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The Value of Genetics in the Identification of Treatable Rare Diseases. The Paradigm of Inborn Errors of Metabolism

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A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (20 November 2020) | Viewed by 44895

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Special Issue Editors

Prof. Dr. Domingo González-Lamuño

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Guest Editor

Department of Pediatrics, University Hospital “Marqués de Valdecilla”- University of Cantabria, Instituto de Investigación Valdecilla (IDIVAL), 39005 Santander, Spain
Interests: inborn errors of metabolism; human (pediatric) genetics and genomics; developmental genetics; rare diseases; pediatric nephrology

Dr. Montserrat Morales

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Mitochondrial and Neuromuscular Diseases group, Research Institute "Hospital 12 de Octubre" (i + 12)
Center for Biomedical Research in the Network of Rare Diseases (CIBERER), Madrid, Spain
Interests: inborn errors of metabolism in adults; human genetics and genomics; developmental genetics; rare diseases

Special Issue Information

Dear colleagues,

It is a great pleasure to invite you to submit your research results on Rare Diseases in this monographic publication of Genes in 2020. Genes welcomes your latest research work for our next Special Issue: “The Value of Genetics in the Identification of Treatable Rare Diseases”, coordinated by Domingo González-Lamuño and Montserrat Morales.

Rare diseases are diseases with specific problems raised in relation to their rarity. Science can provide some answers regarding all rare diseases, and it is now possible to diagnose hundreds of them through biological sample tests. Among these, in recent decades, the field of inherited metabolic diseases has evolved from being a limited group of rare, untreatable, and often fatal disorders to being a major cause of acute life-threatening but largely treatable diseases. Innate errors of metabolism are currently one of the hottest topics in medicine, since patients with certain inherited metabolic diseases can now be expected to have a good prognosis with proper management.

Inborn errors of metabolism are rare diseases caused by defects of individual genes which encode enzymes that facilitate the conversion of substrates into metabolites, transporters, receptors, or molecules involved in organelles and cell traffic. Although any inborn error of metabolism is very rare, it generally occurs in 1 in 1500 births, which makes them quite common. These diseases can occur at any age and many of them are treatable; therefore, practical knowledge of these diseases, their presentations, and an appropriate diagnostic-therapeutic approach is essential.

The management of inborn errors of metabolism has traditionally consisted of diet therapy and supportive therapy, but other treatment options have recently become available, including enzyme and coenzyme replacement, removal of harmful substances, cell and organ transplantation, and gene therapy.

The study of these disorders, both in terms of prevention based on neonatal screening tests and genetic counseling as well as their diagnosis and treatment, is within the paradigm of the new precision medicine, which requires customizing diagnoses and treatments assuming participation of the child or adult patient and their family.

Clinicians, nutritionists, and researchers are increasingly working through networks in order to share the results of their research and to advance our knowledge more efficiently.

Knowledge of the natural history of these diseases is improved by the creation of registries. Neonatal screening plays an important role in early diagnosis, and the use of tandem mass spectrometry has increased the number of diseases that can be detected. Genetic analysis is indispensable for definitive diagnosis. On the basis of genetic analysis, it is possible to predict time of onset and complications, and to initiate the necessary treatment at the optimal time point. However, confirmation of diagnosis by genetic analysis is subject to limitations in terms of cost, time, efficiency, etc., and ethical considerations must also be taken into consideration. It is important to carry out genetic analysis when conducting genetic counseling.

Genes has a long history of publishing leading research in genetic disorders, and for this Special Issue we welcome submissions encompassing treatable genetic rare disorders, with a special focus on inborn metabolic diseases.

The Issue will be published in July 2020. Please highlight in your cover letter that the submission is to be considered for this Special Issue. Prospective authors are welcome to send pre-submission enquiries or direct any queries to the Genes Editorial Office.

