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Iacono R, Paragliola FMP, Strazzulli A, Moracci M. A stable GH31 α-glucosidase as a model system for the study of mutations leading to human glycogen storage disease type II. J Enzyme Inhib Med Chem 2025; 40:2468859. [PMID: 39995088 PMCID: PMC11864002 DOI: 10.1080/14756366.2025.2468859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 01/27/2025] [Accepted: 02/11/2025] [Indexed: 02/26/2025] Open
Abstract
GH31 glycosidases are widespread across organisms, but remarkably, less than 1% of them have been biochemically characterised to date. Among them, human lysosomal acid α-glucosidase (GAA) stands out due to its link to Pompe disease, a rare lysosomal storage disorder caused by its deficiency. This disease results in glycogen accumulation, severe cellular damage, motor impairment, and premature death. Structural and functional studies of GAA mutants are challenging due to their instability and lack of activity, hindering their expression and purification. The GH31 enzyme MalA from a hyperthermophilic archaeon is explored here as a stable homolog of GAA. MalA is highly expressible, easy to purify, and structurally characterised. The R400H mutant in MalA, corresponding to the pathogenic GAA R600H mutation, revealed here a 1200-fold drop in specificity constant and >8 °C reduction in thermal stability. We propose MalA's as a robust model for studying GAA mutations and developing therapeutic chaperones.
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Affiliation(s)
- Roberta Iacono
- Department of Biology, University of Naples “Federico II”, Naples, Italy
- NBFC, National Biodiversity Future Center, Palermo, Italy
| | | | - Andrea Strazzulli
- Department of Biology, University of Naples “Federico II”, Naples, Italy
- NBFC, National Biodiversity Future Center, Palermo, Italy
- Task Force on Microbiome Studies, University of Naples “Federico II”, Naples, Italy
| | - Marco Moracci
- Department of Biology, University of Naples “Federico II”, Naples, Italy
- NBFC, National Biodiversity Future Center, Palermo, Italy
- Task Force on Microbiome Studies, University of Naples “Federico II”, Naples, Italy
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Yin Y, Jiang J, Jin Y. A Real-World Data Analysis of Alglucosidase Alfa in the FDA Adverse Event Reporting System (FAERS) Database. Drugs R D 2025; 25:57-66. [PMID: 39833603 PMCID: PMC12011682 DOI: 10.1007/s40268-024-00502-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/10/2024] [Indexed: 01/22/2025] Open
Abstract
BACKGROUND AND OBJECTIVE Alglucosidase alfa for injection is used as an enzyme replacement therapy for the treatment of Pompe disease. The safety profile of alglucosidase alfa-associated adverse events requires a comprehensive evaluation. In this study, we aimed to identify drug safety alert signals and investigate the real-world safety of alglucosidase alfa to guide clinical decision making and optimize the risk-benefit balance. METHODS The adverse event reports from the first quarter of 2006 to the fourth quarter of 2023 were selected by exploring the Food and Drug Administration Adverse Event Reporting System (FAERS) database. The new and unexpected potential adverse event signals were detected using a disproportionality analysis, including the reporting odds ratio, the proportional reporting ratio, the Bayesian confidence propagation neural network, and the empirical Bayes geometric mean. Then, the Medical Dictionary for Regulatory Activities was used to systematically classify the results. RESULTS After analyzing 16,945,027 adverse event reports, a total of 4326 cases of adverse events related to alglucosidase alfa were identified, spanning 27 system organ classes. A total of 359 preferred terms of adverse events for glucosidase alpha were detected. Pyrexia ranked first, followed by pneumonia, dyspnea, respiratory failure, and disease progression according to occurrence frequency. The top three system organ classes were general disorders and administration-site conditions (n = 2466), respiratory, thoracic, and mediastinal disorders (n = 1749), and infections and infestations (n = 1551). In addition to adverse effects mentioned in the product label, our study also discovered rare but high signal intensity adverse events such as chronic recurrent multifocal osteomyelitis. CONCLUSIONS There are many adverse events associated with the clinical use of alglucosidase alfa, which should be closely monitored in the FAERS database. As the most effective enzyme replacement therapy for Pompe disease, it is crucial to closely monitor these adverse events. Ensuring patient safety while balancing drug effectiveness is particularly important.
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Affiliation(s)
- Yi Yin
- Department of Pediatric Intensive Care Unit, Shandong, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jingwu Road, Ji'nan, Shandong, China.
| | - Jie Jiang
- Department of Pediatric Intensive Care Unit, Shandong, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jingwu Road, Ji'nan, Shandong, China
| | - Youpeng Jin
- Department of Pediatric Intensive Care Unit, Shandong, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jingwu Road, Ji'nan, Shandong, China.
