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Parviz S, Hooshyar D. Neonatal Nonketotic Hyperglycinemia: A Severe Case With Prenatal Indicators and Comprehensive Review of Recognition and Management. Clin Case Rep 2025; 13:e70035. [PMID: 39776772 PMCID: PMC11705463 DOI: 10.1002/ccr3.70035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 11/17/2024] [Accepted: 12/15/2024] [Indexed: 01/11/2025] Open
Abstract
Nonketotic hyperglycinemia (NKH), also known as glycine encephalopathy, is a rare inherited neurometabolic disorder caused by a deficiency in the glycine cleavage enzyme system (GCS), leading to the pathological accumulation of glycine in blood and cerebrospinal fluid (CSF). This case report details a neonate presenting with central apnea, profound hypotonia, and refractory seizures, alongside prenatal findings of polyhydramnios and hiccup-like fetal movements, all strongly suggestive of severe NKH. Diagnostic evaluation confirmed markedly elevated glycine levels in serum and CSF, with a CSF-to-plasma glycine ratio exceeding 0.08, and ruled out alternative causes of hyperglycinemia. Brain MRI revealed characteristic malformations, corroborating the diagnosis of severe NKH. Treatment included anticonvulsants for seizure management, sodium benzoate for glycine reduction, and NMDA receptor antagonists (ketamine and dextromethorphan) to modulate neurotoxicity. Despite these therapies, the patient demonstrated poor neurodevelopmental outcomes, with rapid progression to severe impairment. This case highlights the significance of early identification, precise diagnosis, and a comprehensive care strategy in managing NKH, aiming to enhance patient outcomes and quality of life.
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Affiliation(s)
- Samaneh Parviz
- Department of Pediatrics, Clinical Research Development Center of Children's HospitalHormozgan University of Medical ScienceBandar AbbasIran
| | - Dariush Hooshyar
- Student Research Committee, Faculty of MedicineHormozgan University of Medical SciencesBandar AbbasIran
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2
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Kong W, Lu C, Wang L. Global birth prevalence of Pompe disease: A systematic review and meta-analysis. Neuroscience 2024; 563:167-174. [PMID: 39424261 DOI: 10.1016/j.neuroscience.2024.09.043] [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: 04/21/2024] [Revised: 09/16/2024] [Accepted: 09/21/2024] [Indexed: 10/21/2024]
Abstract
BACKGROUND Pompe disease, also known as Glycogen storage disease type II, is an autosomal recessive disorder caused by defects in alpha-glucosidase, resulting in abnormal glycogen accumulation. METHODS To conduct a systematic review and meta-analysis of birth prevalence of Pompe disease, the MEDLINE and EMBASE databases were searched for original research articles on the epidemiology of Pompe disease from inception until July 01, 2024. Meta-analysis was performed to estimate global birth prevalence of Pompe disease. The funnel plot was used to describe potential publication bias. RESULTS Twenty-two studies, screened out of 945 records, were included for data extraction. Studies that fulfilled inclusion criteria involved 15 areas/countries. Global birth prevalence of Pompe disease was 2.0 cases (95% CI: 1.5-2.4) per 100,000 live births. Global birth prevalence of infantile-onset Pompe disease was 1.0 cases (95% CI: 0.5-1.5) per 100,000 live births. Global birth prevalence of late-onset Pompe disease was 2.4 cases (95% CI: 1.8-3.0) per 100,000 live births. The main limitations are that no study was assessed as high-quality and approximately half of the studies were from Europe. CONCLUSIONS Quantitative data on the global epidemiology of Pompe disease could be the fundamental to evaluate the global efforts on building a better world for Pompe disease patients.
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Affiliation(s)
- Weijing Kong
- Department of Pediatrics, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
| | - Cheng Lu
- Beijing Hong Jian Medical Device Company, Beijing 100176, China.
| | - Lichao Wang
- Department of Pediatrics, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
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3
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D'Alessio AM, Boffa I, De Stefano L, Soria LR, Brunetti-Pierri N. Liver gene transfer for metabolite detoxification in inherited metabolic diseases. FEBS Lett 2024; 598:2372-2384. [PMID: 38884367 DOI: 10.1002/1873-3468.14957] [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: 04/20/2024] [Revised: 05/28/2024] [Accepted: 06/04/2024] [Indexed: 06/18/2024]
Abstract
Inherited metabolic disorders (IMDs) are a growing group of genetic diseases caused by defects in enzymes that mediate cellular metabolism, often resulting in the accumulation of toxic substrates. The liver is a highly metabolically active organ that hosts several thousands of chemical reactions. As such, it is an organ frequently affected in IMDs. In this article, we review current approaches for liver-directed gene-based therapy aimed at metabolite detoxification in a variety of IMDs. Moreover, we discuss current unresolved challenges in gene-based therapies for IMDs.
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Affiliation(s)
- Alfonso M D'Alessio
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
- Scuola Superiore Meridionale (SSM, School of Advanced Studies), Genomics and Experimental Medicine Program, University of Naples Federico II, Naples, Italy
| | - Iolanda Boffa
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
- Azienda Ospedaliera Universitaria Federico II, Naples, Italy
| | - Lucia De Stefano
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
| | - Leandro R Soria
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
| | - Nicola Brunetti-Pierri
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
- Scuola Superiore Meridionale (SSM, School of Advanced Studies), Genomics and Experimental Medicine Program, University of Naples Federico II, Naples, Italy
- Department of Translational Medicine, Federico II University of Naples, Naples, Italy
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Torres-Sepúlveda MDR, Martínez de Villarreal LE, Villarreal-Pérez JZ, Ruiz Herrera MDC, Arredondo Vázquez PDC, Treviño-Morales AK. Outcome of Expanded Newborn Screening Among 194 000 Neonates at Northeast México. Glob Pediatr Health 2024; 11:2333794X241280830. [PMID: 39315058 PMCID: PMC11418224 DOI: 10.1177/2333794x241280830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 06/24/2024] [Accepted: 08/20/2024] [Indexed: 09/25/2024] Open
Abstract
Objectives. To describe the results of a 16-year experience of a state-coverage expanded newborn screening program (NBSP) in Northeast México. Methods. Between 2002 and 2017, dried blood spots of newborns were screened for congenital hypothyroidism (CH), congenital adrenal hyperplasia (CAH), biotinidase deficiency, galactosemia, cystic fibrosis, and glucose-6-phosphate dehydrogenase (G6PD) deficiency via immunofluorescence and amino and fatty acid disorders and organic acidemias using tandem mass spectrometry. Frequency rates were determined. Results. Overall, 192 487 samples were processed; 99.4% had negative results, and 598 were diagnosed. The frequency was 3.01/1000 newborns. G6PD deficiency, CH, amino acidemia, organic acidemia, cystic fibrosis, CAH, fatty acid oxidation disorder, galactosemia, and biotinidase deficiency cases were 1:773, 1:962, 1:4277, 1:4476, 1:11,322, 1:10,693, 1:10,693, 1:38,497, and 1:64,162, respectively. Conclusion. Using different technologies in NBSP increased the number of conditions detected, facilitating infant morbidity and mortality prevention. The frequency of disorders depends on the population's genetic background and diagnostic capacity.
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Affiliation(s)
- María del Rosario Torres-Sepúlveda
- Universidad Autónoma de Nuevo León, Departamento de Genética, Facultad de Medicina y Hospital Universitario Dr. José Eleuterio González, Monterrey, Nuevo León, México
| | - Laura E. Martínez de Villarreal
- Universidad Autónoma de Nuevo León, Departamento de Genética, Facultad de Medicina y Hospital Universitario Dr. José Eleuterio González, Monterrey, Nuevo León, México
| | - Jesús Zacarías Villarreal-Pérez
- Universidad Autónoma de Nuevo León, Servicio de Endocrinología, Facultad de Medicina y Hospital Universitario Dr. José E. González, Monterrey, Nuevo León, México
| | - María del Consuelo Ruiz Herrera
- Universidad Autónoma de Nuevo León, Departamento de Genética, Facultad de Medicina y Hospital Universitario Dr. José Eleuterio González, Monterrey, Nuevo León, México
| | | | - Ana Karen Treviño-Morales
- Universidad Autónoma de Nuevo León, Departamento de Genética, Facultad de Medicina y Hospital Universitario Dr. José Eleuterio González, Monterrey, Nuevo León, México
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5
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Javed M, Goswami DK, Raj H, Lohana K, Goswami B, Karim A, Warayo A, Farooqi P, Alamy H, Ullah ZO, Mohammad A, Farooqi SA, Ali H, Shuja D, Malik J, Baloch ZQ. Cardiac Manifestations in Inherited Metabolic Diseases. Cardiol Rev 2024:00045415-990000000-00299. [PMID: 38980048 DOI: 10.1097/crd.0000000000000753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/10/2024]
Abstract
Inherited metabolic diseases (IMDs) stem from genetic defects affecting enzyme function within specific metabolic pathways, collectively constituting rare conditions with an incidence of less than 1/100,000 births. While IMDs typically manifest with multisystemic symptoms, cardiac manifestations are common, notably hypertrophic cardiomyopathy. Additionally, they can lead to dilated or restrictive cardiomyopathy, as well as noncompacted left ventricular cardiomyopathy. Rhythm disturbances such as atrioventricular conduction abnormalities, Wolff-Parkinson-White syndrome, and ventricular arrhythmias, along with valvular pathologies and ischemic coronary issues, are also prevalent. This study aims to provide a narrative review of IMDs associated with cardiac involvement, delineating the specific cardiac manifestations of each disorder alongside systemic symptoms pivotal for diagnosis.
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Affiliation(s)
- Mubeena Javed
- From the Department of Medicine, Allama Iqbal Medical College, Lahore, Pakistan
| | - Danish Kumar Goswami
- Department of Medicine, Liaquat University of Medical and Health Sciences, Jamshoro, Pakistan
| | - Hem Raj
- Department of Medicine, Liaquat University of Medical and Health Sciences, Jamshoro, Pakistan
| | - Kiran Lohana
- Department of Medicine, Liaquat University of Medical and Health Sciences, Jamshoro, Pakistan
| | - Barkha Goswami
- Department of Medicine, Liaquat University of Medical and Health Sciences, Jamshoro, Pakistan
| | - Ali Karim
- Department of Medicine, Liaquat University of Medical and Health Sciences, Jamshoro, Pakistan
| | - Allah Warayo
- Department of Medicine, Liaquat University of Medical and Health Sciences, Jamshoro, Pakistan
| | - Palwasha Farooqi
- Department of Medicine, Kabul University of Medical Sciences, Kabul, Afghanistan
| | - Haroon Alamy
- Department of Medicine, Kabul University of Medical Sciences, Kabul, Afghanistan
| | - Zainab Obaid Ullah
- Department of Medicine, Fatima Jinnah Medical University, Lahore, Pakistan
| | - Aamer Mohammad
- Department of Medicine, Rajiv Gandhi University of Health Sciences, Bengaluru, India
| | - Syed Ahmad Farooqi
- Department of Medicine, Liaquat University of Medical and Health Sciences, Jamshoro, Pakistan
| | - Hafsah Ali
- Department of Medicine, Jinnah Sindh Medical University, Karachi, Pakistan
| | - Darab Shuja
- Department of Medicine, Services Hospital, Lahore, Pakistan
| | - Jahanzeb Malik
- Department of Cardiovascular Medicine, Cardiovascular Analytics Group, Islamabad, Pakistan
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Cuenca-Gómez JÁ, Lara-Rojas CM, Bonilla-López A. Cardiac manifestations in inherited metabolic diseases. Curr Probl Cardiol 2024; 49:102587. [PMID: 38653442 DOI: 10.1016/j.cpcardiol.2024.102587] [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: 04/16/2024] [Accepted: 04/20/2024] [Indexed: 04/25/2024]
Abstract
Inherited metabolic diseases (IMD) are caused by the functional defect of an enzyme, of genetic origin, that provokes a blockage in a specific metabolic pathway. Individually, IMD are considered rare diseases, with an incidence of less than 1/100,000 births. The symptoms are usually multisystemic, but frequently include cardiac manifestations. Of these, the most common are cardiomyopathies, especially hypertrophic cardiomyopathy. In addition, they can cause dilated or restrictive cardiomyopathy and non-compacted cardiomyopathy of the left ventricle. Characteristic signs also include rhythm alterations (atrio-ventricular conduction disturbances, Wolff-Parkinson-White syndrome or ventricular arrhythmias), valvular pathology and ischaemic coronary pathologies. The aim of this study is to present a narrative review of the IMD that may produce cardiac involvement. We describe both the specific cardiac manifestations of each disease and the systemic symptoms that guide diagnosis.
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Affiliation(s)
- José Ángel Cuenca-Gómez
- Internal Medicine Service Hospital de Poniente El Ejido, Almería, Spain; Working Group on Minority Diseases of the Spanish Society of Internal Medicine (GTEM-SEMI), Almería, Spain.
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7
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Abdelhamed W, El-Kassas M. Rare liver diseases in Egypt: Clinical and epidemiological characterization. Arab J Gastroenterol 2024; 25:75-83. [PMID: 38228442 DOI: 10.1016/j.ajg.2023.12.002] [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: 09/23/2022] [Revised: 12/04/2023] [Accepted: 12/16/2023] [Indexed: 01/18/2024]
Abstract
Illnesses that afflict a tiny number of individuals are referred to as rare diseases (RDs), sometimes called orphan diseases. The local healthcare systems are constantly under financial, psychological, and medical strain due to low incidence rates, unusual presentations, flawed diagnostic standards, and a lack of treatment alternatives for these RDs. The effective management of the once widely spread viral hepatitis B and C has altered the spectrum of liver diseases in Egypt during the last several years. The detection of uncommon disorders such as autoimmune, cholestatic, and hereditary liver diseases has also been made easier by the increasing knowledge and greater accessibility of specific laboratory testing. Finally, despite Egypt's large population, there are more uncommon liver disorders than previously thought. This review article discusses the clinical and epidemiological characteristics of a few uncommon liver disorders and the information currently accessible concerning these illnesses in Egypt.
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Affiliation(s)
- Walaa Abdelhamed
- Endemic Medicine Department, Faculty of Medicine, Sohag University, Sohag, Egypt
| | - Mohamed El-Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt.
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8
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Saeed Z, Mashkani B, Alaei A, Varasteh A, Keyfi F. Determining the Reference Range of Amino Acids in Healthy Neonatal Blood Samples in Northeast Iran Using LC-MS/MS. Rep Biochem Mol Biol 2024; 13:87-98. [PMID: 39582819 PMCID: PMC11580130 DOI: 10.61186/rbmb.13.1.87] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Accepted: 12/23/2023] [Indexed: 11/26/2024]
Abstract
Background Amino acid analysis is an important tool for the diagnosis of metabolic disorders in newborns. Today, Liquid Chromatography tandem mass spectrometry (LC-MS/MS) has emerged as a powerful technique for amino acid analysis. We aimed to determine the local normal range of amino acids in dried blood spot (DBS) samples of neonates using LC-MS/MS. Methods A total of 1005 samples from healthy neonates of northeast and east of Iran aged 2-7 days were utilized for normal range determination. The amino acids were extracted from dried blood spot samples using organic solvent and then analyzed using LC-MS/MS system. The 1%, 2.5%, 97.5%, and 99% percentiles were calculated, and the results were compared to the global cut-off values. Results The results showed that glutamic acid has the highest concentration range among amino acids evaluated in this study (178.94 - 421.31µmol/L). Moreover, the plasma concentrations of Glycine (142.65 - 397.06 µmol/L), Alanine (97.00-349.72 µmol/L), Proline (63.77 - 236.53 µmol/L), and Tyrosine (25.79 - 150.58 µmol/L) were in the next ranks. Comparing the obtained results with the global values obtained in the R4S study indicated a slight difference between the obtained local normal values and the global values. Conclusions The calculated values were slightly different from global values obtained in the R4S study and regional values calculated in other studies. This further emphasized the importance of the local establishment of reference values, which facilitates the correct interpretation and diagnosis in the Newborn Screening Programs.
