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Metabolites
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New Advancements and Challenges in Clinical Metabolomics for Inborn Errors...
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New Advancements and Challenges in Clinical Metabolomics for Inborn Errors of Metabolism and Rare Diseases

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Endocrinology and Clinical Metabolic Research".

Deadline for manuscript submissions: 31 October 2024 | Viewed by 3574

Special Issue Editors

Dr. Adam D. Kennedy

E-Mail Website
Guest Editor
Metabolon, Inc., Morrisville, NC, USA
Interests: metabolomics; rare diseases; multiomics for rare genetic disorders; diagnostics; mechanisms of action for therapeutic interventions; biochemical diagnostics; validation of diagnostic assays; clinical studies for diagnostic assay validation and therapeutic interventions
Prof. Dr. Sarah H. Elsea

E-Mail Website
Guest Editor
Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
Interests: molecular and biochemical basis of rare disease; genomic disorders; metabolomics; diagnostics; neurodevelopmental disorders; caregiver concerns

Special Issue Information

Dear Colleagues,

Rare diseases and inborn errors of metabolism provide a significant medical challenge and often result in patients experiencing a long diagnostic odyssey prior to receiving a conclusive diagnosis. Many patients receive multiple incorrect diagnoses, and the development of new diagnostics and research tools are providing an avenue to identify biomarker signatures earlier and with significant accuracy. One of the major complications for diagnosing patients is that over 7,000 rare diseases are estimated to exist. However, many of these newer technologies can be leveraged together in order to provide conclusive diagnoses for patients, resulting in patients being treated earlier. Rare disease screening is becoming more popular throughout the world, and the screening of children and newborns will have an opportunity to add more diseases to these newborn screening panels as technologies increase the number of biomarkers that are identified, either through genomics, enzymatic assays, proteomic biomarkers, or metabolomics. Strong validation protocols, quality controls procedures, and rigorous biomarker identification are needed to identify the best tools to identify patients as soon as possible, and with the greatest sensitivity and specificity possible. By identifying these patients, clinicians can then begin therapeutic interventions, where these same above-mentioned technologies could play a significant role in helping monitor these therapeutic interventions (nutritional and medicinal) to determine if patients are responding to their treatment. By identifying more biomarkers and mechanisms of disease, clinical research will be able to develop more therapeutic interventions for the thousands of rare diseases that exist, of which only 5-10% have approved therapies to date. Identifying biomarkers of disease, delineating mechanisms of disease, developing new therapeutic interventions, and monitoring these therapies are all needed to treat patients that have a rare disease or inborn error of metabolism.

The Special Issue of Metabolites entitled “New Challenges in Clinical Metabolomics for Inborn Errors of Metabolism and Rare Diseases” will be dedicated to identifying and addressing the most current challenges in the field of diagnosing and treating rare diseases. In addition to clinical studies, basic research including animal models and cell culture studies will also be included to provide a robust picture of the latest results in the field. New bioinformatics approaches for data analysis and tools to analyze large data sets are of interest and will be considered for this Special Issue.

Dr. Adam D. Kennedy
Prof. Dr. Sarah H. Elsea
Guest Editors

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. Metabolites is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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

  • metabolic diseases
  • rare diseases
  • clinical metabolomics
  • genomics
  • inborn errors of metabolism

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Published Papers (4 papers)

