dysfunction. > Overall, the pathogenesis of HHH syndrome is complex and not completely understood. It is likely that different mechanisms, including the impact of low mitochondrial ornithine on UC flux, the presence of hyperammonemic crises and the disturbance of other pathways in major organs play a role in determining the heterogeneous clinical presentation of ORC1 deficiency. > In addition, as molecular studies failed to disclose a correlation between type of mutations or ornithine transport capacity and disease severity, an effect of genetic modifiers, such as ORC genes redundancy, seems to be likely, but further studies are certainly needed to clarify this point.

[3] Changes in Serum Proteomic Profiles at Different Stages of Pregnancy Toxemia in Goats

• Authors: M. Uzti̇mür, C. N. Ünal, Gurler Akpinar
• Year: 2025
• Venue: Journal of Veterinary Internal Medicine
• URL: https://www.semanticscholar.org/paper/4b9c488b5dbd65d7b26fd2ad9aed70e8c4b59942
• DOI: 10.1111/jvim.70139
• PMID: 40492724
• PMCID: 12150350
• Summary: Understanding the serum proteome profiles of goats with pregnancy toxemia might help identify the proteomes and pathways responsible for the development of this disease and improve diagnosis and treatment.
• Evidence snippets:
• Snippet 1 (score: 0.386) > The pathophysiology and progression of this disease are not fully understood. > Traditional biomedical research has focused on the analysis of single genes, proteins, metabolites, or metabolic pathways in diseases. This molecular reductionist approach is based on the assumption that identifying genetic variations and molecular components will lead to new treatments for diseases [13][14][15][16]. However, many diseases are complex and multifactorial, and in order to determine the phenotype of such diseases, it is necessary to understand the changes that occur in more than one gene, pathway, protein, or metabolite at the cellular, tissue, and organismal levels [17][18][19]. Therefore, in recent years, proteomics, as one field of multi-omics technologies, has helped in evaluating the complex pathogenetic mechanisms of different diseases from a broad perspective and has made substantial contributions [20,21]. In veterinary medicine, proteomic analysis of metabolic diseases such as ketosis [16], hypocalcemia [22], and fatty liver [23] in dairy cows has contributed valuable insights for the definition of new pathophysiological pathways and new diagnosis and treatment protocols for these diseases. The proteomic approach can contribute importantly to a broad and detailed understanding of the changes that occur at the organismal level associated with the increase in BHBA concentration in goats with pregnancy toxemia. Our aim was to evaluate the serum protein profiles of goats with SPT or CPT using proteomic techniques to determine the proteomic profiles of these animals and to identify the relevant pathophysiological mechanisms.

[4] Therapies for Mitochondrial Disease: Past, Present, and Future

• Authors: Megan Ball, Nicole J. Van Bergen, A. Compton, David R Thorburn, S. Rahman et al.
• Year: 2025
• Venue: Journal of Inherited Metabolic Disease
• URL: https://www.semanticscholar.org/paper/196ee50a950f29bc4134cfb8fe6bdfa9a3a1468b
• DOI: 10.1002/jimd.70065
• PMID: 40714961
• PMCID: 12301291
• Citations: 3
• Summary: The latest developments in the pursuit to identify effective treatments for mitochondrial disease are examined and the barriers impeding their success in translation to clinical practice are discussed.
• Evidence snippets:
• Snippet 1 (score: 0.373) > Mitochondrial disease is a diverse group of clinically and genetically complex disorders caused by pathogenic variants in nuclear or mitochondrial DNA‐encoded genes that disrupt mitochondrial energy production or other important mitochondrial pathways. Mitochondrial disease can present with a wide spectrum of clinical features and can often be difficult to recognize. These conditions can be devastating; however, for the majority, there is no targeted treatment. In the last 60 years, mitochondrial medicine has experienced significant evolution, moving from the pre‐molecular era to the Age of Genomics in which considerable gene discovery and advancement in our understanding of the pathophysiology of mitochondrial disease have been made. In the last decade, in response to the urgent need for effective treatments, a wide range of emerging therapies have been developed, driven by innovative approaches addressing both the genetic and cellular mechanisms underpinning the diseases. Emerging therapies include dietary intervention, small molecule therapies aimed to restore mitochondrial function, stem cell or liver transplantation, and gene or RNA‐based therapies. However, despite these advances, translation to clinical practice is complicated by the sheer genetic and clinical complexity of mitochondrial disease, difficulty in efficient and precise delivery of therapies to affected tissues, rarity of individual genetic conditions, lack of reliable biomarkers and clinically relevant outcome measures, and the dearth of natural history data. This review examines the latest developments in the pursuit to identify effective treatments for mitochondrial disease and discusses the barriers impeding their success in translation to clinical practice. While treatment for mitochondrial disease may be on the horizon, many challenges must be addressed before it can become a reality.

