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Genetic Research in Metabolic Diseases

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

Deadline for manuscript submissions: closed (10 March 2023) | Viewed by 63410

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Special Issue Editors

Prof. Dr. Maurizio Scarpa

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Guest Editor

Regional Coordinating Center for Rare Diseases, European Reference Network for Hereditary Metabolic Diseases (MetabERN), Udine University Hospital, Piazzale Santa Maria della Misericordia 15, 33100 Udine, Italy
Interests: inherited metabolic diseases (IMDs); lysosomal storage disorders (LSD); newborn screening; gene therapy; artificial intelligence
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Peter Witters

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Department of Pediatrics, Universitair Ziekenhuis Leuven, Leuven, Belgium
Interests: inherited metabolic diseases (IMDs); congenital disorders of glycosylation (CDG); hepatology; liver disease

Special Issue Information

Dear Colleagues,

With more than 1,400 different genetic diseases affecting a variety of biochemical pathways, the field of metabolic diseases represents a dynamic and expanding field of genetic research. In recent years, the increased knowledge in genetics, biochemistry, and molecular biology, together with technological advancements, especially in genomic sequencing and artificial intelligence, has animated researchers and clinicians who are dealing with the complexity of inherited metabolic diseases (IMDs). In particular, the areas of lysosomal storage disorders (LSD), congenital disorders of glycosylation (CDG), and mitochondrial disorders have seen important advancements and discoveries. From newborn screening programs to gene therapy, these diseases offer a wide range of possibilities in genetic research, with the potential of an unprecedented impact on those affected. At the same time, the field is characterized by unique technical and ethical challenges.

This Special Issue on Genetic Research in Metabolic Diseases will provide an updated overview, novel insights, and critical perspectives in the pathophysiology, diagnosis, and treatment of inherited metabolic disorders such as LSD, CDG, and mitochondrial disorders. Given the complexity and broadness of these topics, contributions from experts in the field through research papers and reviews are welcome.

Prof. Dr. Maurizio Scarpa
Prof. Dr. Peter Witters
Guest Editors

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Keywords

Genetics of inherited metabolic diseases
IMDs classification
Lysosomal storage disorders
LSD
Congenital disorders of glycosylation
CDG
Mitochondrial disease
Newborn screening
Gene therapy
Artificial intelligence

Published Papers (13 papers)

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Research

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17 pages, 2152 KiB

Open AccessArticle

Clinical and Genetic Characteristics of Hypophosphatasia in Chinese Adults

by Xiang Li, Na Ren, Ziyuan Wang, Ya Wang, Yunqiu Hu, Weiwei Hu, Jiemei Gu, Wei Hong, Zhenlin Zhang and Chun Wang

Genes 2023, 14(4), 922; https://0-doi-org.brum.beds.ac.uk/10.3390/genes14040922 - 16 Apr 2023

Viewed by 1945

Abstract

Hypophosphatasia (HPP) is an inherited disease caused by ALPL mutation, resulting in decreased alkaline phosphatase (ALP) activity and damage to bone and tooth mineralization. The clinical symptoms of adult HPP are variable, making diagnosis challenging. This study aims to clarify the clinical and genetic characteristics of HPP in Chinese adults. There were 19 patients, including 1 with childhood-onset and 18 with adult-onset HPP. The median age was 62 (32–74) years and 16 female patients were involved. Common symptoms included musculoskeletal symptoms (12/19), dental problems (8/19), fractures (7/19), and fatigue (6/19). Nine patients (47.4%) were misdiagnosed with osteoporosis and six received anti-resorptive treatment. The average serum ALP level was 29.1 (14–53) U/L and 94.7% (18/19) of patients had ALP levels below 40 U/L. Genetic analysis found 14 ALPL mutations, including three novel mutations—c.511C>G (p.His171Ala), c.782C>A (p.Pro261Gln), and 1399A>G (p.Met467Val). The symptoms of two patients with compound heterozygous mutations were more severe than those with heterozygous mutations. Our study summarized the clinical characteristics of adult HPP patients in the Chinese population, expanded the spectrum of pathogenic mutations, and deepened clinicians’ understanding of this neglected disease. Full article

(This article belongs to the Special Issue Genetic Research in Metabolic Diseases)

