Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Brachyolmia. Core disease mechanisms, molecular and cellular pathways, inv...

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: 0.390) > 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] 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: 0.383) > 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

[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: 0.380) > 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] Exploring the molecular mechanisms of subarachnoid hemorrhage and potential therapeutic targets: insights from bioinformatics and drug prediction

• Authors: Yi Liu, Yang Zhang, Huan Wei, Li Wang, Lishang Liao
• Year: 2025
• Venue: Scientific Reports
• URL: https://www.semanticscholar.org/paper/19a91d9c8cabec6a5a186729d545077e252ecb67
• DOI: 10.1038/s41598-025-97642-8
• PMID: 40229542
• PMCID: 11997208
• Summary: The findings not only elucidate the molecular mechanisms underlying SAH but also provide robust bioinformatics and experimental evidence supporting IRN as a promising therapeutic candidate, offering novel insights for future intervention strategies in SAH.
• Evidence snippets:
• Snippet 1 (score: 0.373) > involved in SAH pathology. As a result, our understanding of the cellular composition and microenvironment in SAH remains incomplete 8 . > Advances in bioinformatics provide powerful tools to analyze large-scale gene expression data and understand complex biological processes. By integrating transcriptomic data with immune cell infiltration analysis, we can gain a deeper understanding of the molecular mechanisms underlying SAH and identify potential key genes as therapeutic targets 9,10 . Previous studies have indicated that inflammation, oxidative stress, and cell death play crucial roles in the development of SAH, processes that are often closely associated with changes in specific cell types and immune responses 11 . > The goal of this study is to explore the molecular mechanisms of SAH, with a focus on immune cell infiltration and its role in disease progression. We aim to identify key genes and signaling pathways associated with SAH and investigate potential therapeutic strategies. Specifically, we will examine Isorhynchophylline (IRN) as a potential treatment for SAH and analyze its effects on relevant targets and signaling pathways. Through a comprehensive understanding of the pathological features of SAH, this study aims to provide valuable insights into future clinical interventions and treatment strategies.

[5] Organoids in gastrointestinal diseases: from bench to clinic

• Authors: Qinying Wang, Fanying Guo, Qinyuan Zhang, Tingting Hu, Yutao Jin et al.
• Year: 2024
• Venue: MedComm
• URL: https://www.semanticscholar.org/paper/9b8880d8b9d45670da950197d7e353794f51d09e
• DOI: 10.1002/mco2.574
• PMID: 38948115
• PMCID: 11214594
• Citations: 12
• Summary: A comprehensive and systematical depiction of organoids models is drawn, providing a novel insight into the utilization of organoids models from bench to clinic and clinical adhibition.
• Evidence snippets:
• Snippet 1 (score: 0.367) > Organoids models offer a robust platform for investigating the potential mechanisms of GI diseases and evaluating potential therapeutic interventions.By culturing organoids derived from patients' tissues or stem cells, researchers can delve into disease-specific cellular and molecular pathways, encompassing aberrant cell signaling, perturbed immune responses, and dysfunctional metabolic processes.These disease-specific phenotypes enable the study of disease progression, screening of prospective therapeutics, as well as identification of novel drug targets and mechanisms of action for GI diseases in a clinically relevant context.

[6] Differential Tissue Metabolic Signatures in IgG4-Related Ophthalmic Disease and Orbital Mucosa-Associated Lymphoid Tissue Lymphoma

• Authors: Hiroyuki Shimizu, Y. Usui, R. Wakita, Yasuko Aita, Atsumi Tomita et al.
• Year: 2021
• Venue: Investigative Ophthalmology & Visual Science
• URL: https://www.semanticscholar.org/paper/566565fe15563034f1302745d5d466be356f2d9e
• DOI: 10.1167/iovs.62.1.15
• PMID: 33439228
• PMCID: 7814356
• Citations: 17
• Summary: Purpose To identify tissue metabolomic profiles in biopsy specimens with IgG4-related ophthalmic disease (IgG4-ROD) and mucosa-associated lymphoid tissue (MALT) lymphoma and investigate their potential implication in the disease pathogenesis and biomarkers. Methods We conducted a comprehensive analysis of the metabolomes and lipidomes of biopsy-proven IgG4-ROD (n = 22) and orbital MALT lymphoma (n = 21) specimens and matched adjacent microscopically normal adipose tissues using liquid chromat...
• Evidence snippets:
• Snippet 1 (score: 0.366) > progressing to genetic instabilities with chromosomal abnormalities, causing the transformation of a clone of normal lymphoid cells to MALT lymphoma. 7 However, the pathogenic mechanisms of IgG4-ROD and orbital MALT lymphoma are poorly characterized. Notably, IgG4-ROD occasionally involves regional and/or systemic lymph nodes simultaneously or subsequently and is often clinically and/or histopathologically suspected to be malignant lymphoma. Clinically, IgG4-ROD exhibits similar clinical and imaging (magnetic resonance imaging and computed tomography) features as orbital MALT lymphoma. 8,9 Furthermore, some orbital MALT lymphomas are associated with elevated serum IgG4 levels 9 and infiltration of numerous IgG4positive plasma cells in the affected tissue. 10 Orbital MALT lymphoma can arise from IgG4-ROD 11 and IgG4-producing MALT lymphoma. 12 Elevated serum IgG4 is not sufficiently sensitive or specific for diagnostic purpose. 13,14 Therefore, discriminating IgG4-ROD from orbital MALT lymphoma is sometimes challenging. Moreover, not all patients respond well to treatment, and approximately 50% of patients with IgG4-ROD will develop recurrence or progression after conventional clinical treatment, including with systemic corticosteroids or rituximab. 15,16 Therefore, further elucidation of the underlying molecular mechanisms of IgG4-ROD is required. > Metabolites reflect the integration of upstream processes of genes and proteins. Metabolites function as mediator molecules and comprehensive metabolic analyses may, therefore, provide insights into the features of disease states. Metabolomics, a method for the comprehensive analysis of metabolites, has emerged as a promising tool for the identification of biomarkers, combining advanced analytical chemistry techniques with cheminformatics to characterize thousands of metabolites found in tissues and biofluids. Thus, metabolomics is widely used to characterize disease pathophysiology and metabolic pathways frequently aberrant in inflammatory diseases and cancers. 17,18 Although a recent serum metabolomic study of IgG4-RD has been reported, 19 a comprehensive analysis aiming to reveal the tissue metabolomic

[7] Targeting Hepatic Stellate Cells for the Prevention and Treatment of Liver Cirrhosis and Hepatocellular Carcinoma: Strategies and Clinical Translation

• Authors: Hao Xiong, Jinsheng Guo
• Year: 2025
• Venue: Pharmaceuticals
• URL: https://www.semanticscholar.org/paper/76e92127053136900f7e3f10e2c9278251ced5d2
• DOI: 10.3390/ph18040507
• PMID: 40283943
• PMCID: 12030350
• Citations: 7
• Summary: HSC-targeted approaches using specific surface markers and receptors may enable the selective delivery of drugs, oligonucleotides, and therapeutic peptides that exert optimized anti-fibrotic and anti-HCC effects.
• Evidence snippets:
• Snippet 1 (score: 0.366) > Significant progress has been made in elucidating the cellular and molecular mechanisms of liver fibrosis; however, only a few findings have been successfully translated into clinical applications. Firstly, the high cost of drug development and target validation necessitates prolonged timelines and substantial financial investment. Secondly, as regulatory requirements become more stringent, there is an increasing demand for drugs with well-defined clinical efficacy and safety profiles. Moreover, the efficacy observed in animal models often fails to fully translate to clinical settings due to differences in pharmacokinetics, extracellular matrix (ECM) cross-linking, and disease pathophysiology. Despite advancements in anti-fibrotic drug development, accurately identifying ideal noninvasive biomarkers for fibrotic activity and establishing consensus on optimal clinical endpoints remain significant challenges [113,114]. > Currently, addressing the underlying cause remains the only proven strategy to halt or reverse liver fibrosis progression, while the development of effective anti-fibrotic therapies continues to pose a major challenge in liver disease management. Over the past few decades, substantial progress has been made in elucidating the cellular and molecular mechanisms underlying liver fibrosis. Liver fibrosis is a complex pathological change involving multiple cells, factors, and pathways, and the study of the cellular and molecular mechanisms of its occurrence and development provides an important theoretical basis and therapeutic target for clinical drug development. It is anticipated that improved animal models and well-designed clinical trials will facilitate the successful translation of anti-fibrotic research into effective clinical treatments in the near future.

[8] Heat Shock Proteins in Oxidative Stress and Ischemia/Reperfusion Injury and Benefits from Physical Exercises: A Review to the Current Knowledge

• Authors: Jakub Szyller, I. Bil-Lula
• Year: 2021
• Venue: Oxidative Medicine and Cellular Longevity
• URL: https://www.semanticscholar.org/paper/4ec4bee9f1b89cdf5a3c513d847990f3cfc18bb8
• DOI: 10.1155/2021/6678457
• PMID: 33603951
• PMCID: 7868165
• Citations: 110
• Influential citations: 2
• Summary: The latest research focuses on determining the role of H SPs in OS, their antioxidant activity, and the possibility of using HSPs in the treatment of I/R consequences, where reactive oxygen species play a major role.
• Evidence snippets:
• Snippet 1 (score: 0.358) > Heat shock proteins play a cytoprotective role under pathological conditions such as cardiovascular diseases. The knowledge about cellular and molecular mechanisms underlying ROS-mediated modulation of HSP expression can help to better understand the pathophysiology of OS, which is associated with the development of many diseases (cardiovascular, neurodegenerative, etc.). I/R injury is considered a major contributor to tissue damage in multiple clinical situations such as myocardial infarction, stroke, and organ transplantation. Oxidative damage is a key factor in the initiation of I/R. HSP expression is highly sensitive to I/R injury. > Understanding the exact mechanisms of HSP and the structure of the protein interaction network can help to better understand the pathophysiology and treatment of many diseases, as well as to develop new drugs. There is a need to understand the relationship between cell pathways-signaling, metabolism, etc. The relationships between HSP and OS discussed in this work seem to be very complicated and not yet fully understood. Data showed that modulation of HSP expression in reperfusion injuries may result in better treatment of myocardial infarction. This can also help to prepare organs for the transplantation.

