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Biomarkers in Rare Diseases
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Biomarkers in Rare Diseases

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 (31 August 2020) | Viewed by 54104

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 a majority of these conditions, there are no specific therapies whose effectiveness have 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. In order 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”, we are 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
  • Multi-omics
  • End point measures

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Published Papers (16 papers)

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Editorial

Jump to: Research, Review

4 pages, 191 KiB  
Editorial
Biomarkers in Rare Diseases
by Bridget E. Bax
Int. J. Mol. Sci. 2021, 22(2), 673; https://doi.org/10.3390/ijms22020673 - 12 Jan 2021
Cited by 14 | Viewed by 2717
Abstract
There is no single global definition of a rare disease, and for different geographical areas the definition is based on the disease occurrence in that population [...] Full article
(This article belongs to the Special Issue Biomarkers in Rare Diseases)

Research

Jump to: Editorial, Review

14 pages, 2602 KiB  
Article
ChIP-Seq-Based Approach in Mouse Enteric Precursor Cells Reveals New Potential Genes with a Role in Enteric Nervous System Development and Hirschsprung Disease
by Leticia Villalba-Benito, Ana Torroglosa, Berta Luzón-Toro, Raquel María Fernández, María José Moya-Jiménez, Guillermo Antiñolo and Salud Borrego
Int. J. Mol. Sci. 2020, 21(23), 9061; https://doi.org/10.3390/ijms21239061 - 28 Nov 2020
Cited by 4 | Viewed by 2039
Abstract
Hirschsprung disease (HSCR) is a neurocristopathy characterized by intestinal aganglionosis which is attributed to a failure in neural crest cell (NCC) development during the embryonic stage. The colonization of the intestine by NCCs is a process finely controlled by a wide and complex [...] Read more.
Hirschsprung disease (HSCR) is a neurocristopathy characterized by intestinal aganglionosis which is attributed to a failure in neural crest cell (NCC) development during the embryonic stage. The colonization of the intestine by NCCs is a process finely controlled by a wide and complex gene regulatory system. Several genes have been associated with HSCR, but many aspects still remain poorly understood. The present study is focused on deciphering the PAX6 interaction network during enteric nervous system (ENS) formation. A combined experimental and computational approach was performed to identify PAX6 direct targets, as well as gene networks shared among such targets as potential susceptibility factors for HSCR. As a result, genes related to PAX6 either directly (RABGGTB and BRD3) or indirectly (TGFB1, HRAS, and GRB2) were identified as putative genes associated with HSCR. Interestingly, GRB2 is involved in the RET/GDNF/GFRA1 signaling pathway, one of the main pathways implicated in the disease. Our findings represent a new contribution to advance in the knowledge of the genetic basis of HSCR. The investigation of the role of these genes could help to elucidate their implication in HSCR onset. Full article
(This article belongs to the Special Issue Biomarkers in Rare Diseases)
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12 pages, 3622 KiB  
Article
Implications of Splicing Alterations in the Onset and Phenotypic Variability of a Family with Subclinical Manifestation of Peutz–Jeghers Syndrome: Bioinformatic and Molecular Evidence
by Andrea Cerasuolo, Francesca Cammarota, Francesca Duraturo, Annamaria Staiano, Massimo Martinelli, Erasmo Miele, Paola Izzo and Marina De Rosa
Int. J. Mol. Sci. 2020, 21(21), 8201; https://doi.org/10.3390/ijms21218201 - 2 Nov 2020
Cited by 3 | Viewed by 2186
Abstract
Peutz–Jeghers Syndrome (PJS) is an autosomal dominant pre-cancerous disorder caused in 80–90% of cases by germline mutations in the tumor suppressor gene STK11. We performed a genetic test of the STK11 gene in two Italian young sisters suspected of PJS, since they [...] Read more.