In this Special Issue we will focus on the challenges of the relevance of genetics in the diagnosis of treatable rare diseases as well as new therapies on the horizon. The paradigm is inborn errors of metabolism but it will expand on so-called “generic topics” such as clinical trial design, funding for research, digital health, and big data on one hand, and will also focus on individual patients for innovation in drug development and the management of treatable rare genetic diseases.

Prof. Domingo González-Lamuño
Dr. Montserrat Morales
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. Genes 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 2600 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

rare diseases
genetics
diagnoses
therapeutics
inherited metabolic diseases
inborn errors
neonatal screening

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Published Papers (8 papers)

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Research

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16 pages, 4355 KiB

Open AccessArticle

Oxidative Stress, Glutathione Metabolism, and Liver Regeneration Pathways Are Activated in Hereditary Tyrosinemia Type 1 Mice upon Short-Term Nitisinone Discontinuation

by Haaike Colemonts-Vroninks, Jessie Neuckermans, Lionel Marcelis, Paul Claes, Steven Branson, Georges Casimir, Philippe Goyens, Geert A. Martens, Tamara Vanhaecke and Joery De Kock

Genes 2021, 12(1), 3; https://doi.org/10.3390/genes12010003 - 22 Dec 2020

Cited by 9 | Viewed by 6587

Abstract

Hereditary tyrosinemia type 1 (HT1) is an inherited condition in which the body is unable to break down the amino acid tyrosine due to mutations in the fumarylacetoacetate hydrolase (FAH) gene, coding for the final enzyme of the tyrosine degradation pathway. As a consequence, HT1 patients accumulate toxic tyrosine derivatives causing severe liver damage. Since its introduction, the drug nitisinone (NTBC) has offered a life-saving treatment that inhibits the upstream enzyme 4-hydroxyphenylpyruvate dioxygenase (HPD), thereby preventing production of downstream toxic metabolites. However, HT1 patients under NTBC therapy remain unable to degrade tyrosine. To control the disease and side-effects of the drug, HT1 patients need to take NTBC as an adjunct to a lifelong tyrosine and phenylalanine restricted diet. As a consequence of this strict therapeutic regime, drug compliance issues can arise with significant influence on patient health. In this study, we investigated the molecular impact of short-term NTBC therapy discontinuation on liver tissue of Fah-deficient mice. We found that after seven days of NTBC withdrawal, molecular pathways related to oxidative stress, glutathione metabolism, and liver regeneration were mostly affected. More specifically, NRF2-mediated oxidative stress response and several toxicological gene classes related to reactive oxygen species metabolism were significantly modulated. We observed that the expression of several key glutathione metabolism related genes including Slc7a11 and Ggt1 was highly increased after short-term NTBC therapy deprivation. This stress response was associated with the transcriptional activation of several markers of liver progenitor cells including Atf3, Cyr61, Ddr1, Epcam, Elovl7, and Glis3, indicating a concreted activation of liver regeneration early after NTBC withdrawal. Full article

(This article belongs to the Special Issue The Value of Genetics in the Identification of Treatable Rare Diseases. The Paradigm of Inborn Errors of Metabolism)

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10 pages, 575 KiB

Open AccessArticle

Next-Generation Sequencing in the Diagnosis of Patients with Bardet–Biedl Syndrome—New Variants and Relationship with Hyperglycemia and Insulin Resistance

by Krzysztof Jeziorny, Karolina Antosik, Paulina Jakiel, Wojciech Młynarski, Maciej Borowiec and Agnieszka Zmysłowska

