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Galactosemia

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

2026-03-31
Asta MONDO:0018116 Model: Asta Scientific Corpus Retrieval 19 citations

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

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

  • Papers retrieved: 19
  • Snippets retrieved: 20

Relevant Papers

[1] Pathophysiology and targets for treatment in hereditary galactosemia: A systematic review of animal and cellular models

  • Authors: M. Haskovic, A. I. Coelho, Jörgen Bierau, Jo M. Vanoevelen, L. Steinbusch et al.
  • Year: 2019
  • Venue: Journal of Inherited Metabolic Disease
  • URL: https://www.semanticscholar.org/paper/dea4d7499797ec21ed9d0b65b0549abfe1322ff8
  • DOI: 10.1002/jimd.12202
  • PMID: 31808946
  • PMCID: 7317974
  • Citations: 47
  • Influential citations: 1
  • Summary: An overview of the scattered information resulting from animal and cellular studies performed in the past decades is provided, summarising the complex pathophysiological mechanisms underlying hereditary galactosemia and providing insights on potential treatment targets.
  • Evidence snippets:
  • Snippet 1 (score: 0.548) > Since the first description of galactosemia in 1908 and despite decades of research, the pathophysiology is complex and not yet fully elucidated. Galactosemia is an inborn error of carbohydrate metabolism caused by deficient activity of any of the galactose metabolising enzymes. The current standard of care, a galactose‐restricted diet, fails to prevent long‐term complications. Studies in cellular and animal models in the past decades have led to an enormous progress and advancement of knowledge. Summarising current evidence in the pathophysiology underlying hereditary galactosemia may contribute to the identification of treatment targets for alternative therapies that may successfully prevent long‐term complications. A systematic review of cellular and animal studies reporting on disease complications (clinical signs and/or biochemical findings) and/or treatment targets in hereditary galactosemia was performed. PubMed/MEDLINE, EMBASE, and Web of Science were searched, 46 original articles were included. Results revealed that Gal‐1‐P is not the sole pathophysiological agent responsible for the phenotype observed in galactosemia. Other currently described contributing factors include accumulation of galactose metabolites, uridine diphosphate (UDP)‐hexose alterations and subsequent impaired glycosylation, endoplasmic reticulum (ER) stress, altered signalling pathways, and oxidative stress. galactokinase (GALK) inhibitors, UDP‐glucose pyrophosphorylase (UGP) up‐regulation, uridine supplementation, ER stress reducers, antioxidants and pharmacological chaperones have been studied, showing rescue of biochemical and/or clinical symptoms in galactosemia. Promising co‐adjuvant therapies include antioxidant therapy and UGP up‐regulation. This systematic review provides an overview of the scattered information resulting from animal and cellular studies performed in the past decades, summarising the complex pathophysiological mechanisms underlying hereditary galactosemia and providing insights on potential treatment targets.

[2] Classic galactosemia

  • Authors: Haskovic Minela
  • Year: 2020
  • Venue: Definitions
  • URL: https://www.semanticscholar.org/paper/8a8f5e491ba0a05ee08459968beda70d2631f65e
  • DOI: 10.32388/nsn934
  • Citations: 2
  • Summary: The research presented in this dissertation will contribute to alleviate the burden on the healthcare and social systems, and to improve the psycho-social outcomes and quality of life for all galactosemia patients.
  • Evidence snippets:
  • Snippet 1 (score: 0.531) > The studies described in this dissertation add value to the already existing knowledge on galactosemia. > We have successfully developed an international registry for the different types of galactosemia and described the natural history of classic galactosemia in the hitherto largest cohort of patients. This is of great value for patients, their families and healthcare professionals involved in patient care. Our systematic review on the studied pathophysiological mechanisms in cellular and animal models so far will be of great value for future studies and may help reduce the use of more animals in research. In addition, we provided relevant information regarding nucleotide sugar levels in classic galactosemia that shed light on the pathophysiology underlying glycosylation abnormalities observed in this disease. > Towards our ultimate aim to develop new treatment strategies and provide the best possible care to the patients, we evaluated two treatment modalities. The non-mutation-specific mRNA-based approach holds great promise for future research, and eventually, clinical implementation. Our pilot study evaluating the therapeutic potential of arginine showed not to be beneficial in patients homozygous for p.Gln188Arg. The research presented in this dissertation will contribute to alleviate the burden on the healthcare and social systems, and to improve the psycho-social outcomes and quality of life for all galactosemia patients.

