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Advances in Rare Diseases Biomarkers

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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: closed (30 June 2024) | Viewed by 3525

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Prof. Dr. Andrea Bernini

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Guest Editor

Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy
Interests: structural biology; rare diseases; metabolomics; nuclear magnetic resonance; protein dynamics; protein core & surface; transient pockets
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

A rare disease is a health condition with a lower prevalence than common diseases. The World Health Organization defines a rare disease as one that strikes fewer than 65 per 100,000 people. However, their combined effect is significant: around 7000 rare diseases affect approximately 350 million people worldwide.

Biomarkers play a crucial role in diagnosing and monitoring rare diseases, which are often challenging to detect and understand due to their low prevalence and diverse clinical manifestations. Biomarkers serve as measurable indicators of biological processes or conditions in rare diseases, offering valuable insights into disease mechanisms and progression. These markers may include genetic mutations, protein levels, or other molecular signatures unique to a rare condition. The discovery and validation of such biomarkers contribute to early detection and the development of targeted therapies, allowing for more effective and personalised treatment approaches.

As technology advances, the integration of omics technologies, such as genomics, proteomics, and metabolomics, has further expanded the repertoire of potential biomarkers, fostering a deeper understanding of rare diseases and paving the way for innovative diagnostic and therapeutic strategies. Biomarkers enhance our ability to navigate diagnostic challenges and promise to improve patient care and foster breakthroughs in treatment modalities.

For the Special Issue, we continue looking for original research articles and state-of-the-art reviews on novel and established proteomic, metabolomic, or transcriptomic biomarkers that can help us better understand the underlying molecular mechanisms of rare diseases. Additionally, we are interested in biomarkers that can be used to diagnose and predict the prognosis of rare diseases and determine individual responses to therapies.

Prof. Dr. Andrea Bernini
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

Published Papers (5 papers)

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Research

22 pages, 9707 KiB

Open AccessArticle

TLR2 and TLR4 Are Expressed in Epiretinal Membranes: Possible Links with Vitreous Levels of Complement Fragments and DAMP-Related Proteins

by Lucia Dinice, Graziana Esposito, Andrea Cacciamani, Bijorn Omar Balzamino, Pamela Cosimi, Concetta Cafiero, Guido Ripandelli and Alessandra Micera

Int. J. Mol. Sci. 2024, 25(14), 7732; https://doi.org/10.3390/ijms25147732 - 15 Jul 2024

Viewed by 264

Abstract

Previous studies reported the expression of toll-like receptors (TLRs), merely TLR2 and TLR4, and complement fragments (C3a, C5b9) in vitreoretinal disorders. Other than pathogens, TLRs can recognize endogenous products of tissue remodeling as damage-associated molecular pattern (DAMPs). The aim of this study was to confirm the expression of TLR2 and TLR4 in the fibrocellular membranes and vitreal fluids (soluble TLRs) of patients suffering of epiretinal membranes (ERMs) and assess their association with disease severity, complement fragments and inflammatory profiles. Twenty (n = 20) ERMs and twelve (n = 12) vitreous samples were collected at the time of the vitrectomy. Different severity-staged ERMs were processed for: immunolocalization (IF), transcriptomic (RT-PCR) and proteomics (ELISA, IP/WB, Protein Chip Array) analysis. The investigation of targets included TLR2, TLR4, C3a, C5b9, a few selected inflammatory biomarkers (Eotaxin-2, Rantes, Vascular Endothelial Growth Factor (VEGFA), Vascular Endothelial Growth Factor receptor (VEGFR2), Interferon-γ (IFNγ), Interleukin (IL1β, IL12p40/p70)) and a restricted panel of matrix enzymes (Matrix metalloproteinases (MMPs)/Tissue Inhibitor of Metallo-Proteinases (TIMPs)). A reduced cellularity was observed as function of ERM severity. TLR2, TLR4 and myD88 transcripts/proteins were detected in membranes and decreased upon disease severity. The levels of soluble TLR2 and TLR4, as well as C3a, C5b9, Eotaxin-2, Rantes, VEGFA, VEGFR2, IFNγ, IL1β, IL12p40/p70, MMP7 and TIMP2 levels were changed in vitreal samples. Significant correlations were observed between TLRs and complement fragments and between TLRs and some inflammatory mediators. Our findings pointed at TLR2 and TLR4 over-expression at early stages of ERM formation, suggesting the participation of the local immune response in the severity of disease. These activations at the early-stage of ERM formation suggest a potential persistence of innate immune response in the early phases of fibrocellular membrane formation. Full article

