Biomarkers in Genetic Metabolic Disorders

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Endocrinology & Metabolism".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 24742

Special Issue Editors

1. Professor of Pediatrics, Pediatric Gastroenterology, Hepatology and Nutrition Unit, Complejo Hospitalario Universitario Insular Materno-Infantil, Las Palmas, Spain
2. CIBEROBN, University of Las Palmas de Gran Canaria, Las Palmas, Spain
Interests: pediatric nutrition; pediatric gastroenterology; obesity; inborn errors of metabolism
Special Issues, Collections and Topics in MDPI journals
Department of Pediatrics, University Hospital “Marqués de Valdecilla”- University of Cantabria, Instituto de Investigación Valdecilla (IDIVAL), Avenida Cardenal Herrera Oria s/n, 39011 Santander (CANTABRIA), Spain
Interests: inborn errors of metabolism; human (pediatric) genetics and genomics; developmental genetics; rare diseases; pediatric nephrology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Inborn errors of metabolism (IEM), are caused by alterations of specific metabolic reactions, with more than 800 different IEM described and affecting about 1 in every 5000 born babies. Several IEM have already been characterized through the identification of clinical metabolic biomarkers that can explain the pathological phenotype. However, with the surge in the scope and quality of metabolomic measurements, metabolomics is destined to play an even more central role in the near future as an efficient diagnostic tool and as a safety evaluator of treatment responses.

The possibility of studying the complete repertoire of small molecules in biological fluids represents a major and rapidly evolving research field in systems biology and the basis for the clinical management of patients with IEM.  Metabolomics offers, within genomics and proteomics, tools for diagnosing and understanding disease as they can be measured noninvasively in biofluids in a rather straightforward manner. Changes in metabolite levels reflect the actual metabolic state, translating the genotype and environmental factors into the phenotype.

Recent advances in metabolomic approaches enable an expanded newborn screening that improves early diagnosis and treatment in numerous IEM. Consequently, with the introduction of this expanded newborn screening, an increasing number of laboratories is involved in follow-up confirmatory testing and biomarkers. Biomarkers used in the initial diagnosis of disease may be different than the follow-up markers, both related with the prognosis and treatment responses.

The access to human metabolic network models, along with the detailed documentation of all known IEM, gives the opportunity to systematically predict potential metabolic disease biomarkers on a large scale. The discovery of new biomarkers related to any aspect of IEM can substantially advance our understanding of disease pathophysiology, which can be useful in the clinical management of IEM patients.

We invite you to share your research results in our Special Issue entitled “Biomarkers in genetic Inborn Errors of Metabolism”, covering currently used biomarkers as well as markers that are in development. We would be delighted to receive your original studies on biomarkers related to clinical presentation, diagnosis and follow-up, genetics and pathogenesis, treatment and prognosis of patients with IEM.

Prof. Luis Peña-Quintana
Prof. Domingo González-Lamuño
Guest Editors

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Keywords

  • inborn errors of metabolism
  • genetics metabolics disorders
  • biomarkers
  • beta oxidation
  • amino acids
  • vitamins
  • carbohydrates
  • oligoelements
  • metabolomics

Published Papers (8 papers)