[3] Current and Future Treatments for Classic Galactosemia

  • Authors: Britt Delnoy, A. I. Coelho, M. Rubio-Gozalbo
  • Year: 2021
  • Venue: Journal of Personalized Medicine
  • URL: https://www.semanticscholar.org/paper/0560be81b4a0a635942e8493bcd3e08391ce06bd
  • DOI: 10.3390/jpm11020075
  • PMID: 33525536
  • PMCID: 7911353
  • Citations: 32
  • Summary: Novel therapeutic approaches currently being explored focus on several of the pathogenic factors that have been described, aiming to restore GALT activity, influence the cascade of events and address the clinical picture.
  • Evidence snippets:
  • Snippet 1 (score: 0.458) > The pathogenic mechanisms underlying the acute and long-term organ-specific complications of classic galactosemia are complex and remain to be fully elucidated. Currently described contributing factors include accumulation of galactose metabolites (galactitol, galactonate and Gal-1-P) [2,[19][20][21][22][23][24][25][26][27][28][29][30], uridine diphosphate (UDP)-hexose alterations and impaired glycosylation [21,25,[31][32][33][34][35][36], endoplasmic reticulum (ER) stress with subsequent unfolded protein response (UPR), induction and alteration of signaling pathways [2][3][4][37][38][39][40][41][42], and oxidative stress [4,29,43,44] (Figure 1). > In recent years, a number of animal models (mouse, fruit fly, zebrafish, rat) [24,29,45,46] of classic galactosemia have been developed that mimic, at least partly, the biochemical and clinical phenotypes and complement the cellular models, allowing us to advance our comprehension of the complex playing field of the metabolism of galactose. We have learned that there is different expression of the Leloir pathway components and alternative galactose disposal routes in the different tissues, that combined with specific tissue demands, epigenetic and environmental factors, urge to revisit our understanding. GALT activity levels in affected organs (brain, ovaries) do not seem to differ from the activity levels in organs not affected in classic galactosemia and distinct organ-specific levels of GALT activity have been found [19]. This is reflected in the tissue related differences in relative levels of galactose metabolites (galactitol, galactose and Gal-1-P) in the rat galactosemia model [45], as well as in the nucleotide sugar profiles variation through development and in the different tissues in the zebrafish galactosemia model [31].

[4] A case report of classic galactosemia with a GALT gene variant and a literature review

  • Authors: Yong-cai Wang, L. Lan, Xia Yang, Juan Xiao, Hai Liu et al.
  • Year: 2024
  • Venue: BMC Pediatrics
  • URL: https://www.semanticscholar.org/paper/9acb35750148af54732952ea2d8db4132da2b5ba
  • DOI: 10.1186/s12887-024-04769-0
  • PMID: 38778342
  • PMCID: 11110268
  • Citations: 5
  • Summary: Applications of whole-exome sequencing to detect the two variants can improve the detection and early diagnosis of classical galactosemia and, more specifically, may identify individuals who are compound heterozygous with variants in the GALT gene.
  • Evidence snippets:
  • Snippet 1 (score: 0.441) > Ultimately, Glu-1-P enters the glycolytic pathway. > The alternative pathway of galactose metabolism is particularly active when there are deficiencies in Leloir pathway-associated enzymes, which can lead to the accumulation of galactose and other abnormal metabolites in the body, affecting the liver, kidneys, eyes, and brain Fig. 1 Represents the standard Leloir pathway and can be fatal.Due to the toxic effects of galactose metabolites, survivors may develop various long-term complications, such as cataracts, abnormal neurological development, speech impairment, growth restriction, and premature ovarian failure [10,11]. > Blood tandem mass spectrometry screening for galactosemia is not routinely performed in China, while conventional laboratory tests make it challenging to diagnose the disease.In many countries, including those following international guidelines, the enzymatic assay, one of the recommended techniques, is no longer commonly performed and has been largely replaced by the sequencing of the GALT gene.However, in China, genetic sequencing is the primary method for diagnosing certain conditions, but it is often outsourced to third-party institutions, resulting in a long wait time for results.Galactosemia is a rare condition, and clinicians may not always be aware of it, which can result in misdiagnosis or missed diagnosis, as was the case presented in this report.There are no specific drugs for galactosemia treatment.Immediate dietary galactose restriction is required to reverse the acute postnatal symptoms of classic galactosemia. > The prevalence of classical galactosemia among populations of different ethnic backgrounds varies.Its prevalence is much higher in Western populations compared to Asian populations, with prevalence rates of 1:40,000∼1:60,000 in Europe, 1:50,000 in the United States, 1:23,500-1:44,000 in the United Kingdom, 1:42,000 in Lithuania, 1:100,000 in Japan, 1:400,000 in Taiwan, China [12], 1:50,000 in Shenzhen, China 1:50,000, and 1:759,428 in Zhejiang, China 1:759,428 [13].The disease is less reported in China.