[5] From the Matrix to the Nucleus and Back: Mechanobiology in the Light of Health, Pathologies, and Regeneration of Oral Periodontal Tissues

• Authors: M. Dieterle, A. Husari, T. Steinberg, Xiaoling Wang, I. Ramminger et al.
• Year: 2021
• Venue: Biomolecules
• URL: https://www.semanticscholar.org/paper/1f89347b1ccacdd13b2b69e9d3a508850b962353
• DOI: 10.3390/biom11060824
• PMID: 34073044
• PMCID: 8228498
• Citations: 23
• Summary: This review offers insights into the current trends and open aspects of periodontal MT research, and perspectives on future applications of mechanobiological principles are discussed.
• Evidence snippets:
• Snippet 1 (score: 0.373) > Envelopathies additionally include the disease of Lamin-associated proteins, such as Emerin or Nesprin [223]. The most relevant medical syndromes are Charcot-Marie-Tooth neuropathies, Emery-Dreifuss muscular dystrophies, and Hutchinson-Gilford syndrome, which is also known as Progeria [224][225][226]. Mechanically exposed tissues, such as the skeletal muscle, cardiomyocytes and tendons, are often affected by these diseases [26]. > Two different hypotheses in the current literature discuss the reasons of the deleterious effects of the laminopathies. The gene regulation hypothesis claims that the mutations or defects in LINC components or Lamin/Emerin lead to a severe dysregulation of gene expression [227]. Consequently, cellular physiology is dysregulated, impairing, e.g., stem cell differentiation, and thus resulting in the clinical disease manifestations such as premature aging or muscle weakness [228]. Contrary to this, the structural hypothesis states that nuclear deformation and fragility caused by the mutations is the most important step in the disease process. However, a more holistic "MT-hypothesis" of the pathophysiology should actually incorporate both the gene dysregulation and the mechanobiological consequences, as both are highly interdependent [229]. This can be explained by the above-discussed functions of LINC and Lamins. The mutations associated with envelopathies are, therefore, valuable models for elucidating both general and tissue-specific mechanisms of NMT and its integration into the cellular context. One interesting molecular insight is the fact that certain Lamin mutations increase the abundance of phosphorylated Lamin. This subsequently increases the solubility of the protein and promotes its dissociation from the Lamin meshwork and thus creates nuclear fragility [230,231]. Additionally, direct DNA damage and cell-cycle arrest are associated with these mutations [232].

[6] 18O-assisted dynamic metabolomics for individualized diagnostics and treatment of human diseases

• Authors: E. Nemutlu, Song Zhang, N. Juranic, A. Terzic, S. Macura et al.
• Year: 2012
• Venue: Croatian Medical Journal
• URL: https://www.semanticscholar.org/paper/880f053c7f060db4b990e447d0a22c4b69372ddb
• DOI: 10.3325/cmj.2012.53.529
• PMID: 23275318
• PMCID: 3541579
• Citations: 28
• Summary: The potential use of dynamic phosphometabolomic platform for disease diagnostics currently under development at Mayo Clinic is described and discussed briefly.
• Evidence snippets:
• Snippet 1 (score: 0.373) > Living cells represent an integrated and interacting network of genes, transcripts, proteins, small signaling molecules, and metabolites that define cellular phenotype and function. Traditionally the focus of biomedical research was on individual genes, single protein targets, single metabolites, and metabolic or signaling pathways. This "molecular reductionist" paradigm was based on the assumption that identifying genetic variations and molecular components would lead to discovery of cures for human diseases. However, most of diseases are complex and multi-factorial and the disease phenotype is determined by the alterations of multiple genes, pathways, proteins and metabolites (at cellular, tissue, and organismal levels). Therefore, an integrated "omics" approach is more viable direction for uncovering alterations in metabolic networks, disease mechanisms, and mechanisms of drug effects. > Recent advent of large-scale metabolomics and fluxomic (metabolite dynamics and metabolic flux analysis) completed the "omics revolution" (Figure 1), where genomics, transcriptomics, proteomics, metabolomics, and fluxomics all together complement phenotype determination of living organism. Such integrated "omics" cascades provide a framework for advances in system and network biology, integrative physiology, and system medicine as well as system pharmacology and regenerative medicine. Noteworthy is the "reverse omic" approach or "metabolomicsinformed pharmacogenomics, " where discovery of specific metabolite changes have led to discovery of genetic alterations (2). Therefore, bringing new "omics" technologies to clinical practice will improve disease diagnostics and treatment by targeting drugs and procedures for each unique transcriptomic and metabolomic profiles.

[7] 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: 0.372) > 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.

[8] Psychobiotics at the Frontiers of Neurodegenerative and Neuropsychiatric Research