Peutz–Jeghers Syndrome (PJS) is an autosomal dominant pre-cancerous disorder caused in 80–90% of cases by germline mutations in the tumor suppressor gene STK11. We performed a genetic test of the STK11 gene in two Italian young sisters suspected of PJS, since they showed pathognomonic café au lait spots in absence of other symptoms and familiarity. Sequencing of all exons of STK11 gene and other 8 genes, suggested to be involved in hamartomatous syndromes, (PTEN, BMPR1A, SDHB, SDHD, SMAD4, AKT1, ENG, PIK3CA) led to the identification in both the probands of a novel germline silent mutation named c.597 G>A, hitting the last nucleotide of exon 4. Interestingly, genetic testing of the two probands’ parents showed that their unaffected father was carrier of this mutation. Moreover, he carried a second intronic substitution named c.465-51 T>C (rs2075606) which was not inherited by his daughters. We also observed that all the family members carrying the c.597 G>A mutation presented an aberrant splice variant of STK11 mRNA lacking exon 4. Furthermore, in silico analysis of c.465-51 T>C substitution showed that it may activate an Enhancer Splicing Element. Finally, qRT-PCR analysis of STK11 expression levels showed a slight downregulation of the wild type allele in the father and a 2-fold downregulation in the probands compared to the unaffected mother. Our results have led the hypothesis that the c.465-51 T>C intronic variant, which segregates with the wild type allele, could increase the splicing effectiveness of STK11 wild-type allele and compensate the side effect of the c.597 G>A splicing mutation, being responsible for the phenotypic variability observed within this family. This finding highlight the importance of RNA analysis in genetic testing, remarking that silent DNA variant can often be splicing variant involved in disease onset and progression. The identification of these variants has a crucial role to ensure an appropriate follow-up and cancer prevention in at-risk individuals. Full article
(This article belongs to the Special Issue Biomarkers in Rare Diseases)
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9 pages, 1537 KiB  
Article
The Role of CASC2 and miR-21 Interplay in Glioma Malignancy and Patient Outcome
by Daina Skiriute, Rytis Stakaitis, Giedrius Steponaitis, Arimantas Tamasauskas and Paulina Vaitkiene
Int. J. Mol. Sci. 2020, 21(21), 7962; https://doi.org/10.3390/ijms21217962 - 27 Oct 2020
Cited by 10 | Viewed by 1886
Abstract
Recently long non-coding RNAs (lncRNAs) were highlighted for their regulatory role in tumor biology. The novel human lncRNA cancer susceptibility candidate 2 (CASC2) has been characterized as a potential tumor suppressor in several tumor types. However, the roles of CASC2 and [...] Read more.
Recently long non-coding RNAs (lncRNAs) were highlighted for their regulatory role in tumor biology. The novel human lncRNA cancer susceptibility candidate 2 (CASC2) has been characterized as a potential tumor suppressor in several tumor types. However, the roles of CASC2 and its interplay with miR-21 in different malignancy grade patient gliomas remain unexplored. Here we screened 99 different malignancy grade astrocytomas for CASC2, and miR-21 gene expression by real-time quantitative polymerase chain reaction (RT-qPCR) in isocitrate dehydrogenase 1 (IDH1) and O-6-methylguanine methyltransferase (MGMT) assessed gliomas. CASC2 expression was significantly downregulated in glioblastomas (p = 0.0003). Gliomas with low CASC2 expression exhibited a high level of miR-21, which was highly associated with the higher glioma grade (p = 0.0001), IDH1 wild type gliomas (p < 0.0001), and poor patient survival (p < 0.001). Taken together, these observations suggest that CASC2 acts as a tumor suppressor and potentially as a competing endogenous RNA (ceRNA) for miR-21, plays important role in IDH1 wild type glioma pathogenesis and patients’ outcomes. Full article
(This article belongs to the Special Issue Biomarkers in Rare Diseases)
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21 pages, 7175 KiB  
Article
Identification of a Reliable Biomarker Profile for the Diagnosis of Gaucher Disease Type 1 Patients Using a Mass Spectrometry-Based Metabolomic Approach
by Iskren Menkovic, Michel Boutin, Abdulfatah Alayoubi, François E. Mercier, Georges-Étienne Rivard and Christiane Auray-Blais
Int. J. Mol. Sci. 2020, 21(21), 7869; https://doi.org/10.3390/ijms21217869 - 23 Oct 2020
Cited by 11 | Viewed by 2833
Abstract
Gaucher disease (GD) is a rare autosomal recessive multisystemic lysosomal storage disorder presenting a marked phenotypic and genotypic variability. GD is caused by a deficiency in the glucocerebrosidase enzyme. The diagnosis of GD remains challenging because of the large clinical spectrum associated with [...] Read more.