[5] Whole-body galactose oxidation as a robust functional assay to assess the efficacy of gene-based therapies in a mouse model of Galactosemia

  • Authors: B. Balakrishnan, Xinhua Yan, Marshall D McCue, Olivia Bellagamba, A. Guo et al.
  • Year: 2024
  • Venue: Molecular Therapy. Methods & Clinical Development
  • URL: https://www.semanticscholar.org/paper/15caf17098ca72c5d901270d7460d4e09170eb25
  • DOI: 10.1016/j.omtm.2024.101191
  • PMID: 38352271
  • PMCID: 10863324
  • Citations: 6
  • Summary: It is established that whole-body galactose oxidation (WBGO) as a robust, noninvasive, and specific method to assess the in vivo pharmacokinetic and pharmacodynamic parameters of two experimental gene-based therapies that aimed to restore GALT activity in a mouse model of galactosemia.
  • Evidence snippets:
  • Snippet 1 (score: 0.430) > Recent advances in molecular therapeutics and gene-based vaccines have paved the way for new treatment modalities for monogenic diseases such as phenylketonuria and CG. Among these modalities, gene replacement therapies and mRNA-based therapies are gaining popularity because, if successful, these modalities will address the root cause of the diseases-the absence of functional gene productsthus making them attractive and rational choices. Although efficient vectors and nanoparticles have been developed to deliver the cDNA and mRNA, respectively, to the disease-relevant organs, the in situ pharmacokinetics (PK) and pharmacodynamics (PD) assessments for the specific modality could be challenging clinically if the organs of interest are inaccessible for repeated sampling. Consequently, surrogate disease-relevant biomarkers could prove useful for part of the portfolio for the evaluation of effectiveness of the treatments under these circumstances. Ideally, the desired biomarkers are those directly implicated in the pathogenic mechanisms of the diseases so that their changes can truly reflect the change in disease states and phenotypes. However, the underlying pathophysiological mechanisms of many diseases are often not fully elucidated, which further complicates the identification of disease-relevant biomarkers for the evaluation of therapeutic efficacy. > In this study, we tested the hypothesis that whole-body galactose oxidation can be used as a noninvasive, robust, accurate, and functional biomarker for testing the effectiveness of gene-based therapies for CG. 2][3][4][5] Galactosemia patients suffer from a host of neurological complications such as ataxia, and in females, POI. 12,32,33 For decades, diagnosis of the disease relied on the detection of the abnormal accumulation of galactose metabolites such as RBC gal-1P, as well as the absence of RBC GALT activity. 34 This protocol works well for diagnosis because normal RBCs have detectable GALT expression. 35,36

[6] Novel mRNA-Based Therapy Reduces Toxic Galactose Metabolites and Overcomes Galactose Sensitivity in a Mouse Model of Classic Galactosemia.

  • Authors: B. Balakrishnan, D. An, Vi Nguyen, Christine DeAntonis, P. Martini et al.
  • Year: 2020
  • Venue: Molecular therapy : the journal of the American Society of Gene Therapy
  • URL: https://www.semanticscholar.org/paper/07c8805b07f790a3c40921e0fa28d08f11b6ed4d
  • DOI: 10.1016/j.ymthe.2019.09.018
  • PMID: 31604675
  • Citations: 52
  • Influential citations: 4
  • Summary: This study tested whether restoration of hepatic GALT activity alone could decrease galactose-1 phosphate (gal-1P) and plasma GalT-deficient mice in the mouse model and found that repeated dosing reduced plasmaGalactose by 60% or more throughout all four doses.
  • Evidence snippets:
  • Snippet 1 (score: 0.426) > It has been more than a century since classic galactosemia, an inborn error of metabolism (IEM) with an incidence of 1 in 40,000 live births, was first documented, 31 and over four decades since its biochemical basis elucidated. 1,32 Despite the life-saving dietary management during the neonatal period, the continued lack of safe and effective therapies for the long-term debilitating complications has taken a heavy toll in the quality of life of over 2,000 patients worldwide and their caregivers. [33][34][35][36][37][38][39][40] Traditional therapeutic strategies for IEMs focused on ERT and substrate reduction therapy. While ERT enjoys some successes in lysosomal storage diseases, 41 the CNS pathology associated with the diseases remain a challenge because of the inability of the enzymes to cross the blood-brain barrier (BBB). 42 Therefore, the efficacy of ERT in treating the neurological complications of galactosemia could be limited. Substrate reduction therapy through galactose restriction has been instrumental in averting the lethality during the neonatal period of the affected patients, but the galactose-restricted diet alone is insufficient to prevent the long-term complications. Other emerging experimental therapeutic approaches for galactosemia include the targeting of galactokinase 43,44 and aldose reductase, 45 as well as endoplasmic reticulum stress 46,47 by small molecule inhibitors, but none of them have reached the stage for clinical trials at this moment. > Although the environmental and molecular mechanisms for the longterm complications associated with classic galactosemia have not been fully delineated, none will debate that the disease is caused by deleterious mutations in the GALT genes, which result in the complete absence of cellular GALT enzyme activity. In this study, we pursued a nucleic acid-based therapeutic strategy, where we delivered human GALT (hGALT) mRNA into the liver of a GalT-deficient mouse at which the hGALT mRNA will be translated and form functional GALT enzyme. We hypothesized that upon hepatic hGALT gene expression, the liver will act as a "sink" to metabolize all the excess galactose