[9] Identification of Key Biomarkers Related to Lipid Metabolism in Acute Pancreatitis and Their Regulatory Mechanisms Based on Bioinformatics and Machine Learning

• Authors: Liang Zhang, Yujie Jiang, Taojun Jin, Mingxian Zheng, Yixuan Yap et al.
• Year: 2025
• Venue: Biomedicines
• URL: https://www.semanticscholar.org/paper/e7ce2244e2bc25df76718a7b46e860a9c0478c01
• DOI: 10.3390/biomedicines13092132
• PMID: 41007695
• PMCID: 12467098
• Citations: 2
• Summary: Findings are crucial for a deeper understanding of lipid metabolism pathways in AP and for the early implementation of preventive clinical measures, such as the control of blood lipid levels.
• Evidence snippets:
• Snippet 1 (score: 0.357) > FFAs have activated inflammatory cytokines, including tumor necrosis factor (TNF)-α, Interleukin (IL)-6, IL-1β, and monocyte chemoattractant protein (MCP)-1, which exacerbate the inflammatory cascade in AP [12,13]. These findings suggest that lipid metabolism disorders are closely linked to the regulation of the local immune micro-environment of the pancreas. Abnormal expression of specific lipid metabolism-related genes may play a crucial role in AP progression. Notably, ACSL4, a gene involved in cell membrane lipid synthesis, has been shown to be central to AP pathology and may serve as a potential therapeutic target [14]. However, the molecular mechanisms by which lipid metabolism abnormalities regulate AP development remain unclear. A systematic analysis of the expression patterns of relevant genes and their regulatory mechanisms could enhance our understanding of AP pathogenesis and inform personalized treatment strategies. > Advancements in high-throughput sequencing and computational biology have made machine learning and bioinformatics essential tools for exploring disease diagnosis, treatment, and underlying pathological mechanisms. In this study, we conducted a systematic analysis of AP-related lipid metabolism core genes and their regulatory mechanisms by integrating gene expression data, gene enrichment analysis, machine learning, protein interaction networks, and metabolic pathway analysis [15][16][17][18]. We then experimentally validated the candidate genes using an AP mouse model to ensure the reliability and clinical translational value of the identified biomarkers. > This study aims to identify key lipid metabolism-related genes involved in the pathogenesis of acute pancreatitis and elucidate their core regulatory mechanisms through integrative bioinformatics, machine learning, and animal experiments.

[10] Notch1 siRNA and AMD3100 Ameliorate Metabolic Dysfunction-Associated Steatotic Liver Disease

• Authors: Chunli Zhu, Yiheng Cheng, Lei Yang, Yifu Lyu, Jingjing Li et al.
• Year: 2025
• Venue: Biomedicines
• URL: https://www.semanticscholar.org/paper/f3a6939b33db32d6c141825ae843fbc27c1d1ad8
• DOI: 10.3390/biomedicines13020486
• PMID: 40002899
• PMCID: 11853639
• Citations: 2
• Summary: This work demonstrated that in liver cells, siNotch1 combined with AMD3100 not only directly modulated macrophages by downregulating multiple pathways downstream of Notch, exerting anti-inflammatory, anti-migration, and switch of macrophage phenotype, but also modulated macrophage phenotypes through inhibiting NET release.
• Evidence snippets:
• Snippet 1 (score: 0.355) > Metabolic dysfunction-associated steatotic liver disease (MASLD), renamed from non-alcoholic liver disease (NAFLD), is considered one of the most common causes of chronic liver diseases, including progression of hepatic steatosis, metabolic dysfunctionassociated steatohepatitis (MASH), fibrosis, and hepatocellular carcinoma (HCC) [1,2]. Meanwhile, MASLD is a multisystem disease with some extrahepatic complications like cardiovascular disease (CVD), type 2 diabetes mellitus, and chronic kidney disease [3]. MASLD represents a significant and progressively increasing global health and economic burden, while prevalence of MASLD continues to increase substantially worldwide [4]. The good news is that the FDA approved the first drug for the treatment of MASH, Rezdiffra, in 2024, but the long-term efficacy of the drug is still being studied and evaluated [5]. Moreover, other promising drugs targeting mechanisms of MASLD are still under clinical trials. Apart from developing new drugs, considering the complex pathogenesis of MASLD, it is necessary to propose more clinical protocols for drug combination to treat MASLD, as efficacy can be increased and side effects can be reduced in this way [6]. > The Notch signaling pathway is extremely evolutionarily conserved and is extensively involved in various diseases of the nervous, immune, and cardiovascular systems [7]. In MASLD progression, the Notch signaling pathway is associated with hepatic lipid accumulation, insulin resistance (IR), oxidative stress (OS), fibrogenesis, and autophagy progression in MASLD [8]. Specifically, the Notch signaling pathway is involved in the activation and effect of pro-inflammatory macrophages, and it directly regulates the transcription of pro-inflammatory signature genes, such as Il6, Il12b, and Nos2 [9]. In monocytes, the Notch signaling pathway plays a crucial role in cell migration and differentiation [10], and it also mediates the transition between the Ly6C high inflammatory phenotype and the Ly6C low circulating surveillance phenotype through mechanisms similar to those in macrophages [11].

[11] Investigating the role of NPR1 in dilated cardiomyopathy and its potential as a therapeutic target for glucocorticoid therapy

• Authors: Yaomeng Huang, Tongxin Li, Shichao Gao, Shuyu Li, Xiaoran Zhu et al.
• Year: 2023
• Venue: Frontiers in Pharmacology
• URL: https://www.semanticscholar.org/paper/be229f6f2059faab4c97ec0a04bd055adab9dfe1
• DOI: 10.3389/fphar.2023.1290253
• PMID: 38026943
• PMCID: 10662320
• Citations: 3
• Summary: Natriuretic peptide receptor 1 (NPR1) was identified as a core gene associated with DCM through bioinformatics analysis and led to substantial improvements in cardiac and renal function, accompanied by an upregulation of NPR1 expression.
• Evidence snippets:
• Snippet 1 (score: 0.355) > Multiple pathways and molecules are involved in this process; however, the detailed underlying mechanisms remain unclear. In recent years, with the development of high-throughput sequencing and gene chip technologies, the use of bioinformatics technology to explore the occurrence, development, and prognosis of diseases has become a hot topic for scholars worldwide (Hwang et al., 2018;Nayor et al., 2019;Rinschen et al., 2019;Sturm et al., 2019;Montaner et al., 2020). > The present study aimed to use bioinformatics technology to screen for DCM-related genes and investigate their mechanisms, with the purpose of revealing the pathogenesis of DCM and seeking treatment methods. The GSE3586 dataset, containing expression profiles related to DCM, was selected from the Gene Expression Omnibus (GEO) database. This study aimed to predict the core genes that may play crucial roles in disease progression at the molecular level through the enrichment of relevant molecular pathways associated with DCM. Furthermore, the phenotype of the core genes was validated to further support the results of the bioinformatics analysis through basic and clinical experiments. Additionally, the role of glucocorticoids in DCM treatment is discussed in this article with the purpose of providing a theoretical and experimental basis for exploring the pathogenesis of DCM and elucidating therapeutic methods. This study also provides a theoretical reference for the interpretation, early diagnosis, and treatment of DCM.

[12] Modeling psychiatric disorders: from genomic findings to cellular phenotypes

• Authors: Anna Falk, Vivi M. Heine, A. Harwood, Patrick F. Sullivan, M. Peitz et al.
• Year: 2016
• Venue: Molecular Psychiatry
• URL: https://www.semanticscholar.org/paper/235b41240d78140de7ab06a3ad8a7d0b1bdff1a5
• DOI: 10.1038/mp.2016.89
• PMID: 27240529
• PMCID: 4995546
• Citations: 77
• Influential citations: 2
• Summary: The challenges for modeling of psychiatric disorders, potential solutions and how iPSC technology can be used to develop an analytical framework for the evaluation and therapeutic manipulation of fundamental disease processes are critically reviewed.
• Evidence snippets:
• Snippet 1 (score: 0.354) > The key challenge for iPSC-based disease modeling is to identify one or more relevant cellular phenotypes that accurately represent the disease pathophysiology. Increasing numbers of reports have demonstrated that for many diseases specific pathophysiology can be captured in human iPSC-based disease models. These range from cardiovascular disease, 44,45 cancer, 46,47 ocular disease, 48,49 diabetes mellitus 50,51 and neurological disorders of the brain. 52,53 Can the same approach be applied to complex psychiatric disorders? > The problem is that almost all psychiatric disorders are characterized by clinical signs and symptoms, but lack independent verification from objective biomarkers. Thus, how might these clinical phenotypes manifest themselves in terms of cell behavior? The identity of robust cellular 'readouts', which typify any psychiatric disorder, is a crucial unsolved problem and an area of intense study 54 (Table 2). When satisfactorily answered, this will herald a new degree of biological objectivity and quantification for the study of psychiatric disorders. > The aim is to find a single or small number of cell phenotypes or parameters that strongly associate with psychiatric disorders, and establish a cellular profile characteristic of cells derived from the general patient population. Although a consensus set of cellular phenotypes for psychiatric disorder is yet to be established, we can define some of their desired characteristics. First, cellular phenotypes have to relate to the biological pathways identified by genetics. Second, although there are many risk genes in disparate biological pathways, at some level, phenotypes should converge onto a much smaller grouping. Third, phenotypes need to be quantifiable. Finally, to be useful for drug development cellular phenotypes should be reversed by pharmacological treatment, although not necessarily by drugs in current use. > Although human iPSC-based approaches underrepresent the complexity of the human central nervous system, cellular phenotypes are likely to lie more proximal to molecular disease mechanisms than phenotypes seen at the level of a tissue or organism, 55 and thus may bypass compensatory homeostatic (2) Gene expression profiles of SCZ human iPSC neurons identified altered expression of many components of the cyclic AMP and WNT signaling pathways. > (3