• Authors: Guillermo Roberto Jiménez-Pareyón, J. Cristóbal-Luna, Y. García-Martínez, Cynthia Garfias-Noguez, Morayma Ramírez-Damián et al.
• Year: 2025
• Venue: Microorganisms
• URL: https://www.semanticscholar.org/paper/6c92b8101905064ff4e4e8585f4fa86ebfac0826
• DOI: 10.3390/microorganisms13122718
• PMID: 41471921
• PMCID: 12735313
• Summary: A review of current evidence on the GBA’s involvement in conditions such as Alzheimer’s disease, Parkinson’s disease, depression, and anxiety examines how psychobiotics may modulate neuroinflammation, oxidative stress, and neurotransmitter signaling, thereby contributing to cognitive and emotional regulation.
• Evidence snippets:
• Snippet 1 (score: 0.370) > Neurodegenerative diseases (NDs) are a group of disorders characterized by the progressive deterioration of the central or peripheral nervous system. These diseases cause morphological changes in the brain, leading to significant cognitive or motor impairments, debilitating symptoms, and a reduced quality of life [16]. NDs involve complex cellular responses triggered by the accumulation of pathologically altered brain substances, ultimately resulting in irreversible loss of neuronal populations [17]. > The pathophysiology of NDs is multifactorial and intricate, involving cellular, molecular, and genetic mechanisms. These include protein misfolding and aggregation, oxidative stress, mitochondrial dysfunction, cytoskeletal abnormalities, disrupted synaptic networks, neuronal death, aberrant cell proliferation, neuroinflammation, demyelination, altered axonal transport, dysregulated energy metabolism, and abnormal modifications of DNA or RNA [16,[18][19][20][21][22]. > NDs can be classified according to several criteria, such as their etiology, the molecular mechanisms involved, and the anatomical regions affected [23]. Although multiple classification systems exist, these disorders often share overlapping cellular and molecular mechanisms [24], which complicates efforts to categorize them into a single scheme. From a mechanistic perspective, NDs commonly exhibit recurring pathological events such as neuroinflammation, oxidative stress, mitochondrial dysfunction, and the accumulation of misfolded proteins [16]. Recent classification systems increasingly emphasize the type of protein aggregates for diagnostic accuracy [25]. Clinically, NDs can also be classified clinically based on predominant symptoms, such as movement disorders in PD and Huntington's disease, cognitive deficits in AD, or a combination of both [12,26,27]. This approach allows for a better understanding of their heterogeneity and facilitates the development of more specific therapeutic strategies. Among the spectrum of neurodegenerative conditions, AD and PD are the most prevalent and extensively studied (Figure 1).

[9] Transcriptional profiling of Hutchinson-Gilford progeria patients identifies primary target pathways of progerin

• Authors: Sandra Vidak, Sohyoung Kim, Tom Misteli
• Year: 2026
• Venue: Nucleus
• URL: https://www.semanticscholar.org/paper/4bd99b0875508364d8672b6da5a50d024d485a53
• DOI: 10.1080/19491034.2025.2611484
• PMID: 41489464
• PMCID: 12773485
• Summary: To probe the clinical relevance of previously implicated cellular pathways and to address the extent of gene expression heterogeneity between patients, transcriptomic analysis of a comprehensive set of HGPS patients finds misexpression of several cellular pathways, including multiple signaling pathways, the UPR and mesodermal cell fate specification.
• Evidence snippets:
• Snippet 1 (score: 0.368) > Oxidative stress represents another key pathogenic mechanism in HGPS, as impaired NRF2 activity or increased reactive oxygen species (ROS) levels are sufficient to recapitulate HGPSassociated phenotypes [17,32,60]. Collectively, these findings underscore the multifactorial nature of HGPS pathogenesis, implicating interconnected signaling cascades involved in inflammation, oxidative stress, proteostasis, and vascular remodeling. Reassuringly, our findings indicate that many of the major pathways that have been described to contribute to HGPS phenotypes in mouse and cellular disease models are also misregulated in progeria patients, and targeting these pathways may provide therapeutic avenues to mitigate disease severity and improve outcomes in HGPS. > Although individuals with HGPS typically exhibit a characteristic set of clinical features, such as craniofacial abnormalities, growth retardation, and cardiovascular complications, there is notable variability in the age of onset, severity, and progression of symptoms between patients [7,9]. At the cellular level, HGPS is associated with several hallmark abnormalities, including nuclear envelope defects, decreased expression of several nuclear proteins and epigenetic marks, mitochondrial dysfunction, and increased cellular senescence [1,11,30,31,61]. These cellular phenotypes also exhibit considerable variation between patients, possibly contributing to differences in clinical outcomes. Our results indicate that even though some degree of transcriptional heterogeneity between the individual patients exists, the majority of patients exhibit misregulation of a set of shared pathways, suggesting that these pathways are universal driver mechanisms in HGPS. Further work is needed to understand the molecular and genetic factors that underlie inter-individual variability in disease expression and progression. > A limitation of pathway analysis of HGPS patient samples is to distinguish the pathways which are directly targeted by the disease-causing progerin protein and the emergence of adaptive secondary response pathways during progression of the disease in patients during their lifetime. The same caveat applies to the use of cell-based models used in the study of HGPS disease mechanisms.