[7] Experimental Galactose-1-Phosphate Uridylyltransferase (GALT) mRNA Therapy Improves Motor-Related Phenotypes in a Mouse Model of Classic Galactosemia—A Pilot Study

  • Authors: Olivia Bellagamba, A. Guo, Xinhua Yan, Joe Sarkis, B. Balakrishnan et al.
  • Year: 2025
  • Venue: Biomedicines
  • URL: https://www.semanticscholar.org/paper/a4c5a00536a991fa9cfba61ae486e35fac705354
  • DOI: 10.3390/biomedicines13122848
  • PMID: 41462863
  • PMCID: 12731057
  • Summary: A biweekly dosing regimen at 2mg/kg for 2 months could improve the motor performance of the animals in Rotarod and Composite Phenotype Scoring tests and showed that administration of GALT mRNA in the mutant mice restored whole-body galactose oxidation (WBGO), a functional biomarker.
  • Evidence snippets:
  • Snippet 1 (score: 0.423) > Except for the ovarian phenotype, there is considerable variability among other long-term complications. To-date, there is no effective treatment available to prevent or alleviate any of the above-mentioned long-term complications. Yet, regardless of the pathophysiological mechanisms, no one will argue that the root cause of the disease is the absence of GALT enzyme activity in patient cells. Therefore, therapeutic strategies that aim to restore GALT enzyme activity in the patients represent a rational and direct approach to address the unmet medical needs of the patients. Among them, experimental GALT mRNA therapy has emerged as a promising modality [17][18][19]. Indeed, we demonstrated significant efficacy of GALT mRNA in normalizing the disease-relevant biomarkers and restoring whole-body galactose oxidation in a mouse model of classic galactosemia. > Figure 1. The Leloir pathway of galactose metabolism and the proposed pathobiology of galactose-1phosphate uridylyltransferase (GALT) deficiency. Galactose, absorbed via diet or produced endogenously in a cell, is phosphorylated to form galactose-1-phosphate (Gal-1P). In the absence of GALT, the build-up of Gal-1P is thought to induce abnormal integrated response (ISR), which plays a role in the pathophysiology of the disease. Administration of GALT mRNA (green arrow) is expected to restore expression of GALT enzyme, thus effectively eliminating the Gal-1P accumulation. > In this short-term study, we expanded our preclinical proof-of-concept studies to include motor impairment, a disease-relevant phenotype. By doing so, we aimed to address the following three questions: > 1. > Will experimental GALT mRNA therapy improve motor-related phenotypes in a mouse model of classic galactosemia? 2. > Will the improvement, if any, of motor-related phenotypes seen in the treated animals be sustained after the cessation of the experimental GALT mRNA treatment?

[8] Clinical metabolomics in type 2 diabetes mellitus: from pathogenesis to biomarkers

  • Authors: Chuanxin Liu, Hetao Chen, Yujin Ma, Lei Zhang, Lulu Chen et al.
  • Year: 2025
  • Venue: Frontiers in Endocrinology
  • URL: https://www.semanticscholar.org/paper/36f8d26a208b7b96763df2e9aa3211e440031c0e
  • DOI: 10.3389/fendo.2025.1501305
  • PMID: 40070584
  • PMCID: 11893406
  • Citations: 10
  • Summary: The results facilitate understanding the pathophysiology and mechanism of type 2 diabetes mellitus and supports research in accurate diagnosis, risk prediction, curative effect, distinct stages, and prognosis judgment of T2DM.
  • Evidence snippets:
  • Snippet 1 (score: 0.422) > The metabolome is sensitive to a variety of genetic and environmental stimuli and susceptible to genetic, environmental, and gut microbiome pressures, so subtle differences between individuals can lead to large perturbations in metabolite concentrations and fluxes (15, 24). At present, cystatin C has become an ideal endogenous marker for evaluating glomerular filtration function because it is not affected by sex, age or muscle mass (25). In addition, more and more evidence shows that serum CysC is involved in the pathological process of vascular remodeling and neovascularization, which is closely related to the occurrence and development of diabetic microangiopathy (26). > Eighty-four papers were included in this review and obtained through database searches, namely, PubMed, Cochrane Library, China national knowledge internet(CNKI), General Purpose, and VIP Database. The keywords for the searches were "metabolomics" and "type 2 diabetes mellitus" and its complications. The papers were incorporated by reading and summarizing the literature according to the classification standards (27). The profound analysis of clinical differential metabolites identified in type 2 diabetes and its complications were conducted concerning composition, frequency of category, sample type, and pathways to explore the pathological mechanism of type 2 diabetes and its complications to provide a systematic basis for clinical diagnosis, risk stratification, comprehending disease progression, prognosis assessment, and drug efficacy. Our goal is to apply metabolomics to clinical diagnostic biomarkers, metabolic mechanisms, and prognostic observations, and early diagnosis can be made through metabolites to avoid progression to more serious complications.
  • Snippet 2 (score: 0.402) > T2DM is a chronic disease characterized by two primary pathophysiological mechanisms: ① a reduction in the mass and function of pancreatic b cells, ranging from 20% to 65%, which leads to impaired insulin secretion; ② insulin resistance, where cells in muscles, fat, and liver tissues fail to respond adequately to insulin (9). Consequently, higher levels of insulin are required to maintain normal blood glucose concentrations by inhibiting hepatic glucose production and promoting glucose uptake in muscle and adipose tissues. Prolonged exposure to elevated levels of circulating insulin leads to the development of insulin resistance in peripheral tissues, and over time, the pancreas fails to produce sufficient insulin to overcome this cellular resistance (10). However, due to the long latent period and absence of obvious symptoms initially, reversing T2DM with drug intervention is difficult after the symptoms are exposed or clinically confirmed in light of clear diagnostic criteria. According to the literature, the pathogenesis and process of metabolic syndromes such as diabetes and its complications are mainly reflected in the metabolite network, and the mechanism changes at the gene level are also found in the network. Studies have shown that some related metabolites in patients with diabetes have changed before the occurrence of obvious organic damage (11). Therefore, it is necessary to scientifically prevent T2DM in the early stages of disease onset. Fortunately, clinical metabolomics were employed to understand the progression pathologies of T2DM and its corresponding complications in detail (12). Studies have demonstrated that metabolomic analysis enables the exploration of metabolic disorders associated with T2DM, thereby deepening our understanding of disease progression (13,14). This approach has the potential to facilitate novel clinical diagnoses and the development of effective treatment strategies. Moreover, identifying specific metabolites may provide promising biomarkers for the early prediction, prevention, and management of hyperglycemia and its complications (15). In recent years, excellent progress has been made in the study of T2DM and its complications through High throughput sequencing method, i.e., a discipline specifically focused on metabolic small molecules. > Clinical metabolomics is a type of systems biology research closely linked to phenotype.