[13] Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies

• Authors: I. Condò
• Year: 2022
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/6aece75e6947f102b657851b74e8b96df5e654c1
• DOI: 10.3390/ijms23126525
• PMID: 35742964
• PMCID: 9223693
• Citations: 14
• Influential citations: 2
• Summary: A rare disease is defined by its low prevalence in the general population and its presence in a very small number of people.
• Evidence snippets:
• Snippet 1 (score: 0.354) > The selective expression or the particular role of specific genes in a single tissue explains the appearance of organ-specific inherited diseases. This is the case of genetic disorders of the kidney, which include dominant and recessive forms of cystic diseases, and renal tubulopathies. Mutations in polycystin-1 (PKD1) or -2 (PKD2) genes lead to autosomaldominant polycystic kidney disease (ADPKD), whose gender-dependent phenotype was analyzed in the study by Talbi et al. [9]. These results, obtained in mice lacking PKD1 expression, show the involvement of intracellular Ca2+ levels in the more severe phenotype affecting male ADPKD animals. Altogether, identification of the molecular mechanisms underlying enhanced Ca2+ signaling and proliferation in cells from male kidneys may contribute to develop novel therapeutics for ADPKD [9]. The autosomal-recessive form of polycystic kidney disease (ARPKD) mostly arises from defects in the gene named polycystic kidney and hepatic disease 1 (PKHD1), whereas a minority of cases is linked to a second causative gene DZIP1L. To examine the still unclear molecular pathophysiology of ARPKD, Cordido et al. recapitulate known molecular disease mechanisms and possible therapeutic approaches, from cellular and animal models to clinical trials [10]. The knowledge of ARPKD pathogenic pathways, involving the epidermal growth factor receptor (EGFR) axis, the production of adenylyl cyclase adenosine 3 ,5 -cyclic monophosphate (cAMP) and the activation of several protein kinases, begins to stimulate possible pharmacological interventions [10]. Inherited loss of function in various electrolyte transport proteins located along the nephron leads to two types of kidney tubulopathy with overlapping clinical symptoms: Gitelman and Bartter syndromes. The review by Nuñez-Gonzalez et al. aims to explain the different molecular basis of these difficult to diagnose monogenic syndromes. Moreover, the authors provide an overview of current therapeutic approaches and highlight the presence of common and specific options for Gitelman and Bartter patients [11].

[14] 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: 0.352) > 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).

[15] Novel Approaches to Studying SLC13A5 Disease

• Authors: Adriana S. Beltran
• Year: 2024
• Venue: Metabolites
• URL: https://www.semanticscholar.org/paper/8469c534cd81d96f84b61e2d963dead12088feb7
• DOI: 10.3390/metabo14020084
• PMID: 38392976
• PMCID: 10890222
• Citations: 2
• Summary: Current technologies for generating patient-specific induced pluripotent stem cells (iPSCs) and their inherent advantages and limitations are discussed, followed by a summary of the methods for differentiating iPSCs into neurons, hepatocytes, and organoids.
• Evidence snippets:
• Snippet 1 (score: 0.352) > The precise pathophysiology underlying how SLC13A5 loss-of-function results in epilepsy refractory to treatment is a subject of open and ongoing research. Several hypotheses suggest SLC13A5 alters metabolic pathways, leading to neuronal dysfunction. Conversely, therapeutic inhibition of NaCT in the liver is a target to improve metabolic diseases, including non-alcoholic fatty liver disease, obesity, and insulin resistance. Thus, functionally accurate modeling and characterization of the mechanisms involved in citrate transport disruption are critical for understanding its role in human disease. > IPSC-derived cellular systems are a powerful tool for modeling rare human genetic diseases, such as SLC13A5 (Figure 5). IPSCs derived from patients containing the genetic information of the disease can overcome the limitations of animal models, providing access to relevant human cell types that recapitulate the disease phenotype. For instance, patient-derived iPSCs differentiated into neurons or hepatocytes can be used to investigate molecular and cellular mechanisms, including citrate transport and accumulation, energy metabolism, oxidative stress, and other cellular processes. They can also be used to define the spectrum of the disease and how different mutations might lead to various disease severities, screen for potential therapeutic compounds that can restore the transporter function or ameliorate the symptoms, and enable personalized medicine approaches that can tailor treatments to individual patients based on their genetic background and disease severity. > transport disruption are critical for understanding its role in human disease. > IPSC-derived cellular systems are a powerful tool for modeling rare human genetic diseases, such as SLC13A5 (Figure 5). IPSCs derived from patients containing the genetic information of the disease can overcome the limitations of animal models, providing access to relevant human cell types that recapitulate the disease phenotype. For instance, patient-derived iPSCs differentiated into neurons or hepatocytes can be used to investigate molecular and cellular mechanisms, including citrate transport and accumulation, energy metabolism, oxidative stress, and other cellular processes.

[16] Multi-Omics Profiles of Chronic Low Back Pain and Fibromyalgia - Study Protocol

• Authors: Michele Curatolo, Abby P. Chiu, Catherine Chia, Ava Ward, Sandra K Johnston et al.
• Year: 2024
• Venue: Research Square
• URL: https://www.semanticscholar.org/paper/9370990318ae0504a3da39dd2eeb7ca6613d5a04
• DOI: 10.21203/rs.3.rs-4669838/v1
• PMID: 39149502
• PMCID: 11326421
• Citations: 1
• Summary: This study addresses the need for a better understanding of the molecular mechanisms underlying chronic low back pain and fibromyalgia by using a multi-omics approach to identify converging evidence for potential targets of future therapeutic developments, as well as promising candidate biomarkers for further investigation by biomarker validation studies.
• Evidence snippets:
• Snippet 1 (score: 0.351) > Metabolomics studies in chronic pain have been sparse, as we have shown in a previous review (12). Most studies in chronic low back pain had a partial focus, such as on single metabolites or pathways (83), tissue metabolites (84), or association with radiological ndings (85). Comprehensive studies on the metabolome are lacking, and the literature does not provide strong indications on which metabolic pathways are of relevance in chronic low back pain. The metabolic pro le of bromyalgia has been better studied. Some studies have focused on single metabolic pathways, such as purine (86). Other ones adopted a comprehensive metabolomics approach, but the results have not converged to clearly identi ed pathways involved in the pathophysiology of bromyalgia (87-90). Despite the importance of lipid metabolism for the understanding of cellular function and alterations in processes related to disease, such as in ammation, lipidomics studies in low back pain and bromyalgia are sparse and mostly limited to few target lipids (16). Most of the proteomics literature has focused on immune and in ammatory markers (91). A recent systematic review in bromyalgia identi ed dysregulated proteins associated with oxidative stress response, but the correlations with pain outcomes was weak (17). > Our study addresses the need for a better understanding of the molecular mechanisms underlying chronic low back pain and bromyalgia. Using a multi-omics approach, we hope to identify converging evidence for potential targets of future therapeutic developments, as well as promising candidate biomarkers for further investigation by biomarker validation studies. We believe that accurate patient phenotyping will be essential for the discovery process, as both conditions are characterized by high heterogeneity and complexity, likely rendering molecular mechanisms phenotype speci c.

[17] Role of Transcriptomics in Precision Oncology

• Authors: Ruby Srivastava
• Year: 2024
• Venue: Reports of Radiotherapy and Oncology
• URL: https://www.semanticscholar.org/paper/0bd862558bbb7286336111d9dfd232b5f905d3d9
• DOI: 10.5812/rro-142195
• Citations: 4
• Summary: : Transcriptome profiling is one of the most widely used approaches in the field of multiomics research. It plays a crucial role in the prognostic, diagnostic, and predictive treatment of cancer patients. Novel next-generation sequencing (NGS) technologies permit the identification of cancer biomarkers, gene signatures, and their abnormal expression, affecting oncogenic and molecular targets and novel biomarkers for cancer therapies. Multiomics studies have changed the overall understanding o...
• Evidence snippets:
• Snippet 1 (score: 0.351) > : Transcriptome profiling is one of the most widely used approaches in the field of multiomics research. It plays a crucial role in the prognostic, diagnostic, and predictive treatment of cancer patients. Novel next-generation sequencing (NGS) technologies permit the identification of cancer biomarkers, gene signatures, and their abnormal expression, affecting oncogenic and molecular targets and novel biomarkers for cancer therapies. Multiomics studies have changed the overall understanding of cancer and opened a precise perspective for tumor diagnostics and therapy. The use of these approaches has strengthened our understanding of disease pathophysiology and classifications at the molecular level, including specific interference with drug mechanisms of action. Still, it has limited added value in the clinical setting. The omics data on precision medicine include the application of data from genes, transcripts, and proteins for diagnosis, monitoring of diseases, risk factor determination, counseling, and development of novel therapeutics. Bioinformatics applications have expanded statistics-based analysis toward deriving molecular pathways and process models for characterizing phenotypes and drug action mechanisms. In this review, we will discuss transcriptomics and interference analysis that allows the identification of predictive biomarkers at the molecular level to test drug response and analyze the molecular process interface of disease progression-relevant pathophysiology and mechanism of action to propose predictive biomarkers.

