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Hereditary Orotic Aciduria

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Hereditary Orotic Aciduria. Core disease mechanisms, molecular and cellula...

2026-05-11
Asta MONDO:0009797 Model: Asta Scientific Corpus Retrieval 19 citations

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Hereditary Orotic Aciduria. Core disease mechanisms, molecular and cellula...

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

  • Papers retrieved: 19
  • Snippets retrieved: 20

Relevant Papers

[1] Hereditary orotic aciduria identified by newborn screening

  • Authors: O. Staretz-Chacham, N. Damseh, Suha Daas, Nasser Abu Salah, Y. Anikster et al.
  • Year: 2023
  • Venue: Frontiers in Genetics
  • URL: https://www.semanticscholar.org/paper/e81125b819be0480c6e75eb676313877af9f1385
  • DOI: 10.3389/fgene.2023.1135267
  • PMID: 36999056
  • PMCID: 10043439
  • Citations: 1
  • Summary: Newborn screening measuring of orotic acid, now integrated into the routine tandem mass spectrometry panel, is capable of identifying neonates with hereditary orotIC aciduria, and identifies ten Muslim Arab newborns that remain asymptomatic so far.
  • Evidence snippets:
  • Snippet 1 (score: 0.569) > The purpose of newborn screening (NBS) is to identify newborns affected with diseases in which early diagnosis and prompt treatment will significantly change disease outcome (Jones and Bennett, 2002). Methionine and tyrosine as primary targets for core disorders in routine NBS have led to identification of secondary diagnoses such as hypermethioninemia (Couce et al., 2013) and transient tyrosinemia of the newborn (Adnan and Puranik, 2022). The addition of orotic acid analysis to our NBS Program in 2014 has been successful in the identification of a number of patients affected with urea cycle disorders (UCD) (Staretz-Chacham et al., 2021), as well as in identification of ten newborns with hereditary orotic aciduria. The introduction of expanded newborn screening has led to the identification of previously unrecognized, non-disease-causing variants of devastating disorders such as isovaleric acidemia (Ensenauer et al., 2004) and MCAD deficiency (Andresen et al., 2001). Herein, we report an analysis done in a cohort of patients identified by the NBS program with hereditary orotic aciduria based on increased orotic acid levels in DBS followed by confirmatory testing including urinary organic acids and molecular testing. To this day, no treatment has been administered to these patients, and all patients remain asymptomatic. > Hereditary orotic aciduria is an extremely rare condition with fewer than 30 cases reported in the literature. If left untreated, it may result in refractory megaloblastic anemia, neurodevelopmental disabilities, and crystalluria. > To the best of our knowledge, all individuals with hereditary orotic aciduria were reported to carry at least one missense variant allele, while no reports are available presenting affected individuals harboring bi-allelic null variants which are predicted to cause complete loss of UMPS protein function (Rogers et al., 1975;Wortmann et al., 2017). On the other hand, carrier individuals of null or missense variant may have persistent mild increase of urinary orotic acid secretion, lower than expected in OTC.
  • Snippet 2 (score: 0.454) > In additional, orotic aciduria with subsequent orotate crystalluria has occasionally resulted in urinary obstruction in affected individuals later in life (Bailey, 2009). The most recent case reported was a 17-year-old Emirati girl born to a consanguineous couple reported to have a complicated medical history since early infancy. She presented with unexplained megaloblastic bone marrow, immunodeficiency in form of recurrent infections, epilepsy, developmental delay and crystalluria. The patient showed clinical, hematologic, and biochemical improvement after being treated with uridine triacetate (Al Absi et al., 2021). > Three subtypes of hereditary orotic aciduria have been reported in the literature, all caused by deficiencies in UMPS. Subtype I involves a defect of both OPRT and ODC functions, and subtype II involves a defect in ODC only (Fox et al., 1973). These two biochemical subtypes are clinically indistinguishable, both presenting with megaloblastic anemia, orotic aciduria, and growth and developmental abnormalities (Fox et al., 1973). In contrast, subtype III, resulting also from a biochemical defect in ODC, has been reported in only 2 cases, which presented with orotic aciduria but without megaloblastic anemia (OAWA). Since the report of these cases was prior to the molecular era, these two cases may be simply carriers for the disease (Tubergen et al., 1969;Bailey, 2009;Wortmann et al., 2017). In addition, heterozygosity for UMPS variants was recently found to be associated with mild asymptomatic orotic aciduria [OMIM#258900] (Robinson et al., 1984;Wortmann et al., 2017). > Since 2014, and as part of the expanded newborn screening (NBS) program in Israel, orotic acid, and citrulline have been measured in dried blood spots (DBS) for the detection of ornithine transcarbamylase deficiency (OTCD) as a core condition (Staretz-Chacham et al., 2021).