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25 pages, 7059 KiB  
Article
Propionic Acidemia, Methylmalonic Acidemia, and Cobalamin C Deficiency: Comparison of Untargeted Metabolomic Profiles
by Anna Sidorina, Giulio Catesini, Elisa Sacchetti, Cristiano Rizzo and Carlo Dionisi-Vici
Metabolites 2024, 14(8), 428; https://doi.org/10.3390/metabo14080428 - 2 Aug 2024
Viewed by 415
Abstract
Methylmalonic acidemia (MMA), propionic acidemia (PA), and cobalamin C deficiency (cblC) share a defect in propionic acid metabolism. In addition, cblC is also involved in the process of homocysteine remethylation. These three diseases produce various phenotypes and complex downstream metabolic effects. In this [...] Read more.
Methylmalonic acidemia (MMA), propionic acidemia (PA), and cobalamin C deficiency (cblC) share a defect in propionic acid metabolism. In addition, cblC is also involved in the process of homocysteine remethylation. These three diseases produce various phenotypes and complex downstream metabolic effects. In this study, we used an untargeted metabolomics approach to investigate the biochemical differences and the possible connections among the pathophysiology of each disease. The significantly changed metabolites in the untargeted urine metabolomic profiles of 21 patients (seven MMA, seven PA, seven cblC) were identified through statistical analysis (p < 0.05; log2FC > |1|) and then used for annotation. Annotated features were associated with different metabolic pathways potentially involved in the disease’s development. Comparative statistics showed markedly different metabolomic profiles between MMA, PA, and cblC, highlighting the characteristic species for each disease. The most affected pathways were related to the metabolism of organic acids (all diseases), amino acids (all diseases), and glycine and its conjugates (in PA); the transsulfuration pathway; oxidative processes; and neurosteroid hormones (in cblC). The untargeted metabolomics study highlighted the presence of significant differences between the three diseases, pointing to the most relevant contrast in the cblC profile compared to MMA and PA. Some new biomarkers were proposed for PA, while novel data regarding the alterations of steroid hormone profiles and biomarkers of oxidative stress were obtained for cblC disease. The elevation of neurosteroids in cblC may indicate a potential connection with the development of ocular and neuronal deterioration. Full article
(This article belongs to the Special Issue New Advancements and Challenges in Clinical Metabolomics for Inborn Errors of Metabolism and Rare Diseases)
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14 pages, 2895 KiB  
Article
Factors Affecting Non-Enzymatic Protein Acylation by trans-3-Methylglutaconyl Coenzyme A
by Elizabeth A. Jennings, Megan M. Macdonald, Irina Romenskaia, Hao Yang, Grant A. Mitchell and Robert O. Ryan
Metabolites 2024, 14(8), 421; https://doi.org/10.3390/metabo14080421 - 31 Jul 2024
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Abstract
The leucine catabolism pathway intermediate, trans-3-methylglutaconyl (3MGC) CoA, is considered to be the precursor of 3MGC acid, a urinary organic acid associated with specific inborn errors of metabolism (IEM). trans-3MGC CoA is an unstable molecule that can undergo a sequence of [...] Read more.
The leucine catabolism pathway intermediate, trans-3-methylglutaconyl (3MGC) CoA, is considered to be the precursor of 3MGC acid, a urinary organic acid associated with specific inborn errors of metabolism (IEM). trans-3MGC CoA is an unstable molecule that can undergo a sequence of non-enzymatic chemical reactions that lead to either 3MGC acid or protein 3MGCylation. Herein, the susceptibility of trans-3MGC CoA to protein 3MGCylation was investigated. trans-3MGC CoA was generated through the activity of recombinant 3-methylcrotonyl CoA carboxylase (3MCCCase). Following enzyme incubations, reaction mixtures were spin-filtered to remove 3MCCCase. The recovered filtrates, containing trans-3MGC CoA, were then incubated in the presence of bovine serum albumin (BSA). Following this, sample aliquots were subjected to α-3MGC IgG immunoblot analysis to probe for 3MGCylated BSA. Experiments revealed a positive correlation between trans-3MGC CoA incubation temperature and 3MGCylated BSA immunoblot signal intensity. A similar correlation was observed between incubation time and 3MGCylated BSA immunoblot signal intensity. When trans-3MGC CoA hydratase (AUH) was included in incubations containing trans-3MGC CoA and BSA, 3MGCylated BSA immunoblot signal intensity decreased. Evidence that protein 3MGCylation occurs in vivo was obtained in studies with liver-specific 3-hydroxy-3-methylglutaryl (HMG) CoA lyase knockout mice. Therefore, trans-3MGC CoA is a reactive, potentially toxic metabolite, and under normal physiological conditions, lowering trans-3MGC CoA levels via AUH-mediated hydration to HMG CoA protects against aberrant non-enzymatic chemical reactions that lead to protein 3MGCylation and 3MGC acid production. Full article