[18] 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: 0.350) > 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.

[19] 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: 0.350) > 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) [

[20] Aberrant NLRP3 Inflammasome Activation Ignites the Fire of Inflammation in Neuromuscular Diseases

• Authors: Christine Péladeau, J. Sandhu
• Year: 2021
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/763a36db080236fca8cde89b2afcdf056f3584d0
• DOI: 10.3390/ijms22116068
• PMID: 34199845
• PMCID: 8200055
• Citations: 17
• Influential citations: 1
• Summary: Whether therapeutic targeting of the NLRP3 inflammasome components is a viable approach to alleviating the detrimental phenotype of neuromuscular diseases and improving clinical outcomes is examined.
• Evidence snippets:
• Snippet 1 (score: 0.347) > Despite a large number of mechanisms that have been identified in muscle degeneration and nerve cell loss, none have proven to be the primary cause of the disease. There is much need for a deeper understanding of the biology of the pathogeneses and the molecular mechanisms that are activated early in the diseases in order to identify "druggable" targets and disease-modifying treatments for these devastating diseases. > Human iPSC technologies are emerging as useful platforms for disease modeling to study pathogenic mechanisms and discover novel therapeutics for neuromuscular diseases [211,237]. Indeed, patient-derived iPSCs are being used to create a "patient-in-adish" disease model to derive relevant cell types for testing potential therapeutics, paving the way towards personalized medicine. This approach allows drug screening in a dish prior to administration to patients and "bench-to-bedside" translation of potential therapies. Additionally, iPSCs may also be used to stratify patients with various phenotypes and guide future clinical trials for bringing improved therapies to patients. Since multiple cell types are involved in disease pathogenesis, future research efforts need to be focused on deciphering "disease-specific signatures" at single-cell resolution, and not only in neuronal cells but also in non-neuronal cells. The application of modern technologies, including single-cell RNA sequencing and spatial transcriptomics, to neuromuscular diseases, will allow to ascertain cellular vulnerability and cell-specific mechanisms during various stages of disease progression. > The vital roles of the NLRP3 inflammasome in neuromuscular diseases such as DMD, LGMD and ALS, reveal that targeting this pathway is indeed a promising therapeutic strategy. Dysregulation of the NLRP3 inflammasome in muscle tissues by muscle damage, membrane instability, extracellular ATP and Ca 2+ ions or signals from infiltrating immune cells, clearly impacts the progression of neuromuscular and neurodegenerative disorders. Thus, modulation of these pathways involved with activation and assembly of NLRP3 inflammasome could be truly beneficial.

Notes

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

Core Pathophysiology

Brachyolmia is a group of rare genetic osteochondrodysplasias characterized by a disproportionate short trunk, scoliosis, and flattened vertebrae (platyspondyly) with little or no long-bone involvement (www.orpha.net). Underlying these skeletal abnormalities are disruptions in the normal growth and development of cartilage and bone in the axial skeleton (especially the spine). The primary pathophysiological mechanism is defective endochondral ossification in the vertebral column (UBERON:0001130), meaning the conversion of cartilage templates into bone is impaired. This leads to stunted growth of vertebral bodies and abnormal spinal curvature. In brachyolmia, the vertebral growth plates (cartilaginous regions where new bone forms) fail to function properly due to molecular defects, while the appendicular skeleton (limbs) is relatively spared (www.orpha.net). The result is short-trunk dwarfism (disproportionate short stature with a short spine – HP:0003521) accompanied by scoliosis or kyphoscoliosis (abnormal lateral/kyphotic curvature of the spine – HP:0002650) and diffuse platyspondyly (flattened vertebral bodies on imaging – HP:0000926) (pubmed.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov). These bony changes reflect a failure of normal vertebral growth and shape maintenance. Importantly, brachyolmia is genetically heterogeneous, and at least three distinct genes have been implicated – all of which affect cartilage biology in different ways. Despite the distinct genetic causes, a unifying theme is maldifferentiation or dysregulation of chondrocytes (cartilage cells – CL:0000138) in the developing spine, leading to insufficient linear growth of the vertebrae and structural instability of the spine. The cellular mechanisms center on aberrant signaling in cartilage and extracellular matrix dysfunction, which ultimately disturb the balance of chondrocyte proliferation, hypertrophy, and matrix formation needed for normal spine elongation. In summary, brachyolmia’s core pathophysiology is a failure of normal vertebral endochondral growth due to inherited molecular defects, resulting in a short, stiff spine and curvature while limb growth remains near-normal (www.orpha.net). Recent research underscores that these molecular defects converge on common pathways regulating skeletal development, including extracellular matrix composition, growth factor signaling, and mechanotransduction in cartilage (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Each of the known genetic forms of brachyolmia essentially perturbs one of these fundamental processes, as detailed below.

Key Genetic and Molecular Players

Brachyolmia can be caused by both autosomal recessive (AR) and autosomal dominant (AD) mutations, affecting different genes. Despite genetic heterogeneity, the known disease genes all play critical roles in cartilage matrix physiology or signaling:

• PAPSS2 (HGNC:8604) – 3′-Phosphoadenosine 5′-phosphosulfate synthase 2. This enzyme produces PAPS (3′-phosphoadenosine-5′-phosphosulfate), the universal sulfate donor required for sulfation of glycosaminoglycans in proteoglycans (www.genecards.org) (www.genecards.org). AR mutations in PAPSS2 are a well-established cause of brachyolmia (sometimes called “Hobaek/Toledo type” brachyolmia) (www.orpha.net) (www.orpha.net). PAPSS2-deficient chondrocytes cannot adequately sulfate cartilage proteoglycans (like chondroitin sulfate on aggrecan), leading to undersulfated extracellular matrix in growth plate cartilage. Classic experiments in the brachymorphic mouse (the Papss2 mutant mouse) demonstrated that a PAPSS2 mutation leads to reduced PAPS levels and undersulfated cartilage proteoglycans (pmc.ncbi.nlm.nih.gov). In these Papss2 mutants, the cartilage matrix is biochemically abnormal and unable to support normal endochondral bone growth. Undersulfation of chondroitin sulfate disrupts the structural integrity and hydration of the cartilage matrix and also impairs signaling molecule distribution. Notably, Indian hedgehog (Ihh) signaling – a key pathway regulating chondrocyte proliferation in the growth plate – is diminished in PAPSS2 deficiency (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Ihh protein normally binds to chondroitin sulfate-rich proteoglycans in the matrix, but in undersulfated cartilage Ihh cannot form its usual gradient, leading to reduced hedgehog signaling and a marked decrease in chondrocyte proliferation (pmc.ncbi.nlm.nih.gov). This mechanistic link was shown by Cortes et al. (2009), who found that Papss2 mutant mice exhibit abnormal Ihh distribution and significantly reduced chondrocyte proliferation in growth plates (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). In essence, PAPSS2 mutations derail normal cartilage metabolism, causing a cascade of effects: proteoglycan undersulfation, disrupted cell–matrix interactions, impaired growth factor signaling (Ihh and potentially others), and ultimately failure of vertebral growth. Patients with PAPSS2-related brachyolmia show the expected radiographic features of flattened vertebrae with irregular endplates, premature calcification of rib cartilage, and mild epiphyseal changes in peripheral bones (pubmed.ncbi.nlm.nih.gov). These reflect the systemic role of sulfated proteoglycans in skeletal development. Indeed, Miyake et al. (2012) identified PAPSS2 as the disease gene for autosomal recessive brachyolmia, noting that PAPSS2 mutations form a spectrum of skeletal dysplasia phenotypes ranging from isolated brachyolmia to more generalized spondylo-epimetaphyseal dysplasia (pubmed.ncbi.nlm.nih.gov). In summary, PAPSS2 loss-of-function deprives cartilage of sulfate-rich proteoglycans, weakening the extracellular matrix and perturbing signaling pathways necessary for vertebral growth. This molecular mechanism explains the short-trunk stature and occasionally other features such as early costal cartilage ossification in PAPSS2-related brachyolmia (pubmed.ncbi.nlm.nih.gov).