[2] Ribosomopathies: Global process, tissue specific defects

  • Authors: P. Yelick, P. Trainor
  • Year: 2015
  • Venue: Rare Diseases
  • URL: https://www.semanticscholar.org/paper/6af0ef43af428c571b568c38e1a98fa3ed9191bf
  • DOI: 10.1080/21675511.2015.1025185
  • PMID: 26442198
  • PMCID: 4590025
  • Citations: 108
  • Influential citations: 6
  • Summary: This seemingly contradictory finding that globally expressed genes thought to play fundamental housekeeping functions can in fact exhibit tissue and cell type specific functions provides new insight into roles for ribosomes, the protein translational machinery of the cell, in regulating normal development and disease.
  • Evidence snippets:
  • Snippet 1 (score: 0.490) > As mentioned, a deficiency of the next enzyme in the pyrimidine synthesis pathway causes orotic aciduria, which has the classic features one might expect from a reduced amount of pyrimidines, megaloblastic anemia. Orotic aciduria can be effectively treated with uridine, clearly demonstrating that the lack of pyrimidines are driving the disease state. But if POADS is a consequence of reduced amounts of pyrimidines, which in turn affects ribosome synthesis, it doesn't explain why individuals with POADS don't have megaloblastic anemia, or alternatively why individuals with orotic aciduria don't have skeletal deformations. Together, these data suggest that that the underlying basis for POADS may not be restricted to pyrimidine synthesis, and that further biochemical and cellular analyses in suitable animal studies are needed to fully elucidate the molecular mechanisms underlying the POADS phenotype.

[3] Organic acidurias: Major gaps, new challenges, and a yet unfulfilled promise

  • Authors: Bianca Dimitrov, F. Molema, Monique Williams, J. Schmiesing, C. Mühlhausen et al.
  • Year: 2020
  • Venue: Journal of Inherited Metabolic Disease
  • URL: https://www.semanticscholar.org/paper/81262738de4b81f402ac049442e779462a49c991
  • DOI: 10.1002/jimd.12254
  • PMID: 32412122
  • Citations: 42
  • Summary: New insights might bridge the gap between natural history and pathophysiology in OADs, and their exploitation for the development of targeted therapies seems promising.
  • Evidence snippets:
  • Snippet 1 (score: 0.459) > Organic acidurias (OADs) comprise a biochemically defined group of inherited metabolic diseases. Increasing awareness, reliable diagnostic work‐up, newborn screening programs for some OADs, optimized neonatal and intensive care, and the development of evidence‐based recommendations have improved neonatal survival and short‐term outcome of affected individuals. However, chronic progression of organ dysfunction in an aging patient population cannot be reliably prevented with traditional therapeutic measures. Evidence is increasing that disease progression might be best explained by mitochondrial dysfunction. Previous studies have demonstrated that some toxic metabolites target mitochondrial proteins inducing synergistic bioenergetic impairment. Although these potentially reversible mechanisms help to understand the development of acute metabolic decompensations during catabolic state, they currently cannot completely explain disease progression with age. Recent studies identified unbalanced autophagy as a novel mechanism in the renal pathology of methylmalonic aciduria, resulting in impaired quality control of organelles, mitochondrial aging and, subsequently, progressive organ dysfunction. In addition, the discovery of post‐translational short‐chain lysine acylation of histones and mitochondrial enzymes helps to understand how intracellular key metabolites modulate gene expression and enzyme function. While acylation is considered an important mechanism for metabolic adaptation, the chronic accumulation of potential substrates of short‐chain lysine acylation in inherited metabolic diseases might exert the opposite effect, in the long run. Recently, changed glutarylation patterns of mitochondrial proteins have been demonstrated in glutaric aciduria type 1. These new insights might bridge the gap between natural history and pathophysiology in OADs, and their exploitation for the development of targeted therapies seems promising.

