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Summar M. Potential therapeutic uses of L-citrulline beyond genetic urea cycle disorders. J Inherit Metab Dis 2024; 47:1260-1268. [PMID: 39582221 DOI: 10.1002/jimd.12810] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Revised: 10/08/2024] [Accepted: 10/11/2024] [Indexed: 11/26/2024]
Abstract
L-citrulline (referred to hereafter as citrulline), a non-essential amino acid and an intermediate in the urea cycle, is widely recognized for its role in managing genetic urea cycle disorders (UCDs). Recent studies, however, suggest that citrulline's therapeutic potential extends beyond UCDs, particularly in conditions associated with nitric oxide (NO) deficiency, endothelial dysfunction, and oxidative stress. This review explores citrulline's emerging applications in sickle cell disease (SCD), post-operative pulmonary hypertension (PH), hepatic veno-occlusive disease (HVOD), and bronchopulmonary dysplasia (BPD), as well as its speculative use in asthma and acute respiratory distress syndrome (ARDS). In SCD, citrulline may restore NO bioavailability, potentially reducing the incidence and severity of vaso-occlusive crises and preventing complications like pulmonary hypertension. In the context of post-operative PH, citrulline's capacity to enhance NO production can improve pulmonary vascular resistance, decrease right ventricular strain, and reduce the need for mechanical ventilation. Citrulline's protective effects on endothelial function and its ability to mitigate oxidative stress offer promising adjunctive therapy for HVOD, particularly in patients undergoing bone marrow transplantation. In BPD, citrulline could promote alveolar development, reduce inflammation, and improve long-term respiratory outcomes. Despite these promising findings, further research is necessary to determine optimal dosing strategies and to evaluate long-term efficacy and safety. The potential role of citrulline in modulating NO production in conditions like asthma and ARDS also warrants further investigation. This review underscores the versatile therapeutic potential of citrulline and highlights the need for continued research into its applications across various conditions associated with NO deficiency and endothelial dysfunction.
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Yadav R, Seth S, Chowdhary S, Sharma S, Rana S. Uncovering the Tale of a Young Boy with a Husky Voice and an Aversion to Dirt. Indian J Psychol Med 2024:02537176241287808. [PMID: 39564218 PMCID: PMC11572661 DOI: 10.1177/02537176241287808] [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: 11/21/2024] Open
Affiliation(s)
- Ravi Yadav
- Dept. of Psychiatry and Drug De-addiction Centre, Lady Hardinge Medical College & Associated Smt Sucheta Kriplani Hospital, New Delhi, India
| | - Saloni Seth
- Dept. of Psychiatry and Drug De-addiction Centre, Lady Hardinge Medical College & Associated Smt Sucheta Kriplani Hospital, New Delhi, India
| | - Sayoni Chowdhary
- Dept. of Paediatrics, Lady Hardinge Medical College & Associated Kalawati Saran Children's Hospital, New Delhi, India
| | - Suvasini Sharma
- Dept. of Paediatrics (Neurology Division), Lady Hardinge Medical College & Associated Kalawati Saran Children's Hospital, New Delhi, India
| | - Sumit Rana
- Dept. of Psychiatry and Drug De-addiction Centre, Lady Hardinge Medical College & Associated Smt Sucheta Kriplani Hospital, New Delhi, India
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Meier C, Burns K, Manolikos C, Fatovich D, Bell DA. Hyperammonaemia: review of the pathophysiology, aetiology and investigation. Pathology 2024; 56:763-772. [PMID: 39127541 DOI: 10.1016/j.pathol.2024.06.002] [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: 12/07/2023] [Revised: 06/14/2024] [Accepted: 06/18/2024] [Indexed: 08/12/2024]
Abstract
Acute hyperammonaemia is a medical emergency as it can progress to cerebral oedema, seizures, coma and death. Hepatic encephalopathy secondary to cirrhotic disease or portosystemic shunting are relatively well-known causes, but non-cirrhotic aetiologies of acute hyperammonaemia are less well-known, especially in the emergency department. However, an elevated ammonia is not required to make the diagnosis of hepatic encephalopathy. Although measurement of plasma ammonia is recommended for patients with acute, unexplained, altered mental status, as early identification allows early effective management which may prevent irreversible brain damage, there is currently reduced awareness among physicians of the non-cirrhotic aetiologies of acute hyperammonaemia. Furthermore, measurement of ammonia in patients with cirrhosis has been shown to have low sensitivity and specificity, and not to have altered management in the majority of cases; thus, measurement of ammonia is currently not recommended in guidelines for management of hepatic encephalopathy. We sought to describe the pathophysiology of hyperammonaemia and review the non-cirrhotic causes. This was achieved by review of MEDLINE, PubMed and Web of Science databases to include published English literature within the last 20 years. We also present a framework for investigating the acute non-cirrhotic causes of hyperammonaemia to assist both chemical pathologists and clinicians managing these often challenging cases.
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Affiliation(s)
- Ciselle Meier
- The University of Western Australia, Perth, WA, Australia
| | - Kharis Burns
- The University of Western Australia, Perth, WA, Australia; Inborn Errors of Metabolism Service, Department of Endocrinology, Royal Perth Hospital, Perth, WA, Australia
| | - Catherine Manolikos
- Inborn Errors of Metabolism Service, Department of Endocrinology, Royal Perth Hospital, Perth, WA, Australia
| | - Daniel Fatovich
- Centre for Clinical Research in Emergency Medicine, Harry Perkins Institute of Medical Research, Perth, WA, Australia; Emergency Department, Royal Perth Hospital, The University of Western Australia, Perth, WA, Australia
| | - Damon A Bell
- The University of Western Australia, Perth, WA, Australia; Inborn Errors of Metabolism Service, Department of Endocrinology, Royal Perth Hospital, Perth, WA, Australia; PathWest Laboratory Medicine, Department of Biochemistry, Fiona Stanley Hospital Network, Perth, WA, Australia.
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Chanvanichtrakool M, Schreiber JM, Chen WL, Barber J, Zhang A, Ah Mew N, Schulze A, Wilkening G, Nagamani SCS, Gropman A. Unraveling the Link: Seizure Characteristics and Ammonia Levels in Urea Cycle Disorder During Hyperammonemic Crises. Pediatr Neurol 2024; 159:48-55. [PMID: 39121557 PMCID: PMC11381174 DOI: 10.1016/j.pediatrneurol.2024.06.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Revised: 06/02/2024] [Accepted: 06/25/2024] [Indexed: 08/12/2024]
Abstract
BACKGROUND This retrospective clinical study performed at a single clinical center aimed to identify the prevalence of seizures in individuals with urea cycle disorders (UCDs) with and without hyperammonemic (HA) crises. In addition, we sought to correlate the utility of biochemical markers and electroencephalography (EEG) in detecting subclinical seizures during HA. METHODS Medical records of individuals with UCDs enrolled in Urea Cycle Disorders Consortium Longitudinal Study (UCDC-LS) (NCT00237315) at Children's National Hospital between 2006 and 2022 were reviewed for evidence of clinical and subclinical seizuress during HA crises, and initial biochemical levels concurrently. RESULTS Eighty-five individuals with UCD were included in the analyses. Fifty-six of the 85 patients (66%) experienced HA crises, with a total of 163 HA events. Seizures are observed in 13% of HA events. Among all HA events with concomitant EEG, subclinical seizures were identified in 27% of crises of encephalopathy without clinical seizures and 53% of crises with clinical seizures. The odds of seizures increases 2.65 (95% confidence interval [CI], 1.51 to 4.66) times for every 100 μmol/L increase in ammonia and 1.14 (95% CI, 1.04 to 1.25) times for every 100 μmol/L increase in glutamine. CONCLUSIONS This study highlights the utility of EEG monitoring during crises for patients presenting with clinical seizures or encephalopathy with HA. During HA events, measurement of initial ammonia and glutamine can help determine risk for seizures and guide EEG monitoring decisions.
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Affiliation(s)
- Mongkol Chanvanichtrakool
- Faculty of Medicine Siriraj Hospital, Division of Neurology, Department of Pediatrics, Mahidol University, Bangkok, Thailand; Division of Neurogenetics & Developmental Pediatrics, Center for Neuroscience and Behavioral Medicine, Children's National Medical Center, Washington, District of Columbia
| | - John M Schreiber
- Division of Neurogenetics & Developmental Pediatrics, Center for Neuroscience and Behavioral Medicine, Children's National Medical Center, Washington, District of Columbia
| | - Wei-Liang Chen
- Division of Neurogenetics & Developmental Pediatrics, Center for Neuroscience and Behavioral Medicine, Children's National Medical Center, Washington, District of Columbia
| | - John Barber
- Division of Biostatistics and Study Methodology, Children's National Medical Center, Washington, District of Columbia
| | - Anqing Zhang
- Division of Biostatistics and Study Methodology, Children's National Medical Center, Washington, District of Columbia
| | - Nicholas Ah Mew
- Division of Genetics & Metabolism, Children's National Hospital, Washington, District of Columbia
| | - Andreas Schulze
- Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada; Departments of Pediatrics and Biochemistry, University of Toronto, Toronto, Canada
| | - Greta Wilkening
- Department of Pediatrics, Children's Hospital Colorado, University of Colorado, Aurora, Colorado
| | - Sandesh C S Nagamani
- Department of Molecular and Human Genetics, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas
| | - Andrea Gropman
- Division of Neurogenetics & Developmental Pediatrics, Center for Neuroscience and Behavioral Medicine, Children's National Medical Center, Washington, District of Columbia.