• LTBP3 (HGNC:6716) – Latent Transforming Growth Factor Beta Binding Protein 3. AR mutations in LTBP3 cause a syndromic form of brachyolmia with amelogenesis imperfecta (defective tooth enamel) and short stature, historically termed “Dental Anomalies and Short Stature (DASS) syndrome” or brachyolmia-amelogenesis imperfecta . LTBP3 encodes an extracellular matrix glycoprotein that binds to and sequesters latent TGF-β (transforming growth factor beta) complexes in the matrix (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). It is a member of the fibrillin/LTBP family, involved in the proper storage and activation of TGF-β1, -β2, and -β3. LTBP3 is highly expressed in developing cartilage, especially in vertebral primordia, and in tooth-forming tissues (pmc.ncbi.nlm.nih.gov). When LTBP3 is mutated, the activation and localization of TGF-β signaling become dysregulated. TGF-β is a crucial morphogen for bone and tooth development: it regulates chondrocyte differentiation, osteoblast function, and enamel formation by ameloblasts (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Specifically, TGF-β signaling is essential for normal endochondral ossification and osteogenic differentiation – it promotes proliferation of chondroprogenitor cells and the maturation of osteoblasts (pmc.ncbi.nlm.nih.gov). LTBP3 normally helps present TGF-β to these cells at the right time and place. Loss of LTBP3 “reduces TGF-β activation and therefore diminishes associated cell proliferation and osteogenic differentiation” (pmc.ncbi.nlm.nih.gov), as one study noted. In mice, Ltbp3-knockout models confirm a skeletal role: Ltbp3^−/− mice show disturbed TGF-β bioavailability, leading to axial skeletal patterning defects (such as spinal curvature and chest wall deformities) and high bone mass from impaired bone remodeling (pmc.ncbi.nlm.nih.gov). (Interestingly, Ltbp3-knockout mice develop osteopetrosis due to defective osteoclast function (pmc.ncbi.nlm.nih.gov), a phenotype not observed in human LTBP3 patients, highlighting species differences in phenotype severity.) In humans, LTBP3 mutations result in a classic brachyolmia skeletal phenotype (short trunk, platyspondyly, scoliosis) along with severe enamel hypoplasia and tooth anomalies (pubmed.ncbi.nlm.nih.gov). The enamel defect – amelogenesis imperfecta (HP:0006281) – directly ties into TGF-β’s role in tooth development: TGF-β signaling in ameloblasts is required for normal enamel matrix secretion and maturation (pmc.ncbi.nlm.nih.gov). Research has shown that blocking TGF-β in developing teeth causes failure of enamel formation, while overactive TGF-β leads to enamel defects (pmc.ncbi.nlm.nih.gov). Thus, LTBP3 deficiency likely causes insufficient TGF-β availability during enamel formation, explaining the thin, hypoplastic enamel in DASS syndrome. Clinically, this condition (also called brachyolmia-amelogenesis imperfecta syndrome) was first described in consanguineous families and later found to be caused by LTBP3 mutations (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Huckert et al. (2015) identified recessive LTBP3 mutations in patients with short stature, spinal platyspondyly, and enamel defects (pmc.ncbi.nlm.nih.gov). Subsequent studies (e.g. Flex et al., 2021; Nawaz et al., 2023) have expanded the mutational spectrum and confirmed LTBP3’s role. In a 2023 Heliyon study, Nawaz et al. reported novel LTBP3 variants in Egyptian and Pakistani DASS families and emphasized the vital role of LTBP3 in axial skeleton and tooth morphogenesis (pubmed.ncbi.nlm.nih.gov). In summary, LTBP3 mutations cause brachyolmia by disrupting TGF-β signaling, leading to impaired cartilage/bone development in the spine (hence short trunk and scoliosis) and defective enamel formation in teeth. This highlights how growth factor signaling pathways (GO:0007179) like TGF-β are integral to skeletal growth – deregulation of TGF-β “is likely to interfere with axial skeleton patterning” (pmc.ncbi.nlm.nih.gov), consistent with the brachyolmia phenotype.

• TRPV4 (HGNC:18083) – Transient Receptor Potential Vanilloid 4. Autosomal dominant brachyolmia has been linked to gain-of-function mutations in TRPV4 (www.nature.com) (www.nature.com). TRPV4 encodes a Ca²⁺-permeable cation channel expressed in cartilage and other tissues, known to function as a mechanosensitive channel that responds to mechanical stimuli and osmotic changes (www.nature.com) (ojrd.biomedcentral.com). In normal physiology, TRPV4 in chondrocytes helps convert mechanical loading of cartilage into biochemical signals – a process called mechanotransduction. It modulates calcium influx in response to joint movement or sheer stress, thereby influencing chondrocyte activity and extracellular matrix production. Pathogenic TRPV4 mutations (e.g., R616Q, V620I) increase the channel’s activity abnormally. Rock et al. (2008) first identified TRPV4 missense mutations in two brachyolmia families, demonstrating that these mutations cause a “dramatic gain of function” with increased constitutive channel activity and hyper-responsiveness to mechanical or ligand stimulation (www.nature.com). In other words, mutant TRPV4 channels are over-active, allowing excessive Ca²⁺ influx into chondrocytes even without proper cues. This leads to aberrant downstream signaling in cartilage cells. Although the precise molecular pathways affected are still being elucidated, calcium influx can regulate many processes in chondrocytes – from gene expression to matrix homeostasis and cell volume regulation. Unregulated TRPV4 activity likely disturbs the balance of chondrocyte proliferation and differentiation or induces inappropriate expression of catabolic enzymes. Notably, TRPV4-related skeletal dysplasias span a phenotypic spectrum: more severe TRPV4 mutations cause spondylometaphyseal dysplasia or metatropic dysplasia (with long bone involvement), while milder mutations result in the brachyolmia phenotype (spine-limited) (ojrd.biomedcentral.com) (ojrd.biomedcentral.com). Indeed, brachyolmia is considered the mildest end of the TRPV4 dysplasia spectrum, with primarily spinal changes (ojrd.biomedcentral.com) (ojrd.biomedcentral.com). Excessive TRPV4 signaling in growth plate chondrocytes of the spine is thought to alter mechanosensitive pathways and chondrocyte maturation, leading to reduced longitudinal growth of vertebrae. For example, TRPV4 activation can interact with TGF-β signaling pathways in connective tissue cells (pmc.ncbi.nlm.nih.gov). One study noted that TRPV4 integrates mechanical stimuli with TGF-β1 signals during fibroblast-to-myofibroblast differentiation (pmc.ncbi.nlm.nih.gov), suggesting crosstalk between mechanotransduction and growth factor pathways. Thus, a hyperactive TRPV4 might mis-regulate TGF-β or other mechanosensitive signaling in chondrocytes. Moreover, chronic Ca²⁺ influx could trigger abnormal expression of matrix metalloproteinases or other factors that weaken the cartilage matrix. In summary, TRPV4 gain-of-function mutations lead to dysregulated mechanotransduction in cartilage (GO:0006936 for muscle stretch response, analogous processes in chondrocytes) and calcium signaling abnormalities (GO:0019722), which impair the normal growth and architectural maintenance of vertebrae. Clinically, TRPV4-brachyolmia patients have a short trunk, significant platyspondyly, and often progressive kyphoscoliosis of the spine (www.orpha.net). This AD form was initially reported as more severe in terms of spinal curvature (www.orpha.net), possibly because TRPV4 mutations can cause ongoing degeneration or progressive deformity of the spine over time. (By contrast, AR forms can plateau in severity after growth.) Regardless, TRPV4 mutations firmly establish that aberrant chondrocyte mechanosensing is a causal mechanism in brachyolmia. Patch-clamp studies confirmed the biophysical impact of mutant TRPV4 channels, linking the genotype to sustained calcium influx (www.nature.com). Further supporting the mechanistic importance, pharmacologic studies show mutant TRPV4 channels respond abnormally to stimuli like stretch and arachidonic acid (www.nature.com), which could correspond to heightened responses to normal mechanical loads on the spine. In essence, TRPV4-related brachyolmia arises from too much signal in the chondrocyte’s “pressure sensors,” leading to distorted growth plate signaling and structure.

Other molecular components and pathways play supporting roles in these mechanisms. TGF-β (CHEBI:136156) itself is a key chemical messenger (a growth factor protein) in LTBP3-related disease, and calcium ions (Ca²⁺, CHEBI:29108) are the critical second messenger in TRPV4 pathways. Aggrecan, the major chondroitin sulfate proteoglycan of cartilage, is a downstream effector target in PAPSS2-related disease: without sufficient sulfation (a chemical modification), aggrecan cannot maintain the cartilage matrix’s osmotic and biomechanical properties (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Additionally, Indian hedgehog (IHH) is a morphogen (protein signal) whose distribution is altered in PAPSS2 deficiency, as described above (pmc.ncbi.nlm.nih.gov). We also consider the role of collagen fibers and other matrix molecules – while the genes in brachyolmia are not collagens, the cartilage collagen network likely suffers secondary changes (e.g. improper assembly or calcification) when the above pathways are disrupted.

Disrupted Biological Processes (GO annotations)

Given the key players, several biological processes are perturbed in brachyolmia:

• Endochondral Ossification (GO:0001958): This is the process by which cartilage is replaced by bone during growth. It is fundamentally disrupted in brachyolmia. Normally, chondrocytes in the growth plate proliferate, mature (hypertrophy), and are replaced by bone tissue, contributing to longitudinal bone growth. In brachyolmia, endochondral bone growth in the spine is impaired, either due to reduced chondrocyte proliferation (as in PAPSS2 mutation causing low Ihh signaling and thus fewer proliferating chondrocytes (pmc.ncbi.nlm.nih.gov)) or abnormal differentiation (as in TGF-β pathway disruption by LTBP3 mutation, which can alter chondrocyte maturation and osteoblast recruitment (pmc.ncbi.nlm.nih.gov)). The net effect is premature growth plate closure or stunting in vertebral bodies, leading to short, flattened vertebrae instead of normal rectangular ones (pubmed.ncbi.nlm.nih.gov).

• Extracellular Matrix Organization (GO:0030198): Proper assembly and composition of the cartilage extracellular matrix (ECM) are crucial for skeletal development. PAPSS2 mutations cause aberrant ECM composition – specifically, glycosaminoglycan biosynthetic process (GO:0030203) is affected because chondroitin sulfate chains are undersulfated. Sulfation is needed for ECM proteoglycans to function; without it, the matrix cannot retain water and growth factors properly (pmc.ncbi.nlm.nih.gov). This leads to weaker cartilage that is prone to early calcification (explaining the premature calcification of rib cartilage seen in some cases (pubmed.ncbi.nlm.nih.gov)). Defects in LTBP3 also disturb ECM organization: LTBP3 normally incorporates into the matrix alongside fibrillin microfibrils and helps localize TGF-β there (pmc.ncbi.nlm.nih.gov). Mutant LTBP3 means the ECM lacks a proper reservoir of latent TGF-β, altering the signaling milieu in the cartilage extracellular space. Thus, the extracellular space (Cellular Component: GO:0005615) in brachyolmia cartilage has abnormal composition and signaling molecule availability.