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12 pages, 1317 KiB

Open AccessArticle

Optimizing the Phenylalanine Cut-Off Value in a Newborn Screening Program

by Dasa Perko, Barbka Repic Lampret, Ziga Iztok Remec, Mojca Zerjav Tansek, Ana Drole Torkar, Blaz Krhin, Ajda Bicek, Adrijana Oblak, Tadej Battelino and Urh Groselj

Genes 2022, 13(3), 517; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13030517 - 15 Mar 2022

Cited by 4 | Viewed by 2342

Abstract

Phenylketonuria (PKU) was the first disorder for which newborn screening (NBS) was introduced in the early 1960s. Slovenia started the NBS program for PKU in 1979, and the fluorimetric method was implemented in 1992, with a phenylalanine (Phe) cut-off set at 120 mol/L. This value has been in use for almost thirty years and has never been revised. We aimed to analyze the DBS samples and review the data from a large nationwide cohort of newborns to optimize the cut-off values for HFA screening to minimize the number of false positives while maintaining the highest level of sensitivity by detecting all those who needed to be treated. In the first prospective part of the study, we analyzed samples of all newborns in Slovenia in 2019 and 2020, and in the second retrospective part, we reviewed data from all known patients with hyperphenylalaninemia (HFA) in Slovenia born from 2000 to 2018. We defined true screening-positive cases as those that required a low-Phe diet. The sensitivity, specificity and positive predictive values of the modeling elevation of the Phe cut-off value from 120 µmol/L to 200 µmol/L were assessed. The number of recalls at the cut-off of 120 µmol/L was 108 out of 37,784 samples at NBS (2019–2020). Six newborns were defined as true positives and 102 samples as false positives. If the cut-off value was adjusted to 160 µmol/L, only 12 samples exceeded it and all six true positive newborns would be detected. Among the 360,000 samples collected at the NBS between 2000 and 2018, 72 HFA patients in need of a low-Phe diet were found. All the diagnosed cases would have been detected if the cut-off was set to 160 µmol/L. We demonstrated in a large group of newborns (400,000 in 20 years) that using the fluorimetric approach, a cut-off value of 160 µmol/L, rather than 120 mol/L, is safe and that there were no missing true positive patients who required treatment. By increasing the cut-off, this method becomes more precise, resulting in a significantly reduced rate of false positives and thus being less burdensome on both families and the healthcare system. Full article

(This article belongs to the Special Issue Genetic Research in Metabolic Diseases)

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13 pages, 1601 KiB

Open AccessArticle

A Gain-of-Function Mutation on BCKDK Gene and Its Possible Pathogenic Role in Branched-Chain Amino Acid Metabolism

by Alice Maguolo, Giulia Rodella, Alejandro Giorgetti, Marion Nicolodi, Rui Ribeiro, Alice Dianin, Gaetano Cantalupo, Irene Monge, Sarah Carcereri, Margherita Lucia De Bernardi, Massimo Delledonne, Andrea Pasini, Natascia Campostrini, Florina Ion Popa, Giorgio Piacentini, Francesca Teofoli, Monica Vincenzi, Marta Camilot and Andrea Bordugo

Genes 2022, 13(2), 233; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13020233 - 26 Jan 2022

Cited by 4 | Viewed by 4006

Abstract

BCKDK is an important key regulator of branched-chain ketoacid dehydrogenase complex activity by phosphorylating and so inactivating branched-chain ketoacid dehydrogenases, the rate-limiting enzyme of the branched-chain amino acid metabolism. We identified, by whole exome-sequencing analysis, the p.His162Gln variant of the BCKDK gene in a neonate, picked up by newborn screening, with a biochemical phenotype of a mild form of maple syrup urine disease (MSUD). The same biochemical and genetic picture was present in the father. Computational analysis of the mutation was performed to better understand its role. Extensive atomistic molecular dynamics simulations showed that the described mutation leads to a conformational change of the BCKDK protein, which reduces the effect of inhibitory binding bound to the protein itself, resulting in its increased activity with subsequent inactivation of BCKDC and increased plasmatic branched-chain amino acid levels. Our study describes the first evidence of the involvement of the BCKDK gene in a mild form of MSUD. Although further data are needed to elucidate the clinical relevance of the phenotype caused by this variant, awareness of this regulatory activation of BCKDK is very important, especially in newborn screening data interpretation. Full article

(This article belongs to the Special Issue Genetic Research in Metabolic Diseases)