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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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Zhang Y, Han Y, Hou S, Gu S, Han W. The correlation between vitamin D3 and arginine metabolism levels in newborns with amino acid metabolism disorders. Medicine (Baltimore) 2024; 103:e37958. [PMID: 38669372 PMCID: PMC11049773 DOI: 10.1097/md.0000000000037958] [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: 02/26/2024] [Accepted: 03/29/2024] [Indexed: 04/28/2024] Open
Abstract
This study aimed to explore the correlation between vitamin D3 and arginine (Arg) metabolism indicators in newborns with amino acid metabolism disorders. Based on clinical data, 30 newborns with amino acid metabolism diseases admitted to Shijiazhuang Fourth Hospital from June 2021 to June 2022 were selected as the disease group, and 30 healthy newborns from the same period were selected as the healthy group. After enrollment, blood samples were collected to measure the levels of Arg, Glycine (Gly), and vitamin D3 levels. The levels of Arg metabolism indicators and vitamin D3 levels in the 2 groups and the correlation between vitamin D3 levels and Arg metabolism indicators in the affected group were analyzed. The Arg level in the diseased group was higher than that in the healthy group, whereas the Gly and vitamin D3 levels were lower than those in the healthy group (P < .05). There was a significant negative correlation between vitamin D3 and Arg levels in the affected group, and a significant positive correlation with Gly levels (P < .05). Newborns with amino acid metabolism disorders have abnormally high Arg levels, significantly reduced Gly levels, and significantly decreased vitamin D3 levels. The degree of decline was closely related to the levels of indicators of Arg metabolism. Vitamin D3 supplementation can improve the Arg metabolism status of newborns with amino acid metabolism disorders.
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Affiliation(s)
- Yao Zhang
- Department of Blood Transfusion, Shijiazhuang Fourth Hospital, Shijiazhuang City, Hebei Province, China
| | - Yanjie Han
- Department of Blood Transfusion, Shijiazhuang Fourth Hospital, Shijiazhuang City, Hebei Province, China
| | - Shikuan Hou
- Department of Blood Transfusion, Shijiazhuang Fourth Hospital, Shijiazhuang City, Hebei Province, China
| | - Suyan Gu
- Department of Blood Transfusion, Shijiazhuang Fourth Hospital, Shijiazhuang City, Hebei Province, China
| | - Wei Han
- Department of Blood Transfusion, Zhengding County People’s Hospital, Shijiazhuang City, Hebei Province, China
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Sosa-Acosta P, Quiñones-Vega M, Guedes JDS, Rocha D, Guida L, Vasconcelos Z, Nogueira FCS, Domont GB. Multiomics Approach Reveals Serum Biomarker Candidates for Congenital Zika Syndrome. J Proteome Res 2024; 23:1200-1220. [PMID: 38390744 DOI: 10.1021/acs.jproteome.3c00677] [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] [Indexed: 02/24/2024]
Abstract
The Zika virus (ZIKV) can be vertically transmitted, causing congenital Zika syndrome (CZS) in fetuses. ZIKV infection in early gestational trimesters increases the chances of developing CZS. This syndrome involves several pathologies with a complex diagnosis. In this work, we aim to identify biological processes and molecular pathways related to CZS and propose a series of putative protein and metabolite biomarkers for CZS prognosis in early pregnancy trimesters. We analyzed serum samples of healthy pregnant women and ZIKV-infected pregnant women bearing nonmicrocephalic and microcephalic fetuses. A total of 1090 proteins and 512 metabolites were identified by bottom-up proteomics and untargeted metabolomics, respectively. Univariate and multivariate statistical approaches were applied to find CZS differentially abundant proteins (DAP) and metabolites (DAM). Enrichment analysis (i.e., biological processes and molecular pathways) of the DAP and the DAM allowed us to identify the ECM organization and proteoglycans, amino acid metabolism, and arachidonic acid metabolism as CZS signatures. Five proteins and four metabolites were selected as CZS biomarker candidates. Serum multiomics analysis led us to propose nine putative biomarkers for CZS prognosis with high sensitivity and specificity.
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Affiliation(s)
- Patricia Sosa-Acosta
- Proteomics Unit, Department of Biochemistry, Institute of Chemistry, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-909, Brazil
- Laboratory of Proteomics (LabProt), LADETEC, Institute of Chemistry, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-598, Brazil
- Precision Medicine Research Center, Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Mauricio Quiñones-Vega
- Proteomics Unit, Department of Biochemistry, Institute of Chemistry, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-909, Brazil
- Laboratory of Proteomics (LabProt), LADETEC, Institute of Chemistry, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-598, Brazil
- Precision Medicine Research Center, Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Jéssica de S Guedes
- Proteomics Unit, Department of Biochemistry, Institute of Chemistry, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-909, Brazil
- Laboratory of Proteomics (LabProt), LADETEC, Institute of Chemistry, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-598, Brazil
- Precision Medicine Research Center, Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Danielle Rocha
- Fernandes Figueira Institute, Fiocruz, Rio de Janeiro 22250-020, Brazil
| | - Letícia Guida
- Fernandes Figueira Institute, Fiocruz, Rio de Janeiro 22250-020, Brazil
| | | | - Fábio C S Nogueira
- Proteomics Unit, Department of Biochemistry, Institute of Chemistry, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-909, Brazil
- Laboratory of Proteomics (LabProt), LADETEC, Institute of Chemistry, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-598, Brazil
- Precision Medicine Research Center, Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Gilberto B Domont
- Proteomics Unit, Department of Biochemistry, Institute of Chemistry, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-909, Brazil
- Precision Medicine Research Center, Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
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Moedas MF, Simões RJM, Silva MFB. Mitochondrial targets in hyperammonemia: Addressing urea cycle function to improve drug therapies. Biochem Pharmacol 2024; 222:116034. [PMID: 38307136 DOI: 10.1016/j.bcp.2024.116034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 12/27/2023] [Accepted: 01/25/2024] [Indexed: 02/04/2024]
Abstract
The urea cycle (UC) is a critically important metabolic process for the disposal of nitrogen (ammonia) produced by amino acids catabolism. The impairment of this liver-specific pathway induced either by primary genetic defects or by secondary causes, namely those associated with hepatic disease or drug administration, may result in serious clinical consequences. Urea cycle disorders (UCD) and certain organic acidurias are the major groups of inherited rare diseases manifested with hyperammonemia (HA) with UC dysregulation. Importantly, several commonly prescribed drugs, including antiepileptics in monotherapy or polytherapy from carbamazepine to valproic acid or specific antineoplastic agents such as asparaginase or 5-fluorouracil may be associated with HA by mechanisms not fully elucidated. HA, disclosing an imbalance between ammoniagenesis and ammonia disposal via the UC, can evolve to encephalopathy which may lead to significant morbidity and central nervous system damage. This review will focus on biochemical mechanisms related with HA emphasizing some poorly understood perspectives behind the disruption of the UC and mitochondrial energy metabolism, namely: i) changes in acetyl-CoA or NAD+ levels in subcellular compartments; ii) post-translational modifications of key UC-related enzymes, namely acetylation, potentially affecting their catalytic activity; iii) the mitochondrial sirtuins-mediated role in ureagenesis. Moreover, the main UCD associated with HA will be summarized to highlight the relevance of investigating possible genetic mutations to account for unexpected HA during certain pharmacological therapies. The ammonia-induced effects should be avoided or overcome as part of safer therapeutic strategies to protect patients under treatment with drugs that may be potentially associated with HA.
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Affiliation(s)
- Marco F Moedas
- Research Institute for Medicines-iMed.ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal; Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Ricardo J M Simões
- Research Institute for Medicines-iMed.ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal
| | - Margarida F B Silva
- Research Institute for Medicines-iMed.ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
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Rojas CR, Chapman J, Regier D. Hyperammonemia in the Pediatric Emergency Department. Pediatr Emerg Care 2024; 40:156-161. [PMID: 38295195 DOI: 10.1097/pec.0000000000003121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2024]
Abstract
ABSTRACT Hyperammonemia is a serious clinical condition associated with significant morbidity and mortality. In the pediatric population, this is often caused by urea cycle disorders, acute liver failure, or other less common underlying etiologies. Children and teens with hyperammonemia can have a broad range of clinical findings, including vomiting, respiratory distress, and changes in mental status. As ammonia levels worsen, this presentation can progress to respiratory failure, encephalopathy, cerebral edema, seizures, and death. Given the risk of neurologic damage, timely identification and management of hyperammonemia is critical and includes initial resuscitation, early consultation with subspecialists, and initiation of appropriate therapies. It is important for pediatric emergency medicine providers to understand the clinical findings, causes, diagnosis, and management of hyperammonemia because they play a key role in the provision of effective, multidisciplinary care of these patients.