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Peruzzo P, Bergamin N, Bon M, Cappelli S, Longo A, Goina E, Stuani C, Buratti E, Dardis A. Rescue of common and rare exon 2 skipping variants of the GAA gene using modified U1 snRNA. Mol Med 2025; 31:45. [PMID: 39905333 PMCID: PMC11796170 DOI: 10.1186/s10020-025-01090-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 01/16/2025] [Indexed: 02/06/2025] Open
Abstract
BACKGROUND Pompe disease (PD) is an autosomal recessive lysosomal storage disorder caused by the deficient activity of acid alpha glucosidase (GAA) enzyme due to mutations in the GAA gene. As a result, undigested glycogen accumulates within lysosomes causing their dysfunction. From a clinical point of view, the disease can be classified in infantile-onset (IO) and late-onset (LO) forms. The common GAA c.-32-13T>G variant, found in 40-70% of LO-PD alleles, is a leaky splicing mutation interfering with the correct GAA exon 2 recognition by the spliceosome leading to the production of non-functional GAA transcripts. In this study, we used modified, GAA-tailored U1 snRNAs to correct the aberrant splicing determined by the c.-32-13T>G and other GAA exon 2-skipping mutations. METHODS A set of constructs expressing 5 different engineered U1 snRNAs was generated. A functional splicing assay using a GAA hybrid minigene carrying different variants known to affect GAA exon 2 splicing was used to test the effect of engineered U1 snRNAs on exon 2 inclusion. The effect on endogenously expressed GAA transcript and GAA enzymatic activity was assessed by transfecting patient-derived fibroblasts bearing the common c.-32-13T>G with the best performing modified U1 snRNA. RESULTS Modified U1-3, U1+1 and U1+6 snRNAs were all able to increase, in a dose-dependent manner, the inclusion of exon 2 within the transcript derived from the GAA minigene harbouring the c.-32-13T>G variant. The U1+1 was the most effective one (2,5 fold increase). Moreover, U1+1 snRNA partially rescued the correct splicing of GAA minigenes harbouring mutations that affect the 3'ss (c.-32-3C>G, c.-32-2A>G) and the 5'ss (c.546G>A, c.546G>C, c.546G>T). Notably, the treatment of patient-derived fibroblasts carrying the c.-32-13T>G mutation with the U1+1 snRNA increased the amount of normal GAA mRNA by 1,8 fold and the GAA enzymatic activity by 70%. CONCLUSIONS we provide the proof-of-concept for the use of modified GAA-tailored U1 snRNAs, designed to potentiate the recognition of the GAA exon 2 5'ss, as therapeutic tools to correct the aberrant transcripts carrying variants that affect exon 2 splicing, including the common c.-32-13T>G variant.
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Affiliation(s)
- Paolo Peruzzo
- Regional Coordinator Centre for Rare Diseases, University Hospital of Udine, P. Le Santa Maria Della Misericordi 15, 33100, Udine, Italy
| | - Natascha Bergamin
- Regional Coordinator Centre for Rare Diseases, University Hospital of Udine, P. Le Santa Maria Della Misericordi 15, 33100, Udine, Italy
| | - Martina Bon
- Regional Coordinator Centre for Rare Diseases, University Hospital of Udine, P. Le Santa Maria Della Misericordi 15, 33100, Udine, Italy
| | - Sara Cappelli
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Area Science Park, Trieste, Italy
| | - Alessandra Longo
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Area Science Park, Trieste, Italy
| | - Elisa Goina
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Area Science Park, Trieste, Italy
| | - Cristiana Stuani
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Area Science Park, Trieste, Italy
| | - Emanuele Buratti
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Area Science Park, Trieste, Italy
| | - Andrea Dardis
- Regional Coordinator Centre for Rare Diseases, University Hospital of Udine, P. Le Santa Maria Della Misericordi 15, 33100, Udine, Italy.
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Feng Q, Zhang MQ, Ba CX, Zhang YQ. Clinical features and genetic analysis of 5 cases of infantile-type glycogen storage disease type II: Case reports. Medicine (Baltimore) 2024; 103:e39534. [PMID: 39213226 PMCID: PMC11365635 DOI: 10.1097/md.0000000000039534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 08/05/2024] [Accepted: 08/12/2024] [Indexed: 09/04/2024] Open
Abstract
OBJECTIVE Clinical and genetic mutation analysis was performed on 5 infantile glycogen storage disease type II children in Chinese mainland. METHODS Clinical data of 5 children with infantile-type glycogen storage disease type II due to the acidic α-glucosidase (GAA) gene variants diagnosed and treated at Hebei Provincial Children's Hospital from January 2018 to April 2020 were retrospectively analyzed. RESULTS Among the 5 cases, 1 was female and 4 were male, and the age at first diagnosis was from 2 months to 7 months. The first symptoms of all 5 cases showed progressive muscle weakness, hypotonia, and motor developmental backwardness, and all of them had abnormally elevated creatine kinase, and the echocardiograms suggested different degrees of myocardial hypertrophy, with ejection fractions ranging from 44% to 67%. Analysis of GAA gene variations: all 5 cases were compound heterozygous, and a total of 12 variant loci were detected, of which c.2024_2026delACA, c.2853G > A, c.1124G > T, c.574G > A, c.2509C > T, and c.2013G > A were new mutations that had not been reported. FOLLOWUP All 5 children died before 1 year of age, and the age of death ranged from 7 months to 11.5 months, with a mean survival time of 9.8 months. CONCLUSION Peripheral blood GAA gene testing and alpha-glucosidase enzyme activity testing is an effective method for diagnosing this disease.
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Affiliation(s)
- Qi Feng
- Hebei North University, Zhangjiakou, Hebei, China
- Three Departments of respiration, Hebei Children’s Hospital, Shijiazhuang, Hebei, Chinac Hebei Medical University, Shijiazhuang, Hebei, China
| | - Meng Qiao Zhang
- Hebei North University, Zhangjiakou, Hebei, China
- Three Departments of respiration, Hebei Children’s Hospital, Shijiazhuang, Hebei, Chinac Hebei Medical University, Shijiazhuang, Hebei, China
| | - Chun Xiao Ba
- Three Departments of respiration, Hebei Children’s Hospital, Shijiazhuang, Hebei, Chinac Hebei Medical University, Shijiazhuang, Hebei, China
- Hebei Medical University, Shijiazhuang, Hebei, China
| | - Ying Qian Zhang
- Three Departments of respiration, Hebei Children’s Hospital, Shijiazhuang, Hebei, Chinac Hebei Medical University, Shijiazhuang, Hebei, China
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Townsend M, Jeewa A, Khoury M, Cunningham C, George K, Conway J. Unique Aspects of Hypertrophic Cardiomyopathy in Children. Can J Cardiol 2024; 40:907-920. [PMID: 38244986 DOI: 10.1016/j.cjca.2024.01.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Revised: 01/03/2024] [Accepted: 01/14/2024] [Indexed: 01/22/2024] Open
Abstract
Hypertrophic cardiomyopathy (HCM) is a primary heart muscle disease characterized by left ventricular hypertrophy that can be asymptomatic or with presentations that vary from left ventricular outflow tract obstruction, heart failure from diastolic dysfunction, arrhythmias, and/or sudden cardiac death. Children younger than 1 year of age tend to have worse outcomes and often have HCM secondary to inborn errors of metabolism or syndromes such as RASopathies. For children who survive or are diagnosed after 1 year of age, HCM outcomes are often favourable and similar to those seen in adults. This is because of sudden cardiac death risk stratification and medical and surgical innovations. Genetic testing and timely cardiac screening are paving the way for disease-modifying treatment as gene-specific therapies are being developed.
