Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Leri-Weill Dyschondrosteosis. Core disease mechanisms, molecular and cellu...

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

• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] 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: 0.481) > 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.

[2] 19. Jahrestagung der GfH, ÖGH und SGMG, 8.-10. April 2008 in Hannover: Abstracts mit Autorenindex

• Authors: Steffen Schubert, Ingram C.J.E, Raga T.O, E. Bekele, Elamin M.F et al.
• Year: 2008
• Venue: Medizinische Genetik
• URL: https://www.semanticscholar.org/paper/876e56407ab5aba0e08cca16f9f2803a5e8b6dfe
• DOI: 10.1007/s11825-008-0092-0
• PMID: 32288292
• PMCID: 7101744
• Summary: A genetic high-throughput siRNA-based screening approach is used to identify cellular pathways that are involved in microRNA-directed gene silencing and hopes to gain insight into how microRNAs work and how their expression and function is regulated.
• Evidence snippets:
• Snippet 1 (score: 0.433) > Family with Langer mesomelic dysplasia and Léri-Weill Dyschondrosteosis caused by a novel mutation in the SHOX-gene Trübenbach J. 1 , Wildhardt G. 1 , Schönfeld B. 2 , Holinski-Feder E. 2 , Decker H.J. 3 , Steinberger D. 4 1 Bioscientia, Center for Human Genetics, Ingelheim, Germany, 2 MGZ Medizinisch Genetisches Zentrum, München, Germany, 3 Bioscientia, Center for Human Genetics, Ingelheim, and Johannes Gutenberg University, Medical School, Dept. Hematology/Oncology, Mainz, Germany, Hematology/Oncology, Mainz, Germany, 4 Bioscientia, Center for Human Genetics, Ingelheim, and Justus Liebig University, Institute of Human Genetics, Giessen, Germany Short stature homeobox (SHOX)-related haploinsufficiency disorders include a wide spectrum of short stature phenotypes, such as symptoms of Turner syndrome, Léri-Weill Dyschondreosteosis (LWD), Langer mesomelic dysplasia (LMD), and short stature without any specific features (idiopathic short stature, ISS). For most of the patients with symptoms of this disease spectrum mutations affecting the SHOX-gene, its regulatory regions, or the pseudoautosomal regions (PAR1) of the X and Y chromosomes have been described. > Here, we report the results of the molecular genetic analyses of three generations of a family. The index case and his brother presented with clinical symptoms of LMD. For both of them it was shown that they carry the nucleotide change c.478C>G (p.Arg160Gly) in exon 3 of the SHOX-gene in a homozygous state. For the consanguineous parents, a sister of his mother and maternal grandmother of the index case the mutation was detected in heterozygous state. Clinical features seen in the patients affected are discussed in the context of our molecular findings.

[3] 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: 0.421) > 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.

[4] Cellular reprogramming and inherited peripheral neuropathies: perspectives and challenges

• Authors: M. Saporta
• Year: 2015
• Venue: Neural Regeneration Research
• URL: https://www.semanticscholar.org/paper/8c3dabb1b4abf93506e2026564b8a329c0ec37c6
• DOI: 10.4103/1673-5374.158345
• PMID: 26199602
• PMCID: 4498347
• Citations: 4
• Summary: iPSC-based models of neuromuscular disorders, including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and inherited peripheral neuropathies, have successfully reproduced pathophysiological findings from previous animal and cellular models and have also identified new disease mechanisms with potential therapeutical implications.
• Evidence snippets:
• Snippet 1 (score: 0.409) > Inherited peripheral neuropathies (or Charcot-Marie-Tooth disease, CMT) are a phenotypically and genetically heterogeneous group of disorders, which are currently untreatable. They are the most common inherited neuromuscular disorder, affecting around 1 in every 2,500 people (over 120,000 people in the US). Based on clinical neurophysiological and histopathological features, inherited neuropathies can be divided into two major forms: demyelinating (type 1) and axonal (type 2) CMT (Saporta, 2014). From a biological standpoint, these two major forms of CMT are associated with mutations in different sets of genes, affecting Schwann cell development and myelination (type 1) or peripheral axon physiology (type 2), although some overlap does exist (Figure 1). To date, over 70 genes have been associated with a CMT phenotype, making CMT an attractive natural model to study peripheral nervous system biology. Despite significant advances made in our knowledge of disease mechanisms in CMT, findings from animal models have so far translated poorly in clinical trials, underscoring the need for innovative methods to investigate the pathophysiology of these human disorders. Induced pluripotent stem cells (iPSCs) offer an unlimited source of patient specific, disease-relevant cell lines that can be used as a platform for identification of disease mechanisms, discovery of molecular targets and development of phenotypic screens for drug discovery (Saporta et al., 2011). iPSC-based models of neuromuscular disorders, including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and inherited peripheral neuropathies, have successfully reproduced pathophysiological findings from previous animal and cellular models and have also identified new disease mechanisms with potential therapeutical implications.