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6 pages, 682 KiB

Open AccessArticle

Should Patients with Kearns-Sayre Syndrome and Corneal Endothelial Failure Be Genotyped for a TCF4 Trinucleotide Repeat, Commonly Associated with Fuchs Endothelial Corneal Dystrophy?

by Lubica Dudakova, Pavlina Skalicka, Alice E. Davidson, Amanda N. Sadan, Monika Chylova, Helena Jahnova, Nicole Anteneova, Marketa Tesarova, Tomas Honzik and Petra Liskova

Genes 2021, 12(12), 1918; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12121918 - 29 Nov 2021

Viewed by 1738

Abstract

The aim of this study was to describe the ocular phenotype in a case with Kearns-Sayre syndrome (KSS) spectrum and to determine if corneal endothelial cell dysfunction could be attributed to other known distinct genetic causes. Herein, genomic DNA was extracted from blood and exome sequencing was performed. Non-coding gene regions implicated in corneal endothelial dystrophies were screened by Sanger sequencing. In addition, a repeat expansion situated within an intron of TCF4 (termed CTG18.1) was genotyped using the short tandem repeat assay. The diagnosis of KSS spectrum was based on the presence of ptosis, chronic progressive external ophthalmoplegia, pigmentary retinopathy, hearing loss, and muscle weakness, which were further supported by the detection of ~6.5 kb mtDNA deletion. At the age of 33 years, the proband’s best corrected visual acuity was reduced to 0.04 in the right eye and 0.2 in the left eye. Rare ocular findings included marked corneal oedema with central corneal thickness of 824 and 844 µm in the right and left eye, respectively. No pathogenic variants in the genes, which are associated with corneal endothelial dystrophies, were identified. Furthermore, the CTG18.1 genotype was 12/33, which exceeds a previously determined critical threshold for toxic RNA foci appearance in corneal endothelial cells. Full article

(This article belongs to the Special Issue Genetic Research in Metabolic Diseases)

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10 pages, 573 KiB

Open AccessArticle

Genotype-Phenotype Correlations in PMM2-CDG

by Laurien Vaes, Daisy Rymen, David Cassiman, Anna Ligezka, Nele Vanhoutvin, Dulce Quelhas, Eva Morava and Peter Witters

Genes 2021, 12(11), 1658; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12111658 - 21 Oct 2021

Cited by 8 | Viewed by 2304

Abstract

PMM2-CDG is a rare disease, causing hypoglycosylation of multiple proteins, hence preventing full functionality. So far, no direct genotype–phenotype correlations have been identified. We carried out a retrospective cohort study on 26 PMM2-CDG patients. We collected the identified genotype, as well as continuous variables indicating the disease severity (based on Nijmegen Pediatric CDG Rating Score or NPCRS) and dichotomous variables reflecting the patients’ phenotype. The phenotypic effects of patients’ genotype were studied using non-parametric and Chi-Square tests. Seventeen different pathogenic variants have been studied. Variants with zero enzyme activity had no significant impact on the Nijmegen score. Pathogenic variants involving the stabilization/folding domain have a significantly lower total NPCRS (p = 0.017): presence of the p.Cys241Ser mutation had a significantly lower subscore 1,3 and NPCRS (p = 0.04) and thus result in a less severe phenotype. On the other hand, variants involving the dimerization domain, p.Pro113Leu and p.Phe119Leu, resulted in a significantly higher NPCRS score (p = 0.002), which indicates a worse clinical course. These concepts give a better insight in the phenotypic prognosis of PMM2-CDG, according to their molecular base. Full article

(This article belongs to the Special Issue Genetic Research in Metabolic Diseases)

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15 pages, 1133 KiB

Open AccessArticle

Utility of Gene Panels for the Diagnosis of Inborn Errors of Metabolism in a Metabolic Reference Center

by Sofia Barbosa-Gouveia, María E. Vázquez-Mosquera, Emiliano González-Vioque, José V. Álvarez, Roi Chans, Francisco Laranjeira, Esmeralda Martins, Ana Cristina Ferreira, Alejandro Avila-Alvarez and María L. Couce

Genes 2021, 12(8), 1262; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12081262 - 19 Aug 2021