[4] Mitochondrial disease, mitophagy, and cellular distress in methylmalonic acidemia

  • Authors: A. Luciani, M. Denley, Larissa P. Govers, Vincenzo Sorrentino, D. Froese
  • Year: 2021
  • Venue: Cellular and Molecular Life Sciences: CMLS
  • URL: https://www.semanticscholar.org/paper/70cd3e00628c13d54fe63c3fa68a6391a3437fe0
  • DOI: 10.1007/s00018-021-03934-3
  • PMID: 34524466
  • PMCID: 8558192
  • Citations: 30
  • Summary: Using methylmalonic acidemia as a paradigm of complex mitochondrial dysfunction, this Review discusses how mitochondrial directed-signaling circuitries govern the homeostasis and physiology of specialized cell types and how these may be disturbed in disease.
  • Evidence snippets:
  • Snippet 1 (score: 0.433) > Given the crucial roles of the mitochondrial network in cellular energy production and homeostasis, it is not surprising that disorders which disrupt mitochondrial function are of grave consequence to the individual. When inherited, these disorders are often classified as primary or secondary mitochondrial diseases. Primary mitochondrial diseases include inherited disorders that disrupt OXPHOS or mitochondrial structure and function, such as abnormalities in the production of cofactors and vitamins, or other alterations in the TCA cycle and pyruvate metabolism [73]. Of the 1500 proteins estimated to participate in mitochondrial function and maintenance, nearly 400 have been reported to cause primary mitochondrial disease [74], including all 37 mitochondrial encoded genes. Altogether, primary mitochondrial disorders affect approximately 1:4300 births [75]. > The heterogeneity of the processes disturbed by primary mitochondrial disorders is reflected by the phenotypic variability of the patients, in terms of tissues and organs affected, as well as by age of onset and presenting symptoms [73,74]. Patients may exhibit manifestations in almost any tissue or organ, in a multi-systemic or tissue-specific manner, from the first days to weeks of life until after several decades [76]. Nevertheless, along with lactic acidosis, frequently identified symptoms involve encephalopathy, cardiomyopathy, renal insufficiency, and liver failure [73,74] (Fig. 2). Clinical features in these disorders have been expertly reviewed elsewhere [74,77]. > A considerable body of evidence suggests that the mitochondrial stress responses triggered by a primary molecular defect in the organelle, and not defects of OXPHOS per se, are the major contributing factor to the clinical and biochemical features of mitochondrial disorders [3]. Such mechanisms, including the UPR mt , are likely to be activated by secondary mitochondrial diseases-i.e., disorders of genes/ proteins not directly involved in OXPHOS or mitochondrial integrity, but which may indirectly compromise these essential processes through toxic metabolites or missing products. > A prototypical group of secondary mitochondrial disorders are the organic acidurias, a collection of diseases including branched-chain ketoaciduria, isovaleric aciduria, propionic aciduria and methylmalonic aciduria (MMA), whose disrupted pathways take place within the mitochondria [78].

[5] Hyper-IgD syndrome/mevalonate kinase deficiency: what is new?

  • Authors: C. Mulders-Manders, A. Simon
  • Year: 2015
  • Venue: Seminars in Immunopathology
  • URL: https://www.semanticscholar.org/paper/b0c6a9943fcdf22c8aece6bd26c62c9c7e9d31f7
  • DOI: 10.1007/s00281-015-0492-6
  • PMID: 25990874
  • PMCID: 4491100
  • Citations: 57
  • Influential citations: 2
  • Summary: New findings in this disorder that have been published in the last 2 years are discussed, including new insights into pathophysiology, treatment, and the clinical phenotype linked to the genetic defect.
  • Evidence snippets:
  • Snippet 1 (score: 0.421) > valonate aciduria, a severe disease characterized by neurologic involvement with psychomotor retardation, cerebellar ataxia, and facial dysmorphy besides the inflammatory symptoms, leading to early death. MKD forms a continuous spectrum of disease between these two clinical entities. Overlapping clinical syndromes are seen with increasing frequency. As there is no clear border between phenotypes, we will use the term mevalonate kinase deficiency, which encompasses both HIDS and mevalonate aciduria, to describe the disease in this paper. > In this review, we will discuss new findings in MKD that have been published between January 1, 2012 and December 31, 2014. > What is new on the pathophysiological mechanism of MKD? > In the past 30 years, MKD has been proven to be a typical monogenetic autoinflammatory disease with overproduction This article is a contribution to the Special Issue on The Inflammasome and Autoinflammatory Diseases -Guest Editors: Seth L. Masters, Tilmann Kallinich and Seza Ozen of the inflammatory cytokine interleukin-1 beta (IL-1β) as prominent pathophysiological mechanism [3][4][5][6][7]. The importance of this cytokine in MKD is backed up by the beneficial effects of IL-1β-targeting drugs such as anakinra in patients with this disease [8][9][10][11]. > Most studies on the pathophysiology of MKD are based on in vitro cellular models with murine [12][13][14] or human cells with drug-induced block of the mevalonate kinase pathway w i t h e i t h e r H M G -C o A r e d u c t a s e i n h i b i t o r s o r bisphosphonates (Fig. 1). In these models, LPS or other bacterial components are used to mimic the inflammatory stimulus needed for the production of IL-1β. Stimulation of monocytes with LPS leads to increased pro-IL-1β transcription via activation of transcription factor NF-kB [5]. The effects of bisphosphonates