(This article belongs to the Special Issue Advances in Rare Diseases Biomarkers)

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8 pages, 1250 KiB

Open AccessCommunication

A Plasma Pyrophosphate Cutoff Value for Diagnosing Pseudoxanthoma Elasticum

by Isabelle Rubera, Laetitia Clotaire, Audrey Laurain, Alexandre Destere, Ludovic Martin, Christophe Duranton and Georges Leftheriotis

Int. J. Mol. Sci. 2024, 25(12), 6502; https://doi.org/10.3390/ijms25126502 - 13 Jun 2024

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Abstract

Pseudoxanthoma elasticum (PXE) is a rare inherited systemic disease responsible for a juvenile peripheral arterial calcification disease. The clinical diagnosis of PXE is only based on a complex multi-organ phenotypic score and/or genetical analysis. Reduced plasma inorganic pyrophosphate concentration [PPi]p has been linked to PXE. In this study, we used a novel and accurate method to measure [PPi]p in one of the largest cohorts of PXE patients, and we reported the valuable contribution of a cutoff value to PXE diagnosis. Plasma samples and clinical records from two French reference centers for PXE (PXE Consultation Center, Angers, and FAVA-MULTI South Competent Center, Nice) were assessed. Plasma PPi were measured in 153 PXE and 46 non-PXE patients. The PPi concentrations in the plasma samples were determined by a new method combining enzymatic and ion chromatography approaches. The best match between the sensitivity and specificity (Youden index) for diagnosing PXE was determined by ROC analysis. [PPi]p were lower in PXE patients (0.92 ± 0.30 µmol/L) than in non-PXE patients (1.61 ± 0.33 µmol/L, p < 0.0001), corresponding to a mean reduction of 43 ± 19% (SD). The PPi cutoff value for diagnosing PXE in all patients was 1.2 µmol/L, with a sensitivity of 83.3% and a specificity of 91.1% (AUC = 0.93), without sex differences. In patients aged <50 years (i.e., the age period for PXE diagnosis), the cutoff PPi was 1.2 µmol/L (sensitivity, specificity, and AUC of 93%, 96%, and 0.97, respectively). The [PPi]p shows high accuracy for diagnosing PXE; thus, quantifying plasma PPi represents the first blood assay for diagnosing PXE. Full article

(This article belongs to the Special Issue Advances in Rare Diseases Biomarkers)

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12 pages, 1677 KiB

Open AccessCommunication

Comparative Single Vesicle Analysis of Aqueous Humor Extracellular Vesicles before and after Radiation in Uveal Melanoma Eyes

by Shreya Sirivolu, Chen-Ching Peng, Paolo Neviani, Benjamin Y. Xu, Jesse L. Berry and Liya Xu

Int. J. Mol. Sci. 2024, 25(11), 6035; https://doi.org/10.3390/ijms25116035 - 30 May 2024

Viewed by 488

Abstract

Small extracellular vesicles (sEVs) have been shown to promote tumorigenesis, treatment resistance, and metastasis in multiple cancer types; however, sEVs in the aqueous humor (AH) of uveal melanoma (UM) patients have never previously been profiled. In this study, we used single particle analysis to characterize sEV subpopulations in the AH of UM patients by quantifying their size, concentration, and phenotypes based on cell surface markers, specifically the tetraspanin co-expression patterns of CD9, CD63, and CD81. sEVs were analyzed from paired pre- and post-treatment (brachytherapy, a form of radiation) AH samples collected from 19 UM patients. In post-brachytherapy samples, two subpopulations, CD63/81+ and CD9/63/81+ sEVs, were significantly increased. These trends existed even when stratified by tumor location and GEP class 1 and class 2 (albeit not significant for GEP class 2). In this initial report of single vesicle profiling of sEVs in the AH of UM patients, we demonstrated that sEVs can be detected in the AH. We further identified two subpopulations that were increased post-brachytherapy, which may suggest radiation-induced release of these particles, potentially from tumor cells. Further study of the cargo carried by these sEV subpopulations may uncover important biomarkers and insights into tumorigenesis for UM. Full article