Cited by 5 | Viewed by 2493

Abstract

Next-generation sequencing (NGS) technologies have been proposed as a first-line test for the diagnosis of inborn errors of metabolism (IEM), a group of genetically heterogeneous disorders with overlapping or nonspecific phenotypes. Over a 3-year period, we prospectively analyzed 311 pediatric patients with a suspected IEM using four targeted gene panels. The rate of positive diagnosis was 61.86% for intermediary metabolism defects, 32.84% for complex molecular defects, 19% for hypoglycemic/hyperglycemic events, and 17% for mitochondrial diseases, and a conclusive molecular diagnosis was established in 2–4 weeks. Forty-one patients for whom negative results were obtained with the mitochondrial diseases panel underwent subsequent analyses using the NeuroSeq panel, which groups all genes from the individual panels together with genes associated with neurological disorders (1870 genes in total). This achieved a diagnostic rate of 32%. We next evaluated the utility of a tool, Phenomizer, for differential diagnosis, and established a correlation between phenotype and molecular findings in 39.3% of patients. Finally, we evaluated the mutational architecture of the genes analyzed by determining z-scores, loss-of-function observed/expected upper bound fraction (LOEUF), and haploinsufficiency (HI) scores. In summary, targeted gene panels for specific groups of IEMs enabled rapid and effective diagnosis, which is critical for the therapeutic management of IEM patients. Full article

(This article belongs to the Special Issue Genetic Research in Metabolic Diseases)

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Review

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24 pages, 1417 KiB

Open AccessReview

Phenotypes and Genotypes of Inherited Disorders of Biogenic Amine Neurotransmitter Metabolism

by Mario Mastrangelo, Manuela Tolve, Cristiana Artiola, Rossella Bove, Claudia Carducci, Carla Carducci, Antonio Angeloni, Francesco Pisani and Vincenzo Leuzzi

Genes 2023, 14(2), 263; https://0-doi-org.brum.beds.ac.uk/10.3390/genes14020263 - 19 Jan 2023

Cited by 2 | Viewed by 2205

Abstract

Inherited disorders of biogenic amine metabolism are genetically determined conditions resulting in dysfunctions or lack of enzymes involved in the synthesis, degradation, or transport of dopamine, serotonin, adrenaline/noradrenaline, and their metabolites or defects of their cofactor or chaperone biosynthesis. They represent a group of treatable diseases presenting with complex patterns of movement disorders (dystonia, oculogyric crises, severe/hypokinetic syndrome, myoclonic jerks, and tremors) associated with a delay in the emergence of postural reactions, global development delay, and autonomic dysregulation. The earlier the disease manifests, the more severe and widespread the impaired motor functions. Diagnosis mainly depends on measuring neurotransmitter metabolites in cerebrospinal fluid that may address the genetic confirmation. Correlations between the severity of phenotypes and genotypes may vary remarkably among the different diseases. Traditional pharmacological strategies are not disease-modifying in most cases. Gene therapy has provided promising results in patients with DYT-DDC and in vitro models of DYT/PARK-SLC6A3. The rarity of these diseases, combined with limited knowledge of their clinical, biochemical, and molecular genetic features, frequently leads to misdiagnosis or significant diagnostic delays. This review provides updates on these aspects with a final outlook on future perspectives. Full article

(This article belongs to the Special Issue Genetic Research in Metabolic Diseases)

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20 pages, 1667 KiB

Open AccessReview

2022 Overview of Metabolic Epilepsies

by Birute Tumiene, Carlos R. Ferreira and Clara D. M. van Karnebeek

Genes 2022, 13(3), 508; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13030508 - 12 Mar 2022

Cited by 9 | Viewed by 3326

Abstract

Understanding the genetic architecture of metabolic epilepsies is of paramount importance, both to current clinical practice and for the identification of further research directions. The main goals of our study were to identify the scope of metabolic epilepsies and to investigate their clinical presentation, diagnostic approaches and treatments. The International Classification of Inherited Metabolic Disorders and IEMbase were used as a basis for the identification and classification of metabolic epilepsies. Six hundred metabolic epilepsies have been identified, accounting for as much as 37% of all currently described inherited metabolic diseases (IMD). Epilepsy is a particularly common symptom in disorders of energy metabolism, congenital disorders of glycosylation, neurotransmitter disorders, disorders of the synaptic vesicle cycle and some other IMDs. Seizures in metabolic epilepsies may present variably, and most of these disorders are complex and multisystem. Abnormalities in routine laboratory tests and/or metabolic testing may be identified in 70% of all metabolic epilepsies, but in many cases they are non-specific. In total, 111 metabolic epilepsies (18% of all) have specific treatments that may significantly change health outcomes if diagnosed in time. Although metabolic epilepsies comprise an important and significant group of disorders, their real scope and frequency may have been underestimated. Full article