[5] 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: 0.405) > 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.

[6] 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: 0.404) > 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.

[7] Direct Sarcomere Modulators Are Promising New Treatments for Cardiomyopathies

• Authors: O. Tsukamoto
• Year: 2019
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/07467943fe92ce135b52ded5e5dea2bfc2ddf179
• DOI: 10.3390/ijms21010226
• PMID: 31905684
• PMCID: 6982115
• Citations: 16
• Summary: The direct inhibition of sarcomere contractility may be able to suppress the development and progression of HCM with hypercontractile mutations and improve clinical parameters in patients with HCM, and direct activation of sar COMs modulators that can positively influence the natural history of cardiomyopathies represent promising treatment options.
• Evidence snippets:
• Snippet 1 (score: 0.403) > Hereditary DCM can be caused by single point mutations in sarcomere proteins. However, the link between point mutations and clinical phenotypes in DCM is not thoroughly understood in most cases. Recent advances in biochemical, biophysical, stem cell, and gene editing technologies have provided a better understanding of the molecular mechanisms through which the initial insult in DCM (i.e., mutations in a sarcomere protein) induces alterations in cellular organization and contractility, resulting in disease phenotypes. In particular, hiPSC-CMs and genetically modified animals are excellent models because they can capture the initial molecular phenotype that occurs before major compensatory mechanisms mask it.

[8] 8th Meeting of the Irish Society of Human Genetics, Monday 19th September 2005

• Authors: D. Morris, K. Murphy, N. Kenny, N. Williams, Kalwant McGhee et al.
• Year: 2006
• Venue: The Ulster Medical Journal
• URL: https://www.semanticscholar.org/paper/c7336085182ff7719d5a26a54e60343e257ced13
• PMCID: 1891802
• Summary: 8th Meeting of the Irish Society of Human Genetics, Monday 19th September 2005 Postgraduate Centre, Belfast City Hospital.
• Evidence snippets:
• Snippet 1 (score: 0.398) > McConnell V, 1 Zabel B, 2 Wildhardt G, 3 Magee A. 1 1. Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast. 2. Children's hospital, University of Mainz, Germany. 3. Centre of Human Genetics, Bioscientia Institute, Ingelheim, Germany. > The aetiology of short stature is largely unknown. The Short HOmeoboX (SHOX) containing gene located on the pseudoautosomal region of the sex chromosomes has been implicated in short stature, including Turner syndrome (TS). Heterozygous and homozygous deletions of SHOX result in Leri-Weill dyschondrosteosis (LWD) and Langer dysplasia (LD) respectively. The clinical features of Madelung deformity, short fourth metacarpals and high arched palate are common to these three conditions. LWD is further characterised by disproportionate short stature and mesomelic shortening of the forearm and lower leg. > We report a large four-generation Northern Irish pedigree, with seven clinically affected individuals. The proband was referred with learning difficulties and short stature. Both parents and extended families had significant short stature. Examination of the proband and his mother suggested a clinical diagnosis of LWD, confirmed by radiological findings. In other less clinically affected relatives, radiology was needed to confirm the diagnosis. SHOX gene mutation screening in mother and son has demonstrated a heterozygous deletion. > Phenotypic heterogeneity, a recognised feature of LWD, is extensively observed in our pedigree. The use of radiological investigation in apparently clinically unaffected individuals is important. Investigation of short stature is essential, even if present in both parents. > S4. reproducing the haplotype; the role of the 5-lipoxygenase activating protein in ischaemic heart disease in Ireland. > Horan PG, 1 Allen AR, 2 Hughes AE, 3 Patterson CC, 4 Spence MS, 1 McGlinchey PG, 1 Belton C, 2 McKeown PP. 1,2 Introduction: Low-density lipoprotein (LDL) oxidation by leukotrienes and the 5-lipoxygenase activating protein