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Research

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12 pages, 550 KiB  
Article
Lymphocyte Medium-Chain Acyl-CoA Dehydrogenase Activity and Its Potential as a Diagnostic Confirmation Tool in Newborn Screening Cases
by Patricia Alcaide, Isaac Ferrer-López, Leticia Gutierrez, Fatima Leal, Elena Martín-Hernández, Pilar Quijada-Fraile, Marcello Bellusci, Ana Moráis, Consuelo Pedrón-Giner, Dolores Rausell, Patricia Correcher, María Unceta, Sinziana Stanescu, Magdalena Ugarte, Pedro Ruiz-Sala and Belén Pérez
J. Clin. Med. 2022, 11(10), 2933; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm11102933 - 23 May 2022
Viewed by 1669
Abstract
The determination of acylcarnitines (AC) in dried blood spots (DBS) by tandem mass spectrometry in newborn screening (NBS) programs has enabled medium-chain acyl-coA dehydrogenase deficiency (MCADD) to be identified in presymptomatic newborns. Nevertheless, different confirmatory tests must be performed to confirm the diagnosis. [...] Read more.
The determination of acylcarnitines (AC) in dried blood spots (DBS) by tandem mass spectrometry in newborn screening (NBS) programs has enabled medium-chain acyl-coA dehydrogenase deficiency (MCADD) to be identified in presymptomatic newborns. Nevertheless, different confirmatory tests must be performed to confirm the diagnosis. In this work, we have collected and analyzed the NBS results and confirmatory test results (plasma AC, molecular findings, and lymphocyte MCAD activity) of forty individuals, correlating them with clinical outcomes and treatment, with the aim of obtaining useful diagnostic information that could be applied in the follow-up of the patients. Our results led us to classify patients into two groups. The first group (14 cases) had high increased octanoylcarnitine (C8) levels, biallelic pathogenic variants, and severe impaired enzyme activity (<10% of the intra-assay control (IAC)); all of these cases received nutritional therapy and required carnitine supplementation during follow-up, representing the most severe form of the disease. The second group (16 patients) was a heterogeneous group presenting moderate increases in C8, biallelic likely pathogenic/pathogenic variants, and intermediate activity (<41% IAC). All of them are currently asymptomatic and could be considered as having a milder form of the disease. Finally, eight cases presented a normal–mild increase in plasma C8, with only one pathogenic variant detected, and high–intermediate residual activity (15–100%). Based on our results, we confirm that combined evaluation of acylcarnitine profiles, genetic findings, and residual enzyme activities proves useful in predicting the risk of future metabolic decompensation, in making decisions regarding future treatment or follow-up, and also in confirming the clinical effects of unknown clinical variants. Full article
(This article belongs to the Special Issue Biomarkers in Genetic Metabolic Disorders)
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10 pages, 718 KiB  
Article
Relationships between Plasma Pyrophosphate, Vascular Calcification and Clinical Severity in Patients Affected by Pseudoxanthoma Elasticum
by Georges Leftheriotis, Nastassia Navasiolava, Laetitia Clotaire, Christophe Duranton, Olivier Le Saux, Saïd Bendahhou, Audrey Laurain, Isabelle Rubera and Ludovic Martin
J. Clin. Med. 2022, 11(9), 2588; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm11092588 - 05 May 2022
Cited by 9 | Viewed by 1680
Abstract
Pseudoxanthoma elasticum (PXE; OMIM 264800) is an autosomal recessive metabolic disorder characterized by progressive calcification in the skin, the Bruch’s membrane, and the vasculature. Calcification in PXE results from a low level of circulating pyrophosphate (PPi) caused by ABCC6 deficiency. In this study, [...] Read more.