Genes 2020, 11(11), 1283; https://doi.org/10.3390/genes11111283 - 29 Oct 2020

Cited by 16 | Viewed by 2664

Abstract

Bardet-Biedl syndrome (BBS) is a rare autosomal recessively inherited disease with major clinical symptoms such as: obesity, retinal degeneration, polydactyly and renal abnormalities. The aim of the study was to assess the spectrum of gene variants among patients with BBS, identified on the basis of nationwide genetic studies of monogenic diabetes in Polish population. Out of 575 patients enrolled for genetic testing from February 2017 to July 2019, 25 patients with a clinical suspicion of BBS were selected. The identification of pathogenic variants was performed by using targeted next-generation sequencing (NGS) on Illumina NextSeq 550 platform involving the SureSelect assay (Agilent, Santa Clara, CA, USA). BBS was genetically confirmed in 10 of 25 suspected patients. In patients, 14 different variants were found in six genes, mainly in BBS9 and BBS10 gene, including two novel variants. A strong association between hyperglycemia and insulin resistance in patients and the presence of variants in BBS9 gene was observed. Identification of 14 variants, including two new mutations using the NGS method, is the first molecular characteristic of Polish patients with Bardet–Biedl syndrome. It gives hope for earlier proper diagnosis of BBS in future patients selected from children with early childhood obesity and their medical multidisciplinary care. Full article

(This article belongs to the Special Issue The Value of Genetics in the Identification of Treatable Rare Diseases. The Paradigm of Inborn Errors of Metabolism)

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10 pages, 1868 KiB

Open AccessArticle

Identification of a Novel Variant in EARS2 Associated with a Severe Clinical Phenotype Expands the Clinical Spectrum of LTBL

by Sofia Barbosa-Gouveia, Emiliano González-Vioque, Álvaro Hermida, María Unceta Suarez, María Jesús Martínez-González, Filipa Borges, Liesbeth Wintjes, Antonia Kappen, Richard Rodenburg and María-Luz Couce

Genes 2020, 11(9), 1028; https://doi.org/10.3390/genes11091028 - 2 Sep 2020

Cited by 4 | Viewed by 3062

Abstract

The EARS2 nuclear gene encodes mitochondrial glutamyl-tRNA synthetase, a member of the class I family of aminoacyl-tRNA synthetases (aaRSs) that plays a crucial role in mitochondrial protein biosynthesis by catalyzing the charging of glutamate to mitochondrial tRNA(Glu). Pathogenic EARS2 variants have been associated with a rare mitochondrial disorder known as leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL). The targeted sequencing of 150 nuclear genes encoding respiratory chain complex subunits and proteins implicated in the oxidative phosphorylation (OXPHOS) function was performed. The oxygen consumption rate (OCR), and the extracellular acidification rate (ECAR), were measured. The enzymatic activities of Complexes I-V were analyzed spectrophotometrically. We describe a patient carrying two heterozygous EARS2 variants, c.376C>T (p.Gln126*) and c.670G>A (p.Gly224Ser), with infantile-onset disease and a severe clinical presentation. We demonstrate a clear defect in mitochondrial function in the patient’s fibroblasts, suggesting the molecular mechanism underlying the pathogenicity of these EARS2 variants. Experimental validation using patient-derived fibroblasts allowed an accurate characterization of the disease-causing variants, and by comparing our patient’s clinical presentation with that of previously reported cases, new clinical and radiological features of LTBL were identified, expanding the clinical spectrum of this disease. Full article

(This article belongs to the Special Issue The Value of Genetics in the Identification of Treatable Rare Diseases. The Paradigm of Inborn Errors of Metabolism)

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10 pages, 257 KiB

Open AccessArticle

Metabolic Serendipities of Expanded Newborn Screening

by Raquel Yahyaoui, Javier Blasco-Alonso, Montserrat Gonzalo-Marín, Carmen Benito, Juliana Serrano-Nieto, Inmaculada González-Gallego, Pedro Ruiz-Sala, Belén Pérez and Domingo González-Lamuño