[9] Nuclear damages and oxidative stress: new perspectives for laminopathies

• Authors: G. Lattanzi, S. Marmiroli, Andrea Facchini, N. Maraldi
• Year: 2012
• Venue: European Journal of Histochemistry : EJH
• URL: https://www.semanticscholar.org/paper/8611d2c59658a5c3139c153051a0a4d8881c55ea
• DOI: 10.4081/ejh.2012.e45
• PMID: 23361241
• PMCID: 3567764
• Citations: 49
• Influential citations: 3
• Summary: The identification of a mechanism that accounts for accumulation of unrepairable DNA damage due to reactive oxygen species (ROS) generation in laminopathic cells, similar to that found in other muscular dystrophies (MDs) caused by altered expression of extracellular matrix (ECM) components, suggests that anti-oxidant therapeutic strategies might prove beneficial to laminopathies patients.
• Evidence snippets:
• Snippet 1 (score: 0.397) > Mutations in genes encoding nuclear envelope proteins, particularly LMNA encoding the A-type lamins, cause a broad range of diverse diseases, referred to as laminopathies. The astonishing variety of diseased phenotypes suggests that different mechanisms could be involved in the pathogenesis of laminopathies. In this review we will focus mainly on two of these pathogenic mechanisms: the nuclear damages affecting the chromatin organization, and the oxidative stress causing un-repairable DNA damages. Alteration in the nuclear profile and in chromatin organization, which are particularly impressive in systemic laminopathies whose cells undergo premature senescence, are mainly due to accumulation of unprocessed prelamin A. The toxic effect of these molecular species, which interfere with chromatin-associated proteins, transcription factors, and signaling pathways, could be reduced by drugs which reduce their farnesylation and/or stability. In particular, inhibitors of farnesyl transferase (FTIs), have been proved to be active in rescuing the altered cellular phenotype, and statins, also in association with other drugs, have been included into pilot clinical trials. The identification of a mechanism that accounts for accumulation of unrepairable DNA damage due to reactive oxygen species (ROS) generation in laminopathic cells, similar to that found in other muscular dystrophies (MDs) caused by altered expression of extracellular matrix (ECM) components, suggests that anti-oxidant therapeutic strategies might prove beneficial to laminopathic patients.

[10] Decoding Neuromuscular Disorders: The Complex Role of Genetic and Epigenetic Regulators

• Authors: Bladimir Roque‐Ramírez, Karla Estefanía Ríos-López, L. López-Hernández
• Year: 2025
• Venue: Genes
• URL: https://www.semanticscholar.org/paper/f52ef4e8272183d8e1436f01b7e8aa768cec6656
• DOI: 10.3390/genes16060622
• PMID: 40565514
• PMCID: 12192096
• Summary: The interaction of genetic and epigenetic factors in ALS, SMA, and muscular dystrophies is examined, highlighting their combined role in the heterogeneity of these diseases.
• Evidence snippets:
• Snippet 1 (score: 0.396) > Establishing clear genotype-phenotype correlations in NMDs remains challenging due to variable expressivity, incomplete penetrance, and additional mechanisms. For instance, Schwartz et al. (2007) documented an asymptomatic male with a dystrophin exon 16 deletion that is typically pathogenic (that would be expected to cause DMD/BMD) who displayed normal muscle strength and histology [9]. Conversely, Chiba et al. (2003) reported two sisters sharing the same dysferlin pathogenic variant but exhibiting divergent phenotypes: one with Miyoshi myopathy and the other with limb-girdle muscular dystrophy (LGMD) [10]. Such discordances highlight the influence of genetic modifiers and epigenetic factors on disease phenotypes. > Genetic modifiers are genes that alter the phenotypic impact of a primary pathogenic variant without directly causing disease [3,11]. They modulate disease severity, age of onset, or progression by affecting gene expression, protein function, or compensatory pathways [12,13]. Notably, this mechanism differs from oligogenic inheritance, where pathogenic variants in multiple genes are required for disease manifestation. For example, FSHD2 requires both a pathogenic SMCHD1 variant and a permissive D4Z4 allele [3]. The genetic landscape of NMDs extends beyond simple biallelic loss-of-function mutations, encompassing modifier variants, polygenic contributions, and complex allelic interactions that collectively shape disease phenotypes. While autosomal recessive forms classically require biallelic pathogenic variants, the frequent involvement of multiple genes, variant combinations, and modifier alleles creates substantial diagnostic challenges [14]. This genetic complexity underscores the critical need for curated gene-specific databases that integrate genotype-phenotype correlations, functional validation data, and epigenetic annotations. Such resources are indispensable for resolving variant interpretation ambiguities, elucidating polygenic contributions, and advancing precision medicine in NMDs to ultimately bridge the gap between molecular diagnostics and clinical outcomes [15][16][17].