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Affiliation(s)
- Zeinab Saeed
- Department of Clinical Biochemistry, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Baratali Mashkani
- Department of Clinical Biochemistry, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Amin Alaei
- Department of Medical Laboratory Science, Varastegan Institute for Medical Sciences, Mashhad, Iran.
- Division of Metabolic Disorder, Pardis Clinical and Genetic Laboratory, Mashhad, Iran.
- Research Committee, Department of Medical Laboratory Science, Varastegan Institute for Medical Sciences, Mashhad, Iran.
| | - Abdolreza Varasteh
- Department of Medical Laboratory Science, Varastegan Institute for Medical Sciences, Mashhad, Iran.
- Division of Metabolic Disorder, Pardis Clinical and Genetic Laboratory, Mashhad, Iran.
| | - Fatemeh Keyfi
- Department of Medical Laboratory Science, Varastegan Institute for Medical Sciences, Mashhad, Iran.
- Division of Metabolic Disorder, Pardis Clinical and Genetic Laboratory, Mashhad, Iran.
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Cordeiro RA, Rosa Neto NS, Giardini HAM. What should rheumatologists know about Gaucher disease and Fabry disease? Connecting the dots for an overview. Adv Rheumatol 2024; 64:22. [PMID: 38520029 DOI: 10.1186/s42358-024-00362-2] [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: 01/12/2024] [Accepted: 03/13/2024] [Indexed: 03/25/2024] Open
Abstract
Gaucher and Fabry diseases are lysosomal storage disorders in which deficient enzyme activity leads to pathological accumulation of sphingolipids. These diseases have a broad phenotypic presentation. Musculoskeletal symptoms and pain complaints are frequently reported by patients. Thus, rheumatologists can be contacted by these patients, contributing to the correct diagnosis, earlier indication of appropriate treatment and improvement of their prognosis. This review describes important concepts about Gaucher and Fabry diseases that rheumatologists should understand to improve patients' quality of life and change the natural history of these diseases.
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Affiliation(s)
- Rafael Alves Cordeiro
- Division of Rheumatology, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Av Dr Arnaldo, 455, 3 andar, sala 3184, Cerqueira Cesar, Sao Paulo, SP, CEP 01246-903, Brazil.
| | - Nilton Salles Rosa Neto
- Centro de Doenças Raras e da Imunidade, Hospital Nove de Julho, São Paulo, Brazil
- Universidade Santo Amaro, São Paulo, Brazil
| | - Henrique Ayres Mayrink Giardini
- Division of Rheumatology, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Av Dr Arnaldo, 455, 3 andar, sala 3184, Cerqueira Cesar, Sao Paulo, SP, CEP 01246-903, Brazil
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Fishbein SRS, Evbuomwan EM, Dantas G. Conquering homocystinuria with engineered probiotics. Cell Host Microbe 2024; 32:298-300. [PMID: 38484708 DOI: 10.1016/j.chom.2024.02.008] [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: 02/14/2024] [Accepted: 02/15/2024] [Indexed: 03/19/2024]
Abstract
Pyridoxine-unresponsive homocystinuria has lifelong implications for health. In this issue, Perreault and colleagues present evidence that orally delivered engineered probiotic Escherichia Coli Nissle SYNB1353 is a promising candidate in reducing homocysteine, with successful trials in mice, monkeys, and humans. However, further probiotic optimization and safety assessments are required.
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Affiliation(s)
- Skye R S Fishbein
- The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, USA; Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, USA.
| | - Esse M Evbuomwan
- The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, USA; Department of Biomedical Engineering, Washington University in St Louis, St. Louis, MO, USA.
| | - Gautam Dantas
- The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, USA; Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, USA; Department of Biomedical Engineering, Washington University in St Louis, St. Louis, MO, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
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11
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Chang SC, Bergamasco A, Bonnin M, Bisonó TA, Moride Y. A systematic review on the birth prevalence of metachromatic leukodystrophy. Orphanet J Rare Dis 2024; 19:80. [PMID: 38383398 PMCID: PMC10880320 DOI: 10.1186/s13023-024-03044-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 01/19/2024] [Indexed: 02/23/2024] Open
Abstract
BACKGROUND Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by deficiency in arylsulfatase A (ASA) activity arising primarily from ASA gene (ARSA) variants. Late-infantile, juvenile and adult clinical subtypes are defined by symptom onset at ≤ 2.5, > 2.5 to < 16 and ≥ 16 years, respectively. Epidemiological data were sought to address knowledge gaps and to inform decisions regarding the clinical development of an investigational drug. METHODS To synthesize all available estimates of MLD incidence and birth prevalence worldwide and in selected countries, Ovid MEDLINE and Embase were searched systematically (March 11, 2022) using a population, intervention, comparator, outcome, time and setting framework, complemented by pragmatic searching to reduce publication bias. Where possible, results were stratified by clinical subtype. Data were extracted from non-interventional studies (clinical trials, non-clinical studies and case reports were excluded; reviews were used for snowballing only). RESULTS Of the 31 studies included, 14 reported birth prevalence (13 countries in Asia-Pacific, Europe, the Middle East, North America and South America), one reported prevalence and none reported incidence. Birth prevalence per 100,000 live births ranged from 0.16 (Japan) to 1.85 (Portugal). In the three European studies with estimates stratified by clinical subtypes, birth prevalence was highest for late-infantile cases (0.31-1.12 per 100,000 live births). The distribution of clinical subtypes reported in cases diagnosed over various time periods in 17 studies varied substantially, but late-infantile and juvenile MLD accounted for at least two-thirds of cases in most studies. CONCLUSIONS This review provides a foundation for further analysis of the regional epidemiology of MLD. Data gaps indicate the need for better global coverage, increased use of epidemiological measures (e.g. prevalence estimates) and more stratification of outcomes by clinical and genetic disease subtype.
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Affiliation(s)
| | | | | | | | - Yola Moride
- YOLARX Consultants, Inc, Montreal, QC, Canada
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12
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Moutapam-Ngamby-Adriaansen Y, Maillot F, Labarthe F, Lioger B. Blood cytopenias as manifestations of inherited metabolic diseases: a narrative review. Orphanet J Rare Dis 2024; 19:65. [PMID: 38355710 PMCID: PMC10865644 DOI: 10.1186/s13023-024-03074-4] [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: 11/03/2023] [Accepted: 02/03/2024] [Indexed: 02/16/2024] Open
Abstract
Inherited Metabolic Diseases (IMD) encompass a diverse group of rare genetic conditions that, despite their individual rarity, collectively affect a substantial proportion, estimated at as much as 1 in 784 live births. Among their wide-ranging clinical manifestations, cytopenia stands out as a prominent feature. Consequently, IMD should be considered a potential diagnosis when evaluating patients presenting with cytopenia. However, it is essential to note that the existing scientific literature pertaining to the link between IMD and cytopenia is limited, primarily comprising case reports and case series. This paucity of data may contribute to the inadequate recognition of the association between IMD and cytopenia, potentially leading to underdiagnosis. In this review, we synthesize our findings from a literature analysis along with our clinical expertise to offer a comprehensive insight into the clinical presentation of IMD cases associated with cytopenia. Furthermore, we introduce a structured diagnostic approach underpinned by decision-making algorithms, with the aim of enhancing the early identification and management of IMD-related cytopenia.
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Affiliation(s)
- Yannick Moutapam-Ngamby-Adriaansen
- Service de Médecine Interne, CHRU de Tours, Tours Cedex 1, France.
- Service de Médecine Interne Et Polyvalente, 2, Centre Hospitalier de Blois, Mail Pierre Charlot, 41000, Blois, France.
| | - François Maillot
- Service de Médecine Interne, CHRU de Tours, Tours Cedex 1, France
- Reference Center for Inborn Errors of Metabolism ToTeM, CHRU de Tours, Hôpital Clocheville, 49 Bd Béranger, 37000, Tours, France
- INSERM U1253, iBrain, Université François Rabelais de Tours, 10 Boulevard Tonnellé, 37000, Tours, France
- INSERM U1069, Nutrition, Croissance et Cancer, Faculté de Médecine, Université François Rabelais de Tours, 10 Boulevard Tonnellé, 37000, Tours, France
| | - François Labarthe
- Reference Center for Inborn Errors of Metabolism ToTeM, CHRU de Tours, Hôpital Clocheville, 49 Bd Béranger, 37000, Tours, France
- INSERM U1069, Nutrition, Croissance et Cancer, Faculté de Médecine, Université François Rabelais de Tours, 10 Boulevard Tonnellé, 37000, Tours, France
- Service de Pédiatrie, CHRU de Tours, Tours Cedex 1, France
| | - Bertrand Lioger
- Service de Médecine Interne Et Polyvalente, 2, Centre Hospitalier de Blois, Mail Pierre Charlot, 41000, Blois, France
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Ago Y, Rintz E, Musini KS, Ma Z, Tomatsu S. Molecular Mechanisms in Pathophysiology of Mucopolysaccharidosis and Prospects for Innovative Therapy. Int J Mol Sci 2024; 25:1113. [PMID: 38256186 PMCID: PMC10816168 DOI: 10.3390/ijms25021113] [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: 12/11/2023] [Revised: 01/09/2024] [Accepted: 01/10/2024] [Indexed: 01/24/2024] Open
Abstract
Mucopolysaccharidoses (MPSs) are a group of inborn errors of the metabolism caused by a deficiency in the lysosomal enzymes required to break down molecules called glycosaminoglycans (GAGs). These GAGs accumulate over time in various tissues and disrupt multiple biological systems, including catabolism of other substances, autophagy, and mitochondrial function. These pathological changes ultimately increase oxidative stress and activate innate immunity and inflammation. We have described the pathophysiology of MPS and activated inflammation in this paper, starting with accumulating the primary storage materials, GAGs. At the initial stage of GAG accumulation, affected tissues/cells are reversibly affected but progress irreversibly to: (1) disruption of substrate degradation with pathogenic changes in lysosomal function, (2) cellular dysfunction, secondary/tertiary accumulation (toxins such as GM2 or GM3 ganglioside, etc.), and inflammatory process, and (3) progressive tissue/organ damage and cell death (e.g., skeletal dysplasia, CNS impairment, etc.). For current and future treatment, several potential treatments for MPS that can penetrate the blood-brain barrier and bone have been proposed and/or are in clinical trials, including targeting peptides and molecular Trojan horses such as monoclonal antibodies attached to enzymes via receptor-mediated transport. Gene therapy trials with AAV, ex vivo LV, and Sleeping Beauty transposon system for MPS are proposed and/or underway as innovative therapeutic options. In addition, possible immunomodulatory reagents that can suppress MPS symptoms have been summarized in this review.
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Affiliation(s)
- Yasuhiko Ago
- Nemours Children’s Health, 1600 Rockland Rd., Wilmington, DE 19803, USA; (Y.A.); (K.S.M.); (Z.M.)
| | - Estera Rintz
- Department of Molecular Biology, Faculty of Biology, University of Gdansk, 80-308 Gdansk, Poland;
| | - Krishna Sai Musini
- Nemours Children’s Health, 1600 Rockland Rd., Wilmington, DE 19803, USA; (Y.A.); (K.S.M.); (Z.M.)
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
| | - Zhengyu Ma
- Nemours Children’s Health, 1600 Rockland Rd., Wilmington, DE 19803, USA; (Y.A.); (K.S.M.); (Z.M.)
| | - Shunji Tomatsu
- Nemours Children’s Health, 1600 Rockland Rd., Wilmington, DE 19803, USA; (Y.A.); (K.S.M.); (Z.M.)
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
- Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu 501-1112, Japan
- Department of Pediatrics, Thomas Jefferson University, Philadelphia, PA 19144, USA
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Moritz L, Schumann A, Pohl M, Köttgen A, Hannibal L, Spiekerkoetter U. A systematic review of metabolomic findings in adult and pediatric renal disease. Clin Biochem 2024; 123:110703. [PMID: 38097032 DOI: 10.1016/j.clinbiochem.2023.110703] [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: 06/16/2023] [Revised: 12/03/2023] [Accepted: 12/07/2023] [Indexed: 12/29/2023]
Abstract
Chronic kidney disease (CKD) affects over 0.5 billion people worldwide across their lifetimes. Despite a growingly ageing world population, an increase in all-age prevalence of kidney disease persists. Adult-onset forms of kidney disease often result from lifestyle-modifiable metabolic illnesses such as type 2 diabetes. Pediatric and adolescent forms of renal disease are primarily caused by morphological abnormalities of the kidney, as well as immunological, infectious and inherited metabolic disorders. Alterations in energy metabolism are observed in CKD of varying causes, albeit the molecular mechanisms underlying pathology are unclear. A systematic indexing of metabolites identified in plasma and urine of patients with kidney disease alongside disease enrichment analysis uncovered inborn errors of metabolism as a framework that links features of adult and pediatric kidney disease. The relationship of genetics and metabolism in kidney disease could be classified into three distinct landscapes: (i) Normal genotypes that develop renal damage because of lifestyle and / or comorbidities; (ii) Heterozygous genetic variants and polymorphisms that result in unique metabotypes that may predispose to the development of kidney disease via synergistic heterozygosity, and (iii) Homozygous genetic variants that cause renal impairment by perturbing metabolism, as found in children with monogenic inborn errors of metabolism. Interest in the identification of early biomarkers of onset and progression of CKD has grown steadily in the last years, though it has not translated into clinical routine yet. This systematic review indexes findings of differential concentration of metabolites and energy pathway dysregulation in kidney disease and appraises their potential use as biomarkers.
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Affiliation(s)
- Lennart Moritz
- Laboratory of Clinical Biochemistry and Metabolism, Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany; Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
| | - Anke Schumann
- Laboratory of Clinical Biochemistry and Metabolism, Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany; Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
| | - Martin Pohl
- Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
| | - Anna Köttgen
- Institute of Genetic Epidemiology, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
| | - Luciana Hannibal
- Laboratory of Clinical Biochemistry and Metabolism, Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany.
| | - Ute Spiekerkoetter
- Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany.
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15
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Zelei T, Kovács S, Finn P, Nagy D, Sikirica V, Carlson KB, Vokó Z. Systematic literature review of the epidemiology of glycogen storage disease type 1a. J Pediatr Endocrinol Metab 2023; 36:809-817. [PMID: 37615591 DOI: 10.1515/jpem-2023-0127] [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: 03/22/2023] [Accepted: 07/27/2023] [Indexed: 08/25/2023]
Abstract
Glycogen storage disease (GSD) type 1a is an inherited autosomal recessive metabolic disease caused by a deficiency in glucose-6-phosphatase activity. The objectives of this research were to systematically review the published literature on the epidemiology of GSD 1a and to assess the performance of reported epidemiology measures in a simulation model. In this systematic literature review 2,539 record titles and abstracts were screened. Of these, only 11 studies contained relevant data on GSD 1a disease epidemiology. Reported disease frequency ranged from 0.085/100,000 to 10.3/100,000 newborns when considering all the GSD literature. When this was narrowed to GSD 1 and GSD 1a, the range was tightened to 0.25-3.02/100,000 and 0.085-4.9/100,000 newborns, respectively. Most of the identified studies counted the number of diagnoses in a defined period and related to the number of births in the same (Dx method) or different time period (DoB method). The simulation model results indicate that in most of the situations, the Dx method provides a closer estimate to the true disease incidence than the DoB method. Despite the scarcity of epidemiology data, the results of this systematic review strongly support that GSD 1a and its parent disease groups (GSD and GSD 1) are rare diseases.