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

  • Authors: Arnab Mukherjee, S. Abraham, Akshita Singh, S. Balaji, K. Mukunthan
  • Year: 2024
  • Venue: Molecular Biotechnology
  • URL: https://www.semanticscholar.org/paper/04593d2268ccd7c26b5296d8342b468ca84ae7b1
  • DOI: 10.1007/s12033-024-01133-6
  • PMID: 38565775
  • PMCID: 11928429
  • Citations: 74
  • Influential citations: 2
  • Summary: This review navigates the expansive omics landscape, showcasing tailored assays for each molecular layer through genomes to metabolomes, and aims to illuminate the transformative impact of multi-omics in the big data era, shaping the future of biological research.
  • Evidence snippets:
  • Snippet 1 (score: 0.401) > Biological processes and molecular functions arise from intricate interactions among thousands of molecules, constituting inherent complexity. Integration of metabolomics data with other omics data holds significant promise for achieving a holistic understanding of disease mechanisms. Metabolomics, which focuses on the comprehensive analysis of small molecule metabolites within biological systems, provides unique insights into the functional status and metabolic phenotypes associated with various physiological and pathological conditions [160,161]. The integration of omics datasets with computational models and network analysis tools elucidates the complex interplay between genes, proteins, metabolites, and cellular processes underlying disease phenotypes. > Despite recent progress in omics technologies, the underlying genetic factors contributing to numerous metabolic phenotypes remain elusive. Metabolite biomarkers can be integrated with genomics and clinical parameters to enhance diagnostic accuracy or refine disease risk prediction models. Metabolites can also serve as intermediate phenotypes for genetic investigations, offering insights into underlying genetic mechanisms [162]. The integration of metabolomics data with either whole-exome sequencing or WGS-data presents a promising systematic strategy for pinpointing disease-causing variants and holds potential utility within the framework of a specific pathway under investigation [163]. Furthermore, at a more intricate biological and analytical level, metabolomics can be combined with various omic platforms, facilitating a comprehensive understanding of complex biological systems and interactions (Fig. 4). > The alterations in metabolite levels, perturbations in metabolic pathways, and the onset of disease states can be elucidated by assessing the epigenetic alterations. This approach offers molecular insights into the intricate interplay among genetic, epigenetic, and metabolic factors during the disease progression. Through the integration of epigenomic Fig. 4 The workflow for integration of metabolomics with other omics for a holistic understanding of disease progression and metabolomic data, the intricate relationships between epigenetic alterations and metabolic pathways in disease pathogenesis can be uncovered. In recent years, metabolomics and epigenomics have experienced notable advancement as prominent molecular and analytical methodologies for biomarker identification [164,165].

[7] New therapeutic targets in rare genetic skeletal diseases

  • Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
  • Year: 2015
  • Venue: Expert Opinion on Orphan Drugs
  • URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
  • DOI: 10.1517/21678707.2015.1083853
  • PMID: 26635999
  • PMCID: 4643203
  • Citations: 38
  • 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.

[8] Mitochondrial transplantation as a promising therapy for mitochondrial diseases