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Affiliation(s)
- Madeleine Townsend
- Department of Cardiology, Cleveland Clinic Children's Hospital, Cleveland, Ohio, USA
| | - Aamir Jeewa
- Division of Cardiology, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Michael Khoury
- Division of Pediatric Cardiology, Stollery Children's Hospital, Edmonton, Alberta, Canada
| | | | - Kristen George
- Division of Cardiology, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Jennifer Conway
- Division of Pediatric Cardiology, Stollery Children's Hospital, Edmonton, Alberta, Canada.
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Weiss L, Carrer M, Shmara A, Cheng C, Yin H, Ta L, Boock V, Fazeli Y, Chang M, Paguio M, Lee J, Yu H, Martin A, Raben N, Weiss J, Grossman T, Jafar-Nejad P, Kimonis V. Skeletal muscle effects of antisense oligonucleotides targeting glycogen synthase 1 in a mouse model of Pompe disease. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.22.580414. [PMID: 38464319 PMCID: PMC10925133 DOI: 10.1101/2024.02.22.580414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/12/2024]
Abstract
Pompe disease (PD) is a progressive myopathy caused by the aberrant accumulation of glycogen in skeletal and cardiac muscle resulting from the deficiency of the enzyme acid alpha-glucosidase (GAA). Administration of recombinant human GAA as enzyme replacement therapy (ERT) works well in alleviating the cardiac manifestations of PD but loses sustained benefit in ameliorating the skeletal muscle pathology. The limited efficacy of ERT in skeletal muscle is partially attributable to its inability to curb the accumulation of new glycogen produced by the muscle enzyme glycogen synthase 1 (GYS1). Substrate reduction therapies aimed at knocking down GYS1 expression represent a promising avenue to improve Pompe myopathy. However, finding specific inhibitors for GYS1 is challenging given the presence of the highly homologous GYS2 in the liver. Antisense oligonucleotides (ASOs) are chemically modified oligomers that hybridize to their complementary target RNA to induce their degradation with exquisite specificity. In the present study, we show that ASO-mediated Gys1 knockdown in the Gaa -/- mouse model of PD led to a robust reduction in glycogen accumulation in skeletal and cardiac muscle. In addition, combining Gys1 ASO with ERT further reduced glycogen content in muscle, eliminated autophagic buildup and lysosomal dysfunction, and improved motor function in Gaa -/- mice. Our results provide a strong foundation for further validation of the use of Gys1 ASO, alone or in combination with ERT, as a therapy for PD. We propose that early administration of Gys1 ASO in combination with ERT may be the key to preventative treatment options in PD.
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Zhang M, Niu J, Xu M, Wei E, Liu P, Sheng G. Interplay between mitochondrial dysfunction and lysosomal storage: challenges in genetic metabolic muscle diseases with a focus on infantile onset Pompe disease. Front Cardiovasc Med 2024; 11:1367108. [PMID: 38450370 PMCID: PMC10916335 DOI: 10.3389/fcvm.2024.1367108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 02/08/2024] [Indexed: 03/08/2024] Open
Abstract
Background Pompe disease (PD) is a rare, progressive autosomal recessive lysosomal storage disorder that directly impacts mitochondrial function, leading to structural abnormalities and potentially culminating in heart failure or cardiogenic shock. The clinical course and molecular mechanisms of the disease remain incompletely understood. Methods We performed a retrospective analysis to examine the clinical manifestations, genetic traits, and the relationship between PD and mitochondrial function in a pediatric patient. This comprehensive evaluation included the use of ultrasound echocardiograms, computed tomography (CT) scans, electrocardiograms, mutagenesis analysis, and structural analysis to gain insights into the patient's condition and the underlying mechanisms of PD. For structural analysis and visualization, the structure of protein data bank ID 5KZX of human GAA was used, and VMD software was used for visualization and analysis. Results The study revealed that a 5-month-old male infant was admitted due to fever, with physical examination finding abnormal cardiopulmonary function and hepatomegaly. Laboratory tests and echocardiography confirmed heart failure and hypertrophic cardiomyopathy. Despite a week of treatment, which normalized body temperature and reduced pulmonary inflammation, cardiac abnormalities did not show significant improvement. Further genetic testing identified a homozygous mutation c.2662G>T (p.E888) in the GAA gene, leading to a diagnosis of Infantile-Onset Pompe Disease (IOPD). Conclusions Although enzyme replacement therapy can significantly improve the quality of life for patients with PD, enhancing mitochondrial function may represent a new therapeutic strategy for treating PD.
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Affiliation(s)
| | | | | | | | | | - Guangyao Sheng
- Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Hahn P, Siefen RG, Benz K, Jackowski J, Köhler C, Lücke T. [Diagnosis and Management of Late-Onset Pompe Disease]. FORTSCHRITTE DER NEUROLOGIE-PSYCHIATRIE 2024; 92:33-40. [PMID: 37494148 DOI: 10.1055/a-2095-2977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/28/2023]
Abstract
Pompe disease is a lysosomal storage disorder, with onset between the first weeks after birth and adulthood, depending on its phenotype. It can affect multiple organ systems and presents itself with a wide variety of symptoms. Thus, recognizing Pompe disease is difficult. Especially since enzyme replacement therapy for Pompe disease was introduced (in Germany in 2006), early diagnosis by means of enzyme activity determination from dried blood spot analysis and genetic verification has become important for outcome and quality of life. When facing an obscure muscular disorder, it is crucial to consider Pompe disease. This article provides an overview about Pompe disease and focuses on the diagnosis of the late onset type. The most important aspects of interdiciplinary care for patients with Pompe disease are presented. Additionally, it contains a section focusing on psychosocial challenges for children with Pompe disease and their families, which may include mental disorders and social retreat, and gives advice on how to support parents of affected children.