(This article belongs to the Special Issue Genetic Research in Metabolic Diseases)

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10 pages, 1257 KiB

Open AccessEditor’s ChoiceReview

Mucopolysaccharidosis-Plus Syndrome, a Rapidly Progressive Disease: Favorable Impact of a Very Prolonged Steroid Treatment on the Clinical Course in a Child

by Martha Caterina Faraguna, Francesca Musto, Viola Crescitelli, Maria Iascone, Luigina Spaccini, Davide Tonduti, Tiziana Fedeli, Gaia Kullmann, Francesco Canonico, Alessandro Cattoni, Fabiola Dell’Acqua, Carmelo Rizzari and Serena Gasperini

Genes 2022, 13(3), 442; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13030442 - 28 Feb 2022

Cited by 8 | Viewed by 3035

Abstract

Mucopolysaccharidosis-plus syndrome (MPS-PS) is a novel autosomal recessive disorder caused by a mutation in the VPS33A gene. This syndrome presents with typical symptoms of mucopolysaccharidosis, as well as congenital heart defects, renal, and hematopoietic system disorders. To date, twenty-four patients have been described. There is no specific therapy for MPS-PS; clinical management is therefore limited to symptoms management. The clinical course is rapidly progressive, and most patients die before 1–2 years of age. We describe a currently 6-year-old male patient with MPS-PS presenting with multiorgan involvement. Symptoms started at four months of age when he progressively suffered from numerous acute and potentially life-threatening events. When he was two years old, he developed secondary hemophagocytic lymphohistiocytosis (HLH), which was successfully treated with steroids. To date, this child represents the oldest patient affected by MPS-PS described in the literature and the first one presenting with a life-threatening secondary HLH. The prolonged steroid treatment allowed a stabilization of his general and hematological conditions and probably determined an improvement of his psychomotor milestones and new neurological acquisitions with an improvement of quality of life. HLH should be suspected and adequately treated in MPS-PS patients presenting with suggestive symptoms of the disease. The usefulness of a prolonged steroid treatment to improve the clinical course of children with MPS-PS deserves further investigation. Full article

(This article belongs to the Special Issue Genetic Research in Metabolic Diseases)

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24 pages, 4236 KiB

Open AccessReview

The Ehlers–Danlos Syndromes against the Backdrop of Inborn Errors of Metabolism

by Tim Van Damme, Marlies Colman, Delfien Syx and Fransiska Malfait

Genes 2022, 13(2), 265; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13020265 - 29 Jan 2022

Cited by 4 | Viewed by 31068

Abstract

The Ehlers–Danlos syndromes are a group of multisystemic heritable connective tissue disorders with clinical presentations that range from multiple congenital malformations, over adolescent-onset debilitating or even life-threatening complications of connective tissue fragility, to mild conditions that remain undiagnosed in adulthood. To date, thirteen different EDS types have been recognized, stemming from genetic defects in 20 different genes. While initial biochemical and molecular analyses mainly discovered defects in genes coding for the fibrillar collagens type I, III and V or their modifying enzymes, recent discoveries have linked EDS to defects in non-collagenous matrix glycoproteins, in proteoglycan biosynthesis and in the complement pathway. This genetic heterogeneity explains the important clinical heterogeneity among and within the different EDS types. Generalized joint hypermobility and skin hyperextensibility with cutaneous fragility, atrophic scarring and easy bruising are defining manifestations of EDS; however, other signs and symptoms of connective tissue fragility, such as complications of vascular and internal organ fragility, orocraniofacial abnormalities, neuromuscular involvement and ophthalmological complications are variably present in the different types of EDS. These features may help to differentiate between the different EDS types but also evoke a wide differential diagnosis, including different inborn errors of metabolism. In this narrative review, we will discuss the clinical presentation of EDS within the context of inborn errors of metabolism, give a brief overview of their underlying genetic defects and pathophysiological mechanisms and provide a guide for the diagnostic approach. Full article

(This article belongs to the Special Issue Genetic Research in Metabolic Diseases)

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18 pages, 365 KiB

Open AccessReview

Preclinical Research in McArdle Disease: A Review of Research Models and Therapeutic Strategies

by Mónica Villarreal-Salazar, Astrid Brull, Gisela Nogales-Gadea, Antoni L. Andreu, Miguel A. Martín, Joaquín Arenas, Alfredo Santalla, Alejandro Lucia, John Vissing, Thomas O. Krag and Tomàs Pinós