• TGF-β Signaling Pathway (GO:0007179): In LTBP3-related brachyolmia, the TGF-β signaling process is blunted. Normally, latent TGF-β is stored in the matrix bound to LTBP3 and released in a controlled manner to activate TGF-β receptors on chondrocytes and osteoblasts. Without functional LTBP3, TGF-β signaling in the developing spine is reduced, which interferes with osteoblast differentiation and bone formation in the vertebrae (pmc.ncbi.nlm.nih.gov). TGF-β also has a role in regulating chondrocyte maturation; deregulation can lead to disorganized growth plates. This is why deregulation of TGF-β signaling is likely to interfere with axial skeleton patterning (pmc.ncbi.nlm.nih.gov). Additionally, TGF-β signaling is important for tooth development and enamel biomineralization (a biological process involving ameloblast differentiation and enamel matrix secretion). Disruption of this pathway explains the dental anomalies in LTBP3 mutation patients (pmc.ncbi.nlm.nih.gov).

• Proteoglycan Metabolic Process: The sulfation of glycosaminoglycans (part of GO:0030204, chondroitin sulfate biosynthesis) is directly affected by PAPSS2 mutation. The biochemical process of PAPS synthesis and sulfate transfer to proteoglycans is interrupted, leading to accumulation of undersulfated chondroitin. This has downstream effects on cell signaling as described (e.g. Ihh pathway). It may also impact FGF and BMP signaling, as these morphogens can bind to heparan or chondroitin sulfate in the matrix; if those binding sites are altered, signaling gradients could be disrupted (pmc.ncbi.nlm.nih.gov). In brachymorphic (Papss2-deficient) mice, aside from hedgehog signaling, there were hints that other pathways (Wnt, FGF, PTHrP signaling) might also be secondarily affected due to ECM changes (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

• Chondrocyte Differentiation & Proliferation (GO:0002062 & GO:0050673): All forms of brachyolmia ultimately alter the normal progression of chondrocytes through the growth plate. In PAPSS2 deficiency, proliferative chondrocytes are fewer (Ihh down, less proliferation (pmc.ncbi.nlm.nih.gov)), and those present may undergo hypertrophy abnormally or too early. In TRPV4 GOF, chondrocytes may receive improper mechanical signals that trigger them to hypertrophy or undergo apoptosis inappropriately, possibly leading to premature loss of growth plate cartilage. In LTBP3 loss, chondrocyte proliferation could be reduced due to lowered TGF-β (which normally can promote cell proliferation and matrix production in growth plate). Thus, the orderly process of chondrocyte maturation is disrupted, causing growth plates that are disorganized or fuse early. Evidence for disordered chondrocyte behavior can be inferred from pathology reports and mouse models: Ltbp3-null mice had abnormal synchondrosis (cartilage joint) closure in the skull (pmc.ncbi.nlm.nih.gov), and Papss2-mutant mice show reduced chondrocyte zones due to low proliferation (pmc.ncbi.nlm.nih.gov).

• Mechanical Signal Transduction (GO:0009612, response to mechanical stimulus): Specifically for TRPV4-related brachyolmia, mechanotransduction in cartilage is altered. Normally, mechanical loading of the spine (from posture, gravity, movement) stimulates moderate Ca²⁺ influx via TRPV4, which helps cartilage adapt (for example, promoting matrix synthesis up to a point). In TRPV4 GOF, this process goes awry: even normal levels of mechanical strain cause excessive calcium signaling. As a result, the biomechanical properties of cartilage may change – for instance, overactive TRPV4 can lead to increased expression of degradative enzymes or altered cytoskeletal organization, making cartilage less resilient. One study on TRPV4 R616Q mutants suggested the mutant channel had altered interaction with membrane cholesterol, affecting its regulation (www.sciencedirect.com). Although detailed pathways are still being studied, mechanosensitive gene expression (like RUNX2 or MMP13 activation) could be upregulated inappropriately, contributing to abnormal bone remodeling or early growth plate closure.

• Cellular Calcium Homeostasis (GO:0006874): As an extension of the above, TRPV4 GOF affects the cellular calcium ion homeostasis in chondrocytes. Calcium acts as a signal for many cellular processes (e.g., activating calmodulin-dependent pathways, NFAT transcription factors, etc.). Chronic calcium elevation in growth plate chondrocytes could trigger stress responses or apoptosis (if Ca²⁺ overloads mitochondria or ER). There is evidence that TRPV4 activation can induce chondrocyte matrix calcification and cell hypertrophy, linking to pathways of cartilage degeneration seen in osteoarthritis research (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). While speculative in brachyolmia, it’s plausible that dysregulated calcium signaling contributes to the abnormal endplate calcification and disc degeneration seen in some brachyolmia patients as they age (pubmed.ncbi.nlm.nih.gov) (narrow intervertebral discs were noted radiographically (pubmed.ncbi.nlm.nih.gov)).

In summary, brachyolmia involves disruption of critical developmental processes: skeletal development pathways like endochondral ossification and TGF-β signaling, matrix biosynthesis, and mechanosensory feedback in cartilage are all affected. These GO processes, when perturbed, collectively result in the failure of the spine to grow normally.

Cellular and Subcellular Context (Key Cellular Components)

At the cellular level, brachyolmia’s pathology is rooted in the growth plate cartilage of the spine. The primary cell type impacted is the chondrocyte (CL:0000138) – specifically, those in the vertebral growth plates and cartilage endplates. These chondrocytes reside in the epiphyseal cartilage of vertebral bodies (UBERON:0005844) during childhood and adolescence, driving vertebral height growth. In brachyolmia, chondrocytes are either biochemically impaired (PAPSS2), deprived of signals (LTBP3), or mis-activated (TRPV4).

Key cellular components and locations involved include:

• Extracellular Matrix (GO:0031012): The cartilage ECM is where LTBP3 and proteoglycans function. LTBP3 is an ECM protein; it localizes in the fibrillar matrix bound to fibrillin fibers and latent TGF-β complexes (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Thus, the extracellular region is a critical site: in LTBP3 mutations, the ECM lacks these TGF-β reservoirs. In PAPSS2 mutations, the cartilage extracellular matrix is undersulfated and functionally deficient, affecting its ability to bind growth factors (like Ihh) and resist compressive forces (pmc.ncbi.nlm.nih.gov). Notably, aggrecan proteoglycans in the ECM normally provide cartilage its load-bearing properties; undersulfation means the cartilage matrix cannot retain as much water, becoming less cushiony and possibly predisposing to premature cartilage calcification (as seen in costal cartilages (pubmed.ncbi.nlm.nih.gov)). The ECM is also where Ihh and TGF-β ligands diffuse; its composition changes will alter their distribution.

• Plasma Membrane (GO:0005886): TRPV4 is a transmembrane channel protein situated in the plasma membrane of chondrocytes (and other cells). It may also localize to the primary cilium of chondrocytes – some TRP channels are known to function in the ciliary membrane of mechanosensory cells, though TRPV4’s ciliary localization is not definitively established for chondrocytes. Still, the membrane compartment is crucial because that’s where TRPV4 channels open and allow Ca²⁺ influx. In TRPV4-related brachyolmia, the chondrocyte plasma membrane exhibits abnormally high calcium permeability due to mutant channels (www.nature.com). Also on the cell surface are TGF-β receptors; in LTBP3 deficiency, the activation of these receptors (such as TGFBR1/2) on chondrocytes and osteoblasts is reduced, which happens at the cell membrane level when less active TGF-β is available to bind.

• Cytosol (GO:0005829): The cytosol of chondrocytes (and other cells) is where PAPSS2 enzyme functions. PAPSS2 resides in the cytosol and possibly the Golgi apparatus, generating PAPS from ATP and sulfate (www.genecards.org). PAPS is then utilized in the Golgi by sulfotransferase enzymes to sulfate proteoglycans. In PAPSS2 deficiency, the cytosolic PAPS pool is depleted, so Golgi-resident sulfotransferases cannot properly sulfinate the GAG chains on proteoglycans. The Golgi apparatus (GO:0005794) is thus another relevant organelle: it’s the site of proteoglycan post-translational modifications. A failure in this step (due to lack of PAPS) means proteoglycans are secreted into the ECM incompletely sulfated.

• Mitochondria (GO:0005739) and ER (GO:0005783): These organelles might be secondarily involved, especially in TRPV4 GOF scenarios. Excessive Ca²⁺ entry can strain the ER and mitochondria, potentially triggering ER stress or mitochondrial dysfunction in chondrocytes. While not proven in brachyolmia specifically, chronic ER stress could contribute to chondrocyte apoptosis, and mitochondrial overload with Ca²⁺ could affect energy production needed for matrix synthesis.

• Bone tissue (GO:0005677): In later disease stages, the bony vertebrae themselves (comprised of osteoblasts and osteoclasts in a mineralized matrix) can be affected. LTBP3’s role in bone was evident in mice as osteoclast dysfunction leading to osteopetrosis (pmc.ncbi.nlm.nih.gov). In humans with LTBP3 mutations, there isn’t frank osteopetrosis, but there could be subtle changes in bone remodeling – perhaps contributing to dense vertebral bodies or altered trabecular structure (noted in some x-rays qualitatively). Osteoblasts in the vertebra depend on TGF-β for normal function; reduced TGF-β could lead to imbalanced remodeling. Meanwhile, in PAPSS2-related brachyolmia, mild metaphyseal and epiphyseal changes in long bones (like short femoral necks or mild epiphyseal dysplasia) have been reported (pubmed.ncbi.nlm.nih.gov), indicating that growth plate cartilage in long bones is also somewhat affected, albeit to a lesser degree than the spine (perhaps because spinal growth plates are under different mechanical loads or express these genes differently).