  • Authors: Tian-Guang Zhang, Chaoyu Miao
  • Year: 2022
  • Venue: Acta Pharmaceutica Sinica. B
  • URL: https://www.semanticscholar.org/paper/72802097939b0bffc319c93d05128d7e3160e0eb
  • DOI: 10.1016/j.apsb.2022.10.008
  • PMID: 36970208
  • PMCID: 10031255
  • Citations: 85
  • Influential citations: 1
  • Summary: Different techniques used in mitochondrial isolation and delivery, mechanisms of mitochondrial internalization and consequences of mitochondrial transplantation, along with challenges for clinical application are presented.
  • Evidence snippets:
  • Snippet 1 (score: 0.389) > Mitochondria, the vital organelles of eukaryotic cells, are integrators of various cellular metabolic pathways, including oxidative phosphorylation, fatty acid oxidation, urea cycle, Krebs cycle, ketogenesis and gluconeogenesis 1 . Mitochondria are also important in many other essential cellular processes such as calcium homeostasis, lipid metabolism, amino acid metabolism, biosynthesis of heme, and thermogenesis 2 . However, they also have important roles in many pathways which can cause both apoptosis and necrosis 3 . Therefore, the importance of the mitochondrion in the maintenance of cellular homeostasis is well established, meanwhile a large amount of evidence shows that mitochondrial dysfunction is deleterious 4 . > Due to the essential function of mitochondria in the human body, mitochondrial dysfunction causes a great variety of mitochondrial diseases, which can affect almost all the organs in the body and present at any age 4,5 . Mitochondrial diseases are a group of metabolic disorders characterized by energy metabolism dysfunction. The pathophysiology is further complicated by the involvement of genetic mutations in nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) which encode mitochondrial proteins. This means that mitochondrial diseases may result from inheritance for nDNA mutations and maternal inheritance for mtDNA mutations. The estimated minimum prevalence of mitochondrial diseases is 1 in 5000, whereas it could be higher 6 . > As advances in molecular and biochemical methodologies led to a better understanding of the mechanisms of mitochondrial disorders for various diseases, mitochondria have become a major target for research institutions and pharma companies. Pharmacological approaches include dietary supplements such as agents increasing respiratory chain function (coenzyme Q10 and riboflavin), agents inducing mitochondrial biogenesis (AICAR and bezafibrate), antioxidants (vitamin C and vitamin E), mitochondrial substrates (L-carnitine) and so on 7,8 . However, these agents fail to significantly alleviate disease symptoms or effectively slow disease progressions, there has therefore been no satisfactory therapeutic strategy available for mitochondrial diseases so far 9 . In addition, all new drugs under clinical trials for treatment of mitochondrial diseases are unable to cure these diseases permanently 9 .

[9] Respiratory manifestations in patients with inherited metabolic diseases

  • Authors: F. Santamaria, S. Montella, V. Mirra, S. De Stefano, G. Andria et al.
  • Year: 2013
  • Venue: European Respiratory Review
  • URL: https://www.semanticscholar.org/paper/f84e5324a6ba3db2c3248567ee91d5edbcdb3219
  • DOI: 10.1183/09059180.00008012
  • PMID: 24293461
  • PMCID: 9639176
  • Citations: 24
  • Influential citations: 3
  • Summary: This review will describe the most exemplary respiratory manifestations of inherited metabolic diseases in childhood and adulthood and suggest the most appropriate care to children and adults with inherited metabolic disease.
  • Evidence snippets:
  • Snippet 1 (score: 0.389) > Approximately 400 human diseases due to inborn errors of metabolism are recognised. This number is increasing as novel techniques become available and allow for the identification of new biochemical and molecular abnormalities [1]. The vast majority of inherited metabolic diseases are caused by enzymes and transport protein abnormalities. > Because most inherited metabolic diseases are systemic, virtually all organs may be involved. During the past decades, research has expanded and multidisciplinary efforts by several specialists have succeeded in defining the complex phenotype [2]. Many disorders cause respiratory disease, which is often not immediately associated with inherited metabolic disease. Regrettably, the literature mainly describes anecdotal cases or small series reports. > Respiratory manifestations are part of the clinical picture of several inherited metabolic diseases, either at presentation or as late-onset features. Laryngeal stridor was reported as a leading presentation of biotinidase deficiency [3]. Polypnoea is a frequent neonatal feature of congenital lactic acidoses [2]. Interstitial lung disease (ILD) and pulmonary hypertension are by far the most frequently described complications in lysosomal storage disorders. Pulmonary hypertension may be seen in non-ketotic hyperglycaemia [4], and was described in glycogenoses type I [5,6], inborn errors of intracellular cobalamin metabolism [7], HUPRA (hyperuricaemia, pulmonary hypertension, renal failure and alkalosis) syndrome and in Wolman disease [8,9]. Several inherited metabolic diseases involve nervous or neuromuscular systems, are usually progressive, and often cause chronic airway aspiration and respiratory infections. This is the case of some organic acidaemia [10,11] and of several mitochondrial disorders [12]. Immune defects, such as chronic neutropenia or lymphocyte impairment, are described in some inherited metabolic diseases (glycogenosis Ib and hereditary orotic aciduria), and may explain the development of marked susceptibility to airway infections [13,14]. Inherited metabolic disorders with neurological involvement leading to severe disability can be associated with progressive chest and spine deformities, which predispose to respiratory insufficiency as a consequence of mechanical impairment.