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

  • Authors: M. Uzti̇mür, C. N. Ünal, Gurler Akpinar
  • Year: 2025
  • Venue: Journal of Veterinary Internal Medicine
  • URL: https://www.semanticscholar.org/paper/4b9c488b5dbd65d7b26fd2ad9aed70e8c4b59942
  • DOI: 10.1111/jvim.70139
  • PMID: 40492724
  • PMCID: 12150350
  • Summary: Understanding the serum proteome profiles of goats with pregnancy toxemia might help identify the proteomes and pathways responsible for the development of this disease and improve diagnosis and treatment.
  • Evidence snippets:
  • Snippet 1 (score: 0.419) > The pathophysiology and progression of this disease are not fully understood. > Traditional biomedical research has focused on the analysis of single genes, proteins, metabolites, or metabolic pathways in diseases. This molecular reductionist approach is based on the assumption that identifying genetic variations and molecular components will lead to new treatments for diseases [13][14][15][16]. However, many diseases are complex and multifactorial, and in order to determine the phenotype of such diseases, it is necessary to understand the changes that occur in more than one gene, pathway, protein, or metabolite at the cellular, tissue, and organismal levels [17][18][19]. Therefore, in recent years, proteomics, as one field of multi-omics technologies, has helped in evaluating the complex pathogenetic mechanisms of different diseases from a broad perspective and has made substantial contributions [20,21]. In veterinary medicine, proteomic analysis of metabolic diseases such as ketosis [16], hypocalcemia [22], and fatty liver [23] in dairy cows has contributed valuable insights for the definition of new pathophysiological pathways and new diagnosis and treatment protocols for these diseases. The proteomic approach can contribute importantly to a broad and detailed understanding of the changes that occur at the organismal level associated with the increase in BHBA concentration in goats with pregnancy toxemia. Our aim was to evaluate the serum protein profiles of goats with SPT or CPT using proteomic techniques to determine the proteomic profiles of these animals and to identify the relevant pathophysiological mechanisms.

[10] Functional analysis of GALT variants found in classic galactosemia patients using a novel cell‐free translation method

  • Authors: D. Canson, C. Silao, S. Caoili
  • Year: 2019
  • Venue: JIMD Reports
  • URL: https://www.semanticscholar.org/paper/04704668a3819e473c38d0d8357badc16fc897eb
  • DOI: 10.1002/jmd2.12037
  • PMID: 31392114
  • PMCID: 6606980
  • Citations: 2
  • Influential citations: 1
  • Summary: Biochemical and computational data support the classification of p.Leu116Pro and p.Met178Arg variants as pathogenic and the protein expression method developed has utility for future studies of GALT variants.
  • Evidence snippets:
  • Snippet 1 (score: 0.404) > Classic galactosemia is an autosomal recessive disorder caused by deleterious variants in the galactose‐1‐phosphate uridylyltransferase (GALT) gene. GALT enzyme deficiency leads to an increase in the levels of galactose and its metabolites in the blood causing neurodevelopmental and other clinical complications in affected individuals. Two GALT variants NM_000155.3:c.347T>C (p.Leu116Pro) and NM_000155.3:c.533T>G (p.Met178Arg) were previously detected in Filipino patients. Here, we determine their functional effects on the GALT enzyme through in silico analysis and a novel experimental approach using a HeLa‐based cell‐free protein expression system. Enzyme activity was not detected for the p.Leu116Pro protein variant, while only 4.5% of wild‐type activity was detected for the p.Met178Arg protein variant. Computational analysis of the variants revealed destabilizing structural effects and suggested protein misfolding as the potential mechanism of enzymological impairment. Biochemical and computational data support the classification of p.Leu116Pro and p.Met178Arg variants as pathogenic. Moreover, the protein expression method developed has utility for future studies of GALT variants.