• Tooth enamel and Ameloblasts: In the LTBP3 subtype, another “component” to mention is the enamel layer of teeth (UBERON:0001755) and the ameloblasts (enamel-secreting epithelial cells, CL:0000079). These cells are located in the developing tooth organ. LTBP3 is expressed in ameloblasts and odontoblasts during tooth development (pmc.ncbi.nlm.nih.gov). In absence of LTBP3, ameloblasts fail to produce normal enamel because TGF-β signaling in the extracellular space of the enamel organ is perturbed. The enamel layer ends up hypoplastic (thin and weak), which is observed clinically as early tooth wear and discoloration in brachyolmia-DASS patients (pubmed.ncbi.nlm.nih.gov).

Overall, the lesions in brachyolmia are localized to cartilaginous tissues of the axial skeleton – the cartilage growth plates in the spine (and to some extent the hips and ribs), as well as the dental enamel organ in the LTBP3 subtype. The pathology unfolds at the interfaces of cells and matrix: in the ECM (where LTBP3 and proteoglycans operate), at the cell membrane (where TRPV4 and receptors transduce signals), and in the secretory pathway (where PAPSS2 provides a co-factor for matrix molecule modification). By understanding these cellular locations, we see how a molecular defect translates to a tissue-level failure: for example, a missing ECM protein (LTBP3) means growth factor can’t signal to cells, or a missing co-factor (PAPS) means matrix molecules are built incorrectly.

Disease Progression

Brachyolmia is fundamentally a developmental bone disorder, so the disease progression follows the growth and maturation of the skeleton. Onset is in childhood – typically, children with brachyolmia are not significantly short at birth, but growth retardation of the trunk becomes evident in late infancy or early childhood (www.orpha.net). As the child grows, the stature falls behind in a disproportionate way: sitting height is much reduced while leg length is relatively preserved (a hallmark of short-trunk dwarfism). Parents or physicians often notice progressive curvature of the spine (scoliosis/kyphosis) developing during early childhood. The sequence of events likely begins prenatally (as the spinal cartilage model forms abnormally) but doesn’t manifest clinically until postnatal growth stresses the abnormal vertebrae.

If we map a rough timeline: in infancy, the vertebrae may appear only mildly flattened on an X-ray, but as the child grows and the impaired growth plates yield poor vertebral height increase, the difference accumulates. By the time of rapid growth (around puberty), the trunk is conspicuously short. Scoliosis often progresses during the growth spurt of adolescence, as the structurally weakened spine can develop curvature under asymmetric forces. In TRPV4-related cases, some evidence suggests the scoliosis may be more progressive, possibly requiring bracing or surgery in teenage years (www.orpha.net). In PAPSS2-related cases, scoliosis is usually mild to moderate (www.orpha.net), but there can be variability. For example, Bownass et al. (2019) described phenotypic variation in 18 PAPSS2-deficient patients, where some had significant spinal curvatures while others did not (www.malacards.org).

As growth concludes (late teens), the disease does not typically worsen in adulthood, since the pathological process is mainly a failure of growth rather than a degenerative process. Adult height in brachyolmia is mildly to moderately short (mild short stature, often in the range of 140–150 cm depending on severity), and the short stature is mostly due to the truncal shortening (www.orpha.net). The limbs remain near normal length, so once growth stops, the body proportions stay fixed. Adults may experience chronic back pain or early degenerative changes in the spine because the vertebrae and discs were formed abnormally (pubmed.ncbi.nlm.nih.gov). Indeed, narrow intervertebral discs and irregular vertebral endplates can predispose to early-onset osteoarthritis or disc degeneration in the spine. Some patients report nonspecific back pain even in adolescence (www.orpha.net).

Distinct stages or phases of brachyolmia can be outlined as: (1) Early childhood: emergence of short-trunk phenotype and detection of skeletal changes on X-ray (platyspondyly evident, sometimes misdiagnosed as other dwarfism initially); (2) Late childhood/adolescence: progression of spinal curvature (scoliosis/kyphosis) and need for orthopedic monitoring; potentially, this is when dental issues become apparent in LTBP3-related cases – the secondary teeth come in with enamel defects. (In fact, amelogenesis imperfecta in these patients can be identified when primary teeth erupt in toddlerhood, providing an early clue to the syndrome .) (3) Adulthood: a stable phase where stature is finalized; residual deformities of the spine remain (some may undergo corrective surgery for severe scoliosis), and attention shifts to managing any chronic pain or mobility issues.

It’s important to note that brachyolmia is generally non-life-threatening and non-progressive after growth. The prognosis is usually good with a normal lifespan (www.orpha.net). Unlike some other skeletal dysplasias, brachyolmia typically does not involve major joint degeneration or neurological compromise, aside from possible moderate spinal cord compression if severe kyphosis develops (rare). The spinal deformity, if significant, might require intervention, but many patients only have mild curvatures.

One emerging aspect is that severity can vary even within the same genetic subtype. For instance, PAPSS2 truncating mutations might cause more severe phenotypes (in one 2024 report, a fetus with a PAPSS2 truncation had early-onset brachyolmia signs on prenatal ultrasound (www.malacards.org)), whereas milder missense changes produce less severe short stature (www.malacards.org). Similarly, TRPV4 mutations range in effect: some mutations cause only brachyolmia, while others cause the more severe metatropic dysplasia – indicating variable penetrance of the mechanotransduction defect. There may not be clearly demarcated “stages” of molecular pathology, but there is a continuum from mild to severe skeletal dysplasia depending on mutation severity (ojrd.biomedcentral.com). In all cases, the bulk of the pathological changes (flattened vertebrae, etc.) are established by the end of growth. From that point, the condition is static except for issues secondary to the structural anomalies (like early arthritis).

In summary, disease progression in brachyolmia involves early developmental defects manifesting as growth failure of the spine, with potential progression of spinal curvature during growth, then a relatively stable adulthood with residual anatomic changes. This progression underscores the developmental (rather than degenerative) nature of brachyolmia – the damage is done during growth by aberrant cellular function in the growth plates.

Phenotypic Manifestations and Clinical Correlates

The clinical phenotype of brachyolmia directly reflects its pathophysiological roots in skeletal development. The cardinal features are:

• Short trunk, mild short stature – A disproportional short stature where sitting height is significantly reduced (often >2 SD below mean) but arm span and leg length are near normal. This results from the cumulative effect of platyspondyly (flattened vertebral bodies). Radiologically, vertebrae are flattened (sometimes “wedged” or rectangular in shape) with irregular endplates (pubmed.ncbi.nlm.nih.gov). The platyspondyly (HP:0000926) is generalized throughout the spine (cervical, thoracic, lumbar). This causes the thorax and abdomen to be shortened in vertical dimension (hence a short trunk/short back appearance). Despite the short stature, patients typically have normal head size and face, and normal intelligence (brachyolmia is a skeletal condition without neurological deficits (www.orpha.net)). The limbs are proportionate to each other and relatively long compared to the trunk, so the arm span may exceed height (a clue to short-trunk dwarfism). This phenotype is visible by school age.

• Spinal curvature (scoliosis/kyphosis) – Scoliosis (HP:0002650) is common in brachyolmia. Many patients develop a mild to moderate scoliosis during growth (www.orpha.net). In AD (TRPV4) brachyolmia, kyphoscoliosis can be prominent (www.orpha.net), meaning there is both lateral curvature and a forward bending (hunchback) of the thoracic spine. This may be because TRPV4-related dysplasia sometimes overlaps with SMD Kozlowski type which features progressive kyphoscoliosis (ojrd.biomedcentral.com) (ojrd.biomedcentral.com). In any case, the curvature is a mechanical consequence of having flattened, irregular vertebrae that don’t stack perfectly. Back pain is reported by some patients, likely due to muscle strain from the abnormal spinal alignment (www.orpha.net). Severe curvatures are relatively uncommon but can occur, potentially requiring bracing or surgery.

• Broad, short torso and neck – On examination, patients have a shortened thoracic cage and often a short neck. The iliac crests may appear high (approaching the lower ribs) because of the reduced vertebral column length. Orphanet notes “broad ilia” on X-ray in some cases (pubmed.ncbi.nlm.nih.gov), which is part of the skeletal dysplasia. A barrel-shaped chest can be present due to the combination of scoliosis and short trunk.

• Normal limbs with minor aberrations – Generally, long bones are of normal length and there is no significant long bone bowing or deformity (www.orpha.net). This distinguishes brachyolmia from many other dwarfing conditions. However, subtle changes have been observed: for example, short femoral necks with coxa valga (wide angle of the hip) were described in LTBP3 cases (pubmed.ncbi.nlm.nih.gov) and PAPSS2 cases (pubmed.ncbi.nlm.nih.gov). Mild shortening of the metacarpals or other tubular bones can also occur in PAPSS2-related brachyolmia (pubmed.ncbi.nlm.nih.gov), though these usually don’t affect function. These minor limb findings suggest that while the spine is the primary site, the molecular defect can have body-wide effects on the skeleton (especially in more severe variants on the spectrum of the disease). For instance, PAPSS2 mutations in some patients cause spondylo-epi-metaphyseal dysplasia with more obvious limb involvement (pubmed.ncbi.nlm.nih.gov). But in classical brachyolmia, limb function and appearance are essentially normal – patients do not have the joint misalignment or severe bowing seen in other skeletal dysplasias.