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Affiliation(s)
- Tamás Zelei
- Syreon Research Institute, Budapest, Hungary
| | | | | | - Dávid Nagy
- Syreon Research Institute, Budapest, Hungary
| | | | | | - Zoltán Vokó
- Syreon Research Institute, Budapest, Hungary
- Semmelweis University, Budapest, Hungary
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Vaidyanathan K, Member, IFCC-ISNS Task Force for Newborn Screening. Inborn Metabolic Disorders: The Winding Path Ahead, in the Road Less Traveled. Indian J Clin Biochem 2023; 38:285-286. [PMID: 37234189 PMCID: PMC10205919 DOI: 10.1007/s12291-023-01135-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Affiliation(s)
- K. Vaidyanathan
- Department of Biochemistry, Believers Church Medical College Hospital, Thiruvalla, Kerala India
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Sugiyama Y, Murayama K. Acute Encephalopathy Caused by Inherited Metabolic Diseases. J Clin Med 2023; 12:jcm12113797. [PMID: 37297992 DOI: 10.3390/jcm12113797] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 05/22/2023] [Accepted: 05/26/2023] [Indexed: 06/12/2023] Open
Abstract
Acute encephalopathy is a critical medical condition that typically affects previously healthy children and young adults and often results in death or severe neurological sequelae. Inherited metabolic diseases that can cause acute encephalopathy include urea cycle disorders, amino acid metabolism disorders, organic acid metabolism disorders, fatty acid metabolism disorders, mutations in the thiamine-transporter gene, and mitochondrial diseases. Although each inherited metabolic disease is rare, its overall incidence is reported as 1 in 800-2500 patients. This narrative review presents the common inherited metabolic diseases that cause acute encephalopathy. Since diagnosing inherited metabolic diseases requires specific testing, early metabolic/metanolic screening tests are required when an inherited metabolic disease is suspected. We also describe the symptoms and history associated with suspected inherited metabolic diseases, the various tests that should be conducted in case of suspicion, and treatment according to the disease group. Recent advancements made in the understanding of some of the inherited metabolic diseases that cause acute encephalopathy are also highlighted. Acute encephalopathy due to inherited metabolic diseases can have numerous different causes, and recognition of the possibility of an inherited metabolic disease as early as possible, obtaining appropriate specimens, and proceeding with testing and treatment in parallel are crucial in the management of these diseases.
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Affiliation(s)
- Yohei Sugiyama
- Department of Metabolism, Chiba Children's Hospital, Chiba 266-0007, Japan
- Department of Pediatrics, Faculty of Medicine, Juntendo University, Tokyo 113-8431, Japan
| | - Kei Murayama
- Center for Medical Genetics, Chiba Children's Hospital, Chiba 266-0007, Japan
- Diagnostics and Therapeutics of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo 113-8431, Japan
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Carvalho S, Santos JI, Moreira L, Gonçalves M, David H, Matos L, Encarnação M, Alves S, Coutinho MF. Neurological Disease Modeling Using Pluripotent and Multipotent Stem Cells: A Key Step towards Understanding and Treating Mucopolysaccharidoses. Biomedicines 2023; 11:biomedicines11041234. [PMID: 37189853 DOI: 10.3390/biomedicines11041234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 04/18/2023] [Accepted: 04/19/2023] [Indexed: 05/17/2023] Open
Abstract
Despite extensive research, the links between the accumulation of glycosaminoglycans (GAGs) and the clinical features seen in patients suffering from various forms of mucopolysaccharidoses (MPSs) have yet to be further elucidated. This is particularly true for the neuropathology of these disorders; the neurological symptoms are currently incurable, even in the cases where a disease-specific therapeutic approach does exist. One of the best ways to get insights on the molecular mechanisms driving that pathogenesis is the analysis of patient-derived cells. Yet, not every patient-derived cell recapitulates relevant disease features. For the neuronopathic forms of MPSs, for example, this is particularly evident because of the obvious inability to access live neurons. This scenario changed significantly with the advent of induced pluripotent stem cell (iPSC) technologies. From then on, a series of differentiation protocols to generate neurons from iPSC was developed and extensively used for disease modeling. Currently, human iPSC and iPSC-derived cell models have been generated for several MPSs and numerous lessons were learnt from their analysis. Here we review most of those studies, not only listing the currently available MPS iPSC lines and their derived models, but also summarizing how they were generated and the major information different groups have gathered from their analyses. Finally, and taking into account that iPSC generation is a laborious/expensive protocol that holds significant limitations, we also hypothesize on a tempting alternative to establish MPS patient-derived neuronal cells in a much more expedite way, by taking advantage of the existence of a population of multipotent stem cells in human dental pulp to establish mixed neuronal and glial cultures.
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Affiliation(s)
- Sofia Carvalho
- Research and Development Unit, Department of Human Genetics, National Institute of Health Doutor Ricardo Jorge, INSA I.P., Rua Alexandre Herculano, 321, 4000-055 Porto, Portugal
- Center for the Study of Animal Science-Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto, CECA-ICETA, University of Porto, Praça Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal
- Associate Laboratory for Animal and Veterinary Sciences, AL4AnimalS, Faculdade de Medicina Veterinária Avenida da Universidade Técnica, 1300-477 Lisboa, Portugal
- Faculty of Pharmacy, University of Coimbra, Polo das Ciências da Saúde, Azinhaga de SantaComba, 3000-548 Coimbra, Portugal
| | - Juliana Inês Santos
- Research and Development Unit, Department of Human Genetics, National Institute of Health Doutor Ricardo Jorge, INSA I.P., Rua Alexandre Herculano, 321, 4000-055 Porto, Portugal
- Center for the Study of Animal Science-Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto, CECA-ICETA, University of Porto, Praça Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal
- Associate Laboratory for Animal and Veterinary Sciences, AL4AnimalS, Faculdade de Medicina Veterinária Avenida da Universidade Técnica, 1300-477 Lisboa, Portugal
- Biology Department, Faculty of Sciences, University of Porto, Rua do Campo Alegre, 4169-007 Porto, Portugal
| | - Luciana Moreira
- Research and Development Unit, Department of Human Genetics, National Institute of Health Doutor Ricardo Jorge, INSA I.P., Rua Alexandre Herculano, 321, 4000-055 Porto, Portugal
- Center for the Study of Animal Science-Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto, CECA-ICETA, University of Porto, Praça Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal
- Associate Laboratory for Animal and Veterinary Sciences, AL4AnimalS, Faculdade de Medicina Veterinária Avenida da Universidade Técnica, 1300-477 Lisboa, Portugal
| | - Mariana Gonçalves
- Research and Development Unit, Department of Human Genetics, National Institute of Health Doutor Ricardo Jorge, INSA I.P., Rua Alexandre Herculano, 321, 4000-055 Porto, Portugal
- Center for the Study of Animal Science-Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto, CECA-ICETA, University of Porto, Praça Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal
- Associate Laboratory for Animal and Veterinary Sciences, AL4AnimalS, Faculdade de Medicina Veterinária Avenida da Universidade Técnica, 1300-477 Lisboa, Portugal
- Centre for the Research and Technology of Agro-Environmental and Biological Sciences, CITAB, Inov4Agro, University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
| | - Hugo David
- Research and Development Unit, Department of Human Genetics, National Institute of Health Doutor Ricardo Jorge, INSA I.P., Rua Alexandre Herculano, 321, 4000-055 Porto, Portugal
- Center for the Study of Animal Science-Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto, CECA-ICETA, University of Porto, Praça Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal
- Associate Laboratory for Animal and Veterinary Sciences, AL4AnimalS, Faculdade de Medicina Veterinária Avenida da Universidade Técnica, 1300-477 Lisboa, Portugal
- Biology Department, Faculty of Sciences, University of Porto, Rua do Campo Alegre, 4169-007 Porto, Portugal
| | - Liliana Matos
- Research and Development Unit, Department of Human Genetics, National Institute of Health Doutor Ricardo Jorge, INSA I.P., Rua Alexandre Herculano, 321, 4000-055 Porto, Portugal
- Center for the Study of Animal Science-Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto, CECA-ICETA, University of Porto, Praça Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal
- Associate Laboratory for Animal and Veterinary Sciences, AL4AnimalS, Faculdade de Medicina Veterinária Avenida da Universidade Técnica, 1300-477 Lisboa, Portugal
| | - Marisa Encarnação
- Research and Development Unit, Department of Human Genetics, National Institute of Health Doutor Ricardo Jorge, INSA I.P., Rua Alexandre Herculano, 321, 4000-055 Porto, Portugal
- Center for the Study of Animal Science-Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto, CECA-ICETA, University of Porto, Praça Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal
- Associate Laboratory for Animal and Veterinary Sciences, AL4AnimalS, Faculdade de Medicina Veterinária Avenida da Universidade Técnica, 1300-477 Lisboa, Portugal
| | - Sandra Alves
- Research and Development Unit, Department of Human Genetics, National Institute of Health Doutor Ricardo Jorge, INSA I.P., Rua Alexandre Herculano, 321, 4000-055 Porto, Portugal
- Center for the Study of Animal Science-Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto, CECA-ICETA, University of Porto, Praça Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal
- Associate Laboratory for Animal and Veterinary Sciences, AL4AnimalS, Faculdade de Medicina Veterinária Avenida da Universidade Técnica, 1300-477 Lisboa, Portugal
| | - Maria Francisca Coutinho
- Research and Development Unit, Department of Human Genetics, National Institute of Health Doutor Ricardo Jorge, INSA I.P., Rua Alexandre Herculano, 321, 4000-055 Porto, Portugal
- Center for the Study of Animal Science-Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto, CECA-ICETA, University of Porto, Praça Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal
- Associate Laboratory for Animal and Veterinary Sciences, AL4AnimalS, Faculdade de Medicina Veterinária Avenida da Universidade Técnica, 1300-477 Lisboa, Portugal
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Senarathne UD, Indika NLR, Jezela-Stanek A, Ciara E, Frye RE, Chen C, Stepien KM. Biochemical, Genetic and Clinical Diagnostic Approaches to Autism-Associated Inherited Metabolic Disorders. Genes (Basel) 2023; 14:genes14040803. [PMID: 37107561 PMCID: PMC10138025 DOI: 10.3390/genes14040803] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 03/22/2023] [Accepted: 03/22/2023] [Indexed: 03/29/2023] Open
Abstract
Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders characterized by impaired social interaction, limited communication skills, and restrictive and repetitive behaviours. The pathophysiology of ASD is multifactorial and includes genetic, epigenetic, and environmental factors, whereas a causal relationship has been described between ASD and inherited metabolic disorders (IMDs). This review describes biochemical, genetic, and clinical approaches to investigating IMDs associated with ASD. The biochemical work-up includes body fluid analysis to confirm general metabolic and/or lysosomal storage diseases, while the advances and applications of genomic testing technology would assist with identifying molecular defects. An IMD is considered likely underlying pathophysiology in ASD patients with suggestive clinical symptoms and multiorgan involvement, of which early recognition and treatment increase their likelihood of achieving optimal care and a better quality of life.
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Affiliation(s)
- Udara D. Senarathne
- Department of Biochemistry, Faculty of Medical Sciences, University of Sri Jayewardenepura, Nugegoda 10250, Sri Lanka
- Department of Chemical Pathology, Monash Health Pathology, Monash Health, Melbourne, VIC 3168, Australia
| | - Neluwa-Liyanage R. Indika
- Department of Biochemistry, Faculty of Medical Sciences, University of Sri Jayewardenepura, Nugegoda 10250, Sri Lanka
| | - Aleksandra Jezela-Stanek
- Department of Genetics and Clinical Immunology, National Institute of Tuberculosis and Lung Diseases, 01-138 Warsaw, Poland
| | - Elżbieta Ciara
- Department of Medical Genetics, The Children’s Memorial Health Institute, 04-730 Warsaw, Poland
| | - Richard E. Frye
- Autism Discovery and Treatment Foundation, Phoenix, AZ 85050, USA
| | - Cliff Chen
- Clinical Neuropsychology Department, Manchester Centre for Clinical Neurosciences, Salford Royal NHS Foundation Trust, Salford M6 8HD, UK
| | - Karolina M. Stepien
- Adult Inherited Metabolic Diseases, Mark Holland Unit, Salford Royal NHS Foundation Trust, Salford M6 8HD, UK
- Division of Diabetes, Endocrinology and Gastroenterology, University of Manchester, Manchester M13 9PL, UK
- Correspondence:
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Epstein Weiss T, Erez O, Hazan I, Babiev AS, Staretz Chacham O. Characterization of pregnancy outcome of women with an offspring with inborn errors of metabolism: A population-based study. Front Genet 2022; 13:1030361. [PMID: 36437917 PMCID: PMC9683332 DOI: 10.3389/fgene.2022.1030361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 10/10/2022] [Indexed: 11/10/2022] Open
Abstract
Introduction: Inborn errors of metabolism (IEM) are scarce, and their diagnosis is often made after birth. This has led to the perception that most fetuses affected by these disorders do not become clinically apparent during pregnancy. Our aim was to determine the obstetrical characteristics of women with an offspring affected by IEM.Methods: This population-based retrospective cohort study included all women who delivered at the Soroka University Medical Center (SUMC) from 1988 to 2017 who met the inclusion criteria. Mothers who had an offspring with IEM were included in the study group, and those who had offsprings without IEM comprised the comparison group.Results: A total of 388,813 pregnancies were included in the study, and 184 of them were complicated by a fetus with IEM. The number of Bedouin women was higher in the IEM-affected infant group than in the comparison group (90.8% vs. 53.3%, p < 0.001); women who had a fetus with IEM had a higher rate of polyhydramnios (7.1% vs. 3.2%, p = 0.005), HELLP syndrome (3.3% vs. 1.1%, p = 0.014), and preterm birth (20.7% vs. 10.1%, p < 0.001); neonates with IEM had lower mean birth weight (p < 0.001), lower Apgar scores at 1′ and 5′ minutes (p < 0.001), and a higher rate of fetal growth restriction (FGR) (p < 0.001), postpartum death <28 days (p < 0.001), and neonatal death (p < 0.001) than those in the comparison group. Pregnancies with IEM fetuses were independently associated with preterm birth (OR 2.00; CI 1.4–3), polyhydramnios (OR 2.08; CI 1.17–3.71), and FGR (OR 2.24; CI 1.2–4.19). Each family of metabolic diseases is independently associated with specific pregnancy complications (i.e., mitochondrial diseases are associated with HELLP syndrome (OR 5.6; CI 1.8–17), and lysosomal storage disease are associated with nonimmune hydrops fetalis (OR 26.4; CI 3.39–206).Conclusion: This study reports for the first time, an independent association of IEM with specific complications of pregnancy. This observation has clinical implications, as the identification of specific pregnancy complications in a population at risk for IEM can assist in the prenatal diagnosis of an affected fetus.
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Ning JJ, Li F, Li SQ. Clinical and genetic analysis of nonketotic hyperglycinemia: A case report. World J Clin Cases 2022; 10:7982-7988. [PMID: 36158497 PMCID: PMC9372859 DOI: 10.12998/wjcc.v10.i22.7982] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 05/19/2022] [Accepted: 07/06/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Nonketotic hyperglycinemia (NKH) is a rare autosomal recessive genetic disorder of abnormal glycine metabolism caused by insufficient activity of the glycine cleavage enzyme system. Glycine is believed to function mainly as an inhibitory neurotransmitter, but it can also act as a co-agonist of the N-methyl-D-aspartate (NMDA) receptor. The accumulation of a large amount of glycine in the brain leads to neuronal and axonal injury via overactivation of NMDA receptors located in the hippocampus, cerebral cortex, olfactory bulb, and cerebellum and to stimulation of the inhibitory function of glycine receptors located in the spinal cord and brain stem, resulting in central apnea, hiccups, and hypotonia in the early stage of the disease.