Gaucher disease (GD) is a rare autosomal recessive multisystemic lysosomal storage disorder presenting a marked phenotypic and genotypic variability. GD is caused by a deficiency in the glucocerebrosidase enzyme. The diagnosis of GD remains challenging because of the large clinical spectrum associated with the disease. Moreover, GD biomarkers are often not sensitive enough and can be subject to polymorphic variations. The main objective of this study was to perform a metabolomic study using an ultra-performance liquid chromatography system coupled to a time-of-flight mass spectrometer to identify novel GD biomarkers. Following the analysis of plasma samples from patients with GD, and age- and gender-matched control samples, supervised statistical analyses were used to find the best molecules to differentiate the two groups. Targeted biomarkers were structurally elucidated using accurate mass measurements and tandem mass spectrometry. This metabolomic study was successful in highlighting seven biomarkers associated with GD. Fragmentation tests revealed that these latter biomarkers were lyso-Gb1 (glucosylsphingosine) and four related analogs (with the following modifications on the sphingosine moiety: -C2H4, -H2, -H2+O, and +H2O), sphingosylphosphorylcholine, and N-palmitoyl-O-phosphocholineserine. Based on the plasma biomarker distribution, we suggest the evaluation of this GD biomarker profile, which might facilitate early diagnosis, monitoring, and follow-up of patients. Full article
(This article belongs to the Special Issue Biomarkers in Rare Diseases)
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26 pages, 2228 KiB  
Article
Serum-Based Proteomics Profiling in Adult Patients with Cystic Fibrosis
by Hicham Benabdelkamel, Hanadi Alamri, Meshail Okla, Afshan Masood, Mai Abdel Jabar, Ibrahim O. Alanazi, Assim A. Alfadda, Imran Nizami, Majed Dasouki and Anas M. Abdel Rahman
Int. J. Mol. Sci. 2020, 21(19), 7415; https://doi.org/10.3390/ijms21197415 - 8 Oct 2020
Cited by 12 | Viewed by 3228
Abstract
Cystic fibrosis (CF), the most common lethal autosomal recessive disorder among Caucasians, is caused by mutations in the CF transmembrane conductance regulator (CFTR) chloride channel gene. Despite significant advances in the management of CF patients, novel disease-related biomarkers and therapies must be identified. [...] Read more.
Cystic fibrosis (CF), the most common lethal autosomal recessive disorder among Caucasians, is caused by mutations in the CF transmembrane conductance regulator (CFTR) chloride channel gene. Despite significant advances in the management of CF patients, novel disease-related biomarkers and therapies must be identified. We performed serum proteomics profiling in CF patients (n = 28) and healthy subjects (n = 10) using the 2D-DIGE MALDI-TOF proteomic approach. Out of a total of 198 proteins identified, 134 showed a statistically significant difference in abundance and a 1.5-fold change (ANOVA, p < 0.05), including 80 proteins with increased abundance and 54 proteins with decreased abundance in CF patients. A multiple reaction monitoring-mass spectrometry analysis of six differentially expressed proteins identified by a proteomic approach (DIGE-MALD-MS) showed a significant increase in C3 and CP proteins and a decrease in APOA1, Complement C1, Hp, and RBP4proteins compared with healthy controls. Fifteen proteins were identified as potential biomarkers for CF diagnosis. An ingenuity pathway analysis of the differentially regulated proteins indicates that the central nodes dysregulated in CF subjects involve pro-inflammatory cytokines, ERK1/2, and P38 MAPK, which are primarily involved in catalytic activities and metabolic processes. The involved canonical pathways include those related to FXR/RXR, LXR/RXR, acute phase response, IL12, nitric oxide, and reactive oxygen species in macrophages. Our data support the current efforts toward augmenting protease inhibitors in patients with CF. Perturbations in lipid and vitamin metabolism frequently observed in CF patients may be partly due to abnormalities in their transport mechanism. Full article
(This article belongs to the Special Issue Biomarkers in Rare Diseases)
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15 pages, 3961 KiB  
Article
Anti-Telomerase CD4+ Th1 Immunity and Monocytic-Myeloid-Derived-Suppressor Cells Are Associated with Long-Term Efficacy Achieved by Docetaxel, Cisplatin, and 5-Fluorouracil (DCF) in Advanced Anal Squamous Cell Carcinoma: Translational Study of Epitopes-HPV01 and 02 Trials
by Laurie Spehner, Stefano Kim, Angélique Vienot, Eric François, Bruno Buecher, Olivier Adotevi, Dewi Vernerey, Syrine Abdeljaoued, Aurélia Meurisse and Christophe Borg
Int. J. Mol. Sci. 2020, 21(18), 6838; https://doi.org/10.3390/ijms21186838 - 17 Sep 2020
Cited by 19 | Viewed by 2652
Abstract
Docetaxel, cisplatin and 5-fluorouracil (DCF) chemotherapy regimen is highly effective in advanced anal squamous cell carcinoma (SCCA), as demonstrated by the Epitopes-HPV02 study results. Here, we analyzed the impact of DCF regimen and the prognostic value of adaptive immune responses and immunosuppressive cells [...] Read more.