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Edelblut J, Skaar JR, Hilton J, Seibt M, Martin K, Hadker N, Quartel A, Steiner RD. Quantifying preferences for urea cycle disorder treatments using a discrete choice experiment. J Med Econ 2024; 27:506-517. [PMID: 38491962 DOI: 10.1080/13696998.2024.2330846] [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: 01/23/2024] [Accepted: 03/12/2024] [Indexed: 03/18/2024]
Abstract
AIMS Urea cycle disorders (UCDs) can cause ammonia accumulation and central nervous system toxicity. Nitrogen-binding medications can be efficacious, but certain attributes may negatively impact adherence. This study sought to quantify the administration-related attributes influencing overall prescription selection and patient adherence. METHODS A web-based, quantitative survey including discrete choice experiment (DCE) methodology captured responses from health care providers for patients with UCDs. A series of hypothetical treatment profile sets with attributes such as route of administration, taste/odor, preparation instructions, packaging, dose measurement, and weight use restrictions were presented. From 16 sets of 3 hypothetical product profiles, respondents evaluated attributes most preferred for prescription selection or patient adherence. Attributes assumed a higher overall preference if relative importance (RI) scores were >16.67% (the value if all attributes were of equal importance). Preference weight scores were assessed. A nine-point Likert scale assessed respondent attitudes, such as satisfaction. RESULTS A total of 51 respondents completed the survey. Respondents reported dissatisfaction with current treatments (mean [SD] = 5.4 [1.7]). For prescription selection, four attributes achieved RI >16.67%: taste/odor (24%), weight restrictions (21%), preparation instructions (18%), and route of administration (17%). For adherence, three attributes related to administration achieved RI >16.67%: taste/odor (28%), preparation instructions (21%), and route of administration (17%). Preference weights for "taste/odor masked" were higher than "not taste/odor masked" for prescription selection (mean [SD]; 1.52 [1.10] vs -1.52 [1.10]) and treatment adherence (73.8 [55.2] vs -73.8 [55.2]). LIMITATIONS This study contained a relatively small sample size. Survey respondent selection, the use of hypothetical product profiles, and exclusion of non-pharmacologic treatment options could have contributed to potential biases. CONCLUSIONS Among attributes tested, taste/odor was the most important attribute influencing overall preference for both prescribing and patient adherence, with taste/odor masking preferred. Optimizing nitrogen-binding medications through masking taste/odor may support improved patient adherence and outcomes in UCDs.
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Affiliation(s)
| | | | - John Hilton
- Acer Therapeutics, Newton, MA, USA, a wholly owned subsidiary of Zevra Therapeutics
| | - Matthew Seibt
- Acer Therapeutics, Newton, MA, USA, a wholly owned subsidiary of Zevra Therapeutics
| | | | | | - Adrian Quartel
- Acer Therapeutics, Newton, MA, USA, a wholly owned subsidiary of Zevra Therapeutics
| | - Robert D Steiner
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
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11
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Pappas KB. Newborn Screening. Pediatr Clin North Am 2023; 70:1013-1027. [PMID: 37704344 DOI: 10.1016/j.pcl.2023.06.003] [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] [Indexed: 09/15/2023]
Abstract
The goal of newborn screening is to identify medical conditions that can cause significant morbidity and/or mortality if not treated early in life. Pediatricians often play a vital role in the initial disclosure of newborn screening results and coordination of confirmatory testing, treatment, and referral to specialty care. The goal of this article is to provide an overview of current newborn screening in the United States, focusing on the various disorders, their manifestations, the newborn screening process, the confirmatory testing, and treatments. Some practical considerations will be discussed as well.
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Affiliation(s)
- Kara B Pappas
- Division of Genetics, Genomics and Metabolic Disorders, Children's Hospital of Michigan, Detroit, MI, USA; Department of Pediatrics, Central Michigan University, Mount Pleasant, MI, USA.
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12
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Forsyth R, Peretz RH, Dempsey A, Britton J, Kratz L, Hamosh A, Vernon H, Batshaw ML, Valle D. The remarkable journey of one female individual with ornithine transcarbamylase deficiency diagnosed post-mortem. JIMD Rep 2023; 64:233-237. [PMID: 37151362 PMCID: PMC10159862 DOI: 10.1002/jmd2.12361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 01/12/2023] [Accepted: 01/16/2023] [Indexed: 01/31/2023] Open
Abstract
Urea cycle disorders (UCDs) comprise a group of inborn errors of metabolism with impaired ammonia clearance and an incidence of ~1:35 000 individuals. First described in the 1970s, the diagnosis and management of these disorders has evolved dramatically. We report on a 59-year-old woman with a UCD who contributed to advances in the understanding and treatment of this group of disorders. This individual was diagnosed with carbamoyl phosphate synthetase 1 deficiency based on a biochemical assay under a research context predating genetic sequencing, treated longitudinally as having this metabolic disorder, and was among the first participants to trial UCD pharmaceutical therapies. She ultimately succumbed to a SARS-CoV-2 infection while maintaining unexpectedly normal ammonium levels. Postmortem genetic testing revealed ornithine transcarbamylase deficiency. This individual's contributions to the field of UCDs is discussed herein.
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Affiliation(s)
- RaeLynn Forsyth
- Department of Genetic MedicineJohns Hopkins University School of MedicineBaltimoreMarylandUSA
| | - Ryan H. Peretz
- National Human Genome Research InstituteNational Institutes of HealthBethesdaMarylandUSA
| | - Angela Dempsey
- Department of Genetic MedicineJohns Hopkins University School of MedicineBaltimoreMarylandUSA
| | - Jacquelyn Britton
- Department of Genetic MedicineJohns Hopkins University School of MedicineBaltimoreMarylandUSA
| | - Lisa Kratz
- Biochemical Genetics LaboratoryKennedy Krieger InstituteBaltimoreMarylandUSA
| | - Ada Hamosh
- Department of Genetic MedicineJohns Hopkins University School of MedicineBaltimoreMarylandUSA
| | - Hilary Vernon
- Department of Genetic MedicineJohns Hopkins University School of MedicineBaltimoreMarylandUSA
| | - Mark L. Batshaw
- Center for Genetic Medicine ResearchChildren's National HospitalWashingtonDCUSA
| | - David Valle
- Department of Genetic MedicineJohns Hopkins University School of MedicineBaltimoreMarylandUSA
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Zarante Bahamón AM, Navarro Marroquin S, Suarez-Obando F, Ramón Gómez JL. Recomendaciones de manejo de la hiperamonemia en neonatos. UNIVERSITAS MÉDICA 2023. [DOI: 10.11144/javeriana.umed63-4.rmhn] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
La hiperamonemia se define como el aumento de las concentraciones de amonio en el plasma, de forma aguda o crónica. Frecuentemente, se presenta en diversos tipos de errores innatos del metabolismo, enfermedades que deben diagnosticarse y manejarse de manera inmediata y adecuada, debido a que el retraso en su manejo genera secuelas neurológicas graves y permanentes, así como desenlaces fatales. El objetivo del artículo es aportar herramientas al clínico para la sospecha, el abordaje diagnóstico y el manejo del recién nacido con hiperamonemia primaria, teniendo en cuenta la correlación entre fisiopatología, etiología, aproximación clínica y de laboratorio, así como recomendaciones de manejo farmacológico y no farmacológico.
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14
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Grazioli A, Podell JE, Iacono A, Krupnik AS, Madathil RJ, Shah SR. Treatment of hyperammonemia using in-line renal replacement and hyperosmolar therapies within an extracorporeal membrane oxygenation circuit. Perfusion 2023; 38:193-196. [PMID: 34320858 DOI: 10.1177/02676591211035939] [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] [Indexed: 01/24/2023]
Abstract
After orthotopic lung transplantation, hyperammonemia can be a rare complication secondary to infection by organisms that produce urease or inhibit the urea cycle. This can cause neurotoxicity, cerebral edema, and seizures. Ammonia is unique in that it has a large volume of distribution. However, it is also readily dialyzable given its small molecular weight. As such, removal of ammonia requires renal replacement modalities that can both rapidly remove ammonia from the plasma space and allow for continuous removal to prevent rebound accumulation from intracellular stores. Prevention of iatrogenic osmotic lowering in this setting is required to prevent worsening of cerebral edema. Herein, we describe use of sequential in-line renal replacement therapy using both intermittent hemodialysis and continuous venovenous hemofiltration within an extracorporeal membrane oxygenation circuit in conjunction with higher sodium dialysate and 7.5% hypertonic saline to achieve these treatment goals.
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Affiliation(s)
- Alison Grazioli
- Department of Medicine, R Adams Cowley Shock Trauma Center, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Jamie E Podell
- Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Aldo Iacono
- Department of Medicine and Surgery, R Adams Cowley Shock Trauma Center, University of Maryland School of Medicine, Baltimore, MD, USA
| | | | - Ronson J Madathil
- Division of Cardiac Surgery, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Sanjeev R Shah
- Division of Renal Electrolyte and Hypertension, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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15
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Ni B, Qin M, Zhao J, Guo Q. A glance at transient hyperammonemia of the newborn: Pathophysiology, diagnosis, and treatment: A review. Medicine (Baltimore) 2022; 101:e31796. [PMID: 36482558 PMCID: PMC9726343 DOI: 10.1097/md.0000000000031796] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Hyperammonemia is the excessive accumulation of ammonia in the blood, and is usually defined as a plasma level above 100 µmol/L in neonates or above 50 µmol/L in term infants, children, and adolescents. Patients with hyperammonemia usually experience life-threatening neuropsychiatric symptoms, especially newborns. It is routinely caused by inherited metabolic diseases and also by acquired disorders, such as liver failure, portosystemic shunting, gastrointestinal hemorrhage, ureterosigmoidostomy, renal tubular acidosis, hypoxic ischemic encephalopathy, infections with urea-metabolizing organisms, and some drugs. Transient hyperammonemia of the newborn (THAN) is a special type of hyperammonemia acknowledged in the field of metabolic disease as an inwell-defined or well-understood entity, which can be diagnosed only after the exclusion of genetic and acquired causes of hyperammonemia. Although the prognosis for THAN is good, timely identification and treatment are essential. Currently, THAN is underdiagnosed and much less is mentioned for early diagnosis and vigorous treatment. Herein, we present common themes that emerge from the pathogenesis, diagnosis, and management of THAN, based on current evidence. When a newborn presents with sepsis, intracranial hemorrhage, or asphyxia that cannot explain coma and seizures, doctors should always keep this disease in mind.