CASE SUMMARY The child described in this report had typical clinical manifestations of NKH, such as hiccups, disturbance of consciousness, hypotonia, and convulsions, within the first week after birth. Whole-exome genetic testing revealed that the child had a compound heterozygous mutation, namely, c.395C>A (p.S132X) and c.2182G>A (p.G728R), in the GLDC gene, and he was diagnosed with NKH. For treatment, we administered an oral levetiracetam solution and added topiramate and prednisone for epilepsy control, but the epilepsy remained uncontrollable. Ketogenic diet therapy was started at 6 mo of age, his seizures were significantly reduced, and there were no obvious adverse reactions during ketogenic treatment. Furthermore, we found that with the development of the disease, high levels of serum glycine decreased or even disappeared without intervention, and as the disease progressed, the corpus callosum became dysplastic.
CONCLUSION This case shows that plasma glycine levels cannot be used to evaluate the prognosis of NKH, that the development of the corpus callosum can be affected by NKH, and that a ketogenic diet may be effective for seizure control in NKH patients.
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Affiliation(s)
- Jun-Jie Ning
- Department of Pediatric Intensive Care Unit, First People's Hospital of Zigong City, Zigong 643000, Sichuan Province, China
| | - Feng Li
- Department of Pediatric Intensive Care Unit, First People's Hospital of Zigong City, Zigong 643000, Sichuan Province, China
| | - Sheng-Qiu Li
- Department of Pediatric Intensive Care Unit, First People's Hospital of Zigong City, Zigong 643000, Sichuan Province, China
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Bae YS, Yoon SH, Kim YS, Oh SP, Song WS, Cha JH, Kim MH. Suppression of exaggerated NMDAR activity by memantine treatment ameliorates neurological and behavioral deficits in aminopeptidase P1-deficient mice. EXPERIMENTAL & MOLECULAR MEDICINE 2022; 54:1109-1124. [PMID: 35922532 PMCID: PMC9440093 DOI: 10.1038/s12276-022-00818-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 05/12/2022] [Accepted: 05/17/2022] [Indexed: 11/25/2022]
Abstract
Inborn errors of metabolism (IEMs) are common causes of neurodevelopmental disorders, including microcephaly, hyperactivity, and intellectual disability. However, the synaptic mechanisms of and pharmacological interventions for the neurological complications of most IEMs are unclear. Here, we report that metabolic dysfunction perturbs neuronal NMDA receptor (NMDAR) homeostasis and that the restoration of NMDAR signaling ameliorates neurodevelopmental and cognitive deficits in IEM model mice that lack aminopeptidase P1. Aminopeptidase P1-deficient (Xpnpep1–/–) mice, with a disruption of the proline-specific metalloprotease gene Xpnpep1, exhibit hippocampal neurodegeneration, behavioral hyperactivity, and impaired hippocampus-dependent learning. In this study, we found that GluN1 and GluN2A expression, NMDAR activity, and the NMDAR-dependent long-term potentiation (LTP) of excitatory synaptic transmission were markedly enhanced in the hippocampi of Xpnpep1–/– mice. The exaggerated NMDAR activity and NMDAR-dependent LTP were reversed by the NMDAR antagonist memantine. A single administration of memantine reversed hyperactivity in adult Xpnpep1–/– mice without improving learning and memory. Furthermore, chronic administration of memantine ameliorated hippocampal neurodegeneration, hyperactivity, and impaired learning and memory in Xpnpep1–/– mice. In addition, abnormally enhanced NMDAR-dependent LTP and NMDAR downstream signaling in the hippocampi of Xpnpep1–/– mice were reversed by chronic memantine treatment. These results suggest that the metabolic dysfunction caused by aminopeptidase P1 deficiency leads to synaptic dysfunction with excessive NMDAR activity, and the restoration of synaptic function may be a potential therapeutic strategy for the treatment of neurological complications related to IEMs. Addressing neurological symptoms may offer new treatments for inborn errors of metabolism (IEMs) affecting neurodevelopment. In such IEMs, mutation of an enzyme disrupts a metabolic pathway, causing buildup or lack of key molecules, with symptoms including hyperactivity, developmental delay, and intellectual disability. Because the detailed pathological mechanisms of most IEMs are unknown, there are no treatments for resulting neurological issues. Myoung-Hwan Kim at Seoul National University and co-workers investigated whether they could treat the neurological symptoms of the IEM, aminopeptidase P1 (APP1) deficiency. They found that APP1 deficiency in mice caused an increase in the neural receptor NMDAR. Suppressing NMDAR reduced both neurological and behavioral symptoms. These findings suggest potential treatments for APP1 deficiency, and indicate that neurodevelopmental disorders in IEMs may be treated by repairing the neural circuitry instead of the root metabolic cause.
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Affiliation(s)
- Young-Soo Bae
- Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Korea
| | - Sang Ho Yoon
- Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Korea.,Neuroscience Research Institute, Seoul National University Medical Research Center, Seoul, 03080, Korea
| | - Young Sook Kim
- Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Korea
| | - Sung Pyo Oh
- Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Korea
| | - Woo Seok Song
- Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Korea.,Neuroscience Research Institute, Seoul National University Medical Research Center, Seoul, 03080, Korea
| | - Jin Hee Cha
- Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Korea
| | - Myoung-Hwan Kim
- Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Korea. .,Neuroscience Research Institute, Seoul National University Medical Research Center, Seoul, 03080, Korea. .,Seoul National University Bundang Hospital, Seongnam, Gyeonggi, 13620, Korea.
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23
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Global Epidemiology of Gaucher Disease: an Updated Systematic Review and Meta-analysis. J Pediatr Hematol Oncol 2022; 45:181-188. [PMID: 35867706 PMCID: PMC10115488 DOI: 10.1097/mph.0000000000002506] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 05/01/2022] [Indexed: 11/27/2022]
Abstract
BACKGROUND Gaucher disease [GD], an autosomal recessive lysosomal storage disorder, is characterized by progressive lysosomal storage of glucocerebroside in macrophages predominantly in bone, bone marrow, liver, and spleen. Meta-analysis of global GD epidemiology was not available before this study. METHODS To provide a systematic review and meta-analysis of birth prevalence and prevalence of GD in multiple countries. MEDLINE and EMBASE databases were searched for original research articles on the epidemiology of GD from inception until July 21, 2021. Meta-analysis, adopting a random-effects logistic model, was performed to estimate the birth prevalence and prevalence of GD. RESULTS Eighteen studies that were screened out of 1874 records were included for data extraction. The studies that fulfilled the criteria for inclusion involved 15 areas/countries. The global birth prevalence of GD was 1.5 cases [95% confidence interval: 1.0 to 2.0] per 100,000 live births. The global prevalence of GD was 0.9 cases [95% confidence interval: 0.7 to 1.1] per 100,000 inhabitants. CONCLUSIONS This is the first comprehensive systematic review that presented quantitative data of GD global epidemiology. Quantitative data on global epidemiology of GD could be the fundamental to evaluate the global efforts on building a better world for GD patients.
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24
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Almeida LS, Pereira C, Aanicai R, Schröder S, Bochinski T, Kaune A, Urzi A, Spohr TCLS, Viceconte N, Oppermann S, Alasel M, Ebadat S, Iftikhar S, Jasinge E, Elsayed SM, Tomoum H, Marzouk I, Jalan AB, Cerkauskaite A, Cerkauskiene R, Tkemaladze T, Nadeem AM, El Din Mahmoud IG, Mossad FA, Kamel M, Selim LA, Cheema HA, Paknia O, Cozma C, Juaristi-Manrique C, Guatibonza-Moreno P, Böttcher T, Vogel F, Pinto-Basto J, Bertoli-Avella A, Bauer P. An integrated multiomic approach as an excellent tool for the diagnosis of metabolic diseases: our first 3720 patients. Eur J Hum Genet 2022; 30:1029-1035. [PMID: 35614200 PMCID: PMC9437014 DOI: 10.1038/s41431-022-01119-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 04/11/2022] [Accepted: 05/05/2022] [Indexed: 11/09/2022] Open
Abstract
To present our experience using a multiomic approach, which integrates genetic and biochemical testing as a first-line diagnostic tool for patients with inherited metabolic disorders (IMDs). A cohort of 3720 patients from 62 countries was tested using a panel including 206 genes with single nucleotide and copy number variant (SNV/CNV) detection, followed by semi-automatic variant filtering and reflex biochemical testing (25 assays). In 1389 patients (37%), a genetic diagnosis was achieved. Within this cohort, the highest diagnostic yield was obtained for patients from Asia (57.5%, mainly from Pakistan). Overall, 701 pathogenic/likely pathogenic unique SNVs and 40 CNVs were identified. In 620 patients, the result of the biochemical tests guided variant classification and reporting. Top five diagnosed diseases were: Gaucher disease, Niemann-Pick disease type A/B, phenylketonuria, mucopolysaccharidosis type I, and Wilson disease. We show that integrated genetic and biochemical testing facilitated the decision on clinical relevance of the variants and led to a high diagnostic yield (37%), which is comparable to exome/genome sequencing. More importantly, up to 43% of these patients (n = 610) could benefit from medical treatments (e.g., enzyme replacement therapy). This multiomic approach constitutes a unique and highly effective tool for the genetic diagnosis of IMDs.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | - Solaf M Elsayed
- Medical Genetics Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Hoda Tomoum
- Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Iman Marzouk
- Alexandria University Children Hospital, Alexandria, Egypt
| | - Anil B Jalan
- Navi Mumbai Institute of Research In Mental And Neurological Handicap (NIRMAN) / Pediatric Geneticist, Navi Mumbai, India
| | | | | | - Tinatin Tkemaladze
- Department of Molecular and Medical Genetics, Tbilisi State Medical University, Tbilisi, Georgia
| | - Anjum Muhammad Nadeem
- Pediatric Gastroenterology, Hepatology and Nutrition, the Children's Hospital and Institute of Child Health, Lahore, Pakistan
| | - Iman Gamal El Din Mahmoud
- Cairo University Children Hospital (Abu El Reesh Children's Hospital), Metabolic, Neurology, Cairo, Egypt
| | - Fawzia Amer Mossad
- Cairo University Children Hospital (Abu El Reesh Children's Hospital), Metabolic, Neurology, Cairo, Egypt
| | - Mona Kamel
- Cairo University Children Hospital (Abu El Reesh Children's Hospital), Metabolic, Neurology, Cairo, Egypt
| | - Laila Abdel Selim
- Cairo University Children Hospital (Abu El Reesh Children's Hospital), Metabolic, Neurology, Cairo, Egypt
| | - Huma Arshad Cheema
- Pediatric Gastroenterology, Hepatology and Nutrition, the Children's Hospital and Institute of Child Health, Lahore, Pakistan
| | | | | | | | | | | | | | | | | | - Peter Bauer
- CENTOGENE GmbH, 18055, Rostock, Germany.,Department of Oncology, University Medical Center Rostock, Rostock, Germany
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25
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Guilder LL, Kronick JB. Organic Acidemias. Pediatr Rev 2022; 43:123-134. [PMID: 35229111 DOI: 10.1542/pir.2020-000562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Affiliation(s)
- Laura L Guilder
- Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Jonathan B Kronick
- Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada
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26
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Ramoser G, Caferri F, Radlinger B, Brunner‐Krainz M, Herbst S, Huemer M, Hufgard‐Leitner M, Kircher SG, Konstantopoulou V, Löscher W, Möslinger D, Plecko B, Spenger J, Stulnig T, Sunder‐Plassmann G, Wortmann S, Scholl‐Bürgi S, Karall D, Austrian IMD Registry Group. 100 years of inherited metabolic disorders in Austria-A national registry of minimal birth prevalence, diagnosis, and clinical outcome of inborn errors of metabolism in Austria between 1921 and 2021. J Inherit Metab Dis 2022; 45:144-156. [PMID: 34595757 PMCID: PMC9297958 DOI: 10.1002/jimd.12442] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Revised: 09/27/2021] [Accepted: 09/28/2021] [Indexed: 12/29/2022]
Abstract
Inherited metabolic disorders (IMDs) are a heterogeneous group of rare disorders characterized by disruption of metabolic pathways. To date, data on incidence and prevalence of IMDs are limited. Taking advantage of a functioning network within the Austrian metabolic group, our registry research aimed to update the data of the "Registry for Inherited Metabolic Disorders" started between 1985 and 1995 with retrospectively retrieved data on patients with IMDs according to the Society for the Study of Inborn Errors of Metabolism International Classification of Diseases 11 (SSIEM ICD11) catalogue. Included in this retrospective register were 2631 patients with an IMD according to the SSIEM ICD11 Classification, who were treated in Austria. Thus, a prevalence of 1.8/10 000 for 2020 and a median minimal birth prevalence of 16.9/100 000 (range 0.7/100 000-113/100 000) were calculated for the period 1921 to February 2021. We detected a male predominance (m:f = 1.2:1) and a mean age of currently alive patients of 17.6 years (range 5.16 months-100 years). Most common diagnoses were phenylketonuria (17.7%), classical galactosaemia (6.6%), and biotinidase deficiency (4.2%). The most common diagnosis categories were disorders of amino acid and peptide metabolism (819/2631; 31.1%), disorders of energy metabolism (396/2631; 15.1%), and lysosomal disorders (395/2631; 15.0%). In addition to its epidemiological relevance, the "Registry for Inherited Metabolic Disorders" is an important tool for enhancing an exchange between care providers. Moreover, by pooling expertise it prospectively improves patient treatment, similar to pediatric oncology protocols. A substantial requirement for ful filling this goal is to regularly update the registry and provide nationwide coverage with inclusion of all medical specialties.
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Affiliation(s)
- Gabriele Ramoser
- Clinic for Pediatrics I, Inherited Metabolic DisordersMedical University of InnsbruckInnsbruckAustria
| | - Federica Caferri
- Clinic for Pediatrics IIIMedical University of InnsbruckInnsbruckAustria
| | - Bernhard Radlinger
- Clinic for Internal Medicine IMedical University of InnsbruckInnsbruckAustria
| | | | - Sybille Herbst
- Clinic for Pediatrics I, Inherited Metabolic DisordersMedical University of InnsbruckInnsbruckAustria
| | | | | | - Susanne G. Kircher
- Center of Pathobiochemistry and GeneticsMedical University of ViennaViennaAustria
| | | | - Wolfgang Löscher
- Department of NeurologyMedical University InnsbruckInnsbruckAustria
| | | | - Barbara Plecko
- Clinic for PediatricsUniversity Hospital GrazGrazAustria
| | - Johannes Spenger
- Clinic for Pediatrics, Inherited Metabolic DisordersMedical University SalzburgSalzburgAustria
| | - Thomas Stulnig
- Clinic for Internal Medicine IIIUniversity Hospital ViennaViennaAustria
| | - Gere Sunder‐Plassmann
- Department of Medicine III, Division of Nephrology and DialysisMedical University of ViennaViennaAustria
| | - Saskia Wortmann
- Clinic for Pediatrics, Inherited Metabolic DisordersMedical University SalzburgSalzburgAustria
| | - Sabine Scholl‐Bürgi
- Clinic for Pediatrics I, Inherited Metabolic DisordersMedical University of InnsbruckInnsbruckAustria
| | - Daniela Karall
- Clinic for Pediatrics I, Inherited Metabolic DisordersMedical University of InnsbruckInnsbruckAustria
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27
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Ouattara A, Resseguier N, Cano A, De Lonlay P, Arnoux JB, Brassier A, Schiff M, Pichard S, Fabre A, Hoebeke C, Guffon N, Fouilhoux A, Broué P, Touati G, Dobbelaere D, Mention K, Labarthe F, Tardieu M, De Parscau L, Feillet F, Bonnemains C, Kuster A, Labrune P, Barth M, Damaj L, Lamireau D, Berbis J, Auquier P, Chabrol B. Determinants of Quality of Life in Children with Inborn Errors of Metabolism Receiving a Restricted Diet. J Pediatr 2022; 242:192-200.e3. [PMID: 34788681 DOI: 10.1016/j.jpeds.2021.11.021] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 11/09/2021] [Accepted: 11/10/2021] [Indexed: 12/26/2022]
Abstract
OBJECTIVE To investigate the determinants of quality of life (QoL) in children with inborn errors of metabolism with restricted diet (IEMRDs) using a single theory-based multidimensional model. STUDY DESIGN In this multicenter cross-sectional study, data from children aged 8-17 years with IEMRDs (except phenylketonuria) and their parents were collected from January 2015 to December 2017. Measurements included a child's self-reported QoL, self-rated behavioral problems and anxiety, and parental anxiety. Based on hypotheses from a literature-built theoretical model linking demographic, clinical, family environment, and psychosocial characteristics to QoL either directly or indirectly, associations of these factors with a child's self-rated QoL were examined using a structural equation modeling approach. RESULTS A total of 312 children (mean [SD] age, 12.2 [2.6] years; 51% boys [n = 160]) were included. Higher levels of trait anxiety and behavioral problems in children were the most important factors associated with poorer QoL (standardized path coefficients, -0.71 and -0.23, respectively). In addition, higher parent trait anxiety, younger age at diagnosis, and a disease requiring an emergency diet were associated with poorer QoL in these children. The final model fit the data closely according to conventional goodness-of-fit statistics and explained 86% of the QoL variance. CONCLUSIONS Psychosocial factors appear to be major determinants of QoL impairment in children with IEMRDs. These factors should be addressed in clinical practice as part of the global treatment plan for a child with IEMRD. Future studies based on a longitudinal design should consider coping strategies when exploring potential predictive factors of QoL.