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

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

[11] Insights into energy balance dysregulation from a mouse model of methylmalonic aciduria

  • Authors: Marie Lucienne, R. Gerlini, B. Rathkolb, J. Calzada-Wack, P. Forny et al.
  • Year: 2021
  • Venue: Human Molecular Genetics
  • URL: https://www.semanticscholar.org/paper/39122c688b326a3f749ea82f1c47f5cbfa7a0bb8
  • DOI: 10.1093/hmg/ddad100
  • PMID: 37369025
  • PMCID: 10460489
  • Citations: 3
  • Summary: It is found Mmut mutant mice to have reduced appetite, energy expenditure and body mass compared to littermate controls, along with a relative reduction in lean mass but increase in fat mass, which indicates hypometabolism, energetic inflexibility and increased stores at the expense of active tissue as energy shortage consequences.
  • Evidence snippets:
  • Snippet 1 (score: 0.381) > Together, these primary and secondary disease mechanisms lead to a complex clinical picture characterized by a failure to thrive and acute crises, often triggered by a catabolic state, and by chronic progression with long-term complications in the kidney, brain and liver (7)(8)(9). > Clinical management of patients with methylmalonic aciduria is performed through pharmacological and dietary regimens that aim at keeping patients in an anabolic state, while limiting ingestion of precursor amino acids, and by replacing missing or potentially helpful molecules such as carnitine (7). Nevertheless, many long-term complications are progressive and patients remain metabolically unstable (7,8), suggesting that the energetic and metabolic needs of affected individuals are not fully met by these symptomatic treatments. A likely explanation is that affected individuals have an incomplete or maladaptive response to chronic energy shortage that is not addressed by current measures. > It was our hypothesis that the long-term complications in methylmalonic aciduria might relate to chronic energy shortage. To investigate this, we have performed an in-depth whole animal metabolic phenotyping in a hemizygous mouse model of methylmalonic aciduria. This model combines a knock-in (ki) allele based on the MMUT-p.Met700Lys patient missense mutation with a knock-out (ko) allele of the same gene (Mmut-ko/ki) (10). It has the advantage of circumventing the neonatal lethality of Mmut-ko/ko null mutants (10,11) and displays a strong metabolic phenotype accompanied by many clinical features of methylmalonic aciduria including a pronounced failure to thrive, which are strengthened when challenged with a 51%-protein diet from day 12 of life (12). Here, we interrogated metabolic adaptations from the whole animal to the molecular level, using body composition analysis, indirect calorimetry, blood biochemistry, histological analysis and transcriptomics.

[12] Modifier variants in metabolic pathways are associated with an increased penetrance of Leber’s Hereditary Optic Neuropathy

  • Authors: Eszter Sara Arany, Catarina Olimpio, I. Paramonov, R. Horváth
  • Year: 2025
  • Venue: European Journal of Human Genetics
  • URL: https://www.semanticscholar.org/paper/3359897a8293b6ab2fc62e2d7580a86affa58dee
  • DOI: 10.1038/s41431-025-01860-7
  • PMID: 40346165
  • PMCID: 12859036
  • Citations: 1
  • Summary: Understanding of LHON’s pathophysiology is deepened and a new framework for identifying novel disease-modifying targets is provided, proposing that in addition to the primary mitochondrial variants, disruption in these nuclear-encoded pathways drives the clinical manifestation of LHON.
  • Evidence snippets:
  • Snippet 1 (score: 0.374) > Leber’s hereditary optic neuropathy (LHON) is a debilitating mitochondrial disease characterised by bilateral painless vision loss. Despite being the most prevalent mitochondrial disorder, the precise pathophysiological mechanisms underlying the penetrance of LHON remain poorly understood. Nuclear modifier genes have been long suspected to affect phenotype-severity, however, specific cellular pathways implicated in the disease penetrance have been only suggested recently. In recent years, autosomal recessive variants in nuclear genes involved in complex I function and metabolic pathways were recognised to cause a typical LHON phenotype. This was proposed as a new autosomal recessive disease mechanism for LHON (arLHON). The association between nuclear variants and the LHON phenotype makes the nuclear pathways disrupted in arLHON the strongest candidates to act as modifiers of mitochondrial LHON (mLHON). In this study we systematically investigated a large cohort of 23 symptomatic and 28 asymptomatic individuals carrying one of the three primary mitochondrial LHON variants. We identified several heterozygous pathogenic nuclear variants amongst the affected individuals that were consistently linked to metabolic and complex I related pathways, mirroring those disrupted in arLHON. Our findings are consistent with the presence of a second hit in specific biological pathways impairing ATP production. We propose that in addition to the primary mitochondrial variants, disruption in these nuclear-encoded pathways drives the clinical manifestation of LHON. Genes involved in the same pathways also emerge as exciting candidates for future association with arLHON. The present study deepens our understanding of LHON’s pathophysiology and provides a new framework for identifying novel disease-modifying targets.