[11] 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: 0.404) > 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.

[12] 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: 0.402) > 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.

[13] Lactate metabolism and lactylation in kidney diseases: insights into mechanisms and therapeutic opportunities

  • Authors: Yuhua Cheng, Linjuan Guo
  • Year: 2025
  • Venue: Renal Failure
  • URL: https://www.semanticscholar.org/paper/6208b88884af543f7c97d2e70ed6b727dcfb4f58
  • DOI: 10.1080/0886022X.2025.2469746
  • PMID: 40012230
  • PMCID: 11869332
  • Citations: 9
  • Summary: A review examines the role of lactate esters, especially lactylation, in kidney diseases, with a focus on their regulatory mechanisms and potential as therapeutic targets.
  • Evidence snippets:
  • Snippet 1 (score: 0.395) > Lactate metabolism and its post-translational modifications, particularly lactylation, play critical roles in the pathophysiology of various kidney diseases, including AKI, DKD, and ccRCC (Figure 1). The kidney's ability to metabolize lactate is crucial for maintaining renal function under normal conditions. However, in pathological states, impaired lactate metabolism leads to its accumulation, exacerbating renal dysfunction and disease progression. For more details on lactate metabolism and kidney diseases, refer to previous reviews [2,3,25]. > Lactylation influences gene transcription, protein function, and cellular metabolism, contributing to inflammatory responses, mitochondrial dysfunction, and tumor progression. > Understanding the mechanisms of lactate metabolism and lactylation in kidney diseases opens new avenues for therapeutic interventions. Targeting these metabolic pathways could mitigate renal injury and improve patient outcomes. Future research should focus on elucidating the specific pathways and molecular targets affected by lactate and lactylation and developing inhibitors to modulate these processes. Clinical trials are necessary to validate the efficacy and safety of these therapies. Overall, the lactate-lactylation axis is a promising target for novel therapeutic strategies aimed at treating kidney diseases and improving renal health.

[14] Mitochondrial Dysfunction in Diabetes: Shedding Light on a Widespread Oversight

  • Authors: F. Iheagwam, A. J. Joseph, E. D. Adedoyin, Olawumi Toyin Iheagwam, Samuel Akpoyowvare Ejoh
  • Year: 2025
  • Venue: Pathophysiology
  • URL: https://www.semanticscholar.org/paper/dbf8042761c1a5fc50f8cd894cc498505abac7cb
  • DOI: 10.3390/pathophysiology32010009
  • PMID: 39982365
  • PMCID: 12077258
  • Citations: 23
  • Summary: This review aims to elucidate the complex link between mitochondrial dysfunction and diabetes, covering the spectrum of diabetes types, the role of mitochondria in insulin resistance, highlighting pathophysiological mechanisms, mitochondrial DNA damage, and altered mitochondrial biogenesis and dynamics.
  • Evidence snippets:
  • Snippet 1 (score: 0.394) > The landscape of DM research is continuously evolving, with emerging technologies and approaches offering new insights into the pathophysiology of the disease and potential therapeutic targets. Advancements in omics technologies, encompassing genomes, transcriptomics, proteomics, and metabolomics, have transformed the molecular mechanisms underlying DM [134]. High-throughput sequencing techniques enable comprehensive analysis of genetic variants, gene expression profiles, protein abundance, and metabolite levels associated with DM and its complications [135]. Single-cell omics approaches provide unprecedented resolution and granularity, allowing researchers to dissect cellular heterogeneity and identify novel cell types, subpopulations, and signalling pathways involved in DM pathogenesis. Integrating multi-omics data sets offers a systems-level perspective of DM, unravelling complex networks of molecular interactions and regulatory circuits underlying disease progression [136]. > In addition to omics technologies, advances in imaging modalities, such as MRI, PET, and optical imaging, enable non-invasive visualisation and quantification of metabolic, functional, and structural changes. Molecular imaging probes targeting specific biomarkers and metabolic pathways provide valuable insights into disease mechanisms and treatment responses in preclinical and clinical settings [85]. Despite significant progress in DM research, numerous unanswered questions and knowledge gaps persist, hindering the ability to develop effective prevention and treatment strategies. Key areas requiring further investigation include the role of epigenetics, environmental factors, and the microbiome in DM susceptibility and progression. Moreover, the interaction between environmental cues and genetic predisposition remains incompletely understood, highlighting the need for comprehensive multi-omics studies and large-scale epidemiological analyses to identify gene-environment interactions and modifiable risk factors for DM [137]. Furthermore, the heterogeneity of DM phenotypes and clinical outcomes poses a challenge for personalised medicine approaches, necessitating robust biomarkers and predictive models to stratify patients based on disease subtypes, prognosis, and treatment response [138].