[10] The ties that bind: functional clusters in limb-girdle muscular dystrophy

• Authors: E. Barton, C. A. Pacak, Whitney L. Stoppel, P. Kang
• Year: 2020
• Venue: Skeletal Muscle
• URL: https://www.semanticscholar.org/paper/653422e1a9dc9cc7f16758b10f3f203155bc68c9
• DOI: 10.1186/s13395-020-00240-7
• PMID: 32727611
• PMCID: 7389686
• Citations: 24
• Summary: A deeper understanding of these disease pathways could yield a new generation of precision therapies that would each be expected to treat a broader range of LGMD patients than a single subtype, thus expanding the scope of the molecular medicines that may be developed for this complex array of muscular dystrophies.
• Evidence snippets:
• Snippet 1 (score: 0.366) > Pyridine nucleotide-disulfide reductase [55] Many of the protein functions listed require further confirmation or are disputed these methodologies. Those patients with moderate disease phenotypes regardless of the underlying causative gene mutation would likely fall into a category where there may be interest in testing a pharmacological treatment (that could be halted) but reduced interest in a more permanent experimental strategy. For all of the above-mentioned reasons, the identification of unifying therapeutic targets applicable to multiple subtypes of > LGMDs is highly desirable. > To identify such targets, we should first consider the question: What binds all of these LGMDs together? The two core phenotypic features are progressive proximal muscle weakness, along with characteristic signs of muscle fiber destruction on biopsy, referred to as "dystrophic" features. Nuances in clinical presentation have helped to distinguish some of the LGMDs, such as the frequent occurrence of difficulty walking on tiptoes in LGMD R2 (LGMD2B), caused by dysferlin deficiency. However, heterogeneity associated with variable ages of onset and ranges of severity makes it generally difficult to distinguish and diagnose LGMD subtypes based on clinical presentation alone. A change in perspective is in order to aid in understanding disease pathways responsible for clinical features even when the genetic mutation is unknown. Further, given the large number of genespecific LGMD subtypes, it could very well be that several major disease mechanisms may be shared across the family of diseases. Yet despite careful studies that have collectively determined the cellular localization of most proteins associated with LGMD (Fig. 1), there is limited knowledge of potentially unifying molecular disease mechanisms. We assert that the identification of functional clusters of these proteins, grouped by such common mechanisms, will streamline our understanding of the disease processes and identify therapeutic targets relevant to individuals in multiple disease subgroups, including individuals whose pathogenic mutations have not been found. By extension, this approach may serve as a tool to not only find common mechanisms, but may also help to distinguish LGMD subtypes that do not share similar functional patterns, and afford further refinement of potential treatments.

[11] The ties that bind: functional clusters in limb-girdle muscular dystrophy

• Authors: E. Barton, C. A. Pacak, Whitney L. Stoppel, Peter B. Kang
• Year: 2020
• Venue: Skeletal Muscle
• URL: https://www.semanticscholar.org/paper/3493c658bb8716d789a05ddf292162832e064e47
• DOI: 10.1186/s13395-020-00240-7
• Summary: A deeper understanding of these disease pathways could yield a new generation of precision therapies that would each be expected to treat a broader range of LGMD patients than a single subtype, thus expanding the scope of the molecular medicines that may be developed for this complex array of muscular dystrophies.
• Evidence snippets:
• Snippet 1 (score: 0.366) > Pyridine nucleotide-disulfide reductase [55] Many of the protein functions listed require further confirmation or are disputed these methodologies. Those patients with moderate disease phenotypes regardless of the underlying causative gene mutation would likely fall into a category where there may be interest in testing a pharmacological treatment (that could be halted) but reduced interest in a more permanent experimental strategy. For all of the above-mentioned reasons, the identification of unifying therapeutic targets applicable to multiple subtypes of > LGMDs is highly desirable. > To identify such targets, we should first consider the question: What binds all of these LGMDs together? The two core phenotypic features are progressive proximal muscle weakness, along with characteristic signs of muscle fiber destruction on biopsy, referred to as "dystrophic" features. Nuances in clinical presentation have helped to distinguish some of the LGMDs, such as the frequent occurrence of difficulty walking on tiptoes in LGMD R2 (LGMD2B), caused by dysferlin deficiency. However, heterogeneity associated with variable ages of onset and ranges of severity makes it generally difficult to distinguish and diagnose LGMD subtypes based on clinical presentation alone. A change in perspective is in order to aid in understanding disease pathways responsible for clinical features even when the genetic mutation is unknown. Further, given the large number of genespecific LGMD subtypes, it could very well be that several major disease mechanisms may be shared across the family of diseases. Yet despite careful studies that have collectively determined the cellular localization of most proteins associated with LGMD (Fig. 1), there is limited knowledge of potentially unifying molecular disease mechanisms. We assert that the identification of functional clusters of these proteins, grouped by such common mechanisms, will streamline our understanding of the disease processes and identify therapeutic targets relevant to individuals in multiple disease subgroups, including individuals whose pathogenic mutations have not been found. By extension, this approach may serve as a tool to not only find common mechanisms, but may also help to distinguish LGMD subtypes that do not share similar functional patterns, and afford further refinement of potential treatments.

[12] The Classification of Autosomal Recessive Cerebellar Ataxias: a Consensus Statement from the Society for Research on the Cerebellum and Ataxias Task Force