Docetaxel, cisplatin and 5-fluorouracil (DCF) chemotherapy regimen is highly effective in advanced anal squamous cell carcinoma (SCCA), as demonstrated by the Epitopes-HPV02 study results. Here, we analyzed the impact of DCF regimen and the prognostic value of adaptive immune responses and immunosuppressive cells in SCCA patients included in two prospective studies (Epitopes-HPV01 and HPV02). The presence of T-cell responses against Human papillomavirus (HPV)16-E6/E7 and anti-telomerase (hTERT)-antigens was measured by IFNᵧ-ELISpot. Here, we showed that HPV-adaptive immune responses are increased in SCCA patients. SCCA patients also displayed enhanced circulating TH1 T-cells restricted by hTERT. Exposition to DCF increased hTERT immunity but not HPV or common viruses immune responses. Notably, the correlation of hTERT immune responses with SCCA patients’ clinical outcomes highlights that hTERT is a relevant antigen in this HPV-related disease. The influence of peripheral immunosuppressive cells was investigated by flow cytometry. While both regulatory T-cells and monocytic-myeloid-derived suppressive cells (M-MDSC) accumulated in the peripheral blood of SCCA patients, only high levels of M-MDSC were negatively correlated with hTERT adaptive immune responses and predicted poor prognosis. Altogether, our results reveal that hTERT is a relevant antigen in HPV-driven SCCA disease and that M-MDSC levels influence TH1-adaptive immune responses and patients’ survival. Full article
(This article belongs to the Special Issue Biomarkers in Rare Diseases)
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12 pages, 990 KiB  
Article
Levels of Interleukin-6 in Saliva, but Not Plasma, Correlate with Clinical Metrics in Huntington’s Disease Patients and Healthy Control Subjects
by Jody Corey-Bloom, Ryan S. Fischer, Aeri Kim, Chase Snell, Georgia M. Parkin, Douglas A. Granger, Steven W. Granger and Elizabeth A. Thomas
Int. J. Mol. Sci. 2020, 21(17), 6363; https://doi.org/10.3390/ijms21176363 - 2 Sep 2020
Cited by 29 | Viewed by 3395
Abstract
Growing evidence suggests that inflammatory responses, in both the brain and peripheral tissues, contribute to disease pathology in Huntington’s disease (HD), an inherited, progressive neurodegenerative disorder typically affecting adults in their 30–40 s. Hence, studies of inflammation-related markers in peripheral fluids might be [...] Read more.