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Affiliation(s)
- Philipp Hahn
- Universitätsklinik für Kinder- und Jugendmedizin, Ruhr-Universität Bochum, St. Josef-Hospital, Bochum, Germany
| | - Rainer-Georg Siefen
- Universitätsklinik für Kinder- und Jugendmedizin, Ruhr-Universität Bochum, St. Josef-Hospital, Bochum, Germany
| | - Korbinian Benz
- Abteilung Zahnärztliche Chirurgie und Poliklinische Ambulanz der privaten Universität Witten/Herdecke, Universitäts-Zahnklinik, Witten/Herdecke, Germany
| | - Jochen Jackowski
- Abteilung Zahnärztliche Chirurgie und Poliklinische Ambulanz der privaten Universität Witten/Herdecke, Universitäts-Zahnklinik, Witten/Herdecke, Germany
| | - Cornelia Köhler
- Universitätsklinik für Kinder- und Jugendmedizin, Ruhr-Universität Bochum, St. Josef-Hospital, Bochum, Germany
| | - Thomas Lücke
- Universitätsklinik für Kinder- und Jugendmedizin, Ruhr-Universität Bochum, St. Josef-Hospital, Bochum, Germany
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Luca AC, Pădureț IA, Țarcă V, David SG, Mîndru DE, Roșu ST, Roșu EV, Adumitrăchioaiei H, Bernic J, Cojocaru E, Țarcă E. Nutritional Approach in Selected Inherited Metabolic Cardiac Disorders-A Concise Summary of Available Scientific Evidence. Nutrients 2023; 15:4795. [PMID: 38004189 PMCID: PMC10675151 DOI: 10.3390/nu15224795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 11/13/2023] [Accepted: 11/14/2023] [Indexed: 11/26/2023] Open
Abstract
Inborn errors of metabolism (IMDs) are a group of inherited diseases that manifest themselves through a myriad of signs and symptoms, including structural or functional cardiovascular damage. The therapy of these diseases is currently based on enzyme-replacement therapy, chaperone therapy or the administration of supplements and the establishment of personalized dietary plans. Starting from the major signs identified by the pediatric cardiologist that can indicate the presence of such a metabolic disease-cardiomyopathies, conduction disorders or valvular dysplasias-we tried to paint the portrait of dietary interventions that can improve the course of patients with mitochondrial diseases or lysosomal abnormalities. The choice of the two categories of inborn errors of metabolism is not accidental and reflects the experience and concern of the authors regarding the management of patients with such diagnoses. A ketogenic diet offers promising results in selected cases, although, to date, studies have failed to bring enough evidence to support generalized recommendations. Other diets have been successfully utilized in patients with IMDs, but their specific effect on the cardiac phenotype and function is not yet fully understood. Significant prospective studies are necessary in order to understand and establish which diet best suits every patient depending on the inherited metabolic disorder. The most suitable imagistic monitoring method for the impact of different diets on the cardiovascular system is still under debate, with no protocols yet available. Echocardiography is readily available in most hospital settings and brings important information regarding the impact of diets on the left ventricular parameters. Cardiac MRI (magnetic resonance imaging) could better characterize the cardiac tissue and bring forth both functional and structural information.
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Affiliation(s)
- Alina Costina Luca
- Pediatrics Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (A.C.L.); (I.-A.P.); (D.E.M.); (E.V.R.)
| | - Ioana-Alexandra Pădureț
- Pediatrics Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (A.C.L.); (I.-A.P.); (D.E.M.); (E.V.R.)
- Saint Mary Emergency Hospital for Children, 700309 Iasi, Romania; (S.G.D.); (H.A.)
| | - Viorel Țarcă
- Department of Preventive Medicine and Interdisciplinarity, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | | | - Dana Elena Mîndru
- Pediatrics Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (A.C.L.); (I.-A.P.); (D.E.M.); (E.V.R.)
| | - Solange Tamara Roșu
- Nursing Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
| | - Eduard Vasile Roșu
- Pediatrics Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (A.C.L.); (I.-A.P.); (D.E.M.); (E.V.R.)
| | | | - Jana Bernic
- Discipline of Pediatric Surgery, “Nicolae Testemițanu” State University of Medicine and Pharmacy, 2025 Chisinau, Moldova;
| | - Elena Cojocaru
- Department of Morphofunctional Sciences I—Pathology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Elena Țarcă
- Surgery II Department—Pediatric Surgery, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
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Ashrafi AH, Mazwi M, Sweeney N, van Dorn CS, Armsby LB, Eghtesady P, Ringle M, Justice LB, Gray SB, Levy V. Preoperative Management of Neonates With Congenital Heart Disease. Pediatrics 2022; 150:e2022056415F. [PMID: 36317975 DOI: 10.1542/peds.2022-056415f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/29/2022] [Indexed: 11/05/2022] Open
Abstract
Clinicians caring for neonates with congenital heart disease encounter challenges in clinical care as these infants await surgery or are evaluated for further potential interventions. The newborn with heart disease can present with significant pathophysiologic heterogeneity and therefore requires a personalized therapeutic management plan. However, this complex field of neonatal-cardiac hemodynamics can be simplified. We explore some of these clinical quandaries and include specific sections reviewing the anatomic challenges in these patients. We propose this to serve as a primer focusing on the hemodynamics and therapeutic strategies for the preoperative neonate with systolic dysfunction, diastolic dysfunction, excessive pulmonary blood flow, obstructed pulmonary blood flow, obstructed systemic blood flow, transposition physiology, and single ventricle physiology.