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Affiliation(s)
- Beibei Ni
- Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Miao Qin
- Department of Neonatology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jun Zhao
- Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Qie Guo
- Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, China
- * Correspondence: Qie Guo, Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao, Shandong 266003, China (e-mail: )
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16
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Novel compound heterozygote variants: c.4193_4206delinsG (p.Leu1398Argfs*25), c.793C > A (p.Pro265Thr), in the CPS1 gene (NM_001875.4) causing late onset carbamoyl phosphate synthetase 1 deficiency—Lessons learned. Mol Genet Metab Rep 2022; 33:100942. [DOI: 10.1016/j.ymgmr.2022.100942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Revised: 11/17/2022] [Accepted: 11/18/2022] [Indexed: 11/27/2022] Open
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17
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Bazo A, Lantero A, Mauleón I, Neri L, Poms M, Häberle J, Ricobaraza A, Bénichou B, Combal JP, Gonzalez-Aseguinolaza G, Aldabe R. Gene Therapy in Combination with Nitrogen Scavenger Pretreatment Corrects Biochemical and Behavioral Abnormalities of Infant Citrullinemia Type 1 Mice. Int J Mol Sci 2022; 23:14940. [PMID: 36499263 PMCID: PMC9736988 DOI: 10.3390/ijms232314940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 11/22/2022] [Accepted: 11/23/2022] [Indexed: 12/02/2022] Open
Abstract
Citrullinemia type I (CTLN1) is a rare autosomal recessive disorder caused by mutations in the gene encoding argininosuccinate synthetase 1 (ASS1) that catalyzes the third step of the urea cycle. CTLN1 patients suffer from impaired elimination of nitrogen, which leads to neurotoxic levels of circulating ammonia and urea cycle byproducts that may cause severe metabolic encephalopathy, death or irreversible brain damage. Standard of care (SOC) of CTLN1 consists of daily nitrogen-scavenger administration, but patients remain at risk of life-threatening decompensations. We evaluated the therapeutic efficacy of a recombinant adeno-associated viral vector carrying the ASS1 gene under the control of a liver-specific promoter (VTX-804). When administered to three-week-old CTLN1 mice, all the animals receiving VTX-804 in combination with SOC gained body weight normally, presented with a normalization of ammonia and reduction of citrulline levels in circulation, and 100% survived for 7 months. Similar to what has been observed in CTLN1 patients, CTLN1 mice showed several behavioral abnormalities such as anxiety, reduced welfare and impairment of innate behavior. Importantly, all clinical alterations were notably improved after treatment with VTX-804. This study demonstrates the potential of VTX-804 gene therapy for future clinical translation to CTLN1 patients.
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Affiliation(s)
- Andrea Bazo
- Division of Gene Therapy and Regulation of Gene Expression, CIMA, University of Navarra, 31008 Pamplona, Spain
| | | | - Itsaso Mauleón
- Division of Gene Therapy and Regulation of Gene Expression, CIMA, University of Navarra, 31008 Pamplona, Spain
| | - Leire Neri
- Vivet Therapeutics, S.L., 31008 Pamplona, Spain
| | - Martin Poms
- Department of Clinical Chemistry and Biochemistry, University Children’s Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland
| | - Johannes Häberle
- Division of Metabolism, Children’s Research Centre (CRC), University Children’s Hospital Zurich, 8091 Zurich, Switzerland
| | - Ana Ricobaraza
- Division of Gene Therapy and Regulation of Gene Expression, CIMA, University of Navarra, 31008 Pamplona, Spain
| | | | | | - Gloria Gonzalez-Aseguinolaza
- Division of Gene Therapy and Regulation of Gene Expression, CIMA, University of Navarra, 31008 Pamplona, Spain
- Vivet Therapeutics, S.L., 31008 Pamplona, Spain
| | - Rafael Aldabe
- Division of Gene Therapy and Regulation of Gene Expression, CIMA, University of Navarra, 31008 Pamplona, Spain
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18
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Ribas GS, Lopes FF, Deon M, Vargas CR. Hyperammonemia in Inherited Metabolic Diseases. Cell Mol Neurobiol 2022; 42:2593-2610. [PMID: 34665389 PMCID: PMC11421644 DOI: 10.1007/s10571-021-01156-6] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 10/10/2021] [Indexed: 12/13/2022]
Abstract
Ammonia is a neurotoxic compound which is detoxified through liver enzymes from urea cycle. Several inherited or acquired conditions can elevate ammonia concentrations in blood, causing severe damage to the central nervous system due to the toxic effects exerted by ammonia on the astrocytes. Therefore, hyperammonemic patients present potentially life-threatening neuropsychiatric symptoms, whose severity is related with the hyperammonemia magnitude and duration, as well as the brain maturation stage. Inherited metabolic diseases caused by enzymatic defects that compromise directly or indirectly the urea cycle activity are the main cause of hyperammonemia in the neonatal period. These diseases are mainly represented by the congenital defects of urea cycle, classical organic acidurias, and the defects of mitochondrial fatty acids oxidation, with hyperammonemia being more severe and frequent in the first two groups mentioned. An effective and rapid treatment of hyperammonemia is crucial to prevent irreversible neurological damage and it depends on the understanding of the pathophysiology of the diseases, as well as of the available therapeutic approaches. In this review, the mechanisms underlying the hyperammonemia and neurological dysfunction in urea cycle disorders, organic acidurias, and fatty acids oxidation defects, as well as the therapeutic strategies for the ammonia control will be discussed.
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Affiliation(s)
- Graziela Schmitt Ribas
- Departamento de Análises Clínicas, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
- Serviço de Genética Médica, Hospital de Clíınicas de Porto Alegre, Ramiro Barcelos, 2350, Porto Alegre, RS, CEP 90035-003, Brazil.
| | - Franciele Fátima Lopes
- Serviço de Genética Médica, Hospital de Clíınicas de Porto Alegre, Ramiro Barcelos, 2350, Porto Alegre, RS, CEP 90035-003, Brazil
| | - Marion Deon
- Serviço de Genética Médica, Hospital de Clíınicas de Porto Alegre, Ramiro Barcelos, 2350, Porto Alegre, RS, CEP 90035-003, Brazil
| | - Carmen Regla Vargas
- Departamento de Análises Clínicas, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
- Serviço de Genética Médica, Hospital de Clíınicas de Porto Alegre, Ramiro Barcelos, 2350, Porto Alegre, RS, CEP 90035-003, Brazil.
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Jin X, Zeng X, Zhao D, Jiang N. Liver transplantation in rare late-onset ornithine transcarbamylase deficiency with central nervous system injury: A case report and review of the literature. Brain Behav 2022; 12:e2765. [PMID: 36128655 PMCID: PMC9575608 DOI: 10.1002/brb3.2765] [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: 04/20/2022] [Revised: 07/29/2022] [Accepted: 08/28/2022] [Indexed: 11/11/2022] Open
Abstract
BACKGROUND Ornithine transcarbamylase deficiency (OTCD) is a genetic metabolic disease. Its clinical manifestations are mainly central nervous system dysfunction caused by high blood ammonia. Late-onset OTCD combined with central nervous system injury has a poor therapeutic response, which is one of the main factors affecting the prognosis and quality of life of patients. liver transplantation (LT) has gradually become a radical treatment for OTCD, which has achieved good results. However, there is no consensus on the timing of LT and problems of nervous system damage and repair. METHODS We report the development of late-onset OTCD with central nervous system injury in an 11-year-old child who received liver transplantation at our transplant center. His first symptoms were nonprojectile vomiting, followed by irritability and disturbance of consciousness, after which the disease progressed rapidly and finally resulted in a coma. After liver transplantation, the child's consciousness returned to normal, muscle strength of the limbs gradually recovered from grade 0 to grade 4, and muscle tone gradually recovered from grade 4 to grade 1, suggesting that the motor nerves had gradually recovered. However, the child is currently mentally retarded, and the language center has not yet fully recovered.At the same time, we made a literature review of OTCD. CONCLUSION For OTCD patients with central nervous system injury, liver transplantation can fundamentally solve the problem of ammonia metabolism in the liver and avoids further damage to the central nervous system caused by hyperammonemia. At the same time, children's nervous systems are in the developmental stage when neuroplasticity is greatest. If liver transplantation is performed as soon as possible, nerve repair is still possible.
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Affiliation(s)
- Xin Jin
- Division of Liver Surgery and Organ Transplantation Center, Shenzhen Third People's Hospital, Second Affiliated Hospital of Southern University of Science and Technology, National Clinical Research Center for Infectious Disease, Shenzhen, China
| | - Xinchen Zeng
- Division of Liver Surgery and Organ Transplantation Center, Shenzhen Third People's Hospital, Second Affiliated Hospital of Southern University of Science and Technology, National Clinical Research Center for Infectious Disease, Shenzhen, China
| | - Dong Zhao
- Division of Liver Surgery and Organ Transplantation Center, Shenzhen Third People's Hospital, Second Affiliated Hospital of Southern University of Science and Technology, National Clinical Research Center for Infectious Disease, Shenzhen, China
| | - Nan Jiang
- Division of Liver Surgery and Organ Transplantation Center, Shenzhen Third People's Hospital, Second Affiliated Hospital of Southern University of Science and Technology, National Clinical Research Center for Infectious Disease, Shenzhen, China
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Fátima Lopes F, Sitta A, de Moura Coelho D, Schmitt Ribas G, Lamberty Faverzani J, Gomes Dos Reis B, Wajner M, Vargas CR. Clinical findings of patients with hyperammonemia affected by urea cycle disorders with hepatic encephalopathy. Int J Dev Neurosci 2022; 82:772-788. [PMID: 36129623 DOI: 10.1002/jdn.10229] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 08/21/2022] [Accepted: 09/15/2022] [Indexed: 11/10/2022] Open
Abstract
Urea Cycle Disorders (UCD) are a group of genetic diseases caused by deficiencies in the enzymes and transporters involved in the urea cycle. The impairment of the cycle results in ammonia accumulation, leading to neurological dysfunctions and poor outcomes to affected patients. The aim of this study is to investigate and describe UCD patients principal clinical and biochemical presentations to support professionals on urgent diagnosis and quick management, aiming better outcomes for patients. We explored medical records of thirty patients diagnosed in a referral center from Brazil to delineate UCD clinical and biochemical profile. Patients demonstrated a range of signs and symptoms, such as altered levels of consciousness, acute encephalopathy, seizures, progressive loss of appetite, vomiting, coma, and respiratory distress, in most cases combined with high levels of ammonia, which is an immediate biomarker, leading to an UCD suspicion. The most prevalent UCD detected were ornithine transcarbamylase deficiency (11), followed by citrullinemia type I (10), hyperargininemia (5), carbamoyl phosphate synthase 1 deficiency (2) and argininosuccinic aciduria (2). Clinical symptoms were highly severe, being the majority developmental and neurological disabilities, with 20% of death rate. Laboratory analysis revealed high levels of ammonia (mean ± SD: 860 ± 470 μmol/L; reference value: ≤ 80 μmol/L), hypoglycemia, metabolic acidosis, and high excretion of orotic acid in the urine (except in CPS1 deficiency). We emphasize the need of urgent identification of UCD clinical and biochemical conditions, and immediate measurement of ammonia, to enable the correct diagnosis and increase the chances of patients survival, minimizing neurological and psychomotor damage caused by hepatic encephalopathy.