Genes 2020, 11(9), 1018; https://doi.org/10.3390/genes11091018 - 29 Aug 2020

Cited by 7 | Viewed by 2995

Abstract

Incidental findings on newborn screening (NBS) are results that are not the target of screening within a given NBS program, but rather are found as a result of the screening and resulting diagnostic workup for that target. These findings may not have an immediate clinical impact on the newborn, but are sometimes an additional benefit of NBS programs and may be considered secondary targets of NBS programs. This work describes four case reports that had incidental findings on the NBS, which eventually led to the diagnosis of another metabolic disease instead of the one that was initially suspected. The first case was a new defect in the cationic amino acid transporter-2 (CAT-2), which was oriented as an arginase-1 deficiency in the newborn. The second case was a maternal glutaric aciduria type 1 (GA-1) that mimicked a carnitine transporter deficiency in the newborn. The third report was a case of lysinuric protein intolerance (LPI), which appeared as high levels of citrulline on the NBS. The fourth case was a mother with homocystinuria that was diagnosed during the biochemical study of vitamin B₁₂ status. All cases provide new or interesting data that will help guide differential diagnosis in the future. Full article

(This article belongs to the Special Issue The Value of Genetics in the Identification of Treatable Rare Diseases. The Paradigm of Inborn Errors of Metabolism)

13 pages, 1263 KiB

Open AccessArticle

Molecular Analysis of 55 Spanish Patients with Acute Intermittent Porphyria

by María-José Morán-Jiménez, María-José Borrero-Corte, Fátima Jara-Rubio, Inmaculada García-Pastor, Silvia Díaz-Díaz, Francisco-Javier Castelbón-Fernandez, Rafael Enríquez-de-Salamanca and Manuel Méndez

Genes 2020, 11(8), 924; https://doi.org/10.3390/genes11080924 - 12 Aug 2020

Cited by 8 | Viewed by 2991

Abstract

Acute intermittent porphyria (AIP) results from a decreased activity of hepatic hydroxymethylbilane synthase (HMBS), the third enzyme in the heme biosynthetic pathway. AIP is an autosomal dominant disorder with incomplete penetrance, characterized by acute neurovisceral attacks precipitated by several factors that induce the hepatic 5-aminolevulinic acid synthase, the first enzyme in the heme biosynthesis. Thus, a deficiency in HMBS activity results in an overproduction of porphyrin precursors and the clinical manifestation of the disease. Early diagnosis and counselling are essential to prevent attacks, and mutation analysis is the most accurate method to identify asymptomatic carriers in AIP families. In the present study, we have investigated the molecular defects in 55 unrelated Spanish patients with AIP, identifying 32 HMBS gene mutations, of which six were novel and ten were found in more than one patient. The novel mutations included a missense, an insertion, two deletions, and two splice site variants. Prokaryotic expression studies demonstrated the detrimental effect for the missense mutation, whereas reverse transcription-PCR and sequencing showed aberrant splicing caused by each splice site mutation. These results will allow for an accurate diagnosis of carriers of the disease in these families. Furthermore, they increase the knowledge about the molecular heterogeneity of AIP in Spain. Full article

(This article belongs to the Special Issue The Value of Genetics in the Identification of Treatable Rare Diseases. The Paradigm of Inborn Errors of Metabolism)