Pseudoxanthoma elasticum (PXE; OMIM 264800) is an autosomal recessive metabolic disorder characterized by progressive calcification in the skin, the Bruch’s membrane, and the vasculature. Calcification in PXE results from a low level of circulating pyrophosphate (PPi) caused by ABCC6 deficiency. In this study, we used a cohort of 107 PXE patients to determine the pathophysiological relationship between plasma PPi, coronary calcification (CAC), lower limbs arterial calcification (LLAC), and disease severity. Overall, our data showed a deficit in plasma PPi in PXE patients compared to controls. Remarkably, affected females showed higher PPi levels than males, but a lower LLAC. There was a strong correlation between age and PPi in PXE patients (r = 0.423, p < 0.0001) but not in controls (r = 0.059, p = 0.828). A weak correlation was found between PPi and CAC (r = 0.266, p < 0.02); however, there was no statistically significant connection with LLAC (r = 0.068, p = 0.518) or a severity score (r = 0.077, p = 0.429). Surprisingly, we found no significant correlation between plasma alkaline phosphatase activity and PPi (r = 0.113, p = 0.252) or between a 10-year cardiovascular risk score and all other variables. Multivariate analysis confirmed that LLAC and CAC were strongly dependent on age, but not on PPi. Our data showed that arterial calcification is only weakly linked to circulating PPi levels and that time (i.e., age) appears to be the major determinant of disease severity and calcification in PXE. These data are important to better understand the natural history of this disease but also for the follow-up and management of patients, and the design of future clinical trials. Our results also show that PPi is not a good biomarker for the evaluation of disease severity and progression. Full article
(This article belongs to the Special Issue Biomarkers in Genetic Metabolic Disorders)
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13 pages, 1424 KiB  
Article
NTBC Treatment Monitoring in Chilean Patients with Tyrosinemia Type 1 and Its Association with Biochemical Parameters and Liver Biomarkers
by Karen Fuenzalida, María Jesús Leal-Witt, Patricio Guerrero, Valerie Hamilton, María Florencia Salazar, Felipe Peñaloza, Carolina Arias and Verónica Cornejo
J. Clin. Med. 2021, 10(24), 5832; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10245832 - 13 Dec 2021
Cited by 2 | Viewed by 1814
Abstract
Treatment and follow-up in Hereditary Tyrosinemia type 1 (HT-1) patients require comprehensive clinical and dietary management, which involves drug therapy with NTBC and the laboratory monitoring of parameters, including NTBC levels, succinylacetone (SA), amino acids, and various biomarkers of liver and kidney function. [...] Read more.
Treatment and follow-up in Hereditary Tyrosinemia type 1 (HT-1) patients require comprehensive clinical and dietary management, which involves drug therapy with NTBC and the laboratory monitoring of parameters, including NTBC levels, succinylacetone (SA), amino acids, and various biomarkers of liver and kidney function. Good adherence to treatment and optimal adjustment of the NTBC dose, according to clinical manifestations and laboratory parameters, can prevent severe liver complications such as hepatocarcinogenesis (HCC). We analyzed several laboratory parameters for 15 HT-1 patients over one year of follow-up in a cohort that included long-term NTBC-treated patients (more than 20 years), as well as short-term patients (one year). Based on this analysis, we described the overall adherence by our cohort of 70% adherence to drug and dietary treatment. A positive correlation was found between blood and plasma NTBC concentration with a conversion factor of 2.57. Nonetheless, there was no correlation of the NTBC level with SA levels, αFP, liver biomarkers, and amino acids in paired samples analysis. By separating according to the range of the NTBC concentration, we therefore determined the mean concentration of each biochemical marker, for NTBC ranges above 15–25 μmol/L. SA in urine and αFP showed mean levels within controlled parameters in our group of patients. Future studies analyzing a longer follow-up period, as well as SA determination in the blood, are encouraged to confirm the present findings. Full article
(This article belongs to the Special Issue Biomarkers in Genetic Metabolic Disorders)
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11 pages, 1518 KiB  
Article
Urine Phenylacetylglutamine Determination in Patients with Hyperphenylalaninemia
by Fernando Andrade, Ainara Cano, María Unceta Suarez, Arantza Arza, Ana Vinuesa, Leticia Ceberio, Nuria López-Oslé, Gorka de Frutos, Raquel López-Oceja, Elena Aznal, Domingo González-Lamuño and Javier de las Heras
J. Clin. Med. 2021, 10(16), 3674; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10163674 - 19 Aug 2021
Cited by 3 | Viewed by 2038
Abstract