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Affiliation(s)
- Franciele Fátima Lopes
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.,Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - Angela Sitta
- Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | | | | | - Jéssica Lamberty Faverzani
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Bianca Gomes Dos Reis
- Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - Moacir Wajner
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.,Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - Carmen Regla Vargas
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.,Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
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21
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A complex case of delayed diagnosis of ornithine transcarbamylase deficiency in an adult patient with multiple comorbidities. Mol Genet Metab Rep 2022; 33:100916. [PMID: 36620385 PMCID: PMC9817481 DOI: 10.1016/j.ymgmr.2022.100916] [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: 05/13/2022] [Revised: 09/01/2022] [Accepted: 09/02/2022] [Indexed: 01/11/2023] Open
Abstract
We report the case of a medically complex African American adult female with ornithine transcarbamylase (OTC) deficiency diagnosed after lifelong protein aversion and new onset of chronic vomiting and abdominal pain with intermittent lethargy and confusion. Symptomatology was crucial to diagnosis as genetic testing did not identify any pathogenic variants in OTC; however, the patient's diagnosis was delayed despite her having longstanding symptoms of a urea cycle disorder (UCD). Her symptoms improved after treatment with a modified protein-restricted diet, long-term nitrogen-scavenger therapy, and supplemental L-citrulline. Adherence to her UCD management regimen remained a challenge due to her underlying frailty and other medical conditions, which included primary renal impairment (further exasperated by type 2 diabetes mellitus) and decreased left-ventricular function. She passed away 3 years after her OTC deficiency diagnosis due to complications of congestive heart failure. Her OTC deficiency did not have a major impact on her final illness, and appropriate OTC deficiency management was provided until the decision was made to withdraw medical care.
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Key Words
- ALT, alanine aminotransferase
- AST, aspartate aminotransferase
- CT, computed tomography
- Comorbid conditions
- D20W, dextrose 20% in water
- ED, emergency department
- GPB, glycerol phenylbutyrate
- Hepatic encephalopathy
- IBW, ideal body weight
- IV, intravenous
- Late onset
- NAFLD, nonalcoholic fatty liver disease
- NG, nasogastric
- OTC, ornithine transcarbamylase
- Ornithine transcarbamylase deficiency
- UCD, urea cycle disorder
- Urea cycle disorder
- X-linked inheritance
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22
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Feigenbaum A, Lamale-Smith L, Weinstein L. Considerations for prenatal and postpartum management of a female patient with ornithine transcarbamylase deficiency. Mol Genet Metab Rep 2022; 33:100894. [PMID: 36620386 PMCID: PMC9817480 DOI: 10.1016/j.ymgmr.2022.100894] [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: 05/13/2022] [Revised: 06/27/2022] [Accepted: 06/27/2022] [Indexed: 01/11/2023] Open
Abstract
We report on pregnancy management and outcomes in a 27-year-old female patient with ornithine transcarbamylase (OTC) deficiency, the most common inherited enzyme deficiency in the urea cycle. Our patient was diagnosed during childhood after hyperammonemia associated with surgery and steroid treatment and was well-controlled with nitrogen scavenger treatment, low-protein diet, and L-citrulline supplementation. OTC gene sequencing identified a variant of unknown significance that has more recently been classified as likely pathogenic. Women with OTC deficiency are at increased risk of hyperammonemia during pregnancy and the postpartum period, therefore monthly follow up and laboratory assessments are critical in management decision making. Our patient was maintained on glycerol phenylbutyrate, L-citrulline and essential amino acid supplements, along with restricted protein intake during pregnancy. A multidisciplinary approach with the obstetrics, prenatal genetics, high risk obstetric, and anesthesia teams was also necessary for optimal management during pregnancy, throughout labor and delivery, and during the postpartum period. After successful childbirth and discharge, our patient experienced a hyperammonemic crisis related to poor enteral nutrition, and acute management protocols were implemented to stabilize her. For her newborn son, acute hyperammonemia protocols were on standby, and newborn screening and laboratory testing were expedited to assess his risk. He was healthy and did not experience symptoms of concern. In this case report, we emphasize the importance of close collaboration with maternal-fetal medicine team members during and immediately after pregnancy to ensure successful management of a female patient with OTC deficiency and her newborn.
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Key Words
- BCAA, branched-chain amino acids
- BID, twice daily
- D10, 10% dextrose
- EAA, essential amino acids
- GPB, glycerol phenylbutyrate
- IV, intravenous
- NICU, neonatal intensive care unit
- OTC, ornithine transcarbamylase
- Ornithine transcarbamylase deficiency
- PICC, peripherally inserted central catheter
- PO, per os/orally
- Peripartum management
- Pregnancy
- TID, three times daily
- UCD, urea cycle disorder
- Urea cycle disorder
- X-linked, hyperammonemia
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Affiliation(s)
- Annette Feigenbaum
- Department of Pediatrics and Biochemical Genetics, Rady Children's Hospital-San Diego, University of California San Diego, 3020 Children's Way #5031, San Diego, CA 92123, USA
- Corresponding author at: 3020 Children's Way #5031, San Diego, CA 92123, USA.
| | - Leah Lamale-Smith
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California San Diego, 9300 Campus Point Drive, #7433, San Diego, CA 92037, USA
| | - Lawrence Weinstein
- Department of Anesthesiology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
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23
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Benefits of tailored disease management in improving tremor, white matter hyperintensities, and liver enzymes in a child with heterozygous X-linked ornithine transcarbamylase deficiency. Mol Genet Metab Rep 2022; 33:100891. [PMID: 36620387 PMCID: PMC9817482 DOI: 10.1016/j.ymgmr.2022.100891] [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: 05/13/2022] [Revised: 06/23/2022] [Accepted: 06/24/2022] [Indexed: 01/11/2023] Open
Abstract
We report the case of a 19-month-old girl with late-onset ornithine transcarbamylase (OTC) deficiency initially referred to gastroenterology for intermittent vomiting lasting a year and abnormal liver enzymes (AST 730 U/L [reference range 26-55 U/L]; ALT 1213 U/L [reference range 11-30 U/L]) without hepatomegaly. While the patient was hospitalized for liver biopsy, intermittent tremors of the upper extremities with varying severity were noted. The patient was presumed to have hyperammonemia secondary to acute liver failure and was discharged after 5 days; follow-up monitoring led to readmission 7 days later. A brain MRI showed nonspecific bilateral pericallosal and bifrontal white matter FLAIR hyperintensities. These findings raised suspicion for a metabolic disease and prompted a genetics consultation. After inconclusive biochemical testing and worsening clinical status, rapid whole genome sequencing results were obtained identifying a novel, de novo, likely pathogenic, variant c.608C > T (p.Ser203Phe) in the OTC gene. The patient was promptly started on an oral nitrogen scavenger, citrulline supplementation, and protein restriction. Ammonia and glutamine levels normalized within 1 month of treatment and have stayed within the goal ranges with continued tailoring of treatment. Her parents noted resolution of vomiting and improved mood stability. Liver enzymes normalized after 2 months of treatment. The tremor, identified as asterixis, improved and a repeat brain MRI 3 months after the initial imaging showed near-complete resolution of previous white matter hyperintensities.