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17 pages, 751 KiB

Open AccessReview

The Spectrum of Mutations of Homocystinuria in the MENA Region

by Duaa W. Al-Sadeq and Gheyath K. Nasrallah

Genes 2020, 11(3), 330; https://doi.org/10.3390/genes11030330 - 20 Mar 2020

Cited by 24 | Viewed by 11803

Abstract

Homocystinuria is an inborn error of metabolism due to the deficiency in cystathionine beta-synthase (CBS) enzyme activity. It leads to the elevation of both homocysteine and methionine levels in the blood and urine. Consequently, this build-up could lead to several complications such as nearsightedness, dislocated eye lenses, a variety of psychiatric and behavioral disorders, as well as vascular system complications. The prevalence of homocystinuria is around 1/200,000 births worldwide. However, its prevalence in the Gulf region, notably Qatar, is exceptionally high and reached 1:1800. To date, more than 191 pathogenic CBS mutations have been documented. The majority of these mutations were identified in Caucasians of European ancestry, whereas only a few mutations from African-Americans or Asians were reported. Approximately 87% of all CBS mutations are missense and do not target the CBS catalytic site, but rather result in unstable misfolded proteins lacking the normal biological function, designating them for degradation. The early detection of homocystinuria along with low protein and methionine-restricted diet is the best treatment approach for all types of homocystinuria patients. Yet, less than 50% of affected individuals show a significant reduction in plasma homocysteine levels after treatment. Patients who fail to lower the elevated homocysteine levels, through high protein-restricted diet or by B6 and folic acid supplements, are at higher risk for cardiovascular diseases, neurodegenerative diseases, neural tube defects, and other severe clinical complications. This review aims to examine the mutations spectrum of the CBS gene, the disease management, as well as the current and potential treatment approaches with a greater emphasis on studies reported in the Middle East and North Africa (MENA) region. Full article

(This article belongs to the Special Issue The Value of Genetics in the Identification of Treatable Rare Diseases. The Paradigm of Inborn Errors of Metabolism)

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20 pages, 978 KiB

Open AccessReview

The Roles of the NLRP3 Inflammasome in Neurodegenerative and Metabolic Diseases and in Relevant Advanced Therapeutic Interventions

by Rameez Hassan Pirzada, Nasir Javaid and Sangdun Choi

Genes 2020, 11(2), 131; https://doi.org/10.3390/genes11020131 - 27 Jan 2020

Cited by 58 | Viewed by 11123

Abstract

Inflammasomes are intracellular multiprotein complexes in the cytoplasm that regulate inflammation activation in the innate immune system in response to pathogens and to host self-derived molecules. Recent advances greatly improved our understanding of the activation of nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasomes at the molecular level. The NLRP3 belongs to the subfamily of NLRP which activates caspase 1, thus causing the production of proinflammatory cytokines (interleukin 1β and interleukin 18) and pyroptosis. This inflammasome is involved in multiple neurodegenerative and metabolic disorders including Alzheimer’s disease, multiple sclerosis, type 2 diabetes mellitus, and gout. Therefore, therapeutic targeting to the NLRP3 inflammasome complex is a promising way to treat these diseases. Recent research advances paved the way toward drug research and development using a variety of machine learning-based and artificial intelligence-based approaches. These state-of-the-art approaches will lead to the discovery of better drugs after the training of such a system. Full article

(This article belongs to the Special Issue The Value of Genetics in the Identification of Treatable Rare Diseases. The Paradigm of Inborn Errors of Metabolism)

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9 pages, 1947 KiB

Open AccessCase Report

Leigh Syndrome in a Pedigree Harboring the m.1555A>G Mutation in the Mitochondrial 12S rRNA

by Mouna Habbane, Laura Llobet, M. Pilar Bayona-Bafaluy, José E. Bárcena, Leticia Ceberio, Covadonga Gómez-Díaz, Laura Gort, Rafael Artuch, Julio Montoya and Eduardo Ruiz-Pesini

Genes 2020, 11(9), 1007; https://doi.org/10.3390/genes11091007 - 27 Aug 2020

Cited by 7 | Viewed by 2835

Abstract

Background: Leigh syndrome (LS) is a serious genetic disease that can be caused by mutations in dozens of different genes. Methods: Clinical study of a deafness pedigree in which some members developed LS. Cellular, biochemical and molecular genetic analyses of patients’ tissues and cybrid cell lines were performed. Results: mitochondrial DNA (mtDNA) m.1555A>G/MT-RNR1 and m.9541T>C/MT-CO3 mutations were found. The first one is a well-known pathologic mutation. However, the second one does not appear to contribute to the high hearing loss penetrance and LS phenotype observed in this family. Conclusion: The m.1555A>G pathological mutation, accompanied with an unknown nuclear DNA (nDNA) factor, could be the cause of the phenotypic manifestations in this pedigree. Full article

(This article belongs to the Special Issue The Value of Genetics in the Identification of Treatable Rare Diseases. The Paradigm of Inborn Errors of Metabolism)

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