Phenylketonuria (PKU), an autosomal-recessive inborn error of phenylalanine (Phe) metabolism is the most prevalent disorder of amino acid metabolism. Currently, clinical follow-up relies on frequent monitoring of Phe levels in blood. We hypothesize that the urine level of phenylacetylglutamine (PAG), a phenyl-group marker, [...] Read more.
Phenylketonuria (PKU), an autosomal-recessive inborn error of phenylalanine (Phe) metabolism is the most prevalent disorder of amino acid metabolism. Currently, clinical follow-up relies on frequent monitoring of Phe levels in blood. We hypothesize that the urine level of phenylacetylglutamine (PAG), a phenyl-group marker, could be used as a non-invasive biomarker. In this cross-sectional study, a validated liquid chromatography coupled to tandem mass spectrometry (LC-MS) method was used for urinary PAG quantification in 35 participants with hyperphenylalaninemia (HPA) and 33 age- and sex-matched healthy controls. We have found that (a) PKU patients present higher urine PAG levels than healthy control subjects, and that (b) there is a significant correlation between urine PAG and circulating Phe levels in patients with HPA. In addition, we show a significant strong correlation between Phe levels from venous blood samples and from capillary finger-prick dried blood spot (DBS) samples collected at the same time in patients with HPA. Further research in order to assess the potential role of urine PAG as a non-invasive biomarker in PKU is warranted. Full article
(This article belongs to the Special Issue Biomarkers in Genetic Metabolic Disorders)
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14 pages, 1487 KiB  
Article
Transferrin Isoforms, Old but New Biomarkers in Hereditary Fructose Intolerance
by Ainara Cano, Carlos Alcalde, Amaya Belanger-Quintana, Elvira Cañedo-Villarroya, Leticia Ceberio, Silvia Chumillas-Calzada, Patricia Correcher, María Luz Couce, Dolores García-Arenas, Igor Gómez, Tomás Hernández, Elsa Izquierdo-García, Dámaris Martínez Chicano, Montserrat Morales, Consuelo Pedrón-Giner, Estrella Petrina Jáuregui, Luis Peña-Quintana, Paula Sánchez-Pintos, Juliana Serrano-Nieto, María Unceta Suarez, Isidro Vitoria Miñana and Javier de las Herasadd Show full author list remove Hide full author list
J. Clin. Med. 2021, 10(13), 2932; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10132932 - 30 Jun 2021
Cited by 4 | Viewed by 2497
Abstract
Hereditary Fructose Intolerance (HFI) is an autosomal recessive inborn error of metabolism characterised by the deficiency of the hepatic enzyme aldolase B. Its treatment consists in adopting a fructose-, sucrose-, and sorbitol (FSS)-restrictive diet for life. Untreated HFI patients present an abnormal transferrin [...] Read more.
Hereditary Fructose Intolerance (HFI) is an autosomal recessive inborn error of metabolism characterised by the deficiency of the hepatic enzyme aldolase B. Its treatment consists in adopting a fructose-, sucrose-, and sorbitol (FSS)-restrictive diet for life. Untreated HFI patients present an abnormal transferrin (Tf) glycosylation pattern due to the inhibition of mannose-6-phosphate isomerase by fructose-1-phosphate. Hence, elevated serum carbohydrate-deficient Tf (CDT) may allow the prompt detection of HFI. The CDT values improve when an FSS-restrictive diet is followed; however, previous data on CDT and fructose intake correlation are inconsistent. Therefore, we examined the complete serum sialoTf profile and correlated it with FSS dietary intake and with hepatic parameters in a cohort of paediatric and adult fructosemic patients. To do so, the profiles of serum sialoTf from genetically diagnosed HFI patients on an FSS-restricted diet (n = 37) and their age-, sex- and body mass index-paired controls (n = 32) were analysed by capillary zone electrophoresis. We found that in HFI patients, asialoTf correlated with dietary intake of sucrose (R = 0.575, p < 0.001) and FSS (R = 0.475, p = 0.008), and that pentasialoTf+hexasialoTf negatively correlated with dietary intake of fructose (R = −0.386, p = 0.024) and FSS (R = −0.400, p = 0.019). In addition, the tetrasialoTf/disialoTf ratio truthfully differentiated treated HFI patients from healthy controls, with an area under the ROC curve (AUROC) of 0.97, 92% sensitivity, 94% specificity and 93% accuracy. Full article
(This article belongs to the Special Issue Biomarkers in Genetic Metabolic Disorders)
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Review