Growing evidence suggests that inflammatory responses, in both the brain and peripheral tissues, contribute to disease pathology in Huntington’s disease (HD), an inherited, progressive neurodegenerative disorder typically affecting adults in their 30–40 s. Hence, studies of inflammation-related markers in peripheral fluids might be useful to better characterize disease features. In this study, we measured levels of C-reactive protein (CRP), Interleukin-6 (IL-6), interleukin 1 beta (IL-1B), and alpha-amylase (AA) in saliva and plasma from n = 125 subjects, including n = 37 manifest HD patients, n = 36 premanifest patients, and n = 52 healthy controls, using immunoassays. We found increases in salivary levels of IL-6, IL-1B and CRP across different disease groups and increased levels of IL-6 in the plasma of HD patients as compared to premanifest patients and controls. The levels of salivary IL-6 were significantly correlated with each of the other salivary markers, as well as with IL-6 levels measured in plasma. Further, salivary IL-6 and IL-1B levels were significantly positively correlated with Total Motor Score (TMS) and chorea scores and negatively correlated with Total Functional Capacity (TFC) in HD patients, whereby in healthy control subjects, IL-6 was significantly negatively correlated with Montreal Cognitive Assessment (MoCA) and the Symbol Digit Modalities test (SDM). Interestingly, the plasma levels of IL-6 did not show similar correlations to any clinical measures in either HD or control subjects. These findings suggest that salivary IL-6 is particularly relevant as a potential non-invasive biomarker for HD symptoms. The advent of an effective, dependable salivary biomarker would meet the urgent need for a less invasive means of identifying and monitoring HD disease progression. Full article
(This article belongs to the Special Issue Biomarkers in Rare Diseases)
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14 pages, 2146 KiB  
Article
Diurnal Variation of Urinary Fabry Disease Biomarkers during Enzyme Replacement Therapy Cycles
by Michel Boutin, Pamela Lavoie, Iskren Menkovic, Amanda Toupin, Mona Abaoui, Maha Elidrissi-Elawad, Marie-Françoise Arthus, Carole Fortier, Claudia Ménard, Bruno Maranda, Daniel G. Bichet and Christiane Auray-Blais
Int. J. Mol. Sci. 2020, 21(17), 6114; https://doi.org/10.3390/ijms21176114 - 25 Aug 2020
Cited by 3 | Viewed by 2188
Abstract
Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene encoding the α-galactosidase A enzyme. This enzyme cleaves the last sugar unit of glycosphingolipids, including globotriaosylceramide (Gb3), globotriaosylsphingosine (lyso-Gb3), and galabiosylceramide (Ga2). [...] Read more.
Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene encoding the α-galactosidase A enzyme. This enzyme cleaves the last sugar unit of glycosphingolipids, including globotriaosylceramide (Gb3), globotriaosylsphingosine (lyso-Gb3), and galabiosylceramide (Ga2). Enzyme impairment leads to substrate accumulation in different organs, vascular endothelia, and biological fluids. Enzyme replacement therapy (ERT) is a commonly used treatment. Urinary analysis of Gb3 isoforms (different fatty acid moieties), as well as lyso-Gb3 and its analogues, is a reliable way to monitor treatment. These analogues correspond to lyso-Gb3 with chemical modifications on the sphingosine moiety (−C2H4, −C2H4+O, −H2, −H2+O, +O, +H2O2, and +H2O3). The effects of sample collection time on urinary biomarker levels between ERT cycles were not previously documented. The main objective of this project was to analyze the aforementioned biomarkers in urine samples from seven Fabry disease patients (three treated males, three treated females, and one ERT-naïve male) collected twice a day (morning and evening) for 42 days (three ERT cycles). Except for one participant, our results show that the biomarker levels were generally more elevated in the evening. However, there was less variability in samples collected in the morning. No cyclic variations in biomarker levels were observed between ERT infusions. Full article
(This article belongs to the Special Issue Biomarkers in Rare Diseases)
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13 pages, 747 KiB  
Communication
Identification of New Potential LncRNA Biomarkers in Hirschsprung Disease
by Ana Torroglosa, Leticia Villalba-Benito, Raquel María Fernández, Berta Luzón-Toro, María José Moya-Jiménez, Guillermo Antiñolo and Salud Borrego
Int. J. Mol. Sci. 2020, 21(15), 5534; https://doi.org/10.3390/ijms21155534 - 2 Aug 2020
Cited by 12 | Viewed by 2948
Abstract
Hirschsprung disease (HSCR) is a neurocristopathy defined by intestinal aganglionosis due to alterations during the development of the Enteric Nervous System (ENS). A wide spectrum of molecules involved in different signaling pathways and mechanisms have been described in HSCR onset. Among them, epigenetic [...] Read more.