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Key Words
- ALT, alanine transaminase
- AST, aspartate aminotransferase
- Asterixis
- BASC-3, Behavior Assessment System for Children
- BCAA, branched-chain amino acid
- FLAIR, fluid-attenuated inversion recovery
- GGT, gamma-glutamyl transferase
- Late onset
- MRI, magnetic resonance imaging
- MRS, magnetic resonance spectroscopy
- Manifesting heterozygote
- OTC, ornithine transcarbamylase
- Ornithine transcarbamylase deficiency
- PT, prothrombin time
- Partial onset
- TID, 3 times a day
- UCD, urea cycle disorder
- Urea cycle disorder
- WPPSI-IV, Wechsler Preschool and Primary Scale of Intelligence
- X linked
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24
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Squires JE, Horslen SP. CAQ Corner: Genetic liver disease. Liver Transpl 2022; 28:1231-1244. [PMID: 35377526 DOI: 10.1002/lt.26467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 02/25/2022] [Accepted: 03/01/2022] [Indexed: 01/13/2023]
Affiliation(s)
- James E Squires
- Division of Gastroenterology, Hepatology and Nutrition, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Simon P Horslen
- Division of Gastroenterology, Hepatology and Nutrition, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
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25
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Chen Z, Wu S, Zeng Y, Chen Z, Li X, Li J, He L, Chen M. FuZhengHuaYuJiangZhuTongLuoFang Prescription Modulates Gut Microbiota and Gut-Derived Metabolites in UUO Rats. Front Cell Infect Microbiol 2022; 12:837205. [PMID: 35669118 PMCID: PMC9165620 DOI: 10.3389/fcimb.2022.837205] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 04/14/2022] [Indexed: 12/14/2022] Open
Abstract
Background Alteration of intestinal flora and metabolites is closely related to chronic kidney disease (CKD) across early to advanced stages. FuZhengHuaYuJiangZhuTongLuoFang prescription (FZHY) is a Chinese herb that has been proven to effectively treat CKD, but the underlying mechanism is not clear. Methods Rats were subjected to intragastric treatment with FZHY 7, 14, and 21 days after unilateral ureteral obstruction (UUO) surgery, and kidney tissue, colon tissue, serum, and stool samples were collected. Results FZHY treatment effectively ameliorated UUO-induced renal function loss, renal injury and renal fibrosis, and colon tissue damage and fibrosis on day 7. The results of 16S flora analysis (day 7) showed that, compared with the UUO group, both the FZHY group and the sham group showed decreased levels of g_Monoglobus, g_Papillibacter, g_Eubacterium_nodatum, and g_Family_XIII_AD3011. Additionally, FZHY obviously induced the reduction of serum citrulline, glycoursodeoxycholic acid, 23-nordeoxycholic acid, 7-ketodeoxycholic acid, kahweol, lipoid B4, 4-(3,4-dihydro-2H-1,5-benzodioxepin-7-yl)-2-methyl-1,3-thiazole, taurolithocholic acid sodium salt, indoline-2-carboxylic acid, 5(S),15(S)-diHETE, and others and the increase of bilirubin, asparagine, and others, which were positively associated with the above four candidate bacteria. Moreover, FZHY increased the levels of ZO-1, occludin, and claudin-1 in the colonic mucosa and reduced the levels of CRP, TNF-α, IL-6, and IL-1 in the serum and LN, FN, Col-I, and Col-III in the tubulointerstitium of UUO rats on day 7. Conclusion Our study revealed that FZHY reduced kidney damage at the early stage of CKD by regulating the above four candidate bacteria biomarkers and gut-derived harmful metabolites, inhibiting the inflammation response and tubulointerstitial fibrosis, providing deep insight into CKD therapeutic strategy.
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Affiliation(s)
- Ziwei Chen
- Department of Nephrology, Affiliated Integrated Traditional Chinese Medicine (TCM) and Western Medicine Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu Integrated Traditional Chinese Medicine (TCM) and Western Medicine Hospital, Chengdu First People's Hospital, Chengdu, China
| | - Shaobo Wu
- Department of Nephrology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yu Zeng
- Department of Clinical Laboratory, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zejun Chen
- Department of Nephrology, Affiliated Integrated Traditional Chinese Medicine (TCM) and Western Medicine Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu Integrated Traditional Chinese Medicine (TCM) and Western Medicine Hospital, Chengdu First People's Hospital, Chengdu, China
| | - Xueying Li
- Department of Nephrology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jing Li
- Department of Nephrology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Long He
- Department of Nephrology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ming Chen
- Department of Nephrology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Scharping M, Brennenstuhl H, Garbade SF, Wild B, Posset R, Zielonka M, Kölker S, Haun MW, Opladen T. Unmet Needs of Parents of Children with Urea Cycle Disorders. CHILDREN 2022; 9:children9050712. [PMID: 35626889 PMCID: PMC9140128 DOI: 10.3390/children9050712] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 05/03/2022] [Accepted: 05/09/2022] [Indexed: 12/26/2022]
Abstract
(1) Background: Phenotypic diversity and long-term health outcomes of individuals with urea cycle disorders (UCDs) have been described in detail. However, there is limited information on the burden on affected families. (2) Methods: To evaluate the family burden in parents with children suffering from UCDs, we used validated questionnaires. Socio-demographic characteristics were evaluated, and an adapted version of the Parental Need Scale for Rare Diseases questionnaire was used. The survey was conducted in families of UCD patients cared for at the University Children’s Hospital Heidelberg. (3) Results: From April to November 2021, 59 participants were interviewed (mothers n = 34, fathers n = 25). The affected patients most frequently suffered from ornithine transcarbamylase deficiency (OTC-D) (female n = 12, male n = 12), followed by argininosuccinate synthetase deficiency (ASS-D, n = 13) and argininosuccinate lyase deficiency (ASL-D, n = 8). About one-third of the participants were “dissatisfied” or “extremely dissatisfied” with health professionals’ disease knowledge. In addition, 30% of the participants reported a medium or high need for “additional information on the development of their children”, and 44% reported a medium or high need “for information on available services”. A majority of 68% reported a need for additional support regarding services such as support groups (42%) or psychological counseling (29%). (4) Conclusions: Our study indicates that there is an unmet need for sufficient information about the development of children with UCDs, as well as for information about available support services for families with UCD patients. Furthermore, the results highlight the importance of establishing or improving family-centered care approaches. This pilot study may serve as a template for the assessment of the family burden associated with other inherited metabolic diseases.
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Affiliation(s)
- Mara Scharping
- Division of Child Neurology and Metabolic Medicine, Centre for Child and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany; (M.S.); (H.B.); (S.F.G.); (R.P.); (M.Z.); (S.K.)
| | - Heiko Brennenstuhl
- Division of Child Neurology and Metabolic Medicine, Centre for Child and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany; (M.S.); (H.B.); (S.F.G.); (R.P.); (M.Z.); (S.K.)
| | - Sven F. Garbade
- Division of Child Neurology and Metabolic Medicine, Centre for Child and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany; (M.S.); (H.B.); (S.F.G.); (R.P.); (M.Z.); (S.K.)
| | - Beate Wild
- Department of General Internal Medicine and Psychosomatics, University Hospital Heidelberg, 69120 Heidelberg, Germany; (B.W.); (M.W.H.)
| | - Roland Posset
- Division of Child Neurology and Metabolic Medicine, Centre for Child and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany; (M.S.); (H.B.); (S.F.G.); (R.P.); (M.Z.); (S.K.)
| | - Matthias Zielonka
- Division of Child Neurology and Metabolic Medicine, Centre for Child and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany; (M.S.); (H.B.); (S.F.G.); (R.P.); (M.Z.); (S.K.)
| | - Stefan Kölker
- Division of Child Neurology and Metabolic Medicine, Centre for Child and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany; (M.S.); (H.B.); (S.F.G.); (R.P.); (M.Z.); (S.K.)
| | - Markus W. Haun
- Department of General Internal Medicine and Psychosomatics, University Hospital Heidelberg, 69120 Heidelberg, Germany; (B.W.); (M.W.H.)
| | - Thomas Opladen
- Division of Child Neurology and Metabolic Medicine, Centre for Child and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany; (M.S.); (H.B.); (S.F.G.); (R.P.); (M.Z.); (S.K.)
- Correspondence:
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Santamaria R, Ballester M, Garcia-Llorens G, Martinez F, Blazquez M, Ribes-Koninckx C, Castell JV, Wuestefeld T, Bort R. Derivation of healthy hepatocyte-like cells from a female patient with ornithine transcarbamylase deficiency through X-inactivation selection. Sci Rep 2022; 12:2308. [PMID: 35145162 PMCID: PMC8831560 DOI: 10.1038/s41598-022-06184-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 01/18/2022] [Indexed: 11/09/2022] Open
Abstract
Autologous cell replacement therapy for inherited metabolic disorders requires the correction of the underlying genetic mutation in patient's cells. An unexplored alternative for females affected from X-linked diseases is the clonal selection of cells randomly silencing the X-chromosome containing the mutant allele, without in vivo or ex vivo genome editing. In this report, we have isolated dermal fibroblasts from a female patient affected of ornithine transcarbamylase deficiency and obtained clones based on inactivation status of either maternally or paternally inherited X chromosome, followed by differentiation to hepatocytes. Hepatocyte-like cells derived from these clones display indistinct features characteristic of hepatocytes, but express either the mutant or wild type OTC allele depending on X-inactivation pattern. When clonally derived hepatocyte-like cells were transplanted into FRG® KO mice, they were able to colonize the liver and recapitulate OTC-dependent phenotype conditioned by X-chromosome inactivation pattern. This approach opens new strategies for cell therapy of X-linked metabolic diseases and experimental in vitro models for drug development for such diseases.