(This article belongs to the Special Issue Advances in Rare Diseases Biomarkers)

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17 pages, 3608 KiB

Open AccessArticle

Exploratory Untargeted Metabolomics of Dried Blood Spot Samples from Newborns with Maple Syrup Urine Disease

by Abeer Z. Alotaibi, Reem H. AlMalki, Maha Al Mogren, Rajaa Sebaa, Mohammad Alanazi, Minnie Jacob, Ahamd Alodaib, Ahmad Alfares and Anas M. Abdel Rahman

Int. J. Mol. Sci. 2024, 25(11), 5720; https://doi.org/10.3390/ijms25115720 - 24 May 2024

Viewed by 569

Abstract

Currently, tandem mass spectrometry-based newborn screening (NBS), which examines targeted biomarkers, is the first approach used for the early detection of maple syrup urine disease (MSUD) in newborns, followed by confirmatory genetic mutation tests. However, these diagnostic approaches have limitations, demanding the development of additional tools for the diagnosis/screening of MUSD. Recently, untargeted metabolomics has been used to explore metabolic profiling and discover the potential biomarkers/pathways of inherited metabolic diseases. Thus, we aimed to discover a distinctive metabolic profile and biomarkers/pathways for MSUD newborns using untargeted metabolomics. Herein, untargeted metabolomics was used to analyze dried blood spot (DBS) samples from 22 MSUD and 22 healthy control newborns. Our data identified 210 altered endogenous metabolites in MSUD newborns and new potential MSUD biomarkers, particularly L-alloisoleucine, methionine, and lysoPI. In addition, the most impacted pathways in MSUD newborns were the ascorbate and aldarate pathways and pentose and glucuronate interconversions, suggesting that oxidative and detoxification events may occur in early life. Our approach leads to the identification of new potential biomarkers/pathways that could be used for the early diagnosis/screening of MSUD newborns but require further validation studies. Our untargeted metabolomics findings have undoubtedly added new insights to our understanding of the pathogenicity of MSUD, which helps us select the appropriate early treatments for better health outcomes. Full article

(This article belongs to the Special Issue Advances in Rare Diseases Biomarkers)

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11 pages, 1536 KiB

Open AccessArticle

Serum Galectin-3 as a Non-Invasive Marker for Primary Sclerosing Cholangitis

by Ganimete Bajraktari, Tanja Elger, Muriel Huss, Johanna Loibl, Andreas Albert, Arne Kandulski, Martina Müller, Hauke Christian Tews and Christa Buechler

Int. J. Mol. Sci. 2024, 25(9), 4765; https://doi.org/10.3390/ijms25094765 - 27 Apr 2024

Viewed by 713

Abstract

Primary sclerosing cholangitis (PSC) is a serious liver disease associated with inflammatory bowel disease (IBD). Galectin-3, an inflammatory and fibrotic molecule, has elevated circulating levels in patients with chronic liver disease and inflammatory bowel disease (IBD). This study aims to clarify whether galectin-3 can differentiate between patients with IBD, PSC, and PSC-IBD. Our study measured serum galectin-3 levels in 38 healthy controls, 55 patients with IBD, and 22 patients with PSC (11 patients had underlying IBD and 11 patients did not), alongside the urinary galectin-3 of these patients and 18 controls. Serum and urinary galectin-3 levels in IBD patients were comparable to those in controls. Among IBD patients, those with high fecal calprotectin, indicating severe disease, exhibited lower serum and elevated urinary galectin-3 levels compared to those with low calprotectin levels. Serum galectin-3 levels were inversely correlated with C-reactive protein levels. PSC patients displayed higher serum and urinary galectin-3 levels than IBD patients, with the highest serum levels observed in PSC patients with coexisting IBD. There was no correlation between serum and urinary galectin-3 levels and laboratory indicators of liver injury in both IBD and PSC patients. In conclusion, this study demonstrates that serum and urinary galectin-3 levels can distinguish IBD from PSC patients, and also reveals higher serum galectin-3 levels in PSC-IBD patients compared to those with isolated PSC. Full article

(This article belongs to the Special Issue Advances in Rare Diseases Biomarkers)

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