[11] 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: 23
• 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: 0.390) > 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 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: 0.390) > 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.

[13] Pathophysiology, Clinical Heterogeneity, and Therapeutic Advances in Amyotrophic Lateral Sclerosis: A Comprehensive Review of Molecular Mechanisms, Diagnostic Challenges, and Multidisciplinary Management Strategies

• Authors: M. González-Sánchez, M. J. Ramírez-Expósito, J. M. Martínez-Martos
• Year: 2025
• Venue: Life
• URL: https://www.semanticscholar.org/paper/068cd6b38871f5b807d15db5e20bb35d9d2610f5
• DOI: 10.3390/life15040647
• PMID: 40283201
• PMCID: 12029092
• Citations: 17
• Influential citations: 1
• Summary: This comprehensive review synthesizes the current knowledge on ALS pathophysiology, clinical heterogeneity, diagnostic frameworks, and evolving therapeutic strategies to highlight the need for patient-centered communication and palliative strategies.
• Evidence snippets:
• Snippet 1 (score: 0.389) > This review on ALS underscores the inherent complexity of this neurodegenerative disease, from its phenotypic heterogeneity to the intricate network of pathophysiological mechanisms that contribute to its progression. ALS manifests as a diagnostic challenge due to its clinical variability, requiring a comprehensive approach that combines a detailed neurological evaluation with complementary tests to confirm upper and lower motor neuron involvement. The application of standardized diagnostic criteria, such as the revised El Escorial criteria, facilitates a more accurate classification of the disease, which in turn allows for better patient stratification and more informed therapeutic decision-making. > Pathophysiology research has revealed the involvement of multiple molecular and cellular pathways in ALS, including alterations in autophagy, RNA metabolism, nucleocytoplasmic transport, and protein aggregate formation. Genes such as C9orf72, SOD1, TDP-43, and FUS play a crucial role in these pathological processes, and their dysfunction contributes to motor neuron degeneration and disease progression. Understanding these underlying mechanisms is critical for the development of targeted therapies that can modify the course of ALS and improve the clinical outcomes. > Treatment of ALS remains a challenge, but advances in multidisciplinary care and the development of new drugs offer hope for patients and their families. Riluzole, edavarone, and tofersen are approved treatments that have been shown to modestly prolong survival in some ALS patients. However, their efficacy is limited, and more effective therapies are urgently needed. A multidisciplinary approach, including physiotherapy, occupational therapy, speech therapy, and psychosocial support, is essential to optimize patients' quality of life and address the multiple symptoms and complications of the disease. > The management of specific symptoms, such as dysphagia, dysarthria, cramping, and sleep disturbances, requires an individualized approach and the application of specific strategies, such as airway clearance techniques, noninvasive ventilation, and neuropathic pain management. The prognosis for ALS remains variable, but ongoing research and advances in clinical care offer promise for improving the quality of life and prolonging the survival of patients affected by this devastating disease.