Hirschsprung disease (HSCR) is a neurocristopathy defined by intestinal aganglionosis due to alterations during the development of the Enteric Nervous System (ENS). A wide spectrum of molecules involved in different signaling pathways and mechanisms have been described in HSCR onset. Among them, epigenetic mechanisms are gaining increasing relevance. In an effort to better understand the epigenetic basis of HSCR, we have performed an analysis for the identification of long non-coding RNAs (lncRNAs) by qRT-PCR in enteric precursor cells (EPCs) from controls and HSCR patients. We aimed to test the presence of a set lncRNAs among 84 lncRNAs in human EPCs, which were previously related with crucial cellular processes for ENS development, as well as to identify the possible differences between HSCR patients and controls. As a result, we have determined a set of lncRNAs with positive expression in human EPCs that were screened for mutations using the exome data from our cohort of HSCR patients to identify possible variants related to this pathology. Interestingly, we identified three lncRNAs with different levels of their transcripts (SOCS2-AS, MEG3 and NEAT1) between HSCR patients and controls. We propose such lncRNAs as possible regulatory elements implicated in the onset of HSCR as well as potential biomarkers of this pathology. Full article
(This article belongs to the Special Issue Biomarkers in Rare Diseases)
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Review

Jump to: Editorial, Research

17 pages, 348 KiB  
Review
Biomarkers in Rare Demyelinating Disease of the Central Nervous System
by Marina Boziki, Styliani-Aggeliki Sintila, Panagiotis Ioannidis and Nikolaos Grigoriadis
Int. J. Mol. Sci. 2020, 21(21), 8409; https://doi.org/10.3390/ijms21218409 - 9 Nov 2020
Cited by 6 | Viewed by 3432
Abstract
Rare neurological diseases are a heterogeneous group corresponding approximately to 50% of all rare diseases. Neurologists are among the main specialists involved in their diagnostic investigation. At the moment, a consensus guideline on which neurologists may base clinical suspicion is not available. Moreover, [...] Read more.
Rare neurological diseases are a heterogeneous group corresponding approximately to 50% of all rare diseases. Neurologists are among the main specialists involved in their diagnostic investigation. At the moment, a consensus guideline on which neurologists may base clinical suspicion is not available. Moreover, neurologists need guidance with respect to screening investigations that may be performed. In this respect, biomarker research has emerged as a particularly active field due to its potential applications in clinical practice. With respect to autoimmune demyelinating diseases of the Central Nervous System (CNS), although these diseases occur in the frame of organ-specific autoimmunity, pathology of the disease itself is orchestrated among several anatomical and functional compartments. The differential diagnosis is broad and includes, but is not limited to, rare neurological diseases. Multiple Sclerosis (MS) needs to be differentially diagnosed from rare MS variants, Acute Disseminated Encephalomyelitis (ADEM), the range of Neuromyelitis Optica Spectrum Disorders (NMOSDs), Myelin Oligodendrocyte Glycoprotein (MOG) antibody disease and other systemic inflammatory diseases. Diagnostic biomarkers may facilitate timely diagnosis and proper disease management, preventing disease exacerbation due to misdiagnosis and false treatment. In this review, we will describe advances in biomarker research with respect to rare neuroinflammatory disease of the CNS. Full article
(This article belongs to the Special Issue Biomarkers in Rare Diseases)
18 pages, 1490 KiB  
Review
Biomarkers in Anderson–Fabry Disease
by Irene Simonetta, Antonino Tuttolomondo, Mario Daidone and Antonio Pinto
Int. J. Mol. Sci. 2020, 21(21), 8080; https://doi.org/10.3390/ijms21218080 - 29 Oct 2020
Cited by 30 | Viewed by 4395
Abstract
Fabry disease is a rare lysosomal storage disorder caused by a deficiency of α-galactosidase A, resulting in multisystemic involvement. Lyso-Gb3 (globotriaosylsphingosine), the deacylated form of Gb3, is currently measured in plasma as a biomarker of classic Fabry disease. Intensive research of biomarkers has [...] Read more.