[15] Language production and working memory in classic galactosemia from a cognitive neuroscience perspective: future research directions

  • Authors: I. Timmers, J. Hurk, F. Di Salle, M. Rubio‐Gozalbo, B. Jansma
  • Year: 2011
  • Venue: Journal of Inherited Metabolic Disease
  • URL: https://www.semanticscholar.org/paper/e4f6397928038f7f2c30b1b2aae8fde3a3f548c8
  • DOI: 10.1007/s10545-010-9266-4
  • PMID: 21290187
  • PMCID: 3063545
  • Citations: 25
  • Summary: Cognitive theories on language production and methods used in cognitive neuroscience are briefly introduced and the possibilities of applying them in experimental paradigms to investigate languageproduction and verbal memory in galactosemia are reviewed.
  • Evidence snippets:
  • Snippet 1 (score: 0.392) > might affect language function. A target method of choice to investigate differences in such information flow within neural circuits, such as the arcuate fasciculus, in galactosemia patients versus healthy controls would be functional connectivity analysis. > Recently, it has been suggested that epigenetic factors may be involved in the pathology of galactosemia. Coman et al. (2010) studied gene expression profiles of four galactosemia patients. They identified several up-or downregulations in gene expressions in these patients. Genes involved in cell signaling pathways, such as the mitogen-activated protein kinase (MAPK) signaling and the calcium signaling pathway, both implicated in neural signaling processes, showed different expression patterns. The most dysregulated gene was Septin 4, of which the expression was decreased 85-fold. Septins are proteins that are involved in a large number of cellular functions, such as membrane dynamics, cytokinesis, vesicle trafficking, exocytosis, and apoptosis (Cao et al. 2009;Haller et al. 2005). Septin 4 (or SEPT4) proteins have been implicated in neurodegenerative diseases, such as Alzheimer's disease or Parkinson's disease. It is expressed in all human tissue, but shows an high expression in the brain (Haller et al. 2005). Further studies will be necessary to elucidate whether these genes are relevant for the origin of the chronic complications. One of the possibilities might be to use ultra high field imaging. With this method, the detection of proteins by producing specifically tailored contrast mechanisms, e.g. by the use of immunoconjugated magnetic nanoparticles (Hilger et al. 2007), might become possible in the future. This in turn might permit to quantify the density of specific substances, among which Septin 4, which can be linked to specific brain regions of functional interest, such as memory or language. > It would be intriguing to examine whether genes encoding for cognitive functions are differentially expressed in galactosemia. One such gene is the FOXP2 transcription factor gene, which has been implicated in speech and language disabilities (Enard et al. 2002;Fisher and Scharff 2009). Such a research would provide another missing link: the link between the genes and

[16] Early postnatal alterations in follicular stress response and survival in a mouse model of Classic Galactosemia

  • Authors: Synneva Hagen-Lillevik, Joshua Johnson, K. Lai
  • Year: 2022
  • Venue: Journal of Ovarian Research
  • URL: https://www.semanticscholar.org/paper/dee9a5865f36dbe98e9ecab78d632b0ea132c4ac
  • DOI: 10.1186/s13048-022-01049-2
  • PMID: 36414970
  • PMCID: 9682695
  • Citations: 8
  • Summary: The findings indicate that abnormal Integrated Stress Response in the Classic Galactosemia model ovary results in accelerated primordial follicle growth activation, sometimes referred to as “burnout,” which helps clarify when/how the primary ovarian insufficiency phenotype arises under galactosemic conditions.
  • Evidence snippets:
  • Snippet 1 (score: 0.391) > Primary ovarian insufficiency is characterized by accelerated loss of primordial follicles, which results in ovarian failure and concomitant menopause before age 40. About 1–3% of females in the general population are diagnosed with POI; however, greater than 80% of females with the inherited disease Classic Galactosemia will develop POI. Classic Galactosemia is caused by mutations in the GALT gene encoding the enzyme galactose-1 phosphate uridylyltransferase. While dietary restriction of galactose is lifesaving in the neonatal period, the development of complications including primary ovarian insufficiency is not mitigated. Additionally, the pattern(s) of follicle loss have not been completely characterized. The chronic accumulation of aberrant metabolites such as galactose-1-phosphate and galactitol are suspected culprits in the development of the sequelae, yet the mechanisms remain elusive. Our group uses a GalT gene-trapped mouse model to study the pathophysiology of primary ovarian insufficiency in Classic Galactosemia. We recently showed that differences in the Integrated Stress Response pathway occur in mutant ovaries that likely contribute to their primary ovarian insufficiency phenotype. Using immunofluorescent staining of histological sections of ovaries at progressive ages, we saw evidence of altered Integrated Stress Response activity in granulosa cells and primordial oocytes consistent with accelerated primordial follicle growth activation, aberrant DNA damage and/or repair, and increased cellular stress/death. Overall, our findings indicate that abnormal Integrated Stress Response in the Classic Galactosemia model ovary results in accelerated primordial follicle growth activation, sometimes referred to as “burnout.” These aberrant early events help further clarify when/how the primary ovarian insufficiency phenotype arises under galactosemic conditions.