[14] Drug Repurposing in Rare Diseases: An Integrative Study of Drug Screening and Transcriptomic Analysis in Nephropathic Cystinosis

• Authors: F. Bellomo, Ester De Leo, A. Taranta, L. Giaquinto, G. di Giovamberardino et al.
• Year: 2021
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/5e45caf9d574a1dc3ebf53a7fcb57c10bb2373f8
• DOI: 10.3390/ijms222312829
• PMID: 34884638
• PMCID: 8657658
• Citations: 18
• Summary: A drug repurposing strategy applied to nephropathic cystinosis, a rare inherited disorder belonging to the lysosomal storage diseases is shown, combining mechanism-based and cell-based screenings, coupled with an affordable computational analysis, which could result very useful to predict therapeutic responses at both molecular and system levels.
• Evidence snippets:
• Snippet 1 (score: 0.388) > Diagnosis and cure for rare diseases represent a great challenge for the scientific community who often comes up against the complexity and heterogeneity of clinical picture associated to a high cost and time-consuming drug development processes. Here we show a drug repurposing strategy applied to nephropathic cystinosis, a rare inherited disorder belonging to the lysosomal storage diseases. This approach consists in combining mechanism-based and cell-based screenings, coupled with an affordable computational analysis, which could result very useful to predict therapeutic responses at both molecular and system levels. Then, we identified potential drugs and metabolic pathways relevant for the pathophysiology of nephropathic cystinosis by comparing gene-expression signature of drugs that share common mechanisms of action or that involve similar pathways with the disease gene-expression signature achieved with RNA-seq.

[15] A Roadmap to Gene Discoveries and Novel Therapies in Monogenic Low and High Bone Mass Disorders

• Authors: M. Formosa, D. Bergen, C. Gregson, A. Maurizi, A. Kämpe et al.
• Year: 2021
• Venue: Frontiers in Endocrinology
• URL: https://www.semanticscholar.org/paper/be13ff3ea01dc5719f2c63b2cbf5d9f77bafd659
• DOI: 10.3389/fendo.2021.709711
• PMID: 34539568
• PMCID: 8444146
• Citations: 21
• Summary: The monogenic forms of rare low and high rare bone Mass disorders known to date are described, a roadmap to unravel the genetic determinants of monogenic rare bone mass disorders is provided, using proper phenotyping and genotyping methods are provided, and different genetic validation approaches paving the way for future treatments are described.
• Evidence snippets:
• Snippet 1 (score: 0.385) > Skeletal development is regulated by numerous genetic factors that guide the growth, modeling and remodeling of skeletal structures starting in early fetal development and continuing throughout life. These processes are crucial for attainment of normal height, skeletal patterning, bone shape, and mobility, but also for maintenance of normal bone mass and fracture resistance. Defects in the involved genes result in a large and heterogeneous group of disorders, collectively called skeletal dysplasias, in which the primary features are confined to the skeleton. More than 460 different forms of skeletal dysplasia, most of them monogenic, have been recognized (1). They are estimated to affect approximately 1/5,000 children (2,3), and can have distinct clinical manifestations and course. Clinical outcomes range in severity from neonatal lethality to only mild growth retardation, deformity or fracture risk. Diagnosis is based on growth pattern and other clinical characteristics, skeletal imaging, bone density testing, biochemical diagnostics, and genetic tests. Although the genetic basis has been described and mutations in the responsible genes identified in a significant proportion of these conditions, for several distinct skeletal dysplasia phenotypes the genetic cause is still not known (1). > Within this large group of genetic skeletal disorders, monogenic disorders affecting bone mass comprise an expanding subgroup (1,4). This includes disorders with low bone mass and skeletal fragility, and disorders leading to increased bone mass, both commonly associated with extraskeletal complications (5,6). Due to significant variability in severity, diagnosis can be challenging. Importantly, the underlying molecular genetic mechanisms for these disorders remain inadequately explored and, in several entities, the causative genetic defect, and underlying cellular and molecular pathophysiology are still uncharacterized. > The various skeletal dysplasia delineated to date have provided important information about the molecular pathways governing skeletal health both in these conditions and in the general population, underscoring the significance of new gene discoveries not only for the individuals affected by the monogenic rare bone mass disorder, but also more widely to the musculoskeletal research field (7). Indeed, the large wealth of data generated from monogenic and polygenic bone mass disorders, frailty and other musculoskeletal traits, have led

[16] Can Multiple Hereditary Exostoses Overlap With Mesomelic Dysplasia?