Fabry disease is a rare lysosomal storage disorder caused by a deficiency of α-galactosidase A, resulting in multisystemic involvement. Lyso-Gb3 (globotriaosylsphingosine), the deacylated form of Gb3, is currently measured in plasma as a biomarker of classic Fabry disease. Intensive research of biomarkers has been conducted over the years, in order to detect novel markers that may potentially be used in clinical practice as a screening tool, in the context of the diagnostic process and as an indicator of response to treatment. An interesting field of application of such biomarkers is the management of female heterozygotes who present difficulty in predictable clinical progression. This review aims to summarise the current evidence and knowledge about general and specific markers that are actually measured in subjects with confirmed or suspected Fabry disease; moreover, we report potential novel markers such as microRNAs. Recent proteomic or metabolomic studies are in progress bringing out plasma proteome profiles in Fabry patients: this assessment may be useful to characterize molecular pathology of the disease, to improve diagnostic process, and to monitor response to treatment. The management of Fabry disease may be improved by the identification of biomarkers that reflect clinical course, severity, and the progression of the disease. Full article
(This article belongs to the Special Issue Biomarkers in Rare Diseases)
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19 pages, 1182 KiB  
Review
The Emerging and Diverse Roles of Bis(monoacylglycero) Phosphate Lipids in Cellular Physiology and Disease
by Megan R. Showalter, Anastasia L. Berg, Alexander Nagourney, Hailey Heil, Kermit L. Carraway III and Oliver Fiehn
Int. J. Mol. Sci. 2020, 21(21), 8067; https://doi.org/10.3390/ijms21218067 - 29 Oct 2020
Cited by 50 | Viewed by 5224
Abstract
Although understudied relative to many phospholipids, accumulating evidence suggests that bis(monoacylglycero)phosphate (BMP) is an important class of regulatory lipid that plays key roles in lysosomal integrity and function. BMPs are rare in most mammalian tissues, comprising only a few percent of total cellular [...] Read more.
Although understudied relative to many phospholipids, accumulating evidence suggests that bis(monoacylglycero)phosphate (BMP) is an important class of regulatory lipid that plays key roles in lysosomal integrity and function. BMPs are rare in most mammalian tissues, comprising only a few percent of total cellular lipid content, but are elevated in cell types such as macrophages that rely heavily on lysosomal function. BMPs are markedly enriched in endosomal and lysosomal vesicles compared to other organelles and membranous structures, and their unique sn-1:sn-1′ stereoconfiguration may confer stability within the hydrolytic lysosomal environment. BMP-enriched vesicles serve in endosomal-lysosomal trafficking and function as docking structures for the activation of lysosomal hydrolytic enzymes, notably those involved in the catabolic breakdown of sphingolipids. BMP levels are dysregulated in lysosomal storage disorders, phospholipidosis, metabolic diseases, liver and kidney diseases and neurodegenerative disorders. However, whether BMP alteration is a mediator or simply a marker of pathological states is unclear. Likewise, although BMP acyl chain composition may be altered with disease states, the functional significance of specific BMP species remains to be resolved. Newly developed tools for untargeted lipidomic analysis, together with a deeper understanding of enzymes mediating BMP synthesis and degradation, will help shed further light on the functional significance of BMPs in cellular physiology and pathology. Full article
(This article belongs to the Special Issue Biomarkers in Rare Diseases)
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24 pages, 1028 KiB  
Review
Key Players and Biomarkers of the Adaptive Immune System in the Pathogenesis of Sarcoidosis
by Emily-Rose Zhou and Sergio Arce
Int. J. Mol. Sci. 2020, 21(19), 7398; https://doi.org/10.3390/ijms21197398 - 7 Oct 2020
Cited by 22 | Viewed by 6392
Abstract
Sarcoidosis is a systemic inflammatory disease characterized by development of granulomas in the affected organs. Sarcoidosis is often a diagnosis of exclusion, and traditionally used tests for sarcoidosis demonstrate low sensitivity and specificity. We propose that accuracy of diagnosis can be improved if [...] Read more.