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Affiliation(s)
- Abdoulaye Ouattara
- Department of Epidemiology and Health Economics, AP-HM/EA 3279, Centre d'Etude et de Recherche sur les Services de Santé et la Qualité de vie, Aix-Marseille University, Marseille, France
| | - Noemie Resseguier
- Department of Epidemiology and Health Economics, AP-HM/EA 3279, Centre d'Etude et de Recherche sur les Services de Santé et la Qualité de vie, Aix-Marseille University, Marseille, France.
| | - Aline Cano
- Reference Center of Inherited Metabolic Disorders, Timone Enfants Hospital, Marseille, France
| | - Pascale De Lonlay
- Reference Center of Inherited Metabolic Disorders, Necker Hospital, Paris, France
| | - Jean-Baptiste Arnoux
- Reference Center of Inherited Metabolic Disorders, Necker Hospital, Paris, France
| | - Anais Brassier
- Reference Center of Inherited Metabolic Disorders, Necker Hospital, Paris, France
| | - Manuel Schiff
- Reference Center of Inherited Metabolic Disorders, Necker Hospital, Paris, France
| | - Samia Pichard
- Reference Center of Inherited Metabolic Disorders, Robert Debré Hospital, Paris, France
| | - Alexandre Fabre
- Reference Center of Inherited Metabolic Disorders, Timone Enfants Hospital, Marseille, France
| | - Celia Hoebeke
- Reference Center of Inherited Metabolic Disorders, Timone Enfants Hospital, Marseille, France
| | - Nathalie Guffon
- Reference Center of Inherited Metabolic Disorders, Femme Mère Enfant Hospital, Lyon, France
| | - Alain Fouilhoux
- Reference Center of Inherited Metabolic Disorders, Femme Mère Enfant Hospital, Lyon, France
| | - Pierre Broué
- Reference Center of Inherited Metabolic Disorders, Purpan Hospital, Toulouse, France
| | - Guy Touati
- Reference Center of Inherited Metabolic Disorders, Purpan Hospital, Toulouse, France
| | - Dries Dobbelaere
- Reference Center of Inherited Metabolic Disorders, Jeanne de Flandres Hospital, Lille, France
| | - Karine Mention
- Reference Center of Inherited Metabolic Disorders, Jeanne de Flandres Hospital, Lille, France
| | - Francois Labarthe
- Reference Center of Inherited Metabolic Disorders, Clocheville Hospital, Tours, France
| | - Marine Tardieu
- Reference Center of Inherited Metabolic Disorders, Clocheville Hospital, Tours, France
| | - Loïc De Parscau
- Competence Center of Inherited Metabolic Disorders, Brest Hospital, Brest, France
| | - Francois Feillet
- Reference Center of Inherited Metabolic Disorders, Brabois Hospital, Nancy, France
| | - Chrystèle Bonnemains
- Reference Center of Inherited Metabolic Disorders, Brabois Hospital, Nancy, France
| | - Alice Kuster
- Pediatric Intensive Care Unit, Nantes Hospital, Nantes, France
| | - Philippe Labrune
- Reference Center of Rare Liver Disease, Antoine Beclere Hospital, Clamart, France
| | - Magalie Barth
- Competence Center of Inherited Metabolic Disorders, Angers Hospital, Angers, France
| | - Lena Damaj
- Competence Center of Inherited Metabolic Disorders, Rennes Hospital, Rennes, France
| | - Delphine Lamireau
- Competence Center of Inherited Metabolic Disorders, Pellegrin Hospital, Bordeaux, France
| | - Julie Berbis
- Department of Epidemiology and Health Economics, AP-HM/EA 3279, Centre d'Etude et de Recherche sur les Services de Santé et la Qualité de vie, Aix-Marseille University, Marseille, France
| | - Pascal Auquier
- Department of Epidemiology and Health Economics, AP-HM/EA 3279, Centre d'Etude et de Recherche sur les Services de Santé et la Qualité de vie, Aix-Marseille University, Marseille, France
| | - Brigitte Chabrol
- Reference Center of Inherited Metabolic Disorders, Timone Enfants Hospital, Marseille, France
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28
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Quaio CRDAC, Moreira CM, Chung CH, Perazzio SF, Dutra AP, Kim CA. Frequency of carriers for rare metabolic diseases in a Brazilian cohort of 320 patients. Mol Biol Rep 2022; 49:3911-3918. [PMID: 35229241 DOI: 10.1007/s11033-022-07241-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 02/08/2022] [Indexed: 10/19/2022]
Abstract
BACKGROUND Several metabolic disorders follow an autosomal recessive inheritance pattern. Epidemiological information on these disorders is usually limited in developing countries. Our objective is to assess carrier frequencies of rare autosomal recessive metabolic diseases in a cohort of Brazilian patients that underwent molecular investigation with exome sequencing and estimate the overall frequency of these diseases using the Hardy-Weinberg equation. METHODS AND RESULTS We reviewed the molecular findings of 320 symptomatic patients who had carrier status for recessive diseases actively searched. A total of 205 rare variants were reported in 138 different genes associated with metabolic diseases from 156 patients, which represents that almost half (48.8%) of the patients were carriers of at least one heterozygous pathogenic/likely pathogenic (P/LP) variant for rare metabolic disorders. Most of these variants are harbored by genes associated with multisystemic involvement. We estimated the overall frequency for rare recessive metabolic diseases to be 10.96/10,000 people, while the frequency of metabolic diseases potentially identified by newborn screening was estimated to be 2.93/10,000. CONCLUSIONS This study shows the potential research utility of exome sequencing to determine carrier status for rare metabolic diseases, which may be a possible strategy to evaluate the clinical and social burden of these conditions at the population level and guide the optimization of health policies and newborn screening programs.
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Affiliation(s)
- Caio Robledo D' Angioli Costa Quaio
- Instituto da Criança (Children's Hospital), Hospital das Clínicas (HCFMUSP), Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil. .,Fleury Medicina e Saúde, São Paulo, SP, Brazil. .,Laboratório Clínico, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil. .,Instituto da Criança do Hospital das Clínicas da FMUSP - Unidade de Genética, Av. Dr. Enéas Carvalho de Aguiar, 647. Cerqueira César, São Paulo, SP, CEP 05403-900, Brazil.
| | | | | | - Sandro Felix Perazzio
- Fleury Medicina e Saúde, São Paulo, SP, Brazil.,Division of Rheumatology, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | | | - Chong Ae Kim
- Instituto da Criança (Children's Hospital), Hospital das Clínicas (HCFMUSP), Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil
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29
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Biochemical testing for inborn errors of metabolism: experience from a large tertiary neonatal centre. Eur J Pediatr 2022; 181:3725-3732. [PMID: 35945291 PMCID: PMC9508208 DOI: 10.1007/s00431-022-04588-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 07/14/2022] [Accepted: 08/05/2022] [Indexed: 11/25/2022]
Abstract
UNLABELLED Inborn errors of metabolism are an individually rare but collectively significant cause of mortality and morbidity in the neonatal period. They are identified by either newborn screening programmes or clinician-initiated targeted biochemical screening. This study examines the relative contribution of these two methods to the identification of inborn errors of metabolism and describes the incidence of these conditions in a large, tertiary, neonatal unit. We also examined which factors could impact the reliability of metabolic testing in this cohort. This is a retrospective, single-site study examining infants in whom a targeted metabolic investigation was performed from January 2018 to December 2020 inclusive. Data was also provided by the national newborn screening laboratory regarding newborn screening diagnoses. Two hundred and four newborns received a clinician-initiated metabolic screen during the time period examined with 5 newborns being diagnosed with an inborn error of metabolism (IEM) (2.4%). Of the 25,240 infants born in the hospital during the period examined, a further 11 newborns had an inborn error of metabolism diagnosed on newborn screening. This produced an incidence in our unit over the time described of 6.34 per 10,000 births. This number reflects a minimum estimate, given that the conditions diagnosed refer to early-onset disorders and distinctive categories of IEM only. Efficiency of the clinician-initiated metabolic screening process was also examined. The only statistically significant variable in requiring repeat metabolic screening was early day of life (z-score = - 2.58, p = 0.0098). A total of 28.4% was missing one of three key metabolic investigation parameters of blood glucose, ammonia or lactate concentration with ammonia the most common investigation missing. While hypoglycemia was the most common clinical rationale for a clinician-initiated metabolic test, it was a poor predictor of inborn error of metabolism with no newborns of 25 screened were diagnosed with a metabolic disorder. CONCLUSION Clinician-targeted metabolic screening had a high diagnostic yield given the relatively low prevalence of inborn errors of metabolism in the general population. Thoughts should be given to the rationale behind each targeted metabolic test and what specific metabolic disease or category of inborn error of metabolism they are concerned along with commencing targeted testing. WHAT IS KNOWN • Inborn errors of metabolism are a rare but potentially treatable cause of newborn mortality and morbidity. • A previous study conducted in a tertiary unit in an area with limited newborn screening demonstrated a diagnostic yield of 5.4%. WHAT IS NEW • Clinician-initiated targeted metabolic screening has a good diagnostic performance even with a more expanded newborn screening programme. • Further optimisation could be achieved by examining the best timing and also the rationale of metabolic testing in the newborn period.
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30
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Majid H, Jafri L, Ali ZZ, Afroze B. Is diagnosing patients with Organic Acidurias and Aminoacidopathies enough? Conundrums of a low middle-income country. Pak J Med Sci 2021; 37:1896-1901. [PMID: 34912414 PMCID: PMC8613019 DOI: 10.12669/pjms.37.7.3887] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 01/13/2021] [Accepted: 06/15/2021] [Indexed: 11/15/2022] Open
Abstract
Objective: This study was done to determine the factors responsible for non-treatment of inherited metabolic disorders (IMDs) requiring food for special medical purposes (FSMPs) in Pakistan. Methods: A descriptive cross-sectional study was conducted by Departments of Pediatrics & Child Health and Pathology & Laboratory Medicine, Aga Khan University. Patients diagnosed with IMDs from January 2013 to December 2016 requiring FSMPs were surveyed after a year of initial diagnosis to collect the details of treatment advised, mortality status, and reasons of non-treatment, including not prescribed by physician, non-acceptance by family, non-availability or non-affordability. Results: Over four years period, 311 patients were identified with IMDs; Median age of patients was 1.0 yrs (0.0.2-3.65) with 54% (n=168) being male. Of the total 38.2% (n=119) required FSMPs, 9% (n=28) patients were excluded due to unavailability of diagnostics information. Parents of 58 patients requiring FSMPs out of 119 participated in survey. The leading causes of non-treatment were, FSMPs not prescribed by physicians (n= 30, 51.7%) followed by non-affordability (n=23, 39.6%), families’ unacceptance in (n=9, 18%) patients, non-availability of FSMPs (n=2, 3.4%) and early death of patient (n=1, 1.7%). Conclusion: The main factors responsible for non-treatment of FSMPs requiring IMDs were non-prescription by physician and non-affordability.
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Affiliation(s)
- Hafsa Majid
- Dr. Hafsa Majid, FCPS. Section of Chemical Pathology, Department of Pathology and Laboratory Medicine, Aga Khan University, Stadium Road, P.O. Box 3500. Karachi 74800, Pakistan
| | - Lena Jafri
- Dr. Lena Jafri, FCPS, Section of Chemical Pathology, Department of Pathology and Laboratory Medicine, Aga Khan University, Stadium Road, P.O. Box 3500. Karachi 74800, Pakistan
| | - Zeba Zulfiqar Ali
- Zeba Zulfiqar Ali, Clinical Nurse Coordinator, Department of Paediatrics & Child Health. Aga Khan University, Stadium Road, P.O. Box 3500. Karachi 74800, Pakistan
| | - Bushra Afroze
- Dr. Bushra Afroze, FCPS, Department of Paediatrics & Child Health, Aga Khan University, Stadium Road, P.O. Box 3500. Karachi 74800, Pakistan
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Gold NB, Kritzer A, Weiner DL, Michelson KA. Emergency Laboratory Evaluations for Patients With Inborn Errors of Metabolism. Pediatr Emerg Care 2021; 37:e1154-e1159. [PMID: 31738301 DOI: 10.1097/pec.0000000000001936] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Children with inborn errors of metabolism (IEM) are at risk for metabolic crises triggered by acute illnesses. Crises are identified through laboratory evaluations. OBJECTIVES Our objective was to determine national adherence to minimum laboratory evaluations for patients with IEM in emergency departments (EDs), as well as factors associated with laboratory evaluation adherence. METHODS Using the Pediatric Health Information System, we identified visits to 48 EDs from 2012 to 2017 by children with IEM. We analyzed visits for catabolic conditions (dehydration, gastroenteritis, or vomiting) and determined variation in minimum laboratory evaluation adherence. Multivariable models were created to determine predictors of adherence. RESULTS Among the visits by children with disorders of the urea cycle, organic acid metabolism, and fatty acid oxidation, 1457 (76.3%) of 1909 adhered to the minimum laboratory evaluation. Median ED-level adherence was 78.2% (interquartile range, 67.4-92.5). Factors associated with adherence were disorder [fatty acid oxidation vs urea cycle disorder; adjusted odds ratio (aOR), 9.35; 95% confidence interval (CI), 4.07-21.47], annual ED volume of patients with IEM (quartile 4 vs 1; aOR, 3.58; 95% CI, 1.51-8.49), and presence of a biochemical genetics fellowship (aOR, 0.29; 95% CI, 0.14-0.62). CONCLUSIONS Patients with IEM frequently did not receive minimum laboratory evaluations for catabolic conditions. Measures to improve laboratory use in children with IEM should be undertaken.