• Authors: M. Beaudin, A. Matilla-Dueñas, B. Soong, J. Pedroso, O. Barsottini et al.
• Year: 2019
• Venue: Cerebellum (London, England)
• URL: https://www.semanticscholar.org/paper/8be333265c4faffaeb605213aa48cb23b33981c1
• DOI: 10.1007/s12311-019-01052-2
• PMID: 31267374
• PMCID: 6867988
• Citations: 49
• Summary: A consensus is built on the classification of autosomal recessive ataxias in order to develop a general approach to a patient presenting with ataxia, organize disorders according to clinical presentation, and define this field of research by identifying common pathogenic molecular mechanisms in these disorders.
• Evidence snippets:
• Snippet 1 (score: 0.366) > The importance of a proper recessive ataxia classification goes beyond the clinical diagnosis perspective. Autosomal recessive ataxias can be regrouped according to the deficient cellular and metabolic pathways involved, which provide a better understanding of cerebellar physiology and of its selective vulnerability to certain metabolic defects. This is also essential from a therapeutic perspective, as disorders that belong to the same metabolic pathway may to the same treatment options, indicating potential for drug repurposing. Figure 3 presents a pathophysiological classification of autosomal recessive ataxias. Certain genes are presented more than once since some proteins are involved in several metabolic pathways or may interfere with other cellular processes as they accumulate in neurons or glial cells. Table 3 presents a more detailed listing of the pathogenic pathways involved along with relevant references. Certain pathways are predominantly involved, notably mitochondrial dysfunction, which may result from abnormal mitochondrial DNA maintenance with progressive mutagenesis, defective mitochondrial protein synthesis and quality control, increased levels of reactive oxygen species and oxidative stress, deficient coenzyme Q10 metabolism, altered mitochondrial dynamics, defective mitochondrial chain assembly, or abnormal mitochondrial RNA maturation and processing (Table 3). Interestingly, many of the disorders caused by mitochondrial dysfunction also present with a mitochondrial clinical syndrome as shown in Fig. 1. Disorders of DNA repair mechanisms are also common, with double-strand break repair pathway or single-strand break repair complexes predominantly involved. Pathogenic mutations in these genes are also associated with a susceptibility to ionizing radiations and predisposition for cancers, but the neurological syndrome is characterized by cerebellar involvement and extrapyramidal movement disorders. It remains debated whether defective DNA repair is the main pathogenic mechanism causing the neurological phenotype [230], but the fact that several interacting genes in this pathway are involved in degenerative cerebellar ataxias suggests that the cerebellum has a peculiar susceptibility to DNA damage for which the underlying mechanism is not understood. Finally, altered synaptic morphology or synaptic dysfunction of Purkinje cells (PC) is frequently involved in recessive ataxias and is associated with aberrant Fig. 1 Clinical classification of autosomal recessive ataxias.

[13] Deciphering the Basis of Molecular Biology of Selected Cardiovascular Diseases: A View on Network Medicine

• Authors: Noora Alhajri, Mohammad Rustom, Adedayo Adegbile, Weshah Ahmed, Salsabeel Kilidar et al.
• Year: 2022
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/744c5858fb22cea747b94b7511da2f10feb603aa
• DOI: 10.3390/ijms231911421
• PMID: 36232723
• PMCID: 9569471
• Citations: 4
• Summary: The principal molecular and genetic mechanisms of common cardiac pathophysiologies are summarized as well as the existing knowledge on therapeutic strategies to prevent, halt, or reverse these pathologies are discussed.
• Evidence snippets:
• Snippet 1 (score: 0.365) > The modern application of scientific knowledge to understand the mechanism of disease pathophysiology for the delivery of efficient therapeutic interventions has been guided by the "Oslerian Principles of Disease Definition" (Osler, William. The principles and practice of medicine. D. Appleton and Company, 1912). The "Oslerian Principle" defines the disease process by clinical and pathological correlations, and now in the modern era, by the molecular or genetic alterations that contribute to the disease presentation. Inherent to this principle are fundamental concepts that specific key factors function in simple molecular circuits that regulate and control disease pathology, including where interventions can target these molecules to ameliorate disease processes [1]. > Although the Oslerian principle has increased our appreciation and understanding of disease processes at the molecular level, it oversimplifies the underlying basis of certain pathologies and thus limits our full understanding of the complex interaction of multiple factors that contribute to the disease process. Since the advent of molecular biology, it has become increasingly clear that a single gene mutation can result in disease pathogenesis. However, disease manifestations rarely result from an individualized abnormality in an effector; rather they are almost always the net result of interaction between multiple pathways that interact through a complex network composed of numerous molecules and genes [2,3]. > Molecular cardiology is an innovative and rapidly expanding branch of molecular biology that aims to use results from translational cardiovascular research to diagnose, treat, and prevent cardiovascular diseases. This emerging discipline has increased our knowledge and understanding of the molecular mechanisms of various cardiovascular diseases and provided novel diagnostic and therapeutic tools. For instance, molecular and genetic cardiology has increased the awareness of possible mechanisms of inheritance of certain chronic cardiac diseases (e.g., heart failure and congenital heart anomalies) and their links to specific gene mutations [4][5][6]. In this modern era of molecular medicine, we now have a framework of potential interaction between complex pathways and molecules known as the "interactome". The interactome describes the network of interactions between various molecules in the human cells. It consists of nearly 1000 metabolites, 25,000 protein-coding genes, and a significant number of functional RNA molecules, post-translationally modified proteins, and other cellular components, together exceeding 100,000 molecules [7].

[14] Solving the Evidence Interpretability Crisis in Health Technology Assessment: A Role for Mechanistic Models?