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Affiliation(s)
- Ramon Santamaria
- Experimental Hepatology Unit, Instituto de Investigación Sanitaria La Fe, CIBERehd, Hospital Universitari i Politècnic La Fe, Avda. Fernando Abril Martorell 106, 46026, Valencia, Spain
| | - Maria Ballester
- Experimental Hepatology Unit, Instituto de Investigación Sanitaria La Fe, CIBERehd, Hospital Universitari i Politècnic La Fe, Avda. Fernando Abril Martorell 106, 46026, Valencia, Spain
| | - Guillem Garcia-Llorens
- Experimental Hepatology Unit, Instituto de Investigación Sanitaria La Fe, CIBERehd, Hospital Universitari i Politècnic La Fe, Avda. Fernando Abril Martorell 106, 46026, Valencia, Spain
- Biochemistry and Molecular Biology Department, Universidad de Valencia, Valencia, Spain
| | - Francisco Martinez
- Genetics Unit, Instituto de Investigación Sanitaria La Fe, Hospital Universitari i Politècnic La Fe, 46026, Valencia, Spain
| | - Marina Blazquez
- Experimental Hepatology Unit, Instituto de Investigación Sanitaria La Fe, CIBERehd, Hospital Universitari i Politècnic La Fe, Avda. Fernando Abril Martorell 106, 46026, Valencia, Spain
| | - Carmen Ribes-Koninckx
- Coeliac Disease and Inmunopathology Research Unit, Instituto de Investigación Sanitaria La Fe, Pediatric Gastroenterology, Hospital Universitari i Politècnic La Fe, 46026, Valencia, Spain
| | - Jose V Castell
- Experimental Hepatology Unit, Instituto de Investigación Sanitaria La Fe, CIBERehd, Hospital Universitari i Politècnic La Fe, Avda. Fernando Abril Martorell 106, 46026, Valencia, Spain
- Biochemistry and Molecular Biology Department, Universidad de Valencia, Valencia, Spain
| | - Torsten Wuestefeld
- Laboratory for In Vivo Genetics & Gene Therapy, Genome Institute of Singapore, A*STAR & National Cancer Centre Singapore, School of Biological Science, SingHealth & Adj. Ass.-Prof. Nanyang Technological University, 60 Biopolis Street, #02-01 Genome, Singapore, 138672, Singapore
| | - Roque Bort
- Experimental Hepatology Unit, Instituto de Investigación Sanitaria La Fe, CIBERehd, Hospital Universitari i Politècnic La Fe, Avda. Fernando Abril Martorell 106, 46026, Valencia, Spain.
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Hyperammonaemic Encephalopathy Caused by Adult-Onset Ornithine Transcarbamylase Deficiency. Brain Sci 2022; 12:brainsci12020231. [PMID: 35203994 PMCID: PMC8870301 DOI: 10.3390/brainsci12020231] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Revised: 02/01/2022] [Accepted: 02/02/2022] [Indexed: 02/01/2023] Open
Abstract
Hyperammonaemic encephalopathy in adults is a rare condition in the absence of liver disease and is associated with a high mortality and risk of permanent neurological deficits. Seldomly, the condition is caused by an inborn error of metabolism in the urea cycle, triggered by an exogenic factor such as gastrointestinal haemorrhage, gastric bypass surgery, starvation, seizures, vigorous exercise, burn injuries, or drugs hampering the elimination of ammonia. Here, we present a fatal case of an unrecognized genetic ornithine transcarbamylase deficiency (OTCD) presenting with a subacute progressive encephalopathy. We review the current literature and discuss the differential diagnosis and treatment options. As swift diagnosis and initiation of treatment is vital, awareness of hyperammonaemic encephalopathy and its possible causes can help improve the prognosis of this condition.
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Ravindranath A, Sarma MS. Mitochondrial hepatopathy: Anticipated difficulties in management of fatty acid oxidation defects and urea cycle defects. World J Hepatol 2022; 14:180-194. [PMID: 35126847 PMCID: PMC8790400 DOI: 10.4254/wjh.v14.i1.180] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 08/19/2021] [Accepted: 12/02/2021] [Indexed: 02/06/2023] Open
Abstract
Fatty acid oxidation defects (FAOD) and urea cycle defects (UCD) are among the most common metabolic liver diseases. Management of these disorders is dotted with challenges as the strategies differ based on the type and severity of the defect. In those with FAOD the cornerstone of management is avoiding hypoglycemia which in turn prevents the triggering of fatty acid oxidation. In this review, we discuss the role of carnitine supplementation, dietary interventions, newer therapies like triheptanoin, long-term treatment and approach to positive newborn screening. In UCD the general goal is to avoid excessive protein intake and indigenous protein breakdown. However, one size does not fit all and striking the right balance between avoiding hyperammonemia and preventing deficiencies of essential nutrients is a formidable task. Practical issues during the acute presentation including differential diagnosis of hyperammonemia, dietary dilemmas, the role of liver transplantation, management of the asymptomatic individual and monitoring are described in detail. A multi-disciplinary team consisting of hepatologists, metabolic specialists and dieticians is required for optimum management and improvement in quality of life for these patients.
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Affiliation(s)
- Aathira Ravindranath
- Division of Pediatric Gastroenterology, Institute of Gastrointestinal Sciences, Apollo BGS Hospitals, Mysore 570023, Karnataka, India
| | - Moinak Sen Sarma
- Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
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Eminoğlu FT, Koç Yekedüz M, Doğulu N, Öncül Ü, Köse E, Okulu E, Erdeve Ö, Atasay B, Arsan S. Inherited metabolic disorders in the neonatal intensive care unit: Red flags to look out for. Pediatr Int 2022; 64:e14953. [PMID: 34390086 DOI: 10.1111/ped.14953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 07/17/2021] [Accepted: 08/11/2021] [Indexed: 12/01/2022]
Abstract
BACKGROUND We aimed to assess symptoms, laboratory findings, and radiological abnormalities in patients diagnosed with inherited metabolic disorders (IMDs) in the neonatal intensive care unit. METHODS A total of 6,150 newborns treated in a third-level neonatal intensive care unit between 2012 and 2020 in Turkey were screened, of which 195 consulted with a suspicion of metabolic disease based on their clinical, laboratory, or radiological findings were included in the present study. RESULTS The prevalence of IMDs in the patients was 1:94.6. Those consulted in the department of pediatric metabolism were divided into two groups, with the 65 diagnosed with IMDs assigned as Group I, and the 130 patients who were not diagnosed with IMDs as Group II. The most common IMDs were organic acidemias (29.23%) and urea cycle disorders (UCDs) (26.15%). The rates of consanguinity marriage (75.3% vs 37.6%, P < 0.001), siblings diagnosed with an IMD (27.6% vs 3.8%, P < 0.001), and sibling death (56.9% vs 14.6%, P < 0.001) were higher in Group I than in Group II. Hyperammonemia (61.5% vs 18.4%, P < 0.001) was the most common laboratory finding in Group I, and anemia (Group I 60.0% vs 43.0% P = 0.033), metabolic acidosis (53.8% vs 36.9%, P = 0.028) and respiratory alkalosis (16.9% vs 1.5%, P < 0.001) were all higher in Group I. CONCLUSIONS This retrospective study found that the results of clinical findings and basic laboratory tests could be strong indicators of IMDs, although extensive newborn screening tests and advanced biochemical and genetic tests should be carried out for the diagnosis of IMDs in newborns.
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Affiliation(s)
- Fatma Tuba Eminoğlu
- Department of Pediatric Metabolism, Faculty of Medicine, Ankara University, Ankara, Turkey
| | - Merve Koç Yekedüz
- Department of Pediatric Metabolism, Faculty of Medicine, Ankara University, Ankara, Turkey
| | - Neslihan Doğulu
- Department of Pediatric Metabolism, Faculty of Medicine, Ankara University, Ankara, Turkey
| | - Ümmühan Öncül
- Department of Pediatric Metabolism, Faculty of Medicine, Ankara University, Ankara, Turkey
| | - Engin Köse
- Department of Pediatric Metabolism, Faculty of Medicine, Ankara University, Ankara, Turkey
| | - Emel Okulu
- Department of Neonatology, Faculty of Medicine, Ankara University, Ankara, Turkey
| | - Ömer Erdeve
- Department of Neonatology, Faculty of Medicine, Ankara University, Ankara, Turkey
| | - Begüm Atasay
- Department of Neonatology, Faculty of Medicine, Ankara University, Ankara, Turkey
| | - Saadet Arsan
- Department of Neonatology, Faculty of Medicine, Ankara University, Ankara, Turkey
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Mukherjee S, Ray SK. Inborn Errors of Metabolism Screening in Neonates: Current Perspective with Diagnosis and Therapy. Curr Pediatr Rev 2022; 18:274-285. [PMID: 35379134 DOI: 10.2174/1573396318666220404194452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 01/24/2022] [Accepted: 02/14/2022] [Indexed: 11/22/2022]
Abstract
Inborn errors of metabolism (IEMs) are rare hereditary or acquired disorders resulting from an enzymatic deformity in biochemical and metabolic pathways influencing proteins, fats, carbohydrate metabolism, or hampered some organelle function. Even though individual IEMs are uncommon, together, they represent a diverse class of genetic diseases, with new issues and disease mechanisms being portrayed consistently. IEM includes the extraordinary multifaceted nature of the fundamental pathophysiology, biochemical diagnosis, molecular level investigation, and complex therapeutic choices. However, due to the molecular, biochemical, and clinical heterogeneity of IEM, screening alone will not detect and diagnose all illnesses included in newborn screening programs. Early diagnosis prevents the emergence of severe clinical symptoms in the majority of IEM cases, lowering morbidity and death. The appearance of IEM disease can vary from neonates to adult people, with the more serious conditions showing up in juvenile stages along with significant morbidity as well as mortality. Advances in understanding the physiological, biochemical, and molecular etiologies of numerous IEMs by means of modalities, for instance, the latest molecular-genetic technologies, genome engineering knowledge, entire exome sequencing, and metabolomics, have prompted remarkable advancement in detection and treatment in modern times. In this review, we analyze the biochemical basis of IEMs, clinical manifestations, the present status of screening, ongoing advances, and efficiency of diagnosis in treatment for IEMs, along with prospects for further exploration as well as innovation.
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Affiliation(s)
- Sukhes Mukherjee
- Department of Biochemistry, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh-462020, India
| | - Suman Kumar Ray
- Independent Researcher, Bhopal, Madhya Pradesh-462020, India
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32
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Diagnosis and Management of Inborn Errors of Metabolism in Adult Patients in the Emergency Department. Diagnostics (Basel) 2021; 11:diagnostics11112148. [PMID: 34829496 PMCID: PMC8621113 DOI: 10.3390/diagnostics11112148] [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: 10/30/2021] [Revised: 11/12/2021] [Accepted: 11/16/2021] [Indexed: 12/30/2022] Open
Abstract
Inborn errors of metabolism (IEM) constitute an important group of conditions characterized by an altered metabolic pathway. There are numerous guidelines for the diagnosis and management of IEMs in the pediatric population but not for adults. Given the increasing frequency of this group of conditions in adulthood, other clinicians in addition to pediatricians should be aware of them and learn to identify their characteristic manifestations. Early recognition and implementation of an appropriate therapeutic approach would improve the clinical outcome of many of these patients. This review presents when and how to investigate a metabolic disorder with the aim of encouraging physicians not to overlook a treatable disorder.
