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Biomarkers in Rare Diseases 3.0
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Biomarkers in Rare Diseases 3.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 25 May 2024 | Viewed by 8074

Special Issue Editor

Dr. Bridget E. Bax

E-Mail Website
Guest Editor
Molecular and Clinical Sciences, St. George’s, University of London, London SW17 0RE, UK
Interests: MNGIE; EE-TP; rare diseases; cell therapies
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The definition of a rare disease in the European Union is a disease that affects fewer than 1 in 2000 individuals within the general population. There are over 7000 known rare diseases, and new conditions are regularly reported in the literature. However, for most of these conditions, there are no specific therapies whose effectiveness has been evidenced in clinical trial studies.

Clinical trials of investigational therapies require validated endpoint measures to assess the way a patient feels, functions, or survives and, subsequently, the efficacy of treatment. Designing clinical trials for rare diseases presents considerable challenges due to small patient populations, phenotypic heterogeneity, incomplete knowledge of the disease pathophysiology or natural history, and an absence of prior clinical studies. Consequently, the selection of clinical trial endpoints can be an arduous process, particularly as validated endpoints appropriate for the disease are often unavailable.

Distinct biomarkers are often detected in rare diseases, and these have the potential to provide an invaluable tool for monitoring disease progression, prognosis, and response to drug treatment and to ultimately accelerate the discovery of therapeutics for rare diseases. To expedite the development of drugs for rare disorders, regulatory agencies have endorsed the need for flexibility in the review process and may consider approving a therapy based on a surrogate endpoint or biomarker, as these may provide a better predictor of treatment efficacy compared with approved clinical endpoints employed for more common disorders.

For this Special Issue titled “Biomarkers in Rare Diseases 3.0”, we continue looking for original research articles and state-of-the-art reviews on novel or established proteomic, metabolomic, or transcriptomic biomarkers that contribute to the understanding of the underlying molecular mechanisms of rare diseases and/or that can be used for the diagnosis and prognosis of disease and individuals’ responses to therapies.

Dr. Bridget E. Bax
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • orphan diseases
  • rare diseases
  • inborn errors of metabolism
  • mitochondrial disorders
  • biomarker discovery
  • biomarker panels
  • multiomics
  • endpoint measures

Related Special Issues

Published Papers (5 papers)