Genes 2022, 13(1), 74; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13010074 - 28 Dec 2021

Cited by 4 | Viewed by 2815

Abstract

McArdle disease is an autosomal recessive disorder of muscle glycogen metabolism caused by pathogenic mutations in the PYGM gene, which encodes the skeletal muscle-specific isoform of glycogen phosphorylase. Clinical symptoms are mainly characterized by transient acute “crises” of early fatigue, myalgia and contractures, which can be accompanied by rhabdomyolysis. Owing to the difficulty of performing mechanistic studies in patients that often rely on invasive techniques, preclinical models have been used for decades, thereby contributing to gain insight into the pathophysiology and pathobiology of human diseases. In the present work, we describe the existing in vitro and in vivo preclinical models for McArdle disease and review the insights these models have provided. In addition, despite presenting some differences with the typical patient’s phenotype, these models allow for a deep study of the different features of the disease while representing a necessary preclinical step to assess the efficacy and safety of possible treatments before they are tested in patients. Full article

(This article belongs to the Special Issue Genetic Research in Metabolic Diseases)

18 pages, 2625 KiB

Open AccessReview

Inherited Proteoglycan Biosynthesis Defects—Current Laboratory Tools and Bikunin as a Promising Blood Biomarker

by Walid Haouari, Johanne Dubail, Christian Poüs, Valérie Cormier-Daire and Arnaud Bruneel

Genes 2021, 12(11), 1654; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12111654 - 20 Oct 2021

Cited by 5 | Viewed by 2133

Abstract

Proteoglycans consist of proteins linked to sulfated glycosaminoglycan chains. They constitute a family of macromolecules mainly involved in the architecture of organs and tissues as major components of extracellular matrices. Some proteoglycans also act as signaling molecules involved in inflammatory response as well as cell proliferation, adhesion, and differentiation. Inborn errors of proteoglycan metabolism are a group of orphan diseases with severe and irreversible skeletal abnormalities associated with multiorgan impairments. Identifying the gene variants that cause these pathologies proves to be difficult because of unspecific clinical symptoms, hardly accessible functional laboratory tests, and a lack of convenient blood biomarkers. In this review, we summarize the molecular pathways of proteoglycan biosynthesis, the associated inherited syndromes, and the related biochemical screening techniques, and we focus especially on a circulating proteoglycan called bikunin and on its potential as a new biomarker of these diseases. Full article

(This article belongs to the Special Issue Genetic Research in Metabolic Diseases)

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Other

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9 pages, 837 KiB

Open AccessCase Report

Treatment Dilemma in Children with Late-Onset Pompe Disease

by Martha Caterina Faraguna, Viola Crescitelli, Anna Fornari, Silvia Barzaghi, Salvatore Savasta, Thomas Foiadelli, Daniele Veraldi, Matteo Paoletti, Anna Pichiecchio and Serena Gasperini

Genes 2023, 14(2), 362; https://0-doi-org.brum.beds.ac.uk/10.3390/genes14020362 - 30 Jan 2023

Cited by 3 | Viewed by 1862

Abstract

In recent years, there has been a significant increase in the diagnosis of asymptomatic Late-Onset Pompe Disease (LOPD) patients, who are detected via family screening or Newborn Screening (NBS). The dilemma is when to start Enzyme Replacement Therapy (ERT) in patients without any clinical sign of the disease, considering its important benefits in terms of loss of muscle but also its very high cost, risk of side effects, and long-term immunogenicity. Muscle Magnetic Resonance Imaging (MRI) is accessible, radiation-free, and reproducible; therefore, it is an important instrument for the diagnosis and follow-up of patients with LOPD, especially in asymptomatic cases. European guidelines suggest monitoring in asymptomatic LOPD cases with minimal MRI findings, although other guidelines consider starting ERT in apparently asymptomatic cases with initial muscle involvement (e.g., paraspinal muscles). We describe three siblings affected by LOPD who present compound heterozygosis and wide phenotypic variability. The three cases differ in age at presentation, symptoms, urinary tetrasaccharide levels, and MRI findings, confirming the significant phenotypic variability of LOPD and the difficulty in deciding when to start therapy. Full article

(This article belongs to the Special Issue Genetic Research in Metabolic Diseases)

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