(This article belongs to the Special Issue New Advancements and Challenges in Clinical Metabolomics for Inborn Errors of Metabolism and Rare Diseases)
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15 pages, 1353 KiB  
Article
Amino Acid Profile Alterations in Phenylketonuria: Implications for Clinical Practice
by Eliza Matuszewska, Joanna Matysiak, Łukasz Kałużny, Dariusz Walkowiak, Szymon Plewa, Monika Duś-Żuchowska, Natalia Rzetecka, Małgorzata Jamka, Agnieszka Klupczyńska-Gabryszak, Marcin Piorunek, Jan Matysiak and Jarosław Walkowiak
Metabolites 2024, 14(7), 397; https://doi.org/10.3390/metabo14070397 - 21 Jul 2024
Viewed by 692
Abstract
Patients with phenylketonuria (PKU) must restrict their intake of phenylalanine, which can also affect the levels of other essential and non-essential amino acids due to inadequate supply. Therefore, our objective was to assess amino acids in serum samples from 20 PKU patients and [...] Read more.
Patients with phenylketonuria (PKU) must restrict their intake of phenylalanine, which can also affect the levels of other essential and non-essential amino acids due to inadequate supply. Therefore, our objective was to assess amino acids in serum samples from 20 PKU patients and compare them with results from 51 healthy subjects. A sample analysis was conducted using liquid chromatography–tandem mass spectrometry. We obtained levels of 28 substances, including amino acids, biogenic amines, carnitine, and acetylcarnitine. Kynurenine (p = 0.000001), tyrosine (p = 0.0002), asparagine (p = 0.001), proline (p = 0.012), and the kynurenine/tryptophan ratio (p < 0.000001) were identified as features that differed between the studied groups, being significantly lower in patients with PKU. Glycine (p = 0.000012), putrescine (p = 0.0055), asymmetric dimethylarginine (p = 0.01), creatinine (p = 0.035) levels, as well as the total level of glucogenic amino acids (p = 0.0018), and the ratios of putrescine/ornithine (p = 0.003) and citrulline/ornithine (p = 0.0043) were significantly higher in the PKU group. In conclusion, the amino acid profiles in patients with PKU differ significantly from those in healthy peers, with potential clinical implications. These findings confirm the importance of metabolic testing in clinical practice and highlight the necessity for adequate dietary monitoring and adjustment. Full article
(This article belongs to the Special Issue New Advancements and Challenges in Clinical Metabolomics for Inborn Errors of Metabolism and Rare Diseases)
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11 pages, 1367 KiB  
Case Report
Integrating Genome Sequencing and Untargeted Metabolomics in Monozygotic Twins with a Rare Complex Neurological Disorder
by Rulan Shaath, Aljazi Al-Maraghi, Haytham Ali, Jehan AlRayahi, Adam D. Kennedy, Karen L. DeBalsi, Sura Hussein, Najwa Elbashir, Sujitha S. Padmajeya, Sasirekha Palaniswamy, Sarah H. Elsea, Ammira A. Akil, Noha A. Yousri and Khalid A. Fakhro
Metabolites 2024, 14(3), 152; https://doi.org/10.3390/metabo14030152 - 4 Mar 2024
Viewed by 1540
Abstract
Multi-omics approaches, which integrate genomics, transcriptomics, proteomics, and metabolomics, have emerged as powerful tools in the diagnosis of rare diseases. We used untargeted metabolomics and whole-genome sequencing (WGS) to gain a more comprehensive understanding of a rare disease with a complex presentation affecting [...] Read more.
Multi-omics approaches, which integrate genomics, transcriptomics, proteomics, and metabolomics, have emerged as powerful tools in the diagnosis of rare diseases. We used untargeted metabolomics and whole-genome sequencing (WGS) to gain a more comprehensive understanding of a rare disease with a complex presentation affecting female twins from a consanguineous family. The sisters presented with polymicrogyria, a Dandy–Walker malformation, respiratory distress, and multiorgan dysfunctions. Through WGS, we identified two rare homozygous variants in both subjects, a pathogenic variant in ADGRG1(p.Arg565Trp) and a novel variant in CNTNAP1(p.Glu910Val). These genes have been previously associated with autosomal recessive polymicrogyria and hypomyelinating neuropathy with/without contractures, respectively. The twins exhibited symptoms that overlapped with both of these conditions. The results of the untargeted metabolomics analysis revealed significant metabolic perturbations relating to neurodevelopmental abnormalities, kidney dysfunction, and microbiome. The significant metabolites belong to essential pathways such as lipids and amino acid metabolism. The identification of variants in two genes, combined with the support of metabolic perturbation, demonstrates the rarity and complexity of this phenotype and provides valuable insights into its underlying mechanisms. Full article
(This article belongs to the Special Issue New Advancements and Challenges in Clinical Metabolomics for Inborn Errors of Metabolism and Rare Diseases)
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