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Affiliation(s)
| | - Mjaye Mazwi
- Hospital for Sick Children, Toronto, Ontario
| | | | | | | | | | - Megan Ringle
- Lucile Packard Children's Hospital, Palo Alto, California
| | | | - Seth B Gray
- Hospital for Sick Children, Toronto, Ontario
| | - Victor Levy
- Lucile Packard Children's Hospital, Palo Alto, California
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Carrasco-Rozas A, Fernández-Simón E, Suárez-Calvet X, Piñol-Jurado P, Alonso-Pérez J, de Luna N, Schoser B, Meinke P, Domínguez-González C, Hernández-Laín A, Paradas C, Rivas E, Illa I, Olivé M, Gallardo E, Díaz-Manera J. BNIP3 Is Involved in Muscle Fiber Atrophy in Late-Onset Pompe Disease Patients. THE AMERICAN JOURNAL OF PATHOLOGY 2022; 192:1151-1166. [PMID: 35605642 DOI: 10.1016/j.ajpath.2022.05.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 04/25/2022] [Accepted: 05/04/2022] [Indexed: 11/25/2022]
Abstract
Late-onset Pompe disease (LOPD) is a rare genetic disorder produced by mutations in the GAA gene and is characterized by progressive muscle weakness. LOPD muscle biopsies show accumulation of glycogen along with the autophagic vacuoles associated with atrophic muscle fibers. The expression of molecules related to muscle fiber atrophy in muscle biopsies of LOPD patients was studied using immunofluorescence and real-time PCR. BCL2 and adenovirus E1B 19-kDa interacting protein 3 (BNIP3), a well-known atrogene, was identified as a potential mediator of muscle fiber atrophy in LOPD muscle biopsies. Vacuolated fibers in LOPD patient muscle biopsies were smaller than nonvacuolated fibers and expressed BNIP3. The current data suggested that BNIP3 expression is regulated by inhibition of the AKT-mammalian target of rapamycin pathway, leading to phosphorylation of Unc-51 like autophagy activating kinase 1 (ULK1) at Ser317 by AMP-activated protein kinase. Myoblasts and myotubes obtained from LOPD patients and age-matched controls were studied to confirm these results using different molecular techniques. Myotubes derived from LOPD patients were likewise smaller and expressed BNIP3. Conclusively, transfection of BNIP3 into control myotubes led to myotube atrophy. These findings suggest a cascade that starts with the inhibition of the AKT-mammalian target of rapamycin pathway and activation of BNIP3 expression, leading to progressive muscle fiber atrophy. These results open the door to potential new treatments targeting BNIP3 to reduce its deleterious effects on muscle fiber atrophy in Pompe disease.
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Affiliation(s)
- Ana Carrasco-Rozas
- Neuromuscular Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau and Biomedical Research Institute Sant Pau, Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Esther Fernández-Simón
- Neuromuscular Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau and Biomedical Research Institute Sant Pau, Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain; John Walton Muscular Dystrophy Research Center, Newcastle University Translational and Clinical Research Institute, Newcastle Upon Tyne, United Kingdom
| | - Xavier Suárez-Calvet
- Neuromuscular Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau and Biomedical Research Institute Sant Pau, Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigaciones Biomédicas en Red en Enfermedades Raras (CIBERER), Madrid, Spain
| | - Patricia Piñol-Jurado
- Neuromuscular Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau and Biomedical Research Institute Sant Pau, Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain; John Walton Muscular Dystrophy Research Center, Newcastle University Translational and Clinical Research Institute, Newcastle Upon Tyne, United Kingdom
| | - Jorge Alonso-Pérez
- Neuromuscular Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau and Biomedical Research Institute Sant Pau, Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Noemí de Luna
- Neuromuscular Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau and Biomedical Research Institute Sant Pau, Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigaciones Biomédicas en Red en Enfermedades Raras (CIBERER), Madrid, Spain
| | - Benedikt Schoser
- Friedrich-Baur-Institute, Department of Neurology, LMU Klinikum, Munich, Germany
| | - Peter Meinke
- Friedrich-Baur-Institute, Department of Neurology, LMU Klinikum, Munich, Germany
| | - Cristina Domínguez-González
- Centro de Investigaciones Biomédicas en Red en Enfermedades Raras (CIBERER), Madrid, Spain; Department of Neurology, Neuromuscular Unit, 12 de Octubre University Hospital, Madrid, Spain; Research Institute of Hospital 12 de Octubre (i+12), Madrid, Spain
| | - Aurelio Hernández-Laín
- Centro de Investigaciones Biomédicas en Red en Enfermedades Raras (CIBERER), Madrid, Spain; Research Institute of Hospital 12 de Octubre (i+12), Madrid, Spain; Department of Pathology (Neuropathology), 12 de Octubre University Hospital, Madrid, Spain
| | - Carmen Paradas
- Neuromuscular Disorders Unit, Department of Neurology, Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío/Centro Superior de Investigaciones Científicas/Universidad de Sevilla, Seville, Spain; Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - Eloy Rivas
- Department of Pathology, Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío/Centro Superior de Investigaciones Científicas/Universidad de Sevilla, Sevilla, Spain
| | - Isabel Illa
- Neuromuscular Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau and Biomedical Research Institute Sant Pau, Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigaciones Biomédicas en Red en Enfermedades Raras (CIBERER), Madrid, Spain
| | - Montse Olivé
- Neuromuscular Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau and Biomedical Research Institute Sant Pau, Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigaciones Biomédicas en Red en Enfermedades Raras (CIBERER), Madrid, Spain
| | - Eduard Gallardo
- Neuromuscular Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau and Biomedical Research Institute Sant Pau, Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigaciones Biomédicas en Red en Enfermedades Raras (CIBERER), Madrid, Spain.
| | - Jordi Díaz-Manera
- Neuromuscular Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau and Biomedical Research Institute Sant Pau, Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain; John Walton Muscular Dystrophy Research Center, Newcastle University Translational and Clinical Research Institute, Newcastle Upon Tyne, United Kingdom; Centro de Investigaciones Biomédicas en Red en Enfermedades Raras (CIBERER), Madrid, Spain.