• Authors: E. Courcelles, J. Boissel, J. Massol, I. Klingmann, R. Kahoul et al.
• Year: 2022
• Venue: Frontiers in Medical Technology
• URL: https://www.semanticscholar.org/paper/877d5b1b75599745f704a9c8371f74601ff17e2f
• DOI: 10.3389/fmedt.2022.810315
• PMID: 35281671
• PMCID: 8907708
• Citations: 6
• Summary: Light is shed on different stakeholder's contributions and needs in the appraisal phase and how mechanistic modeling strategies and reporting can contribute to this effort to implement mechanistic models central in the evidence generation, synthesis, and appraisal of HTA so that the totality of mechanistic and clinical evidence can be leveraged by all relevant stakeholders.
• Evidence snippets:
• Snippet 1 (score: 0.365) > A second limitation in HTA is the fact that currently population (and sometimes stratified) medicine is pursued during clinical Uncertainty not completely addressed in competent authority assessment report Example use of MIDD relevant to address uncertainty potentially also during HTA What is the optimal dosage in the clinical context? > Physiologically based pharmacokinetic models can investigate dosing-regimens relevant for regulatory review and product labels (9) and can also mimic real-life adherence to prescribed treatment regimens (see also below) or pharmacology-relevant characteristics of special populations as well as drug-drug interactions. > What is the duration of the effectiveness, especially with chronic use of a treatment? > Mechanistic models can predict the long-term disease progression by extrapolation of shorter-term findings under the constraints of how the components of the system function (and these constraints convey biological plausibility by design). An example is the use of a mechanism-based disease progression model for comparison of long-term effects of pioglitazone, metformin, and gliclazide on disease processes underlying Type 2 Diabetes Mellitus (10). Another example is prediction of long-term outcomes by short-term marker data as demonstrated by a semi-mechanistic approach in context of osteoporosis treatment (11). > What is the efficacy for relevant clinical outcomes? > Mechanistic models combined with pharmacometric approaches can translate findings for one outcome to a range of other outcomes. An example of survival modeling on the back of a mechanistic description is the modeling framework for CD19-Specific CAR-T cell immunotherapy using a quantitative systems pharmacology model (12). > What is the size of the clinical effect dependent on patient characteristics and extrinsic factors? > Data-driven modeling techniques can capture correlation within clinical data. Describing the clinical effect of a drug can also be based on mechanistic considerations. Such models either (a) link disease phenotypes to increasingly granular mathematical representations of pathophysiologic processes (top-down approach) or (b) derive functional, computable cellular networks from the molecular building blocks of genes and proteins to elucidate the impact of pathologic or therapeutic alterations on network operating states and hence clinical phenotype (bottom-up) [

[15] Towards Mutation-Specific Precision Medicine in Atypical Clinical Phenotypes of Inherited Arrhythmia Syndromes

• Authors: T. Nakajima, S. Tamura, M. Kurabayashi, Y. Kaneko
• Year: 2021
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/3d299f57f344d42eff9d3565d1581dae7fb87a54
• DOI: 10.3390/ijms22083930
• PMID: 33920294
• PMCID: 8069124
• Citations: 6
• Influential citations: 1
• Summary: Since the epileptic phenotype appears to manifest prior to cardiac events in this mutation carrier, identifying KCND3 mutations in patients with epilepsy and providing optimal therapy will help prevent sudden unexpected death in epilepsy.
• Evidence snippets:
• Snippet 1 (score: 0.365) > Recent advances in molecular genetics have identified many causal genes for inherited arrhythmia syndromes (IASs) such as long QT syndrome (LQTS) [1], short QT syndrome (SQTS) [2], Brugada syndrome (BrS) [3,4] and early repolarization (ER) syndrome (ERS) [3,5]. Most causal genes for IASs encode cardiac ion channels or their related proteins. Genotype-phenotype studies and functional analyses of mutant genes, using heterologous expression systems and experimental animal models, have revealed the pathophysiology of IASs and enabled the establishment of causal gene-specific precision medicine [6][7][8]. Furthermore, analyses of patient-specific and/or genome-edited induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have provided further insights into the pathophysiology of IASs and novel promising therapeutic strategies for IASs, although there are still some limitations of using iPSC-CMs, such as immature structure and function and mixed population of atrial, ventricular, and nodal cells, as a standard technology [9]. > The altered function of causal genes that encode cardiac ion channels is caused by multiple mechanisms, including trafficking defects, producing non-functional channels, altered channel gating properties, and a combination thereof. These altered functions of mutant channels underly the clinical phenotypes of IASs [10][11][12]. Particularly, unique electrophysiological properties of mutant channels have been shown to be associated with the atypical clinical phenotypes of IASs [10,13]. Furthermore, the elucidation of the mechanisms underlying the atypical clinical phenotypes of IASs has raised the possibility of mutation-specific precision medicine. > We herein review the current knowledge of genotype-phenotype relationships, underlying molecular and cellular mechanisms, and established pharmacological therapies of IASs, including LQTS, SQTS, and J wave syndrome (BrS and ERS).