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Research

12 pages, 1595 KiB  
Article
New Perspectives in Dried Blood Spot Biomarkers for Lysosomal Storage Diseases
by Justyna Spiewak, Ivan Doykov, Apostolos Papandreou, Jenny Hällqvist, Philippa Mills, Peter T. Clayton, Paul Gissen, Kevin Mills and Wendy E. Heywood
Int. J. Mol. Sci. 2023, 24(12), 10177; https://doi.org/10.3390/ijms241210177 - 15 Jun 2023
Cited by 2 | Viewed by 1722
Abstract
Dried blood spots (DBSs) biomarkers are convenient for monitoring for specific lysosomal storage diseases (LSDs), but they could have relevance for other LSDs. To determine the specificity and utility of glycosphingolipidoses biomarkers against other LSDs, we applied a multiplexed lipid liquid chromatography tandem [...] Read more.
Dried blood spots (DBSs) biomarkers are convenient for monitoring for specific lysosomal storage diseases (LSDs), but they could have relevance for other LSDs. To determine the specificity and utility of glycosphingolipidoses biomarkers against other LSDs, we applied a multiplexed lipid liquid chromatography tandem mass spectrometry assay to a DBS cohort of healthy controls (n = 10) and Gaucher (n = 4), Fabry (n = 10), Pompe (n = 2), mucopolysaccharidosis types I–VI (n = 52), and Niemann–Pick disease type C (NPC) (n = 5) patients. We observed no complete disease specificity for any of the markers tested. However, comparison among the different LSDs highlighted new applications and perspectives of the existing biomarkers. We observed elevations in glucosylceramide isoforms in the NPC and Gaucher patients relative to the controls. In NPC, there was a greater proportion of C24 isoforms, giving a specificity of 96–97% for NPC, higher than 92% for the NPC biomarker N-palmitoyl-O-phosphocholineserine ratio to lyso-sphingomyelin. We also observed significantly elevated levels of lyso-dihexosylceramide in Gaucher and Fabry disease as well as elevated lyso-globotriaosylceramide (Lyso-Gb3) in Gaucher disease and the neuronopathic forms of Mucopolysaccharidoses. In conclusion, DBS glucosylceramide isoform profiling has increased the specificity for the detection of NPC, thereby improving diagnostic accuracy. Low levels of lyso-lipids can be observed in other LSDs, which may have implications in their disease pathogenesis. Full article
(This article belongs to the Special Issue Biomarkers in Rare Diseases 3.0)
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14 pages, 3516 KiB  
Article
Untargeted Metabolomics Identifies Biomarkers for MCADD Neonates in Dried Blood Spots
by Rajaa Sebaa, Maha AlMogren, Wafaa Alseraty and Anas M. Abdel Rahman
Int. J. Mol. Sci. 2023, 24(11), 9657; https://doi.org/10.3390/ijms24119657 - 02 Jun 2023
Cited by 1 | Viewed by 1309
Abstract
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common inherited mitochondrial metabolic disease of fatty acid β-oxidation, especially in newborns. MCADD is clinically diagnosed using Newborn Bloodspot Screening (NBS) and genetic testing. Still, these methods have limitations, such as false negatives or positives [...] Read more.
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common inherited mitochondrial metabolic disease of fatty acid β-oxidation, especially in newborns. MCADD is clinically diagnosed using Newborn Bloodspot Screening (NBS) and genetic testing. Still, these methods have limitations, such as false negatives or positives in NBS and the variants of uncertain significance in genetic testing. Thus, complementary diagnostic approaches for MCADD are needed. Recently, untargeted metabolomics has been proposed as a diagnostic approach for inherited metabolic diseases (IMDs) due to its ability to detect a wide range of metabolic alterations. We performed an untargeted metabolic profiling of dried blood spots (DBS) from MCADD newborns (n = 14) and healthy controls (n = 14) to discover potential metabolic biomarkers/pathways associated with MCADD. Extracted metabolites from DBS samples were analyzed using UPLC-QToF-MS for untargeted metabolomics analyses. Multivariate and univariate analyses were used to analyze the metabolomics data, and pathway and biomarker analyses were also performed on the significantly identified endogenous metabolites. The MCADD newborns had 1034 significantly dysregulated metabolites compared to healthy newborns (moderated t-test, no correction, p-value ≤ 0.05, FC 1.5). A total of 23 endogenous metabolites were up-regulated, while 84 endogenous metabolites were down-regulated. Pathway analyses showed phenylalanine, tyrosine, and tryptophan biosynthesis as the most affected pathways. Potential metabolic biomarkers for MCADD were PGP (a21:0/PG/F1alpha) and glutathione, with an area under the curve (AUC) of 0.949 and 0.898, respectively. PGP (a21:0/PG/F1alpha) was the first oxidized lipid in the top 15 biomarker list affected by MCADD. Additionally, glutathione was chosen to indicate oxidative stress events that could happen during fatty acid oxidation defects. Our findings suggest that MCADD newborns may have oxidative stress events as signs of the disease. However, further validations of these biomarkers are needed in future studies to ensure their accuracy and reliability as complementary markers with established MCADD markers for clinical diagnosis. Full article
(This article belongs to the Special Issue Biomarkers in Rare Diseases 3.0)
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12 pages, 2188 KiB  
Article
Validation of Aspartylglucosaminidase Activity Assay for Human Serum Samples: Establishment of a Biomarker for Diagnostics and Clinical Studies
by Antje Banning, Minna Laine and Ritva Tikkanen
Int. J. Mol. Sci. 2023, 24(6), 5722; https://doi.org/10.3390/ijms24065722 - 16 Mar 2023
Viewed by 1141
Abstract