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Zhang Y, Zhang C, Shu JB, Zhang F. Atypical infantile-onset Pompe disease with good prognosis from mainland China: A case report. World J Clin Cases 2022; 10:3278-3283. [PMID: 35603335 PMCID: PMC9082720 DOI: 10.12998/wjcc.v10.i10.3278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Revised: 01/29/2022] [Accepted: 02/20/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Pompe disease has a broad disease spectrum, including infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD) forms. It is a type of glycogen storage disorder belonging to autosomal recessive genetic disease, for an estimated incidence of 1/40000 among the neonatal population. In severe cases, the natural course is characterized by death due to cardiopulmonary failure in the first year after birth. However, the clinical outcomes have improved since the emergence of enzyme replacement therapy (ERT) was widely used. CASE SUMMARY The reported female case in China was an atypical IOPD, which demonstrates an unusual presentation of glycogen accumulation syndrome type II without obvious skeletal muscle involvement, and reviewed physical examination, biochemical examinations, chest radiograph, and acid α-glucosidase (GAA) mutation analysis. After 4-mo specific ERT, the case received 12-mo follow-up. Moreover, the patient has obtained a very good prognosis under ERT. CONCLUSION For the atypical IOPD patients, early diagnosis and treatment may contribute to good prognosis.
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Affiliation(s)
- Ying Zhang
- Department of Neonatal, Tianjin Children’s Hospital (Tianjin University Children's Hospital), Tianjin 300134, China
| | - Cheng Zhang
- Department of Neonatal, Tianjin Children’s Hospital (Tianjin University Children's Hospital), Tianjin 300134, China
| | - Jian-Bo Shu
- Tianjin Key Laboratory of Birth Defects for Prevention and Treatment, Tianjin Pediatric Research Institute, Tianjin Children’s Hospital (Tianjin University Children's Hospital), Tianjin 300134, China
| | - Fang Zhang
- Department of Neonatal, Tianjin Children’s Hospital (Tianjin University Children's Hospital), Tianjin 300134, China
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13
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Karadağ Gürel A, Gürel S. To detect potential pathways and target genes in infantile Pompe patients using computational analysis. BIOIMPACTS 2022; 12:89-105. [PMID: 35411297 PMCID: PMC8905584 DOI: 10.34172/bi.2022.23467] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 02/08/2021] [Accepted: 02/13/2021] [Indexed: 11/21/2022]
Abstract
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Introduction: Pompe disease (PD) is a disease caused by pathogenic variations in the GAA gene known as glycogen storage disease type II, characterized by heart hypertrophy, respiratory failure, and muscle hypotonia, leading to premature death if not treated early. The only treatment option, enzyme replacement therapy (ERT), significantly improves the prognosis for some patients while failing to help others. In this study, the determination of key genes involved in the response to ERT and potential molecular mechanisms were investigated.
Methods: Gene Expression Omnibus (GEO) data, accession number GSE38680, containing samples of biceps and quadriceps muscles was used. Expression array data were analyzed using BRB-Array Tools. Biceps group patients did not receive ERT, while quadriceps received treatment with rhGAA at 0, 12, and 52 weeks. Differentially expressed genes (DEGs) were deeply analyzed by DAVID, GO, KEGG and STRING online analyses, respectively.
Results: A total of 1727 genes in the biceps group and 1198 genes in the quadriceps group are expressed differently. It was observed that DEGs were enriched in the group that responded poorly to ERT in the 52nd week. Genes frequently changed in the weak response group; the expression of 530 genes increased and 1245 genes decreased compared to 0 and 12 weeks. The GO analysis demonstrated that the DEGs were mainly involved in vascular smooth muscle contraction, lysosomes, autophagy, regulation of actin cytoskeleton, inflammatory response, and the WNT signaling pathway. We also discovered that the WNT signaling pathway is highly correlated with DEGs. Several DEGs, such as WNT11, WNT5A, CTNNB1, M6PR, MYL12A, VCL, TLN, FYN, YES1, and BCL2, may be important in elucidating the mechanisms underlying poor response to ERT.
Conclusion: Early diagnosis and treatment of PD are very important for the clinic of the disease. As a result, it suggests that the enriched genes and new pathways emerging as a result of the analysis may help identify the group that responds poorly to treatment and the outcome of the treatment. Obtained genes and pathways in neonatal screening will guide diagnosis and treatment.
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Affiliation(s)
- Aynur Karadağ Gürel
- Department of Medical Biology, School of Medicine, Usak University, Usak, Turkey
| | - Selçuk Gürel
- Department of Pediatrics, School of Medicine, Bahcesehir University, İstanbul, Turkey
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14
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Pharmacological Chaperone Therapy for Pompe Disease. Molecules 2021; 26:molecules26237223. [PMID: 34885805 PMCID: PMC8659197 DOI: 10.3390/molecules26237223] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 11/25/2021] [Accepted: 11/26/2021] [Indexed: 11/17/2022] Open
Abstract
Pompe disease (PD), a lysosomal storage disease, is caused by mutations of the GAA gene, inducing deficiency in the acid alpha-glucosidase (GAA). This enzymatic impairment causes glycogen burden in lysosomes and triggers cell malfunctions, especially in cardiac, smooth and skeletal muscle cells and motor neurons. To date, the only approved treatment available for PD is enzyme replacement therapy (ERT) consisting of intravenous administration of rhGAA. The limitations of ERT have motivated the investigation of new therapies. Pharmacological chaperone (PC) therapy aims at restoring enzymatic activity through protein stabilization by ligand binding. PCs are divided into two classes: active site-specific chaperones (ASSCs) and the non-inhibitory PCs. In this review, we summarize the different pharmacological chaperones reported against PD by specifying their PC class and activity. An emphasis is placed on the recent use of these chaperones in combination with ERT.