Sarcoidosis is a systemic inflammatory disease characterized by development of granulomas in the affected organs. Sarcoidosis is often a diagnosis of exclusion, and traditionally used tests for sarcoidosis demonstrate low sensitivity and specificity. We propose that accuracy of diagnosis can be improved if biomarkers of altered lymphocyte populations and levels of signaling molecules involved in disease pathogenesis are measured for patterns suggestive of sarcoidosis. These distinctive biomarkers can also be used to determine disease progression, predict prognosis, and make treatment decisions. Many subsets of T lymphocytes, including CD8+ T-cells and regulatory T-cells, have been shown to be dysfunctional in sarcoidosis, and the predominant CD4+ T helper cell subset in granulomas appears to be a strong indicator of disease phenotype and outcome. Studies of altered B cell populations, B cell signaling molecules, and immune complexes in sarcoidosis patients reveal promising biomarkers as well as possible explanations of disease etiology. Furthermore, examined biomarkers raise questions about new treatment methods and sarcoidosis antigens. Full article
(This article belongs to the Special Issue Biomarkers in Rare Diseases)
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20 pages, 354 KiB  
Review
The Progression of Hemophilic Arthropathy: The Role of Biomarkers
by Gianluigi Pasta, Salvatore Annunziata, Alberto Polizzi, Laura Caliogna, Eugenio Jannelli, Alessandro Minen, Mario Mosconi, Francesco Benazzo and Matteo Nicola Dario Di Minno
Int. J. Mol. Sci. 2020, 21(19), 7292; https://doi.org/10.3390/ijms21197292 - 2 Oct 2020
Cited by 14 | Viewed by 2757
Abstract
Background: Hemophilia A and B are X-linked congenital bleeding disorders characterized by recurrent hemarthroses leading to specific changes in the synovium and cartilage, which finally result in the destruction of the joint: this process is called hemophilic arthropathy (HA). This review highlights the [...] Read more.
Background: Hemophilia A and B are X-linked congenital bleeding disorders characterized by recurrent hemarthroses leading to specific changes in the synovium and cartilage, which finally result in the destruction of the joint: this process is called hemophilic arthropathy (HA). This review highlights the most prominent molecular biomarkers found in the literature to discuss their potential use in the clinical practice to monitor bleeding, to assess the progression of the HA and the effectiveness of treatments. Methods: A review of the literature was performed on PubMed and Embase, from 3 to 7 August 2020. Study selection and data extraction were achieved independently by two authors and the following inclusion criteria were determined a priori: English language, available full text and articles published in peer-reviewed journal. In addition, further articles were identified by checking the bibliography of relevant articles and searching for the studies cited in all the articles examined. Results: Eligible studies obtained at the end of the search and screen process were seventy-three (73). Conclusions: Despite the surge of interest in the clinical use of biomarkers, current literature underlines the lack of their standardization and their potential use in the clinical practice preserving the role of physical examination and imaging in early diagnosis. Full article
(This article belongs to the Special Issue Biomarkers in Rare Diseases)
16 pages, 301 KiB  
Review
Biomarkers Suggesting Favorable Prognostic Outcomes in Sudden Sensorineural Hearing Loss
by Jeon Gang Doo, Dokyoung Kim, Yong Kim, Myung Chul Yoo, Sung Su Kim, Jeewon Ryu and Seung Geun Yeo
Int. J. Mol. Sci. 2020, 21(19), 7248; https://doi.org/10.3390/ijms21197248 - 30 Sep 2020
Cited by 33 | Viewed by 4222
Abstract
Sudden sensorineural hearing loss (SSNHL) is a medical emergency, making detailed examination to determine possible causes and early treatment important. However, etiological examinations in SSNHL do not always reveal a cause, and several factors have been found to affect treatment outcomes. Various studies [...] Read more.
Sudden sensorineural hearing loss (SSNHL) is a medical emergency, making detailed examination to determine possible causes and early treatment important. However, etiological examinations in SSNHL do not always reveal a cause, and several factors have been found to affect treatment outcomes. Various studies are being performed to determine the prognosis and effects of treatment in patients who experience sudden hearing loss, and to identify biomarkers associated with this condition. Embase, PubMed, and the Cochrane database were searched using the key words SSNHL, prognostic, and biomarker. This search identified 4 articles in Embase, 28 articles in PubMed, and 36 in the Cochrane database. Of these 68 articles, 3 were duplicates and 37 were unrelated to the research topic. After excluding these articles, the remaining 28 articles were reviewed. Factors associated with SSNHL were divided into six categories: metabolic, hemostatic, inflammatory, immunologic, oxidative, and other factors. The associations between these factors with the occurrence of SSNHL and with patient prognosis were analyzed. Low monocyte counts, low neutrophil/lymphocyte ratio (NLR) and monocyte/high-density lipoproteins (HDL) cholesterol ratio (MHR), and low concentrations of fibrinogen, platelet glycoprotein (GP) IIIa, and TNF-α were found to be associated with good prognosis. However, these factors alone could not completely determine the onset of and recovery from SSNHL, suggesting the need for future basic and clinical studies. Full article
(This article belongs to the Special Issue Biomarkers in Rare Diseases)
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