Novel treatment strategies are emerging for rare, genetic diseases, resulting in clinical trials that require adequate biomarkers for the assessment of the treatment effect. For enzyme defects, biomarkers that can be assessed from patient serum, such as enzyme activity, are highly useful, but [...] Read more.
Novel treatment strategies are emerging for rare, genetic diseases, resulting in clinical trials that require adequate biomarkers for the assessment of the treatment effect. For enzyme defects, biomarkers that can be assessed from patient serum, such as enzyme activity, are highly useful, but the activity assays need to be properly validated to ensure a precise, quantitative measurement. Aspartylglucosaminuria (AGU) is a lysosomal storage disorder caused by the deficiency of the lysosomal hydrolase aspartylglucosaminidase (AGA). We have here established and validated a fluorometric AGA activity assay for human serum samples from healthy donors and AGU patients. We show that the validated AGA activity assay is suitable for the assessment of AGA activity in the serum of healthy donors and AGU patients, and it can be used for diagnostics of AGU and, potentially, for following a treatment effect. Full article
(This article belongs to the Special Issue Biomarkers in Rare Diseases 3.0)
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16 pages, 1067 KiB  
Article
Mass Spectrometry Analysis of Globotriaosylsphingosine and Its Analogues in Dried Blood Spots
by Michel Boutin, Pamela Lavoie, Margot Beaudon, Georges Kabala Ntumba, Daniel G. Bichet, Bruno Maranda and Christiane Auray-Blais
Int. J. Mol. Sci. 2023, 24(4), 3223; https://doi.org/10.3390/ijms24043223 - 06 Feb 2023
Cited by 2 | Viewed by 1383
Abstract
Fabry disease (FD) is an X-linked lysosomal storage disorder where impaired α-galactosidase A enzyme activity leads to the intracellular accumulation of undegraded glycosphingolipids, including globotriaosylsphingosine (lyso-Gb3) and related analogues. Lyso-Gb3 and related analogues are useful biomarkers for screening and should [...] Read more.
Fabry disease (FD) is an X-linked lysosomal storage disorder where impaired α-galactosidase A enzyme activity leads to the intracellular accumulation of undegraded glycosphingolipids, including globotriaosylsphingosine (lyso-Gb3) and related analogues. Lyso-Gb3 and related analogues are useful biomarkers for screening and should be routinely monitored for longitudinal patient evaluation. In recent years, a growing interest has emerged in the analysis of FD biomarkers in dried blood spots (DBSs), considering the several advantages compared to venipuncture as a technique for collecting whole-blood specimens. The focus of this study was to devise and validate a UHPLC-MS/MS method for the analysis of lyso-Gb3 and related analogues in DBSs to facilitate sample collection and shipment to reference laboratories. The assay was devised in conventional DBS collection cards and in Capitainer®B blood collection devices using both capillary and venous blood specimens from 12 healthy controls and 20 patients affected with FD. The measured biomarker concentrations were similar in capillary and venous blood specimens. The hematocrit (Hct) did not affect the correlation between plasma and DBS measurements in our cohort (Hct range: 34.3–52.2%). This UHPLC-MS/MS method using DBS would facilitate high-risk screening and the follow-up and monitoring of patients affected with FD. Full article
(This article belongs to the Special Issue Biomarkers in Rare Diseases 3.0)
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15 pages, 2597 KiB  
Article
Characterization of Mitochondrial Alterations in Aicardi–Goutières Patients Mutated in RNASEH2A and RNASEH2B Genes
by Francesca Dragoni, Jessica Garau, Daisy Sproviero, Simona Orcesi, Costanza Varesio, Silvia De Siervi, Stella Gagliardi, Cristina Cereda and Orietta Pansarasa
Int. J. Mol. Sci. 2022, 23(22), 14482; https://doi.org/10.3390/ijms232214482 - 21 Nov 2022
Cited by 4 | Viewed by 1725
Abstract
Aicardi–Goutières syndrome (AGS) is a rare encephalopathy characterized by neurological and immunological features. Mitochondrial dysfunctions may lead to mitochondrial DNA (mtDNA) release and consequent immune system activation. We investigated the role of mitochondria and mtDNA in AGS pathogenesis by studying patients mutated in [...] Read more.
Aicardi–Goutières syndrome (AGS) is a rare encephalopathy characterized by neurological and immunological features. Mitochondrial dysfunctions may lead to mitochondrial DNA (mtDNA) release and consequent immune system activation. We investigated the role of mitochondria and mtDNA in AGS pathogenesis by studying patients mutated in RNASEH2B and RNASEH2A genes. Lymphoblastoid cell lines (LCLs) from RNASEH2A- and RNASEH2B-mutated patients and healthy control were used. Transmission Electron Microscopy (TEM) and flow cytometry were used to assess morphological alterations, reactive oxygen species (ROS) production and mitochondrial membrane potential variations. Seahorse Analyzer was used to investigate metabolic alterations, and mtDNA oxidation and VDAC1 oligomerization were assessed by immunofluorescence. Western blot and RT-qPCR were used to quantify mtTFA protein and mtDNA release. Morphological alterations of mitochondria were observed in both mutated LCLs, and loss of physiological membrane potential was mainly identified in RNASEH2A LCLs. ROS production and 8-oxoGuanine levels were increased in RNASEH2B LCLs. Additionally, the VDAC1 signal was increased, suggesting a mitochondrial pore formation possibly determining mtDNA release. Indeed, higher cytoplasmic mtDNA levels were found in RNASEH2B LCLs. Metabolic alterations confirmed mitochondrial damage in both LCLs. Data highlighted mitochondrial alterations in AGS patients’ LCLs suggesting a pivotal role in AGS pathogenesis. Full article
(This article belongs to the Special Issue Biomarkers in Rare Diseases 3.0)
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