[13] Long-term neurological outcome of a cohort of 80 patients with classical organic acidurias

  • Authors: Mathilde Nizon, C. Ottolenghi, V. Valayannopoulos, J. Arnoux, V. Barbier et al.
  • Year: 2013
  • Venue: Orphanet Journal of Rare Diseases
  • URL: https://www.semanticscholar.org/paper/606948019911e2a964d1ed4c2ec030ca2291ef10
  • DOI: 10.1186/1750-1172-8-148
  • PMID: 24059531
  • PMCID: 4016503
  • Citations: 81
  • Influential citations: 2
  • Summary: Propionic aciduria had the most severe neurological prognosis and radiological and biochemical data are consistent with a mitochondrial toxicity mechanism, calling for greater efforts to optimize long-term management in these patients.
  • Evidence snippets:
  • Snippet 1 (score: 0.374) > Reports are increasing of long-term complications, such as neurological disorders by degeneration of the basal ganglia, progressive renal failure in MMA, cardiomyopathy in PA and acute pancreatitis in all [3][4][5]. > Specific changes in the levels of urinary and plasma metabolites are the hallmark of the classical forms of the diseases including ketoacidosis, hyperlactatemia, hyperamoniemia, cytopenia in variable proportions. In urine, several organic acids are quite specific for diagnosis, particularly 3-hydroxypropionate and methylcitrate in PA, methylmalonate in MMA and isovalerylglycine in IVA. Enzymatic and genetic analyses confirm the diagnosis. > The pathophysiology of these disorders is not clearly understood and the proposed mechanisms are complex. Metabolite accumulation upstream of the enzymatic block triggers a systemic endogenous intoxication. Furthermore, the metabolic pathway involved in classical organic acidurias contributes to acetyl-coA and succinyl-coA formation, which are required for the tricarboxylic acid cycle. Thus, there is an energetic deficit by mitochondrial dysfunction secondary to substrate insufficiency and specific toxic metabolite accumulation including 3-hydroxypropionate [1]. > The long-term neurological prognosis of these disorders depends on the severity of the disease, the delay of diagnosis and probably specific biochemical and genetic parameters. In particular, several studies attempting the delay to describe the neurological evolution of organic acidurias were hampered by the wide phenotypic variability even in a homogenous genetic population [6]. In order to better delineate the long-term neurological outcome of patients with organic acidurias, we analyzed clinical, radiological, biochemical and genetic parameters of a large cohort of patients.

[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: 30
  • 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: 0.373) > 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] Pathway Reconstruction of Airway Remodeling in Chronic Lung Diseases: A Systems Biology Approach

  • Authors: A. Najafi, A. Masoudi-Nejad, M. Ghanei, M. Nourani, A. Moeini
  • Year: 2014
  • Venue: PLoS ONE
  • URL: https://www.semanticscholar.org/paper/26a4b3b5d38bf3c2dc7b7fc076b0da90bf9845b6
  • DOI: 10.1371/journal.pone.0100094
  • PMID: 24978043
  • PMCID: 4076832
  • Citations: 13
  • Summary: Reconstructing the airway remodeling interactome provides a starting point and reference for the future experimental study of mustard lung, and further analysis and development of these maps will be critical to understanding airway diseases in patients.
  • Evidence snippets:
  • Snippet 1 (score: 0.373) > Our findings demonstrate that the analysis and modeling of complex biological networks are beyond the capabilities of existing computational techniques that are needed for this type of scientific endeavor. Therefore, manual curation and pathway reconstruction was followed after computational results. Current diagnosis of the airway remodeling diseases, in particular mustard lung and COPD, is mainly based on a combination of lung function evaluation and an observation of symptoms. There is no sole and exact clinical or laboratory test available. This highlights the need for biomarkers to diagnose disease or identify disease phenotypes. Therefore, the identification of key candidate genes, and their roles in regulating pathways, shows the need for bringing systems biology to the clinic as a powerful new approach. TFF3, ERBB2, EPAS1, and COL7A1 are the candidate factors identified here as potentially centrally involved in the pathophysiology of airway remodeling in mustard lung. The regulation of these proteins may be potentially useful in the treatment of airway remodeling. Finally, a comprehensive understanding of biological pathways can aid in the development of drugs to target specific cellular mechanisms while avoiding unwanted side effects.