[17] 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: 0.386) > 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.

[18] mTOR pathway diseases: challenges and opportunities from bench to bedside and the mTOR node

  • Authors: Laura Mantoan Ritter, N. M. P. Annear, E. Baple, Leila Y. Ben-Chaabane, Istvan Bodi et al.
  • Year: 2025
  • Venue: Orphanet Journal of Rare Diseases
  • URL: https://www.semanticscholar.org/paper/f30b2504a3b3bbb7264847da72e690aebd2919d7
  • DOI: 10.1186/s13023-025-03740-1
  • PMID: 40426219
  • PMCID: 12107773
  • Citations: 5
  • Summary: How mTOR pathway diseases provide an opportunity to coordinate basic and translational disease research across the group, together with industry, medical research foundations, charities and patient groups, by pooling expertise and driving progress to benefit patients is expound.
  • Evidence snippets:
  • Snippet 1 (score: 0.380) > Mechanistic target of rapamycin (mTOR) is a highly conserved serine/threonine kinase that regulates key cellular processes including cell growth, autophagy and metabolism. Hyperactivation of the mTOR pathway causes a group of rare and ultrarare genetic diseases. mTOR pathway diseases have diverse clinical manifestations that are managed by distinct medical disciplines but share a common underlying molecular basis. There is a now a deep understanding of the molecular underpinning that regulates the mTOR pathway but effective treatments for most mTOR pathway diseases are lacking. Translating scientific knowledge into clinical applications to benefit the unmet clinical needs of patients is a major challenge common to many rare diseases. In this article we expound how mTOR pathway diseases provide an opportunity to coordinate basic and translational disease research across the group, together with industry, medical research foundations, charities and patient groups, by pooling expertise and driving progress to benefit patients. We outline the germline and somatic mutations in the mTOR pathway that cause rare diseases and summarise the prevalence, genetic basis, clinical manifestations, pathophysiology and current treatments for each disease in this group. We describe the challenges and opportunities for progress in elucidating the underlying mechanisms, improving diagnosis and prognosis, as well as the development and approval of new therapies for mTOR pathway diseases. We illustrate the crucial role of patient public involvement and engagement in rare disease and mTOR pathway disease research. Finally, we explain how the mTOR Pathway Diseases node, part of the Research Disease Research UK Platform, will address these challenges to improve the understanding, diagnosis and treatment of mTOR pathway diseases.

[19] Novel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms

  • Authors: M. Yabumoto, Jessica Kianmahd, Meghna Singh, Maria F. Palafox, Angela Wei et al.
  • Year: 2021
  • Venue: Molecular Genetics & Genomic Medicine
  • URL: https://www.semanticscholar.org/paper/3a47a1b1208ba7420900b090d3d7d712ed391719
  • DOI: 10.1002/mgg3.1809
  • PMID: 34519438
  • PMCID: 8580094
  • Citations: 12
  • Influential citations: 2
  • Summary: A range of features previously described for KAT6B‐related syndromes are identified, including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported.
  • Evidence snippets:
  • Snippet 1 (score: 0.380) > Finally, as gene-centric models of disease have started to take hold, understanding the underlying functional mechanisms that are affected can help us elucidate the effect on molecular and cellular phenotypes that are regulated by KAT6B (Klein et al., 2019;Sheikh et al., 2012). We developed a model of KAT6B truncating variants in a human cell line to explore how these variants result in differential regulation of key transcripts. These types of approaches have been performed in a high throughput manner for tumor suppressor genes like BRCA1 (Findlay et al., 2018) and TP53 (Kotler et al., 2018) and can help identify key pathways that are dysregulated by KAT6B-related disorders and could be future targets for translational research. > Here, we analyze 20 clinical cases representing a KAT6B-related clinical spectrum across three domains: their genotype, phenotype, and experience with genetic counseling resources. Furthermore, we developed an in vitro model of KAT6B mutations using CRISPR technology to explore the effect of protein truncation on global transcriptional regulation. Here we demonstrate that the genes that drive core clinical phenotypes are enriched in our in vitro model system. Together, we show that our clinical observations parallel the transcriptional processes in our cell model systems which allow for a further understanding of the mechanisms underlying the KAT6Brelated clinical spectrum.

Notes

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