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Affiliation(s)
| | | | - Debra L Weiner
- Emergency Medicine, Boston Children's Hospital, Boston, Massachusetts
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Jin L, Han X, He F, Zhang C. Prevalence of methylmalonic acidemia among newborns and the clinical-suspected population: a meta-analyse. J Matern Fetal Neonatal Med 2021; 35:8952-8967. [PMID: 34847798 DOI: 10.1080/14767058.2021.2008351] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
IMPORTANCE Knowing the scale of rare inborn errors is important for screening and resource allocation. Evidence on the prevalence of methylmalonic acidemia (MMA) among newborns and the clinical-suspected population from large-scale screening programs needs to be systematically synthesized. OBJECTIVE To estimate the worldwide prevalence of MMA for newborns and the clinical-suspected population and explore the differences in different regions, periods, and diagnostic technologies. DATA SOURCES MEDLINE, Embase, CRD, Cochrane Library, Scopus, CINAHL, and PROSPERO. Study Selection: All studies reporting the epidemiology characteristics of MMA were selected. DATA EXTRACTION AND SYNTHESIS Characteristics of study, subjects, and epidemiology were extracted, random-effect models were used for meta-analyses. MAIN OUTCOME AND MEASURE Pooled prevalence of MMA. RESULTS This study included 111 studies. The pooled prevalence of MMA worldwide was 1.14 per 100,000 newborns (1516/190,229,777 newborns, 95% CI: 0.99-1.29) and 652.11 per 100,000 clinical-suspected patients (1360/4,805,665 clinical-suspected individuals, CI: 544.14-760.07). Asia and Africa got a higher pooled prevalence of MMA. The prevalence of MMA in newborns increased through the years, while that in the clinical-suspected population decreased. Collecting blood ≥ 72 h after birth had a higher pooled prevalence of MMA than collecting during 24 h-72 h after birth. The combining-use of MS/MS and GC/MS had a higher pooled prevalence than the single-use of MS/MS or GC/MS. Prevalence of cbl C, mut, cbl B, cbl A, isolated MMA, combined MMA and homocystinuria, vitamin B12-responsive MMA was synthesized. CONCLUSIONS AND RELEVANCE Prevalence of MMA among newborns was extremely low, but considerably high in the clinical-suspected population, indicating the need for more efficient newborn screening strategies and closer monitoring of the high-risk population for the early signs of MMA. Asia and Africa should attach importance to the high prevalence of MMA. Further diagnostic tests were recommended for the combining-use vs single-use of MS/MS and GC/MS and for collecting blood after 72 h vs during 24-72 h after birth.
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Affiliation(s)
- Lizi Jin
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, P. R. China.,Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P. R. China
| | - Xueyan Han
- Department of Medical Statistics, Peking University First Hospital, Beijing, P. R. China
| | - Falin He
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, P. R. China.,Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P. R. China
| | - Chuanbao Zhang
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, P. R. China.,Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P. R. China
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33
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Kong W, Wu S, Zhang J, Lu C, Ding Y, Meng Y. Global epidemiology of mucopolysaccharidosis type III (Sanfilippo syndrome): an updated systematic review and meta-analysis. J Pediatr Endocrinol Metab 2021; 34:1225-1235. [PMID: 34271605 DOI: 10.1515/jpem-2020-0742] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Accepted: 06/20/2021] [Indexed: 12/31/2022]
Abstract
OBJECTIVES Mucopolysaccharidosis III, an autosomal recessive lysosomal storage disorder, is characterized by progressive mental retardation and behavioral problems. Meta-analysis of global mucopolysaccharidosis III epidemiology, which serves as a fundamental reference for public health decision-making, was not available prior to this study. To provide a systematic review and meta-analysis of birth prevalence of mucopolysaccharidosis III in multiple countries. METHODS MEDLINE and EMBASE databases were searched for original research articles on the epidemiology of mucopolysaccharidosis III from inception until 1st July, 2020. A checklist adapted from STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) was used to assess the quality of all studies involved. Meta-analysis, adopting a random effects logistic model, was performed to estimate pooled birth prevalence of mucopolysaccharidosis III and its subtypes. RESULTS Twenty-five studies screened out of 1,826 records were included for data extraction. The pooled global mucopolysaccharidosis III birth prevalence was 0.76 cases (95% CI: 0.57-0.96) per 100,000 live births. The pooled global birth prevalence of mucopolysaccharidosis III subtypes (A, B, and C) was 0.52 cases (95% CI: 0.33-0.72), 0.21 cases (95% CI: 0.12-0.30) and 0.01 cases (95% CI: 0.005-0.02) per 100,000 live births, respectively. CONCLUSIONS Based on the global population size (7.8 billion) and the life span of patients, there would be 12-19 thousand mucopolysaccharidosis III patients worldwide. To our knowledge, this is the first comprehensive systematic review that presented quantitative data fundamental for evidence-based public health decision-making by evaluating global epidemiology of mucopolysaccharidosis III.
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Affiliation(s)
- Weijing Kong
- Department of Pediatrics, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Shanshan Wu
- Department of Clinical Epidemiology and EBM, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Jing Zhang
- Department of Pediatrics, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Cheng Lu
- Beijing Hong Jian Medical Device Company, Beijing, China
| | - Yingxue Ding
- Department of Pediatrics, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yan Meng
- Department of Pediatrics, Chinese PLA General Hospital, Beijing, China
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34
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Kruger WD. How to fix a broken protein: restoring function to mutant human cystathionine β-synthase. Hum Genet 2021; 141:1299-1308. [PMID: 34636997 DOI: 10.1007/s00439-021-02386-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 10/05/2021] [Indexed: 12/17/2022]
Abstract
Inborn errors of metabolism (IEM) comprise a large class of recessive genetic diseases involving disorders of cellular metabolism that tend to be caused by missense mutations in which a single incorrect amino acid is substituted in the polypeptide chain. Cystathionine beta-synthase (CBS) deficiency is an example of an IEM that causes large elevations of blood total homocysteine levels, resulting in phenotypes in several tissues. Current treatment strategies involve dietary restriction and vitamin therapy, but these are only partially effective and do not work in all patients. Over 85% of the described mutations in CBS-deficient patients are missense mutations in which the mutant protein fails to fold into an active conformation. The ability of CBS to achieve an active conformation is affected by a variety of intracellular protein networks including the chaperone system and the ubiquitin/proteasome system, collectively referred to as the proteostasis network. Proteostasis modulators are drugs that perturb various aspects of these networks. In this article, we will review the evidence that modulation of the intracellular protein folding environment can be used as a potential therapeutic strategy to treat CBS deficiency and discuss the pros and cons of such a strategy.
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Affiliation(s)
- Warren D Kruger
- Cancer Signaling and Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
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35
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Deng K, Zhu J, Yu E, Xiang L, Yuan X, Yao Y, Li X, Liu H. Incidence of inborn errors of metabolism detected by tandem mass spectrometry in China: A census of over seven million newborns between 2016 and 2017. J Med Screen 2021; 28:223-229. [PMID: 33241759 DOI: 10.1177/0969141320973690] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND The incidence of inborn errors of metabolism varies widely across countries. Very few studies have analyzed the incidence of these disorders in Mainland China. We aimed to estimate the overall and disease-specific incidences of inborn errors of metabolism in Chinese newborns and investigate the geographical distribution of these disorders. METHODS A national cross-sectional survey was conducted to investigate newborn inborn errors of metabolism screening by tandem mass spectroscopy in Mainland China between 2016 and 2017. A total of 246 newborn screening centers were surveyed using a standardized questionnaire. We examined the cumulative and disease-specific incidences of inborn errors of metabolism in Mainland China as a whole and in different geographical locations. RESULTS Over 7 million newborns were screened and 2747 were diagnosed with inborn errors of metabolism, yielding an overall incidence of 38.69 per 100,000 births (95% confidence interval: 37.27-40.17). The most common disorders were amino acid disorders (17.14 per 100,000 births, 95% confidence interval: 16.21-18.13), followed by organic acid disorders (12.39 per 100,000 births, 95% confidence interval: 11.60-13.24) and fatty acid oxidation disorders (9.16 per 100,000 births, 95% confidence interval: 8.48-9.89). The overall and disease-specific incidence rates differed significantly across geographical locations (P < 0.001). CONCLUSIONS The overall incidence of inborn errors of metabolism in Chinese newborns is relatively high. It is urgent to establish the recommended uniform screening panel for inborn errors of metabolism to guide the national and regional tandem mass spectroscopy newborn screening programs.
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Affiliation(s)
- Kui Deng
- National Center for Birth Defects Monitoring, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, China
| | - Jun Zhu
- National Center for Birth Defects Monitoring, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, China
| | - Erling Yu
- National Center for Birth Defects Monitoring, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Liangcheng Xiang
- National Center for Birth Defects Monitoring, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Xuelian Yuan
- National Center for Birth Defects Monitoring, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Yongna Yao
- National Center for Birth Defects Monitoring, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Xiaohong Li
- National Center for Birth Defects Monitoring, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, China
| | - Hanmin Liu
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education
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36
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Sestini S, Paneghetti L, Lampe C, Betti G, Bond S, Bellettato CM, Maurizio S. Social and medical needs of rare metabolic patients: results from a MetabERN survey. Orphanet J Rare Dis 2021; 16:336. [PMID: 34344397 PMCID: PMC8329639 DOI: 10.1186/s13023-021-01948-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 07/09/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Many surveys have been performed over the years to assess the medical and social requirements of patients with a rare disease, but no studies have focused specifically on patients in Europe or with an inherited metabolic disease (IMD). To obtain a comprehensive overview of the social and psychological status and needs of IMD patients, especially in Europe, the European Reference Network for Hereditary Metabolic Disorders (MetabERN) has performed a dedicated survey among its metabolic patients. RESULTS A total of 924 patients and caregivers responded to the questionnaire. Most participants were from 25 European countries, with Spain, Italy, and Germany being the most represented; only eight participants were extra-European. The survey showed that most social assistance services, from free educational/development services for those with intellectual disability to transition from childhood to adult care and job placement support, are available for a limited number of patients or are unknown to the majority of patients or their parents/caregivers. Similarly, psychological assistance for the patient or the parent/caregiver is available for a small fraction of respondents, despite the fact that the majority considers this type of support necessary for both the patient and the caregiver. In addition, for most IMD patients local specialised or emergency medical assistance is lacking, although national clinical pathways are defined, and medical professionals of reference are readily available when needed. Lastly, while most national health services in Europe cover all or part of the expenses for medications, medical devices, food supplements, dietary integrators, physiotherapy, and speech therapy, significant gaps in the economic support for healthcare and other expenses still exist. CONCLUSIONS Overall, our survey reveals a widespread lack of social, psychological, and economic support for IMD patients in Europe. More needs to be done to provide daily assistance to IMD patients in order to alleviate the burden on caregivers and to allow patients to become independent and productive adults. Where support is actually available locally or nationally, most IMD patients are not aware of it, so an active dissemination of this information among the metabolic community is essential.
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Affiliation(s)
- Sylvia Sestini
- Italian Association of Patients With Alkaptonuria (aimAKU), Siena, Italy
| | - Laura Paneghetti
- Regional Coordinating Center for Rare Diseases, MetabERN, Udine University Hospital, Udine, Italy
| | - Christina Lampe
- Center for Rare Diseases Giessen (ZSEGI), Department of Child Neurology, Justus-Liebig University, Giessen, Germany
| | - Gianni Betti
- Department of Economics and Statistics, University of Siena, Siena, Italy
| | - Simon Bond
- Regional Coordinating Center for Rare Diseases, MetabERN, Udine University Hospital, Udine, Italy
| | - Cinzia Maria Bellettato
- Regional Coordinating Center for Rare Diseases, MetabERN, Udine University Hospital, Udine, Italy
| | - Scarpa Maurizio
- Regional Coordinating Center for Rare Diseases, MetabERN, Udine University Hospital, Udine, Italy.
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Bayrak H, Yıldız Y, Olgaç A, Kasapkara ÇS, Küçükcongar A, Zenciroğlu A, Yüksel D, Ceylaner S, Kılıç M. Genotypic and phenotypic features in Turkish patients with classic nonketotic hyperglycinemia. Metab Brain Dis 2021; 36:1213-1222. [PMID: 33791923 DOI: 10.1007/s11011-021-00718-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 03/14/2021] [Indexed: 10/21/2022]
Abstract
Nonketotic hyperglycinemia is an autosomal recessive inborn error of glycine metabolism, characterized by deficient activity of the glycine cleavage enzyme system. Classic nonketotic hyperglycinemia is caused by mutations or genomic changes in genes that encode the protein components of the glycine cleavage enzyme system. We aimed to investigate clinical, biochemical, radiological findings and molecular genetic data in ten Turkish patients with classic nonketotic hyperglycinemia. Ten Turkish patients who were diagnosed with classic nonketotic hyperglycinemia in a single center from 2013 to 2019 were included in this study. Their clinical, radiological, electrophysiological and laboratory data were collected retrospectively. Sixty percent of the patients were in neonatal group, while 40 % of the patients were infantile. There were no late-onset patients. 90 % of the patients had the severe form. All patients had developmental delay and seizures. Mortality ratio was 30 % in all groups and 50 % in the neonatal group, while no mortality was seen in infantile group. Median (range) values of cerebrospinal fluid (CSF) glycine levels, plasma glycine levels and CSF/plasma glycine ratios were 148 (15-320) µmol/L, 896 (87-1910) µmol/L, 0.17 (0.09-0.21) respectively. Diffuse hypomyelination and corpus callosum anomaly were the most common cranial MRI findings and multifocal epileptic activity and burst supression pattern were the most common electroencephalographic findings. Six patients had variants in GLDC gene and four in AMT gene; five novel variants including AMT gene deletion were detected. Prognosis was poor and treatment was not effective, especially in the severe form. Classic nonketotic hyperglycinemia causes high morbidity and mortality. Neonatal-onset disease was more common and severe than infantile-onset disease. The ratio of AMT gene variants might be higher in Turkey than other countries. AMT gene deletion also plays a role in the etiology of classic nonketotic hyperglycinemia.
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Affiliation(s)
- Harun Bayrak
- Department of Pediatrics, Sami Ulus Children Hospital, Ankara, Turkey
| | - Yılmaz Yıldız
- Metabolism Unit, Sami Ulus Children Hospital, Babur cad. No: 44, Altındağ, Ankara, 06080, Turkey
| | - Asburçe Olgaç
- Metabolism Unit, Sami Ulus Children Hospital, Babur cad. No: 44, Altındağ, Ankara, 06080, Turkey
| | - Çiğdem Seher Kasapkara
- Metabolism Unit, Sami Ulus Children Hospital, Babur cad. No: 44, Altındağ, Ankara, 06080, Turkey
| | | | | | - Deniz Yüksel
- Neurology Unit, Sami Ulus Children Hospital, Ankara, Turkey
| | - Serdar Ceylaner
- Intergen, Genetic and Rare Disease Diagnosis and Research Center, Genetic Laboratory, Ankara, Turkey
| | - Mustafa Kılıç
- Metabolism Unit, Sami Ulus Children Hospital, Babur cad. No: 44, Altındağ, Ankara, 06080, Turkey.
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Prasad N, Hamosh A, Sponseller P. Orthopaedic Manifestations of Inborn Errors of Metabolism. JBJS Rev 2021; 9:01874474-202107000-00003. [PMID: 34257233 DOI: 10.2106/jbjs.rvw.20.00245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
» Inborn errors of metabolism are disorders of carbohydrate, amino acid, organic acid, or purine and pyrimidine metabolism; disorders of fatty acid oxidation; disorders of metal metabolism; and lysosomal storage defects that can cause metabolic derangements that have secondary musculoskeletal effects. » Orthopaedic surgeons should be aware that patients with inborn errors of metabolism may be at high risk for spasticity, which may cause joint subluxations, scoliosis, and contractures, as well as poor bone quality, which is caused by malnutrition or disordered bone growth. » Multidisciplinary care and follow-up are important to identify musculoskeletal problems in a timely manner in order to provide effective treatment.