[16] Clinical Practice Guidelines for the Management of Atypical Hemolytic Uremic Syndrome in Korea

  • Authors: H. Cheong, S. Jo, S. Yoon, Heeyeon Cho, Jin Seok Kim et al.
  • Year: 2016
  • Venue: Journal of Korean Medical Science
  • URL: https://www.semanticscholar.org/paper/76cd0448de3ff006a1b4440acf6d526885b08eba
  • DOI: 10.3346/jkms.2016.31.10.1516
  • PMID: 27550478
  • PMCID: 4999392
  • Citations: 26
  • Influential citations: 1
  • Summary: These guidelines aim to offer recommendations for the diagnosis and treatment of patients with aHUS in Korea and have largely been adopted from the current guidelines due to the lack of evidence concerning the Korean population.
  • Evidence snippets:
  • Snippet 1 (score: 0.372) > Complement-mediated aHUS aHUS is caused by complement dysregulation. An alternative complement pathway is constitutively activated and tightly regulated in normal conditions by multiple regulators to prevent damage to the endothelium and platelets. However, uncontrolled and excessive activation of this pathway, mostly due to genetic mutations or autoantibodies against numerous regulator proteins in the complement system, occurs in patients with aHUS and causes various clinical manifestations (24,37). The complement cascade can cause lysis of target cells by forming a pore in the cell membrane. Failure of normal control mechanisms to downregulate the alternative pathway may cause endothelial damage. Complement activation triggers several inflammatory responses. Endothelial cells express complement receptors; (43). TMA has been reported in individuals with mutations in the gene encoding methylmalonic aciduria and homocystinuria type C (MMACHC) (44). Homozygosity or compound heterozygosity appears to be required for clinical disease. MMACHC is involved in cobalamin (vitamin B12) metabolism. Infants with cobalamin C disease, a type of methylmalonic acidemia, present with various neurologic and developmental findings. The patients show markedly elevated plasma homocysteine levels, but plasma cobalamin levels are normal. Hyperhomocystein-emia-induced damage to glomerular endothelium has been suggested as the putative mechanism for aHUS (45). Complete responses of this TMA to the accessible and inexpensive therapy with high-dose cobalamin and folinic acid have been reported. Evaluation of these abnormalities in cobalamin metabolism is available by measuring serum homocysteine and methylmalonic acid levels. > Drug-induced TMA (DITMA) has been reported following exposure to several types of drugs, especially those containing quinine. Drug-induced antibodies reactive with endothelial cells and possibly margination of granulocytes in renal glomeruli may be responsible for aHUS (46).

[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: 0.371) > : 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] The Strange Case of Orotic Acid: The Different Expression of Pyrimidines Biosynthesis in Healthy Males and Females

  • Authors: Francesco Chiara, S. Allegra, J. Mula, M. P. Puccinelli, Giuliana Abbadessa et al.
  • Year: 2023
  • Venue: Journal of Personalized Medicine
  • URL: https://www.semanticscholar.org/paper/3edc1179162332e652c36a5963414b11eb0ef896
  • DOI: 10.3390/jpm13101443
  • PMID: 37888054
  • PMCID: 10608620
  • Citations: 4
  • Summary: The LC-MS/MS method was suitable for use in the differential diagnosis of hereditary metabolic disease and metabolic monitoring of anticancer drug-induced toxicity and the analytical protocol was found to be rapid and ideal, and was used in the routine analysis of a clinical chemistry laboratory.
  • Evidence snippets:
  • Snippet 1 (score: 0.371) > Orotic acid (OA) (2,4-dioxo-1H-pyrimidine-6-carboxylic acid; vitamin B13) is an intermediate metabolite of pyrimidine nucleotide biosynthesis and represents a minor diet constituent. The precursors of OA in human metabolism are the cytosolic CP and CA via dihydroorotate, a biosynthesis catalyzed by a CAD gene encoding multifunctional enzyme [1,2]. The multimeric protein called UMP synthase is constituted by two domains that catalyze UMP synthesis: OPRTase (EC 2.4.2.10) and OMPdecase (EC 4.1.1.23) [3]. The complete pathway of OA biosynthesis is reported in Figure 1. The step (5), represented in Figure 1, is directly involved in the metabolism of 5-FU because this anticancer drug is a competitive substrate of OPRTase [4]. In particular, the transferase activity of OPRTase multicomplex enzyme is inhibited by 5-FU at 59% level of control [5]. On the other hand, OPRTase is involved in a variety of metabolic disorders, such as congenital orotic aciduria. Consequently, the urinary OA is quantified in a clinical routine analysis for a differential diagnosis of hereditary metabolic diseases [6][7][8]. > ganic or clinically detectable adaptations. > The determination of OA in urine has been the subject of attention by clini atories, specifically when the phenotypic evidence of OA becomes part of genetic The classes of hereditary pathologies linked to an accumulation of OA are those cern the biosynthesis defects of creatine, the metabolism of pyrimidines and the d the urea cycle (Figure 1).

[19] 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: 0.369) > 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.

Notes

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