[16] Human Dermal Fibroblast: A Promising Cellular Model to Study Biological Mechanisms of Major Depression and Antidepressant Drug Response

• Authors: P. Mesdom, R. Colle, É. Lebigot, S. Trabado, Eric Deflesselle et al.
• Year: 2020
• Venue: Current Neuropharmacology
• URL: https://www.semanticscholar.org/paper/79368e365458486de96794333613c12a6063bf54
• DOI: 10.2174/1570159X17666191021141057
• PMID: 31631822
• PMCID: 7327943
• Citations: 12
• Summary: This review highlights the great and still underused potential of HDF, which stands out as a very promising tool in the understanding of MDD and AD mechanisms of action.
• Evidence snippets:
• Snippet 1 (score: 0.364) > Background: Human dermal fibroblasts (HDF) can be used as a cellular model relatively easily and without genetic engineering. Therefore, HDF represent an interesting tool to study several human diseases including psychiatric disorders. Despite major depressive disorder (MDD) being the second cause of disability in the world, the efficacy of antidepressant drug (AD) treatment is not sufficient and the underlying mechanisms of MDD and the mechanisms of action of AD are poorly understood. Objective The aim of this review is to highlight the potential of HDF in the study of cellular mechanisms involved in MDD pathophysiology and in the action of AD response. Methods The first part is a systematic review following PRISMA guidelines on the use of HDF in MDD research. The second part reports the mechanisms and molecules both present in HDF and relevant regarding MDD pathophysiology and AD mechanisms of action. Results HDFs from MDD patients have been investigated in a relatively small number of works and most of them focused on the adrenergic pathway and metabolism-related gene expression as compared to HDF from healthy controls. The second part listed an important number of papers demonstrating the presence of many molecular processes in HDF, involved in MDD and AD mechanisms of action. Conclusion The imbalance in the number of papers between the two parts highlights the great and still underused potential of HDF, which stands out as a very promising tool in our understanding of MDD and AD mechanisms of action

[17] From Data to Cure: A Comprehensive Exploration of Multi-omics Data Analysis for Targeted Therapies

• Authors: Arnab Mukherjee, S. Abraham, Akshita Singh, S. Balaji, K. Mukunthan
• Year: 2024
• Venue: Molecular Biotechnology
• URL: https://www.semanticscholar.org/paper/04593d2268ccd7c26b5296d8342b468ca84ae7b1
• DOI: 10.1007/s12033-024-01133-6
• PMID: 38565775
• PMCID: 11928429
• Citations: 69
• Influential citations: 2
• Summary: This review navigates the expansive omics landscape, showcasing tailored assays for each molecular layer through genomes to metabolomes, and aims to illuminate the transformative impact of multi-omics in the big data era, shaping the future of biological research.
• Evidence snippets:
• Snippet 1 (score: 0.363) > Biological processes and molecular functions arise from intricate interactions among thousands of molecules, constituting inherent complexity. Integration of metabolomics data with other omics data holds significant promise for achieving a holistic understanding of disease mechanisms. Metabolomics, which focuses on the comprehensive analysis of small molecule metabolites within biological systems, provides unique insights into the functional status and metabolic phenotypes associated with various physiological and pathological conditions [160,161]. The integration of omics datasets with computational models and network analysis tools elucidates the complex interplay between genes, proteins, metabolites, and cellular processes underlying disease phenotypes. > Despite recent progress in omics technologies, the underlying genetic factors contributing to numerous metabolic phenotypes remain elusive. Metabolite biomarkers can be integrated with genomics and clinical parameters to enhance diagnostic accuracy or refine disease risk prediction models. Metabolites can also serve as intermediate phenotypes for genetic investigations, offering insights into underlying genetic mechanisms [162]. The integration of metabolomics data with either whole-exome sequencing or WGS-data presents a promising systematic strategy for pinpointing disease-causing variants and holds potential utility within the framework of a specific pathway under investigation [163]. Furthermore, at a more intricate biological and analytical level, metabolomics can be combined with various omic platforms, facilitating a comprehensive understanding of complex biological systems and interactions (Fig. 4). > The alterations in metabolite levels, perturbations in metabolic pathways, and the onset of disease states can be elucidated by assessing the epigenetic alterations. This approach offers molecular insights into the intricate interplay among genetic, epigenetic, and metabolic factors during the disease progression. Through the integration of epigenomic Fig. 4 The workflow for integration of metabolomics with other omics for a holistic understanding of disease progression and metabolomic data, the intricate relationships between epigenetic alterations and metabolic pathways in disease pathogenesis can be uncovered. In recent years, metabolomics and epigenomics have experienced notable advancement as prominent molecular and analytical methodologies for biomarker identification [164,165].