• Dental anomalies (in LTBP3/DASS subtype) – A very distinct phenotypic feature of the LTBP3-related brachyolmia is amelogenesis imperfecta (AI). Patients have hypoplastic, discolored enamel, leading to weak, small, and brownish teeth that are prone to wear (pubmed.ncbi.nlm.nih.gov). Often both primary and secondary teeth are affected. Tooth agenesis (missing some permanent teeth) has also been reported in some LTBP3 cases (pmc.ncbi.nlm.nih.gov) (indeed, LTBP3 was initially identified in some oligodontia patients before the full syndrome was known (pmc.ncbi.nlm.nih.gov)). This dental phenotype is an important clinical clue: a child with short trunk dwarfism and bad enamel should trigger consideration of LTBP3-related brachyolmia. The AI does not progress per se (enamel, once formed, stays defective), but it requires dental management to prevent cavities and breakdown. The presence of AI differentiates DASS syndrome from other brachyolmia forms; other forms typically have normal tooth development.

• Corneal clouding (in Toledo subtype) – A very small subset of AR brachyolmia (the so-called Toledo type) was noted to have corneal opacities (www.orpha.net). This is a rare feature; most brachyolmia patients have normal eyes. The corneal clouding in Toledo type could be related to glycosaminoglycan deposition in the cornea (reminiscent of metabolic bone diseases), but the genetic basis of the Toledo type was not clear historically. It’s possible that some Toledo cases were actually PAPSS2 mutations (since GAG undersulfation might conceivably affect cornea), but this is speculative. In any event, corneal opacity is not a universal feature – it was described in a few patients and isn’t seen in known molecularly confirmed cases of PAPSS2 or LTBP3 mutations, to our knowledge. It remains a reported but infrequent phenotype.

• Hearing impairment (non-core feature) – Most brachyolmia patients have normal hearing. However, Nawaz et al. (2023) described one consanguineous family where individuals with brachyolmia also had early-onset sensorineural hearing loss, which turned out to be due to a separate gene (CABP2 mutation) in that family (pubmed.ncbi.nlm.nih.gov). So hearing loss is not a direct feature of brachyolmia, but that case highlights the importance of comprehensive genetic analysis if additional symptoms are present.

Functionally, individuals with brachyolmia usually have normal motor development and can walk and run normally (since legs are normal). They might have some restrictions in spinal mobility or reduced pulmonary function if the chest cavity is small, but generally they do well. Pulmonary function can be mildly affected in short-trunk conditions due to a smaller thoracic volume; in brachyolmia this hasn’t been highlighted as a major issue, probably because the chest is short but not extremely narrow. Neurologically, they are normal – no hydrocephalus or spinal cord issues inherently, though severe scoliosis can rarely cause nerve compression if untreated.

From a laboratory perspective, brachyolmia is not associated with abnormal blood tests. It’s diagnosed primarily by clinical and radiographic findings, confirmed by genetic testing. X-ray findings are central to phenotypic description: aside from platyspondyly, radiographs show narrow intervertebral disc spaces in some AR cases (pubmed.ncbi.nlm.nih.gov) (likely from early degeneration or reduced disc height due to small vertebrae), wide iliac wings of the pelvis, and as mentioned, small femoral necks.

To tie phenotypes back to mechanisms: the short trunk is due to insufficient growth of vertebral bodies (PAPSS2 →less matrix expansion; LTBP3 →less proliferative signal; TRPV4 →premature hypertrophy/closure). Scoliosis likely arises because the abnormal vertebrae cannot maintain normal alignment under mechanical forces – possibly one side of the vertebral growth plate is more affected than the other, leading to wedge-shaped vertebrae and curvature. This asymmetry could be stochastic or due to weight-bearing stresses exploiting a weakened spinal column (in TRPV4 GOF, for example, mechanical stress might disproportionately damage certain areas, resulting in progressive curvature). Platyspondyly (flat vertebrae) is literally the radiographic manifestation of too little vertical growth of each vertebra – a direct outcome of growth plate dysfunction. Dental enamel defects reflect the loss of TGF-β modulation in odontogenesis (LTBP3), and corneal opacity (if truly a feature) might reflect GAG abnormalities akin to a mild form of a lysosomal storage disorder effect (though this remains unclear).

Finally, it’s worth noting brachyolmia’s differential diagnosis includes other short-trunk skeletal dysplasias (like spondyloepiphyseal dysplasia congenita, mucopolysaccharidoses, etc.), but those often have additional features (e.g. eye and joint issues in mucopolysaccharidosis). Brachyolmia is relatively isolated to the axial skeleton (with the exception of teeth in the LTBP3 subtype). The lack of epiphyseal irregularities in most cases and normal intellect help differentiate it (www.orpha.net). Genetic testing for PAPSS2, LTBP3, and TRPV4 mutations now provides definitive diagnosis and also helps refine phenotype-genotype correlations for this disorder.

Expert Insights and Recent Developments

Recent studies (2020–2024) have deepened our understanding of brachyolmia’s molecular basis and broadened its known phenotype. For instance, Mustafa et al. (2022) reported a novel PAPSS2 missense mutation and confirmed it causes the classic Hobaek-type brachyolmia, expanding the mutational spectrum (www.malacards.org). Hadid et al. (2023) identified an LTBP3 variant in a Druze family, reinforcing the link between LTBP3 and the short stature with dental anomalies phenotype (www.malacards.org). The Heliyon 2023 study by Nawaz et al. not only found new LTBP3 mutations but also incidentally highlighted the possibility of multiple genetic conditions coexisting (as seen with concurrent hearing loss from a different gene) (pubmed.ncbi.nlm.nih.gov). This underscores the need for comprehensive genomic analysis in atypical cases. A 2024 case report by Biancotto et al. even suggests that brachyolmia can present prenatally in severe forms – they describe ultrasound findings of shortened trunk in a fetus with a PAPSS2 truncating variant (www.malacards.org). This preliminary finding raises the question of whether some unexplained prenatal skeletal abnormalities might be due to brachyolmia genes, especially PAPSS2, when the long bones are normal but the spine is short.

On the mechanistic front, research is starting to connect the dots between seemingly disparate pathways. The 2015 study by Huckert et al. postulated cross-talk between TGF-β signaling, mechanotransduction, and sulfation pathways in bone: for example, they noted that altered TGF-β signaling can reduce PAPSS2 expression and change cartilage biomechanics in mice (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Additionally, TRPV4 has been found to interact with intracellular signaling cascades (like the MAPK pathway) that also respond to TGF-β and osmolarity, suggesting a complex network of regulation. These insights hint that the three known brachyolmia genes may converge on a common developmental network – TGF-β influences matrix production (including Papss2 expression) and mechanosensitivity, while mechanical loading (via TRPV4) can modulate growth factor signaling. This integrated view is still being developed, but it highlights brachyolmia as a useful model for understanding how mechanical forces, matrix composition, and growth factors together shape bone growth (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

In terms of real-world applications, knowing the pathophysiology has not yet yielded a targeted therapy to “cure” the growth problem, since these are developmental issues. However, there have been attempts to address consequences: for instance, a 2025 case report by Long et al. documented growth hormone therapy in a child with PAPSS2-related brachyolmia (pubmed.ncbi.nlm.nih.gov). While GH therapy is not standard (and its efficacy in purely skeletal dysplasias is limited), it reflects efforts to mitigate short stature. Orthopedic interventions (spinal fusion, bracing) are employed for progressing scoliosis. Dental rehabilitation (crowns, veneers) is important for those with amelogenesis imperfecta to protect the teeth. None of these address the root molecular cause, but understanding the cause helps in genetic counseling – families can be informed that brachyolmia follows either autosomal recessive or dominant inheritance depending on the type (www.orpha.net) (www.orpha.net).

In summary, brachyolmia’s pathophysiology centers on molecular disturbances in cartilage development – whether from a missing co-factor (sulfate), a missing growth factor regulator, or an overactive ion channel. These disturbances derail the finely tuned processes of skeletal growth, leading to the defining clinical features of a short, curved spine with otherwise normal anatomy. Ongoing research, especially into the TGF-β–mechanotransduction–matrix interplay, will likely provide further insight into not just brachyolmia but general principles of bone development and homeostasis. Each gene involved offers a window into a different aspect of skeletal biology: PAPSS2 illuminates the importance of proteoglycan sulfation in growth plate signaling, LTBP3 highlights the role of latent growth factor regulation, and TRPV4 underscores the impact of mechanical forces on bone growth. Together, these form the pathophysiological mosaic of brachyolmia – a rare condition that exemplifies how genetic perturbations can lead to specific skeletal growth failure, yielding a distinctive clinical syndrome backed by increasingly well-understood molecular mechanisms.

Evidence: The relationship between these gene defects and the brachyolmia phenotype is supported by multiple studies: PAPSS2 was confirmed as the AR brachyolmia gene by Miyake et al. (2012) (pubmed.ncbi.nlm.nih.gov); LTBP3’s role in the short stature with enamel defects syndrome was established by Huckert et al. (2015) (pmc.ncbi.nlm.nih.gov) and reinforced by recent reports (pubmed.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov); TRPV4’s contribution to AD brachyolmia was discovered by Rock et al. (2008) via linkage analysis and functional assays showing gain-of-function effects (www.nature.com). These landmark findings, along with mechanistic studies in mice (e.g., Papss2^bm^ mouse showing Ihh signaling disruption (pmc.ncbi.nlm.nih.gov), Ltbp3^−/−^ mouse showing axial skeletal defects (pmc.ncbi.nlm.nih.gov), TRPV4 mutant channels studied in vitro (www.nature.com)), form the evidentiary basis for our current understanding of brachyolmia pathophysiology. All point to the molecular derangement of cartilage physiology as the cause of this Mendelian disorder, fulfilling the connection from gene mutation to cellular dysfunction to tissue and organ-level phenotype.