• Authors: A. Al Kaissi, M. Ben Ghachem, Farid Ben Chehida, J. Hofstaetter, F. Grill et al.
• Year: 2016
• Venue: Journal of Clinical Medicine Research
• URL: https://www.semanticscholar.org/paper/38a659aa2984e404f10729f39ee0680bf1a2d8a4
• DOI: 10.14740/jocmr2593w
• PMID: 27429682
• PMCID: 4931807
• Citations: 1
• Summary: The variability in the phenotypic expression of multiple exostosis is emphasized, especially the confusion that might arise when the condition appears both clinically and radiologically to be more complicated, and the overall picture might then be overlapped with one of the other bone dysplasias such as Leri-Weill dyschondrosteosis syndrome.
• Evidence snippets:
• Snippet 1 (score: 0.377) > Their faces were long and they seemed to have sloping shoulders and a thin body habitus giving overall the appearance of tall stature, but the majority were indeed short. We report this family to emphasize how confusing the clinical and radiological features might be and neither the proband with multiple exostosis, nor the male cousin with mesomelia showed genotypic characterizations of the two disorders. The diagnosis and recognition of multiple exostoses might be straightforward in the majority of cases, but as in this family, the Madelungtype forearm deformity in association with mesomelic dysplasia and short limbed dwarfism did cause initial problems with the definite diagnosis. Patients with a Madelung-type deformity may have more complicated disease and multiple exostosis should be excluded as an underlying cause. > The overall clinico-radiographic phenotype in this family can be described as utterly unusual. The constellation of multiple hereditary exostosis, severe short stature, and mesomelic dysplasia in several patients over three generations can be described as a unique pattern of deformities. We would like to emphasize the variability in the phenotypic expression of multiple exostoses, especially the confusion that might arise when the condition appears both clinically and radiologically to be more complicated, and the overall picture might then be confused because of the overlap with Leri-Weill dyschondrosteosis syndrome. > Finally, we wish to stress that whether other genes on the same or a different chromosome affect expression and therefore clinical phenotype, or whether environmental effects are involved, is unclear and in order to approach to the final etiology to explain this unusual overlap, the necessity of further studies and research is mandatory.

[17] Recent Evidences of Epigenetic Alterations in Chronic Obstructive Pulmonary Disease (COPD): A Systematic Review

• Authors: R. Ragusa, Pasquale Bufano, A. Tognetti, M. Laurino, Chiara Caselli
• Year: 2025
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/2660cdbbe1f205c631fe890e5c6a3c8d9b81ce5f
• DOI: 10.3390/ijms26062571
• PMID: 40141213
• PMCID: 11942187
• Citations: 4
• Summary: A systematic review of the latest knowledge on epigenetic modifications that characterize COPD, summarizing epigenetic factors that could serve as potential novel biomarkers and therapeutic targets for the treatment of COPD patients.
• Evidence snippets:
• Snippet 1 (score: 0.374) > The papers included were clustered according to epigenetic mechanisms involved in COPD (molecular and cellular processes, as biomarker or therapeutic target). Tables 4-9 describe the extracted information, including the following: Study = name of first author et al., year; Country (Region) = where the study took place; Number of participants = sample size; Type of sample = biological sample employed; Gene affected = gene or group of genes whose expression can be "regulated" by epigenetic mechanisms; Epigenetic alteration = type of epigenetic alteration observed in the presence of disease; Activity in COPD = involvement of epigenetic elements in different molecular and cellular mechanisms associated with COPD; and Role of epigenetic mechanisms = epigenetic modifications that can be used to explain the pathophysiology of COPD or as biomarkers and therapeutic targets.

[18] 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: 0.373) > 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).