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Affiliation(s)
- Niyathi Prasad
- Departments of Orthopaedic Surgery and Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland
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Elabd HSA, Bastaki F, Khalifa M. Homozygous Novel Variants in the Glycine Decarboxylase Gene Associated with Nonketotic Hyperglycinemia in a Distinct Population. J Pediatr Genet 2021; 12:23-31. [PMID: 36684550 PMCID: PMC9848757 DOI: 10.1055/s-0041-1729741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 03/21/2021] [Indexed: 01/25/2023]
Abstract
Glycine encephalopathy (GE), also known as nonketotic hyperglycinemia (NKH) is an autosomal recessive disorder due to a primary defect in the glycine cleavage enzyme system. It is characterized by elevated levels of glycine in the plasma and cerebrospinal fluid (CSF) and increased CSF to plasma glycine ratio. Mutations in three genes of the mitochondrial glycine cleavage system have been found to cause NKH. Most patients have a mutation in the GLDC . In this report, we present five new patients from Middle Eastern families with NKH. They were all born to consanguineous parents and two of them have family history of similarly affected sibling(s). All patients presented with neonatal encephalopathy associated with seizures. Their diagnoses were suspected clinically and confirmed biochemically. DNA sequence analysis of the five patients revealed five different pathogenic or likely pathogenic variants in the GLDC . Three were missense variants (c.2675C > T; p.Ala892Val), (c.2512A > G; p.Asn838Asp), and (c.2943A > C; p.Lys981Asn); one was an intronic missense variant (c.1402-2A > T) leading to an exonic deletion, and one was a deletion of 42 amino acids (c.1927-?_2052 + ?del.) All variants were novel and homozygous. The pathogenicity of these variants was determined according to the American College of Medical Genetics (ACMG) variant classification and in silico analysis. Another novel homozygous variant (c.1384C > G; p.Leu462Val) was detected, which was classified as likely benign. The novel variants identified in the GLDC in these patients underlie the pathogenesis of NKH, specifically for the Middle Eastern population. This expands the mutation spectrum of NKH to include a distinct ethnic population that has not been studied before.
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Affiliation(s)
- Heba Salah Abdelkhalek Elabd
- Department of Pediatrics Genetics, Latifa Women and Children Hospital, Dubai Health Authority, Dubai, United Arab Emirates,Department of Genetics, Faculty of Medicine, Ain Shams University, Cairo, Egypt,Address for correspondence Heba Salah Abdelkhalek Elabd, MD Latifa Women and Children HospitalOud Metha Road, Al Jadaf, Dubai, PO Box 9115United Arab Emirates
| | - Fatma Bastaki
- Department of Pediatrics Genetics, Latifa Women and Children Hospital, Dubai Health Authority, Dubai, United Arab Emirates
| | - Mohamed Khalifa
- Department of Pediatrics Genetics, Latifa Women and Children Hospital, Dubai Health Authority, Dubai, United Arab Emirates
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40
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Zhao Z, Chen C, Sun X, Zhou D, Huang X, Dong H. Newborn screening for inherited metabolic diseases using tandem mass spectrometry in China: Outcome and cost-utility analysis. J Med Screen 2021; 29:12-20. [PMID: 34102920 DOI: 10.1177/09691413211021621] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
OBJECTIVES Few studies in China have focused on the economic evaluation of newborn screening (NBS) for inherited metabolic disorders (IMDs) by tandem mass spectrometry (MS/MS). This study assesses the total costs, benefits, benefit-cost ratio (BCR), cost-utility ratio (CUR) and incremental cost-utility ratio (ICUR) of NBS using MS/MS compared to the non-screened group. METHODS The NBS outcomes of newborns who underwent MS/MS screening for IMDs in 2009-2018 were retrospectively reviewed. Records were extracted from a screening management system at the NBS Center of Zhejiang province. A cost-benefit analysis of screening was conducted, assessing screening costs for each subject, and direct and indirect treatment costs for IMDs detected by screening. The putative benefit of clinical outcomes related to early diagnosis was assumed to be improvement in quality of life and prolonged life expectancy in the screened group, as compared to the non-screened group. RESULTS Of the 3,040,815 newborns screened, 735 (2.86%) cases were diagnosed through gene sequence analysis. The most frequently occurring types of IMD were amino acid disorders (n = 276), then fatty acid oxidation disorders (n = 248), followed by organic acidaemias (n = 211). The difference in quality-adjusted life-years (QALYs) ranged from 0.78 to 15.4 in the screened group. The CUR was CNY¥ 116,183.89/QALY in the screened group and CNY¥ 3,078,823.65/QALY in the non-screened group. The ICUR was CNY¥ -768,428.76/QALY, and the BCR was 6.09. CONCLUSIONS NBS using MS/MS can be considered cost-effective in China. The nationwide promotion of NBS using MS/MS deserves priority consideration and sufficient publicity.
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Affiliation(s)
- Zixuan Zhao
- Department of Genetics and Metabolism, Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.,Center for Health Policy Studies, School of Public Health, Zhejiang University School of Medicine, Hangzhou, China
| | - Chi Chen
- Department of Genetics and Metabolism, Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Xueshan Sun
- Center for Health Policy Studies, School of Public Health, Zhejiang University School of Medicine, Hangzhou, China
| | - Duo Zhou
- Department of Genetics and Metabolism, Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Xinwen Huang
- Department of Genetics and Metabolism, Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Hengjin Dong
- Center for Health Policy Studies, School of Public Health, Zhejiang University School of Medicine, Hangzhou, China.,The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Diagnosis and management of secondary causes of steatohepatitis. J Hepatol 2021; 74:1455-1471. [PMID: 33577920 DOI: 10.1016/j.jhep.2021.01.045] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 01/09/2021] [Accepted: 01/25/2021] [Indexed: 02/06/2023]
Abstract
The term non-alcoholic fatty liver disease (NAFLD) was originally coined to describe hepatic fat deposition as part of the metabolic syndrome. However, a variety of rare hereditary liver and metabolic diseases, intestinal diseases, endocrine disorders and drugs may underlie, mimic, or aggravate NAFLD. In contrast to primary NAFLD, therapeutic interventions are available for many secondary causes of NAFLD. Accordingly, secondary causes of fatty liver disease should be considered during the diagnostic workup of patients with fatty liver disease, and treatment of the underlying disease should be started to halt disease progression. Common genetic variants in several genes involved in lipid handling and metabolism modulate the risk of progression from steatosis to fibrosis, cirrhosis and hepatocellular carcinoma development in NAFLD, alcohol-related liver disease and viral hepatitis. Hence, we speculate that genotyping of common risk variants for liver disease progression may be equally useful to gauge the likelihood of developing advanced liver disease in patients with secondary fatty liver disease.
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Takano C, Grubbs BH, Ishige M, Ogawa E, Morioka I, Hayakawa S, Miki T. Clinical perspective on the use of human amniotic epithelial cells to treat congenital metabolic diseases with a focus on maple syrup urine disease. Stem Cells Transl Med 2021; 10:829-835. [PMID: 33547875 PMCID: PMC8133340 DOI: 10.1002/sctm.20-0225] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 12/18/2020] [Accepted: 12/20/2020] [Indexed: 12/16/2022] Open
Abstract
Congenital metabolic diseases are a group of hereditary disorders caused by the deficiency of a single specific enzyme activity. Without appropriate therapy, affected patients suffer severe neurologic disability and eventual death. The current mainstays of management attempt to slow disease progression, but are not curative. Several of these diseases have demonstrated significant benefits from liver transplantation; however, this approach is limited by the morbidity associated with this invasive procedure and a shortage of donor organs. Therefore, there is a need to establish a new strategy for improving the quality of a life for these patients. One potential solution is regenerative therapy using hepatocytes generated from stem cells. Herein, we discuss pertinent issues necessary for clinical application of the human amniotic epithelial cell, a type of placental stem cell. Focusing on maple syrup urine disease as an example, where liver replacement is an effective therapy, we explore this approach from a clinician's perspective.
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Affiliation(s)
- Chika Takano
- Division of Microbiology, Department of Pathology and MicrobiologyNihon University School of MedicineTokyoJapan
- Department of Pediatrics and Child HealthNihon University School of MedicineTokyoJapan
| | - Brendan H. Grubbs
- Department of Obstetrics and GynecologyKeck School of Medicine, University of Southern CaliforniaLos AngelesCaliforniaUSA
| | - Mika Ishige
- Department of Pediatrics and Child HealthNihon University School of MedicineTokyoJapan
| | - Erika Ogawa
- Department of Pediatrics and Child HealthNihon University School of MedicineTokyoJapan
| | - Ichiro Morioka
- Department of Pediatrics and Child HealthNihon University School of MedicineTokyoJapan
| | - Satoshi Hayakawa
- Division of Microbiology, Department of Pathology and MicrobiologyNihon University School of MedicineTokyoJapan
| | - Toshio Miki
- Department of PhysiologyNihon University School of MedicineTokyoJapan
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Puckett Y, Mallorga-Hernández A, Montaño AM. Epidemiology of mucopolysaccharidoses (MPS) in United States: challenges and opportunities. Orphanet J Rare Dis 2021; 16:241. [PMID: 34051828 PMCID: PMC8164808 DOI: 10.1186/s13023-021-01880-8] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 05/21/2021] [Indexed: 12/03/2022] Open
Abstract
Background Mucopolysaccharidoses (MPS) are rare, inherited lysosomal storage disorders characterized by progressive multiorgan involvement. Previous studies on incidence and prevalence of MPS mainly focused on countries other than the United States (US), showing considerable variation by country. This study aimed to identify MPS incidence and prevalence in the US at a national and state level to guide clinicians and policy makers. Methods This retrospective study examined all diagnosed cases of MPS from 1995 to 2015 in the US using the National MPS Society database records. Data included year of birth, patient geographic location, and MPS variant type. US population information was obtained from the National Center for Health Statistics. The incidence and prevalence rates were calculated for each disease. Incidence rates were calculated for each state. Results We obtained information from 789 MPS patients during a 20-year period. Incidence of MPS in the US was found to be 0.98 per 100,000 live births. Prevalence was found to be 2.67 per 1 million. MPS I, II, and III had the highest incidence rate at birth (0.26/100,000) and prevalence rates of 0.70–0.71 per million. Birth incidences of MPS IV, VI, and VII were 0.14, 0.04 and 0.027 per 100,000 live births. Conclusions This is the most comprehensive review of MPS incidence and prevalence rates in the US. Due to the large US population and state fragmentation, US incidence and prevalence were found to be lower than other countries. Nonetheless, state-level studies in the US supported these figures. Efforts should be focused in the establishment of a national rare disease registry with mandated reporting from every state as well as newborn screening of MPS.
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Affiliation(s)
- Yana Puckett
- Department of Epidemiology, Saint Louis University College for Public Health and Social Justice, 3545 Lafayette Avenue, St. Louis, MO, 63104, USA.
| | | | - Adriana M Montaño
- Department of Pediatrics, Edward A. Doisy Research Center, Saint Louis University School of Medicine, 1100 South Grand Blvd., Room 313, St. Louis, MO, 63104, USA. .,Department of Biochemistry and Molecular Biology, Edward A. Doisy Research Center, Saint Louis University School of Medicine, St. Louis, MO, USA.
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De Sabbata G, Boisgerault F, Guarnaccia C, Iaconcig A, Bortolussi G, Collaud F, Ronzitti G, Sola MS, Vidal P, Rouillon J, Charles S, Nicastro E, D'Antiga L, Ilyinskii P, Mingozzi F, Kishimoto TK, Muro AF. Long-term correction of ornithine transcarbamylase deficiency in Spf-Ash mice with a translationally optimized AAV vector. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 2021; 20:169-180. [PMID: 33473356 PMCID: PMC7786024 DOI: 10.1016/j.omtm.2020.11.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 11/11/2020] [Indexed: 12/11/2022]
Abstract
Ornithine transcarbamylase deficiency (OTCD) is an X-linked liver disorder caused by partial or total loss of OTC enzyme activity. It is characterized by elevated plasma ammonia, leading to neurological impairments, coma, and death in the most severe cases. OTCD is managed by combining dietary restrictions, essential amino acids, and ammonia scavengers. However, to date, liver transplantation provides the best therapeutic outcome. AAV-mediated gene-replacement therapy represents a promising curative strategy. Here, we generated an AAV2/8 vector expressing a codon-optimized human OTC cDNA by the α1-AAT liver-specific promoter. Unlike standard codon-optimization approaches, we performed multiple codon-optimization rounds via common algorithms and ortholog sequence analysis that significantly improved mRNA translatability and therapeutic efficacy. AAV8-hOTC-CO (codon optimized) vector injection into adult OTCSpf-Ash mice (5.0E11 vg/kg) mediated long-term complete correction of the phenotype. Adeno-Associated viral (AAV) vector treatment restored the physiological ammonia detoxification liver function, as indicated by urinary orotic acid normalization and by conferring full protection against an ammonia challenge. Removal of liver-specific transcription factor binding sites from the AAV backbone did not affect gene expression levels, with a potential improvement in safety. These results demonstrate that AAV8-hOTC-CO gene transfer is safe and results in sustained correction of OTCD in mice, supporting the translation of this approach to the clinic.
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Affiliation(s)
- Giulia De Sabbata
- International Center for Genetic Engineering and Biotechnology (ICGEB), 34149 Trieste, Italy
| | - Florence Boisgerault
- Généthon, 91000 Evry, France.,Université Paris-Saclay, Université Evry, INSERM, Généthon, Integrare Research Unit UMR_S951, 91000 Evry, France
| | - Corrado Guarnaccia
- International Center for Genetic Engineering and Biotechnology (ICGEB), 34149 Trieste, Italy
| | - Alessandra Iaconcig
- International Center for Genetic Engineering and Biotechnology (ICGEB), 34149 Trieste, Italy
| | - Giulia Bortolussi
- International Center for Genetic Engineering and Biotechnology (ICGEB), 34149 Trieste, Italy
| | - Fanny Collaud
- Généthon, 91000 Evry, France.,Université Paris-Saclay, Université Evry, INSERM, Généthon, Integrare Research Unit UMR_S951, 91000 Evry, France
| | - Giuseppe Ronzitti
- Généthon, 91000 Evry, France.,Université Paris-Saclay, Université Evry, INSERM, Généthon, Integrare Research Unit UMR_S951, 91000 Evry, France
| | - Marcelo Simon Sola
- Généthon, 91000 Evry, France.,Université Paris-Saclay, Université Evry, INSERM, Généthon, Integrare Research Unit UMR_S951, 91000 Evry, France
| | - Patrice Vidal
- Généthon, 91000 Evry, France.,Université Paris-Saclay, Université Evry, INSERM, Généthon, Integrare Research Unit UMR_S951, 91000 Evry, France
| | - Jeremy Rouillon
- Généthon, 91000 Evry, France.,Université Paris-Saclay, Université Evry, INSERM, Généthon, Integrare Research Unit UMR_S951, 91000 Evry, France
| | - Severine Charles
- Généthon, 91000 Evry, France.,Université Paris-Saclay, Université Evry, INSERM, Généthon, Integrare Research Unit UMR_S951, 91000 Evry, France
| | | | | | | | - Federico Mingozzi
- Généthon, 91000 Evry, France.,Université Paris-Saclay, Université Evry, INSERM, Généthon, Integrare Research Unit UMR_S951, 91000 Evry, France.,Institut de Myologie, 73013 Paris, France
| | | | - Andrés F Muro
- International Center for Genetic Engineering and Biotechnology (ICGEB), 34149 Trieste, Italy
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Semyachkina AN, Voskoboeva EY, Nikolaeva EA, Zakharova EY. Analysis of long-term observations of the large group of Russian patients with Hunter syndrome (mucopolysaccharidosis type II). BMC Med Genomics 2021; 14:71. [PMID: 33676511 PMCID: PMC7937197 DOI: 10.1186/s12920-021-00922-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 02/25/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND This article presents the results of long-term observations and comparative analysis of genotype-phenotype features in a large group of patients (227 males and one female) with a severe, intermediate and mild form of Hunter syndrome, evaluating the quality and span of their lives, as well as their ability to social adaptation. METHODS We used electrophoresis of glycosaminoglycans of urine, determination of the activity of lysosomal enzymes in plasma, in dried blood spots according to the generally accepted method and DNA analysis. RESULTS The clinical symptomatology of 228 patients with Hunter syndrome was characterized by growth retardation, lesions of the bronchopulmonary, cardiovascular, nervous systems, etc. Thirty-five patients had an attenuated form of the disease. DNA was available from all patients. 19 patients from 10 families had a mild form of the disease. 42 patients from 41 families had an intermediate form of the disease. All other patients had a severe form of the disease. We provide brief clinical examples of some patients with a mild form of Hunter syndrome. Currently, 113 patients with Hunter syndrome receive enzyme replacement therapy (idursulfase or idursulfase beta). CONCLUSION The long-term study of the large number of patients with Hunter syndrome helped identify disease-associated variants leading to severe and mild forms of the disease. The treatment effect and successful social adaptation of patients with a mild form of Hunter syndrome were revealed.