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

• Authors: Jing Zhao, Ping Chen, Yijia Ren, Shurong Li, Weiyi Zhang et al.
• Year: 2025
• Venue: Frontiers in Genetics
• URL: https://www.semanticscholar.org/paper/5caf88001c66b473b6565f9e75eb6a4f1a8c4a0a
• DOI: 10.3389/fgene.2025.1550937
• PMID: 40406061
• PMCID: 12094932
• Citations: 1
• Summary: This study reports a rare familial balanced translocation pedigree, particularly noting that the offspring can suffer from Cri-du-chat syndrome, which suggests a potential new genetic model for this syndrome.
• Evidence snippets:
• Snippet 1 (score: 0.363) > Using the Metascape database for GO enrichment analysis of the region containing 60 OMIM genes from 5p15.33p14.1 revealed the potential molecular mechanisms of the disease. The results showed that OMIM genes in the 5p15.33p14.1 region are mainly enriched in Na+/Cl-dependent neurotransmitter transporters, cell-cell adhesion mediated by cadherin, nephron epithelium development, and other signaling pathways (Figure 5A). Disease enrichment analysis showed that genes in this region are mainly associated with Cri-du-chat syndrome (Figure 5B) . Cri-du-chat syndrome is closely related to developmental abnormalities, neurological defects, and craniofacial malformations. Enrichment analysis supports the involvement of molecular mechanisms related to Wnt signaling, neurotransmitter transport, ubiquitination pathways, particularly through diseasegene associations from DisGeNET and GO functional enrichment. These results provide clues for revealing the molecular network of the disease and guide future research. > Using the Metascape database, GO enrichment analysis of 45 OMIM genes located in the 9p24.3-p22.3 region was performed. The results showed that OMIM genes in the 9p24.3-p22.3 region are mainly enriched in signaling pathways such as positive regulation of leukocyte activation, response to amine, cell population proliferation, positive regulation of cell development, etc. (Figure 5C). Disease enrichment analysis revealed that genes in this region are mainly associated with Chromosome 9p deletion syndrome (Figure 5D). This study, through multidimensional bioinformatics analysis, not only clarified the core biological functions of genes in the 9p24.3-p22.3 region, but also revealed their potential association mechanisms with major diseases, providing important theoretical basis and directional guidance for subsequent gene function validation, molecular mechanism research, and clinical translation. Balanced translocation carriers have the opportunity to produce phenotypically normal offspring, but they are at a higher risk of recurrent miscarriages and offspring with chromosomal abnormalities.

[19] Molecular insights into the premature aging disease progeria

• Authors: Sandra Vidak, R. Foisner
• Year: 2016
• Venue: Histochemistry and Cell Biology
• URL: https://www.semanticscholar.org/paper/60fb3b46bb7e42d5d08cc3b7cbc783b118300c31
• DOI: 10.1007/s00418-016-1411-1
• PMID: 26847180
• PMCID: 4796323
• Citations: 105
• Influential citations: 3
• Summary: Changes in mechanosignaling, altered chromatin organization and impaired genome stability, and changes in signaling pathways, leading to impaired regulation of adult stem cells, defective extracellular matrix production and premature cell senescence are discussed.
• Evidence snippets:
• Snippet 1 (score: 0.361) > The number of molecular biological studies aiming at the identification of lamin-mediated molecular disease mechanisms involved in HGPS increased tremendously following the surprising discovery that LMNA is causally linked to the premature aging disease HGPS in 2003. Despite numerous cellular pathways that were identified to be affected by the expression of the mutant lamin A protein (Fig. 2), the mechanistic details behind these effects are still unclear in most cases. Knowledge based on what was already known on lamin biology before the protein was linked to HGPS and findings on novel roles of lamins in diverse pathways in recent years allowed the launch of translational studies and the efficient search for drug targets and therapeutic approaches within a short time period. The results of the first clinical trials taught us that some improvements of the disease phenotypes can be achieved by FTI treatment, but they also made clear that we need a much better understanding of the underlying disease mechanisms to be able to tackle specific aspects of the disease in a more focused approach. It will also be important to elucidate which of the numerous pathways found to be impaired in HGPS are most relevant for and causally involved in the pathologies, and which ones are just bystanders.

[20] Cardiac Phenotype and Gene Mutations in RASopathies

• Authors: M. Faienza, G. Meliota, D. Mentino, R. Ficarella, Mattia Gentile et al.
• Year: 2024
• Venue: Genes
• URL: https://www.semanticscholar.org/paper/a4087d3b73d20a6e2f46b7fb87eed4017ec9a9be
• DOI: 10.3390/genes15081015
• PMID: 39202376
• PMCID: 11353738
• Citations: 9
• Influential citations: 1
• Summary: The molecular mechanisms underlying the development of cardiac diseases associated particularly with NS are clarified, and the main morphological and clinical characteristics of the two most frequent cardiac disorders, namely pulmonary valve stenosis (PVS) and HCM are discussed.
• Evidence snippets:
• Snippet 1 (score: 0.361) > Cardiac involvement is a major feature of RASopathies, a group of phenotypically overlapping syndromes caused by germline mutations in genes encoding components of the RAS/MAPK (mitogen-activated protein kinase) signaling pathway. In particular, Noonan syndrome (NS) is associated with a wide spectrum of cardiac pathologies ranging from congenital heart disease (CHD), present in approximately 80% of patients, to hypertrophic cardiomyopathy (HCM), observed in approximately 20% of patients. Genotype–cardiac phenotype correlations are frequently described, and they are useful indicators in predicting the prognosis concerning cardiac disease over the lifetime. The aim of this review is to clarify the molecular mechanisms underlying the development of cardiac diseases associated particularly with NS, and to discuss the main morphological and clinical characteristics of the two most frequent cardiac disorders, namely pulmonary valve stenosis (PVS) and HCM. We will also report the genotype–phenotype correlation and its implications for prognosis and treatment. Knowing the molecular mechanisms responsible for the genotype–phenotype correlation is key to developing possible targeted therapies. We will briefly address the first experiences of targeted HCM treatment using RAS/MAPK pathway inhibitors.

Notes

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