[19] Cardiomyocytes Derived from Induced Pluripotent Stem Cells as a Disease Model for Propionic Acidemia

• Authors: Esmeralda Alonso-Barroso, B. Pérez, L. Desviat, E. Richard
• Year: 2021
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/da649a0f04477c53b448c5ac5f873f8762235290
• DOI: 10.3390/ijms22031161
• PMID: 33503868
• PMCID: 7865492
• Citations: 16
• Influential citations: 1
• Summary: The novel results show that PA iPSC-cardiomyocytes represent a promising model for investigating the pathological mechanisms underlying PA cardiomyopathies, also serving as an ex vivo platform for therapeutic evaluation.
• Evidence snippets:
• Snippet 1 (score: 0.373) > The study of the mechanisms involved in disease physiopathology has been mainly performed using the hypomorphic PA mouse model that mimics the biochemical and clinical phenotype [5]. Using this model, bioenergetic failure, oxidative damage and deregulation of miRNAs induced by accumulating propionyl-CoA have been described as potential mechanisms contributing to PA physiopathology [6][7][8]. The limitations of animal models for the study of cardiac energy metabolism [9] and of the commonly available cellular human models such as fibroblasts, underline the importance of generating new relevant cell models to provide deeper insight into the underlying mechanisms of disease. The use of in vitro models with human cellular context is highly recommended and, in this sense, induced pluripotent stem cells (iPSCs) have certain advantages since they provide the genetic background of the patient and represent an unlimited source of biological material for the study of pathophysiology and treatment effectiveness [10]. We have previously generated an iPSC line from a PA patient with defects in the PCCA gene that showed full pluripotency, differentiation capacity and genetic stability [11]. > In the present study, we aimed to establish a platform that served as a disease model to study the cellular and molecular alterations operating in cardiac tissue affected by PA disease. We described the characterization of cardiomyocytes derived from the PCCA iPSC line (PCCA iPSC-CMs) and the analysis of specific pathways potentially involved in cardiac PA physiopathology.

[20] Guidelines for genetic studies in single patients: lessons from primary immunodeficiencies

• Authors: J. Casanova, M. Conley, S. Seligman, L. Abel, L. Notarangelo
• Year: 2014
• Venue: The Journal of Experimental Medicine
• URL: https://www.semanticscholar.org/paper/6f6b8309ebce06da91e67c72a535694969115597
• DOI: 10.1084/jem.20140520
• PMID: 25311508
• PMCID: 4203950
• Citations: 235
• Influential citations: 5
• Summary: The importance of single-patient genetic studies in the discovery of novel primary immunodeficiencies and insight into the standards and criteria that should accompany these studies are offered.
• Evidence snippets:
• Snippet 1 (score: 0.373) > a. A variant in a protein-coding gene can be nonsynonymous (change the amino acid sequence) or, if synonymous, have a proven impact on mRNA structure or amount (e.g., create an abnormal splicing site). A variant in an RNA gene must affect its function (if its expression is detectable). > b. Studies should document whether the variant changes the amount or molecular weight of the gene transcript and of the encoded protein. Ideally, this should be done in control primary cells or iPSC-derived cell lines, and not only in control immortalized cell lines. > c. Computer programs that predict whether a missense variant is damaging are helpful but not conclusive. A variation that is not conservative and that occurs in a region or at a residue of the encoded protein that is highly conserved in evolution provides support for the hypothesis that the amino acid is functionally important. > d. The variants must be loss or gain of function for at least one biological activity. For variants that result in an amino acid substitution, insertion, or deletion, in vitro studies should document a functional change that reveals the mechanism by which the variant causes disease. For example, the protein may be unstable, it may not bind essential cofactors, or it may not localize appropriately. > 3. The causal relationship between the candidate genotype and the clinical phenotype must be established via a relevant cellular or animal phenotype. > a. In all cases, the candidate gene should be known or shown to be normally expressed in cell types relevant to the disease process. These may be cells affected by the disease process, cells which produce factors needed by the affected cells or progenitors of the cell lineage affected by the disease. Some genes are broadly expressed but have a narrow clinical phenotype. > b. For disorders that affect the function of a cell (present in the patient), experimental studies in vitro must indicate that there is a cellular phenotype explained by the candidate genotype (see c). This cellular phenotype should reasonably account for the clinical phenotype because the cell type is known to be involved in the disease process and the clinical phenotype is consistent with it. For example, if the candidate gene can be connected to a known disease-causing gene via a common cellular phenotype (e.g., mutations

Notes

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