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Affiliation(s)
- Alla Nikolaevna Semyachkina
- Department of Clinical Genetics, Research and Clinical Institute of Pediatrics Named After Yuri Veltischev of the Pirogov Russian National Research Medical University of the Russian Ministry of Health, 2 Taldomskaya St., Moscow, 125412 Russia
| | | | - Ekaterina Alexandrovna Nikolaeva
- Department of Clinical Genetics, Research and Clinical Institute of Pediatrics Named After Yuri Veltischev of the Pirogov Russian National Research Medical University of the Russian Ministry of Health, 2 Taldomskaya St., Moscow, 125412 Russia
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Nasrallah F, Ben Chehida A, Kraoua I, Hadj-Taieb S, Sanhaji H, Tebib N, Feki M, Kaabachi N. Non-ketotic hyperglycinaemia: a frequent, but poorly diagnosed and managed genetic disorder in Tunisia. Arch Dis Child 2021; 106:311. [PMID: 32404439 DOI: 10.1136/archdischild-2019-318774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/23/2020] [Indexed: 11/03/2022]
Affiliation(s)
- Fahmi Nasrallah
- University of Tunis El Manar, Faculty of Medicine of Tunis, Tunis, Tunisia
- Laboratory of Biochemistry, LR99ES11, Rabta Hospital, Tunis, Tunisia
- Service of Pediatrics, LR12SP02, Rabta Hospital, Tunis, Tunisia
| | - Amel Ben Chehida
- University of Tunis El Manar, Faculty of Medicine of Tunis, Tunis, Tunisia
- Service of Pediatrics, LR12SP02, Rabta Hospital, Tunis, Tunisia
| | - Ichraf Kraoua
- University of Tunis El Manar, Faculty of Medicine of Tunis, Tunis, Tunisia
- Service of Child Neurology, LR18SP04, National Institute Mongi Ben Hmida of Neuroloy, Tunis, Tunisia
| | - Sameh Hadj-Taieb
- University of Tunis El Manar, Faculty of Medicine of Tunis, Tunis, Tunisia
- Laboratory of Biochemistry, LR99ES11, Rabta Hospital, Tunis, Tunisia
| | - Haifa Sanhaji
- University of Tunis El Manar, Faculty of Medicine of Tunis, Tunis, Tunisia
- Laboratory of Biochemistry, LR99ES11, Rabta Hospital, Tunis, Tunisia
| | - Neji Tebib
- University of Tunis El Manar, Faculty of Medicine of Tunis, Tunis, Tunisia
- Service of Pediatrics, LR12SP02, Rabta Hospital, Tunis, Tunisia
| | - Moncef Feki
- University of Tunis El Manar, Faculty of Medicine of Tunis, Tunis, Tunisia
- Laboratory of Biochemistry, LR99ES11, Rabta Hospital, Tunis, Tunisia
| | - Naziha Kaabachi
- University of Tunis El Manar, Faculty of Medicine of Tunis, Tunis, Tunisia
- Laboratory of Biochemistry, LR99ES11, Rabta Hospital, Tunis, Tunisia
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Stepien KM, Kieć-Wilk B, Lampe C, Tangeraas T, Cefalo G, Belmatoug N, Francisco R, Del Toro M, Wagner L, Lauridsen AG, Sestini S, Weinhold N, Hahn A, Montanari C, Rovelli V, Bellettato CM, Paneghetti L, van Lingen C, Scarpa M. Challenges in Transition From Childhood to Adulthood Care in Rare Metabolic Diseases: Results From the First Multi-Center European Survey. Front Med (Lausanne) 2021; 8:652358. [PMID: 33738294 PMCID: PMC7962750 DOI: 10.3389/fmed.2021.652358] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 02/08/2021] [Indexed: 12/11/2022] Open
Abstract
Inherited Metabolic Diseases (IMDs) are rare diseases caused by genetic defects in biochemical pathways. Earlier diagnosis and advances in treatment have improved the life expectancy of IMD patients over the last decades, with the majority of patients now surviving beyond the age of 20. This has created a new challenge: as they grow up, the care of IMD patients' needs to be transferred from metabolic pediatricians to metabolic physicians specialized in treating adults, through a process called “transition.” The purpose of this study was to assess how this transition is managed in Europe: a survey was sent to all 77 centers of the European Reference Network for Hereditary Metabolic Disorders (MetabERN) to collect information and to identify unmet needs regarding the transition process. Data was collected from 63/77 (81%) healthcare providers (HCPs) from 20 EU countries. Responders were mostly metabolic pediatricians; of these, only ~40% have received appropriate training in health issues of adolescent metabolic patients. In most centers (~67%) there is no designated transition coordinator. About 50% of centers provide a written individualized transition protocol, which is standardized in just ~20% of cases. In 77% of centers, pediatricians share a medical summary, transition letter and emergency plan with the adult team and the patient. According to our responders, 11% of patients remain under pediatric care throughout their life. The main challenges identified by HCPs in managing transition are lack of time and shortage of adult metabolic physician positions, while the implementations that are most required for a successful transition include: medical staff dedicated to transition, a transition coordinator, and specific metabolic training for adult physicians. Our study shows that the transition process of IMD patients in Europe is far from standardized and in most cases is inadequate or non-existent. A transition coordinator to facilitate collaboration between the pediatric and adult healthcare teams should be central to any transition program. Standardized operating procedures, together with adequate financial resources and specific training for adult physicians focused on IMDs are the key aspects that must be improved in the rare metabolic field to establish successful transition processes in Europe.
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Affiliation(s)
- Karolina M Stepien
- Adult Inherited Metabolic Diseases, Salford Royal NHS Foundation Trust, Salford, United Kingdom
| | - Beata Kieć-Wilk
- Department of Metabolic Diseases and Diabetes, Krakow University Hospital, Krakow, Poland.,Department of Metabolic Diseases, Medical College, Jagiellonian University, Krakow, Poland
| | - Christina Lampe
- Department of Child Neurology, Center for Rare Diseases Giessen (ZSEGI), Justus-Liebig University, Giessen, Germany
| | - Trine Tangeraas
- Norwegian National Unit for Newborn Screening, Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway
| | - Graziella Cefalo
- Department of Maternal and Child Health, San Paolo Hospital, University of Milan, ASST Santi Paolo e Carlo, Milan, Italy
| | - Nadia Belmatoug
- Referral Center for Lysosomal Diseases, AP-HP Nord, Beaujon Hospital, Paris University, Clichy, France
| | - Rita Francisco
- Portuguese Association for Congenital Disorders of Glycosylation and other Rare Metabolic Diseases, Lisbon, Portugal
| | - Mireia Del Toro
- Pediatric Neurology Department, University Hospital Vall d'Hebron, Universitat Autónoma de Barcelona, Barcelona, Spain
| | - Leona Wagner
- German-Speaking Self-Help Group for Alkaptonuria (DSAKU) e.V., Stuttgart, Germany
| | - Anne-Grethe Lauridsen
- International Gaucher Alliance, Dursley, United Kingdom.,Gaucher Association Denmark, Holbaek, Denmark
| | - Sylvia Sestini
- Italian Association of Patients With Alkaptonuria (aimAKU), Siena, Italy
| | - Nathalie Weinhold
- Metabolic Unit, Interdisciplinary Centre for Metabolism: Endocrinology, Diabetes and Metabolism (UP) and Children's Hospital, Charité University Hospital Berlin, Berlin, Germany
| | - Andreas Hahn
- Department of Child Neurology, Justus-Liebig University, Giessen, Germany
| | - Chiara Montanari
- Department of Maternal and Child Health, San Paolo Hospital, University of Milan, ASST Santi Paolo e Carlo, Milan, Italy
| | - Valentina Rovelli
- Department of Maternal and Child Health, San Paolo Hospital, University of Milan, ASST Santi Paolo e Carlo, Milan, Italy
| | - Cinzia M Bellettato
- MetabERN, Regional Coordinating Center for Rare Diseases, Udine University Hospital, Udine, Italy
| | - Laura Paneghetti
- MetabERN, Regional Coordinating Center for Rare Diseases, Udine University Hospital, Udine, Italy
| | - Corine van Lingen
- MetabERN, Regional Coordinating Center for Rare Diseases, Udine University Hospital, Udine, Italy
| | - Maurizio Scarpa
- MetabERN, Regional Coordinating Center for Rare Diseases, Udine University Hospital, Udine, Italy
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Epidemiology of Mucopolysaccharidoses Update. Diagnostics (Basel) 2021; 11:diagnostics11020273. [PMID: 33578874 PMCID: PMC7916572 DOI: 10.3390/diagnostics11020273] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 02/03/2021] [Accepted: 02/05/2021] [Indexed: 12/26/2022] Open
Abstract
Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by a lysosomal enzyme deficiency or malfunction, which leads to the accumulation of glycosaminoglycans in tissues and organs. If not treated at an early stage, patients have various health problems, affecting their quality of life and life-span. Two therapeutic options for MPS are widely used in practice: enzyme replacement therapy and hematopoietic stem cell transplantation. However, early diagnosis of MPS is crucial, as treatment may be too late to reverse or ameliorate the disease progress. It has been noted that the prevalence of MPS and each subtype varies based on geographic regions and/or ethnic background. Each type of MPS is caused by a wide range of the mutational spectrum, mainly missense mutations. Some mutations were derived from the common founder effect. In the previous study, Khan et al. 2018 have reported the epidemiology of MPS from 22 countries and 16 regions. In this study, we aimed to update the prevalence of MPS across the world. We have collected and investigated 189 publications related to the prevalence of MPS via PubMed as of December 2020. In total, data from 33 countries and 23 regions were compiled and analyzed. Saudi Arabia provided the highest frequency of overall MPS because of regional or consanguineous marriages (or founder effect), followed by Portugal, Brazil, the Netherlands, and Australia. The newborn screening is an efficient and early diagnosis for MPS. MPS I has been approved for newborn screening in the United States. After the newborn screening of MPS I, the frequency of MPS I increased, compared with the past incidence rates. Overall, we conclude that the current identification methods are not enough to recognize all MPS patients, leading to an inaccurate incidence and status. Differences in ethnic background and/or founder effects impact on the frequency of MPS, which affects the prevalence of MPS. Two-tier newborn screening has accelerated early recognition of MPS I, providing an accurate incidence of patients.
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Mucopolysaccharidoses I and II: Brief Review of Therapeutic Options and Supportive/Palliative Therapies. BIOMED RESEARCH INTERNATIONAL 2020; 2020:2408402. [PMID: 33344633 PMCID: PMC7732385 DOI: 10.1155/2020/2408402] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 11/08/2020] [Accepted: 11/21/2020] [Indexed: 12/30/2022]
Abstract
Purpose. Mucopolysaccharidoses (MPS) are group of inherited lysosomal storage diseases caused by mutations of enzymes involved in catalyzing different glycosaminoglycans (GAGs). MPS I and MPS II exhibit both somatic and neurological symptoms with a relatively high disease incidence. Hematopoietic stem cell therapy (HSCT) and intravenous enzyme replacement therapy (ERT) have had a significant impact on the treatment and comprehension of disease. This review is aimed at providing a comprehensive evaluation of the pros and cons of HSCT and ERT, as well as an up-to-date knowledge of new drugs under development. In addition, multiple disease management strategies for the uncontrollable manifestations of MPS I and MPS II to improve patients' quality of life are presented. Findings. Natural history of MPS I and MPS II shows that somatic and neurological symptoms occur earlier in severe forms of MPS I than in MPS II. ERT increases life expectancy and alleviates some of the somatic symptoms, but musculoskeletal, ophthalmological, and central nervous system (CNS) manifestations are not controlled. Additionally, life-long treatment burdens and immunogenicity restriction are unintended consequences of ERT application. HSCT, another treatment method, is effective in controlling the CNS symptoms and hence has been adopted as the standard treatment for severe types of MPS I. However, it is ineffective in MPS II, which can be explained by the relatively late diagnosis. In addition, several factors such as transplant age limits or graft-versus-host disease in HSCT have limited its application for patients. Novel therapies, including BBB-penetrable-ERT, gene therapy, and substrate reduction therapy, are under development to control currently unmanageable manifestations. BBB-penetrable-ERT is being studied comprehensively in the hopes of being used in the near future as a method to effectively control CNS symptoms. Gene therapy has the potential to “cure” the disease with a one-time treatment rather than just alleviate symptoms, which makes it an attractive treatment strategy. Several clinical studies on gene therapy reveal that delivering genes directly into the brain achieves better results than intravenous administration in patients with neurological symptoms. Considering new drugs are still in clinical stage, disease management with close monitoring and supportive/palliative therapy is of great importance for the time being. Proper rehabilitation therapy, including physical and occupational therapy, surgical intervention, or medications, can benefit patients with uncontrolled musculoskeletal, respiratory, ophthalmological, and neurological manifestations.
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Hazan G, Hershkovitz E, Staretz-Chacham O. Incidence of inherited metabolic disorders in southern Israel: a comparison between consanguinity and non-consanguinity communities. Orphanet J Rare Dis 2020; 15:331. [PMID: 33239050 PMCID: PMC7687810 DOI: 10.1186/s13023-020-01578-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 10/13/2020] [Indexed: 11/29/2022] Open
Abstract
Background Inherited metabolic disorders (IMDs) are group of rare monogenic diseases, usually derived from reduced or absent activity in a single metabolic pathway. Most of the IMDs are inherited in an autosomal recessive manner. The incidence of IMDs varies from country to country and within different ethnic groups, but data is still scarce. Consanguinity rate among populations is highly contributor factor for IMDs incidence. There are no reports comparing the incidence of IMD in consanguineous and non-consanguineous populations from the same geographic region with the same diagnostic capabilities. Our study objective is to compare the incidence of IMDs between between the relatively low consanguineous Jewish population and the consanguineous Bedouin population, both living in the southern of Israel. Results During 1990–2017 there were 393,772 live births in the Negev district, of Southern of Israel. Among them 187,049 were of Jewish origin while 206,723 were of Bedouin-Muslim origin. A total of 223 children were diagnosed in this study period with IMDs. Among those 223 children with IMD, 33 were of Jewish origin while the other 190 children were of Bedouin-Muslim origin. The overall incidence for IMDs of the overall Negev population was 56.6/100,000 live birth. The incidence for IMD's among the Bedouin population was significantly higher than among Jewish population. Conclusions IMDs are extremely more common in the consanguineous Bedouin compared with the relatively non-consanguineous Jewish population of Southern Israel. Health policy makers should consider these data and prepare educational and genetic counselling problems accordingly.
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Affiliation(s)
- G Hazan
- Division of Pediatrics, Soroka University Medical Center, Ben Gurion University, Beer Sheva, Israel
| | - E Hershkovitz
- Division of Pediatrics, Soroka University Medical Center, Ben Gurion University, Beer Sheva, Israel.,Metabolic Clinic, Soroka University Medical Center, Ben Gurion University, 151 Rager Ave., Beer Sheva, Israel
| | - O Staretz-Chacham
- Metabolic Clinic, Soroka University Medical Center, Ben Gurion University, 151 Rager Ave., Beer Sheva, Israel. .,Neonatlogy Unit, Soroka University Medical Center, Ben Gurion University, Beer Sheva, Israel.
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