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17 pages, 2206 KiB  
Review
The Utility of Genomic Testing for Hyperphenylalaninemia
by Elisabetta Anna Tendi, Maria Guarnaccia, Giovanna Morello and Sebastiano Cavallaro
J. Clin. Med. 2022, 11(4), 1061; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm11041061 - 18 Feb 2022
Cited by 4 | Viewed by 2230
Abstract
Hyperphenylalaninemia (HPA), the most common amino acid metabolism disorder, is caused by defects in enzymes involved in phenylalanine metabolism, with the consequent accumulation of phenylalanine and its secondary metabolites in body fluids and tissues. Clinical manifestations of HPA include mental retardation, and its [...] Read more.
Hyperphenylalaninemia (HPA), the most common amino acid metabolism disorder, is caused by defects in enzymes involved in phenylalanine metabolism, with the consequent accumulation of phenylalanine and its secondary metabolites in body fluids and tissues. Clinical manifestations of HPA include mental retardation, and its early diagnosis with timely treatment can improve the prognosis of affected patients. Due to the genetic complexity and heterogeneity of HPA, high-throughput molecular technologies, such as next-generation sequencing (NGS), are becoming indispensable tools to fully characterize the etiology, helping clinicians to promptly identify the exact patients’ genotype and determine the appropriate treatment. In this review, after a brief overview of the key enzymes involved in phenylalanine metabolism, we represent the wide spectrum of genes and their variants associated with HPA and discuss the utility of genomic testing for improved diagnosis and clinical management of HPA. Full article
(This article belongs to the Special Issue Biomarkers in Genetic Metabolic Disorders)
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26 pages, 14619 KiB  
Review
Biochemical Markers for the Diagnosis of Mitochondrial Fatty Acid Oxidation Diseases
by Pedro Ruiz-Sala and Luis Peña-Quintana
J. Clin. Med. 2021, 10(21), 4855; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10214855 - 22 Oct 2021
Cited by 22 | Viewed by 6713
Abstract
Mitochondrial fatty acid β-oxidation (FAO) contributes a large proportion to the body’s energy needs in fasting and in situations of metabolic stress. Most tissues use energy from fatty acids, particularly the heart, skeletal muscle and the liver. In the brain, ketone bodies formed [...] Read more.
Mitochondrial fatty acid β-oxidation (FAO) contributes a large proportion to the body’s energy needs in fasting and in situations of metabolic stress. Most tissues use energy from fatty acids, particularly the heart, skeletal muscle and the liver. In the brain, ketone bodies formed from FAO in the liver are used as the main source of energy. The mitochondrial fatty acid oxidation disorders (FAODs), which include the carnitine system defects, constitute a group of diseases with several types and subtypes and with variable clinical spectrum and prognosis, from paucisymptomatic cases to more severe affectations, with a 5% rate of sudden death in childhood, and with fasting hypoketotic hypoglycemia frequently occurring. The implementation of newborn screening programs has resulted in new challenges in diagnosis, with the detection of new phenotypes as well as carriers and false positive cases. In this article, a review of the biochemical markers used for the diagnosis of FAODs is presented. The analysis of acylcarnitines by MS/MS contributes to improving the biochemical diagnosis, both in affected patients and in newborn screening, but acylglycines, organic acids, and other metabolites are also reported. Moreover, this review recommends caution, and outlines the differences in the interpretation of the biomarkers depending on age, clinical situation and types of samples or techniques. Full article
(This article belongs to the Special Issue Biomarkers in Genetic Metabolic Disorders)
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18 pages, 2381 KiB  
Review
Biomarkers in Fabry Disease. Implications for Clinical Diagnosis and Follow-up
by Clara Carnicer-Cáceres, Jose Antonio Arranz-Amo, Cristina Cea-Arestin, Maria Camprodon-Gomez, David Moreno-Martinez, Sara Lucas-Del-Pozo, Marc Moltó-Abad, Ariadna Tigri-Santiña, Irene Agraz-Pamplona, Jose F Rodriguez-Palomares, Jorge Hernández-Vara, Mar Armengol-Bellapart, Mireia del-Toro-Riera and Guillem Pintos-Morell
J. Clin. Med. 2021, 10(8), 1664; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10081664 - 13 Apr 2021
Cited by 13 | Viewed by 4839
Abstract
Fabry disease (FD) is a lysosomal storage disorder caused by deficient alpha-galactosidase A activity in the lysosome due to mutations in the GLA gene, resulting in gradual accumulation of globotriaosylceramide and other derivatives in different tissues. Substrate accumulation promotes different pathogenic mechanisms in [...] Read more.
Fabry disease (FD) is a lysosomal storage disorder caused by deficient alpha-galactosidase A activity in the lysosome due to mutations in the GLA gene, resulting in gradual accumulation of globotriaosylceramide and other derivatives in different tissues. Substrate accumulation promotes different pathogenic mechanisms in which several mediators could be implicated, inducing multiorgan lesions, mainly in the kidney, heart and nervous system, resulting in clinical manifestations of the disease. Enzyme replacement therapy was shown to delay disease progression, mainly if initiated early. However, a diagnosis in the early stages represents a clinical challenge, especially in patients with a non-classic phenotype, which prompts the search for biomarkers that help detect and predict the evolution of the disease. We have reviewed the mediators involved in different pathogenic mechanisms that were studied as potential biomarkers and can be easily incorporated into clinical practice. Some accumulation biomarkers seem to be useful to detect non-classic forms of the disease and could even improve diagnosis of female patients. The combination of such biomarkers with some response biomarkers, may be useful for early detection of organ injury. The incorporation of some biomarkers into clinical practice may increase the capacity of detection compared to that currently obtained with the established diagnostic markers and provide more information on the progression and prognosis of the disease. Full article
(This article belongs to the Special Issue Biomarkers in Genetic Metabolic Disorders)
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