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15
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Fatehi F, Ashrafi MR, Babaee M, Ansari B, Beiraghi Toosi M, Boostani R, Eshraghi P, Fakharian A, Hadipour Z, Haghi Ashtiani B, Moravej H, Nilipour Y, Sarraf P, Sayadpour Zanjani K, Nafissi S. Recommendations for Infantile-Onset and Late-Onset Pompe Disease: An Iranian Consensus. Front Neurol 2021; 12:739931. [PMID: 34621239 PMCID: PMC8490649 DOI: 10.3389/fneur.2021.739931] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 08/16/2021] [Indexed: 01/12/2023] Open
Abstract
Background: Pompe disease, also denoted as acid maltase or acid α-glucosidase deficiency or glycogen storage disease type II, is a rare, autosomal recessive lysosomal storage disorder. Several reports have previously described Pompe disease in Iran and considering increased awareness of related subspecialties and physicians, the disease's diagnosis is growing. Objective: This guideline's main objective was to develop a national guideline for Pompe disease based on national and international evidence adapting with national necessities. Methods: A group of expert clinicians with particular interests and experience in diagnosing and managing Pompe disease participated in developing this guideline. This group included adult neurologists, pediatric neurologists, pulmonologists, endocrinologists, cardiologists, pathologists, and physiatrists. After developing search terms, four authors performed an extensive literature review, including Embase, PubMed, and Google Scholar, from 1932 to current publications before the main meeting. Before the main consensus session, each panel member prepared an initial draft according to pertinent data in diagnosis and management and was presented in the panel discussion. Primary algorithms for the diagnosis and management of patients were prepared in the panel discussion. The prepared consensus was finalized after agreement and concordance between the panel members. Conclusion: Herein, we attempted to develop a consensus based on Iran's local requirements. The authors hope that disseminating these consensuses will help healthcare professionals in Iran achieve the diagnosis, suitable treatment, and better follow-up of patients with infantile-onset Pompe disease and late-onset Pompe disease.
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Affiliation(s)
- Farzad Fatehi
- Department of Neurology, Neuromuscular Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahmoud Reza Ashrafi
- Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
| | - Marzieh Babaee
- Physical Medicine and Rehabilitation Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Behnaz Ansari
- Isfahan Neurosciences Research Center, Alzahra Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | - Reza Boostani
- Neurology Department, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Peyman Eshraghi
- Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Atefeh Fakharian
- Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zahra Hadipour
- Medical Genetic Department, Atieh Hospital, Pars Hospital and Research Center, Tehran, Iran
| | | | - Hossein Moravej
- Neonatal Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Yalda Nilipour
- Pediatric Pathology Research Center, Research Institute for Children's Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Payam Sarraf
- Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Keyhan Sayadpour Zanjani
- Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
| | - Shahriar Nafissi
- Department of Neurology, Neuromuscular Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
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16
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Shen B, Singla RK. Secondary Metabolites as Treatment of Choice for Metabolic Disorders and Infectious Diseases & their Metabolic Profiling-Part 2. Curr Drug Metab 2021; 21:1070-1071. [PMID: 33413055 DOI: 10.2174/138920022114201230142204] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Bairong Shen
- Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Rajeev K Singla
- Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
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17
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Bor M, Ilhan O, Gumus E, Ozkan S, Karaca M. A Newborn with Infantile-Onset Pompe Disease Improving after Administration of Enzyme Replacement Therapy: Case Report. J Pediatr Intensive Care 2020; 11:62-66. [DOI: 10.1055/s-0040-1714099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 05/26/2020] [Indexed: 10/23/2022] Open
Abstract
AbstractPompe disease (PD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of acid α-1,4-glucosidase enzyme (GAA). PD has two forms, namely the infantile-onset and the late-onset form. In untreated cases, infantile-onset form usually leads to cardio-respiratory failure and death in the first year of life. Herein, we report a newborn with infantile-onset PD characterized by muscular hypotonia, respiratory distress, hypertrophic cardiomyopathy, hepatomegaly, elevated serum enzyme levels of aspartate aminotransferase of 117 IU/L (three times the normal value), alanine aminotransferase of 66 IU/L (1.8 times the normal value), lactate dehydrogenase of 558 IU/L (1.2 times the normal value), and creatine kinase >5,000 IU/L (16 times the normal value). Dried blood spot testing was performed and revealed decreased GAA enzymatic activity (0.07 nmol/mL/h, normal 0.93–7.33 nmol/mL/h). GAA gene analysis performed for confirming the diagnosis showed homozygous mutation c.896T >C (p.Leu299Pro). Initiation of enzyme replacement therapy (ERT) (ERT; 20 mg/kg, once every week) at 28 days of age resulted in weaning off from respiratory support within 1 week after treatment, normalization of cardiac abnormalities, and normal neuromotor development in the 16th month of age. Early diagnosis and early treatment with ERT, especially in the neonatal period, is of great importance to improve cardiac function and motor development in infantile-onset PD.
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Affiliation(s)
- Meltem Bor
- Department of Neonatology, Harran University School of Medicine, Sanliurfa, Turkey
| | - Ozkan Ilhan
- Department of Neonatology, Harran University School of Medicine, Sanliurfa, Turkey
| | - Evren Gumus
- Department of Medical Genetics, Harran University School of Medicine, Sanliurfa, Turkey
| | - Solmaz Ozkan
- Department of General Pediatrics, Kumluca State Hospital, Kumluca, Antalya, Turkey
| | - Meryem Karaca
- Department of Pediatric Metabolism and Nutrition, Harran University School of Medicine, Sanliurfa, Turkey
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18
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Tran ML, Génisson Y, Ballereau S, Dehoux C. Second-Generation Pharmacological Chaperones: Beyond Inhibitors. Molecules 2020; 25:molecules25143145. [PMID: 32660097 PMCID: PMC7397201 DOI: 10.3390/molecules25143145] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 06/29/2020] [Accepted: 07/05/2020] [Indexed: 02/06/2023] Open
Abstract
Protein misfolding induced by missense mutations is the source of hundreds of conformational diseases. The cell quality control may eliminate nascent misfolded proteins, such as enzymes, and a pathological loss-of-function may result from their early degradation. Since the proof of concept in the 2000s, the bioinspired pharmacological chaperone therapy became a relevant low-molecular-weight compound strategy against conformational diseases. The first-generation pharmacological chaperones were competitive inhibitors of mutant enzymes. Counterintuitively, in binding to the active site, these inhibitors stabilize the proper folding of the mutated protein and partially rescue its cellular function. The main limitation of the first-generation pharmacological chaperones lies in the balance between enzyme activity enhancement and inhibition. Recent research efforts were directed towards the development of promising second-generation pharmacological chaperones. These non-inhibitory ligands, targeting previously unknown binding pockets, limit the risk of adverse enzymatic inhibition. Their pharmacophore identification is however challenging and likely requires a massive screening-based approach. This review focuses on second-generation chaperones designed to restore the cellular activity of misfolded enzymes. It intends to highlight, for a selected set of rare inherited metabolic disorders, the strategies implemented to identify and develop these pharmacologically relevant small organic molecules as potential drug candidates.
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Affiliation(s)
| | | | | | - Cécile Dehoux
- Correspondence: (S.B.); (C.D.); Tel.: +33-5-6155-6127 (C.D.)
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19
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Didiasova M, Banning A, Brennenstuhl H, Jung-Klawitter S, Cinquemani C, Opladen T, Tikkanen R. Succinic Semialdehyde Dehydrogenase Deficiency: An Update. Cells 2020; 9:cells9020477. [PMID: 32093054 PMCID: PMC7072817 DOI: 10.3390/cells9020477] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2020] [Revised: 02/14/2020] [Accepted: 02/17/2020] [Indexed: 02/06/2023] Open
Abstract
Succinic semialdehyde dehydrogenase deficiency (SSADH-D) is a genetic disorder that results from the aberrant metabolism of the neurotransmitter γ-amino butyric acid (GABA). The disease is caused by impaired activity of the mitochondrial enzyme succinic semialdehyde dehydrogenase. SSADH-D manifests as varying degrees of mental retardation, autism, ataxia, and epileptic seizures, but the clinical picture is highly heterogeneous. So far, there is no approved curative therapy for this disease. In this review, we briefly summarize the molecular genetics of SSADH-D, the past and ongoing clinical trials, and the emerging features of the molecular pathogenesis, including redox imbalance and mitochondrial dysfunction. The main aim of this review is to discuss the potential of further therapy approaches that have so far not been tested in SSADH-D, such as pharmacological chaperones, read-through drugs, and gene therapy. Special attention will also be paid to elucidating the role of patient advocacy organizations in facilitating research and in the communication between researchers and patients.
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Affiliation(s)
- Miroslava Didiasova
- Institute of Biochemistry, Medical Faculty, University of Giessen, Friedrichstrasse 24, 35392 Giessen, Germany; (M.D.); (A.B.)
| | - Antje Banning
- Institute of Biochemistry, Medical Faculty, University of Giessen, Friedrichstrasse 24, 35392 Giessen, Germany; (M.D.); (A.B.)
| | - Heiko Brennenstuhl
- Division of Neuropediatrics and Metabolic Medicine, Department of General Pediatrics, University Children’s Hospital Heidelberg, 69120 Heidelberg, Germany; (H.B.); (S.J.-K.); (T.O.)
| | - Sabine Jung-Klawitter
- Division of Neuropediatrics and Metabolic Medicine, Department of General Pediatrics, University Children’s Hospital Heidelberg, 69120 Heidelberg, Germany; (H.B.); (S.J.-K.); (T.O.)
| | | | - Thomas Opladen
- Division of Neuropediatrics and Metabolic Medicine, Department of General Pediatrics, University Children’s Hospital Heidelberg, 69120 Heidelberg, Germany; (H.B.); (S.J.-K.); (T.O.)
| | - Ritva Tikkanen
- Institute of Biochemistry, Medical Faculty, University of Giessen, Friedrichstrasse 24, 35392 Giessen, Germany; (M.D.); (A.B.)
- Correspondence: ; Tel.: +49-641-9947-420
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20
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Farah BL, Yen PM, Koeberl DD. Links between autophagy and disorders of glycogen metabolism - Perspectives on pathogenesis and possible treatments. Mol Genet Metab 2020; 129:3-12. [PMID: 31787497 PMCID: PMC7836271 DOI: 10.1016/j.ymgme.2019.11.005] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 11/18/2019] [Accepted: 11/19/2019] [Indexed: 01/17/2023]
Abstract
The glycogen storage diseases are a group of inherited metabolic disorders that are characterized by specific enzymatic defects involving the synthesis or degradation of glycogen. Each disorder presents with a set of symptoms that are due to the underlying enzyme deficiency and the particular tissues that are affected. Autophagy is a process by which cells degrade and recycle unneeded or damaged intracellular components such as lipids, glycogen, and damaged mitochondria. Recent studies showed that several of the glycogen storage disorders have abnormal autophagy which can disturb normal cellular metabolism and/or mitochondrial function. Here, we provide a clinical overview of the glycogen storage disorders, a brief description of autophagy, and the known links between specific glycogen storage disorders and autophagy.
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Affiliation(s)
- Benjamin L Farah
- Department of Pathology, Singapore General Hospital, Singapore, Singapore.
| | - Paul M Yen
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore, Singapore; Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, USA
| | - Dwight D Koeberl
- Division of Medical Genetics, Department of Pediatrics, Duke University Medical School, Durham, NC, USA; Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA..
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