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Kisa PT, Uzun OU, Gunduz M, Bulbul FS, Kose E, Arslan N. Frequency and status of depression and anxiety in mothers of children with inborn errors of metabolism with restricted diet, with and without risk of metabolic crises. Arch Pediatr 2021; 28:702-706. [PMID: 34620546 DOI: 10.1016/j.arcped.2021.09.008] [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] [Indexed: 10/20/2022]
Abstract
OBJECTIVES This study aimed to investigate the frequency and status of depression and anxiety among mothers of children with inborn errors of metabolism (IEM) who were on a restricted diet and previously experienced metabolic crises. METHODS This cross-sectional multicenter descriptive study included 93 children with IEM who were on restricted diet. The patients were divided into two groups: those who had experienced metabolic crises (n=44, urea cycle defect, organic acidemia, maple syrup urine disease, hereditary fructose intolerance) and those who had not experienced previous metabolic crises (n=49; phenylketonuria, galactosemia, and non-ketotic hyperglycinemia). The control group comprised 37 healthy children. The mothers of the patients and control participants answered a questionnaire about their and their children's demographic and clinical characteristics and completed the Beck Depression Inventory (BDI) and the State-Trait Anxiety Inventory (STAI-S and STAI-T). RESULTS The maternal BDI, STAI-S, and STAI-T scores were 6.3±5.2, 36.1±11.2, and 39.9±8.8, respectively, in the control group. The maternal BDI, STAI-S, and STAI-T scores of the children who had experienced (19.2±9.7; 44.0±12.4; 47.9±10.6) and those who had not experienced (13.9±9.1; 40.7 ±8.6; 45.3±8.3) a crisis were significantly higher than for the controls. The BDI score was significantly higher for the mothers of children who had experienced a crisis (p=0.011), whereas no significant difference was determined between the two patient groups regarding STAI-S and STAI-T scores. The mothers of four children who had experienced metabolic crises were on antidepressant therapy. CONCLUSION Although their children were on a similar restricted diet, the mothers of children who previously experienced or who had the risk of experiencing metabolic crises had higher depression scores as compared with the mothers of children who did not experience a previous crisis. Early supportive therapy may be required for the families of these patients to lower the burden of stress.
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Affiliation(s)
- Pelin Teke Kisa
- Dokuz Eylul University Faculty of Medicine, Department of Pediatric Metabolism and Nutrition, Izmir, Turkey; University of Health Sciences, Dr. Behçet Uz Children's Research and Training Hospital, Department of Pediatric Metabolism and Nutrition, Izmir, Turkey
| | - Ozlem Unal Uzun
- Kocaeli University Faculty of Medicine, Department of Pediatric Metabolism and Nutrition, Kocaeli, Turkey
| | - Mehmet Gunduz
- Ministry of Health Ankara City Hospital, Department of Pediatric Metabolism and Nutrition, Ankara, Turkey
| | - Fatma Selda Bulbul
- Kirikkale University Faculty of Medicine, Department of Pediatric Metabolism and Nutrition, Kirikkale, Turkey
| | - Engin Kose
- Ankara University Faculty of Medicine, Department of Pediatric Metabolism and Nutrition, Ankara, Turkey
| | - Nur Arslan
- Dokuz Eylul University Faculty of Medicine, Department of Pediatric Metabolism and Nutrition, Izmir, Turkey; Izmir Biomedicine and Genome Center, Izmir, Turkey.
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35
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Gao H, Wan X, Xiao B, Yang K, Wang Y, Zhang C, Li P, Liu L, Xia T, Wang A, Zhang S. Impacts of PBDE-47 exposure before, during and after pregnancy on the maternal gut microbiome and its association with host metabolism. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2021; 222:112530. [PMID: 34280840 DOI: 10.1016/j.ecoenv.2021.112530] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 07/13/2021] [Accepted: 07/14/2021] [Indexed: 05/06/2023]
Abstract
Maternal gut microbiota play an important role in the modulation of offspring disease susceptibility and gut microbiota dysbiosis has been proposed as a mechanism through which toxic environmental chemicals exert their adverse impacts on health. The brominated flame retardants polybrominated diphenyl ethers (PBDEs) are developmental toxicants and induce dysbiotic gut microbiota in offspring. Yet, whether and how PBDEs impact the maternal gut microbiota remain unclear. Here, we sought to investigate the effect of 2,2',4,4'-tetrabromodiphenyl ether (PBDE-47) exposure from preconception through lactation cessation on maternal gut microbiota and its link to host serum metabolic consequences. Female Sprague-Dawley rats were daily exposed to 10 mg/kg PBDE-47 via oral gavage from ten days before conception until offspring were weaned on postnatal day 21, then maternal fecal and blood samples were collected for microbiome and metabolome analyses by using 16S ribosomal RNA gene sequencing and gas chromatography-mass spectrometry, respectively. Maternal exposure to PBDE-47 showed a distinct profile in gut microbiota compared to control dams, as evidenced by increased Actinobacteria phylum and genera Blautia, Gemella and Phascolarctobacterium, and decreased genera AF12 and Oscillospira. Additionally, global metabolomics analysis identified 26 differential serum metabolites to distinguish PBDE-47 from controls, which were mainly involved in amino acid, lipid, carbohydrate and energy metabolism, further confirmed by pathway analysis. Importantly, the differential serum metabolites are closely correlated with the disturbed gut microbiota in response to PBDE-47. Collectively, our results suggest that maternal gut microbial dysbiosis may serve as a potential mechanism underlying PBDE-47-elicited health hazards to mothers or even offspring.
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Affiliation(s)
- Hui Gao
- Department of Clinical Nutrition, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, China
| | - Xueyan Wan
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, China
| | - Boya Xiao
- Department of Occupational and Environmental Health, MOE Key Laboratory of Environment and Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, China
| | - Kaichao Yang
- Immunization Planning Institute, Henan Provincial Center for Disease Control and Prevention, 105 Nongye South Road, Zhengzhou, China
| | - Yafei Wang
- Department of Occupational and Environmental Health, MOE Key Laboratory of Environment and Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, China
| | - Cheng Zhang
- Department of Occupational Health, Wuhan Prevention and Treatment Center for Occupational Diseases, 18 Jianghan North Road, Wuhan, China
| | - Pei Li
- Department of Occupational and Environmental Health, MOE Key Laboratory of Environment and Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, China
| | - Luming Liu
- Department of Occupational and Environmental Health, MOE Key Laboratory of Environment and Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, China
| | - Tao Xia
- Department of Occupational and Environmental Health, MOE Key Laboratory of Environment and Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, China
| | - Aiguo Wang
- Department of Occupational and Environmental Health, MOE Key Laboratory of Environment and Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, China
| | - Shun Zhang
- Department of Occupational and Environmental Health, MOE Key Laboratory of Environment and Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, China.
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36
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Kolchina AN, Yatsyshina EE, Malysheva LV, Ledentsova EE, Lidyaeva EE, Khaletskaya OV. Diagnostics of Inherited Metabolic Diseases in Newborns with the Hyperammonemia Syndrome at the Onset of Disease (Pilot Study). Sovrem Tekhnologii Med 2021; 13:59-64. [PMID: 34513067 PMCID: PMC8353695 DOI: 10.17691/stm2021.13.1.07] [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: 06/19/2020] [Indexed: 11/23/2022] Open
Abstract
The aim of the study was to develop a diagnostic model that allows with a high degree of probability predicting the development of inherited metabolic disease (IMD) in newborns with the hyperammonemia syndrome at the onset of disease and determine the adequate management tactics for such patients.
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Affiliation(s)
- A N Kolchina
- PhD Student, Department of Hospital Pediatrics, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia
| | - E E Yatsyshina
- Associate Professor, Department of Hospital Pediatrics, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia
| | - L V Malysheva
- Head of the Clinical Diagnostic Laboratory, Children's City Clinical Hospital No.1, 76 Prospect Gagarina, Nizhny Novgorod, 603081, Russia
| | - E E Ledentsova
- Physician of Clinical Laboratory Diagnostics, Children's City Clinical Hospital No.1, 76 Prospect Gagarina, Nizhny Novgorod, 603081, Russia
| | - E E Lidyaeva
- Anesthesiologist-Resuscitator, Resuscitation and Intensive Care Unit, Children's City Clinical Hospital No.1, 76 Prospect Gagarina, Nizhny Novgorod, 603081, Russia
| | - O V Khaletskaya
- Professor, Head of the Department of Hospital Pediatrics, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia
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37
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Kang H, Kim M, Lee JH. Nutritional Management in a Patient with Citrullinemia Type 1. Clin Nutr Res 2021; 10:268-277. [PMID: 34386445 PMCID: PMC8331288 DOI: 10.7762/cnr.2021.10.3.268] [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: 07/05/2021] [Revised: 07/13/2021] [Accepted: 07/13/2021] [Indexed: 11/19/2022] Open
Abstract
For patients with citrullinemia type 1, nutritional management is essential to prevent the occurrence of complications associated with hyperammonemia. This report describes a patient who had been receiving nutrition intervention for more than 3 years. A newborn diagnosed with hyperammonemia due to citrullinemia visited Ajou University Hospital and was referred to the nutrition team. After receiving acute treatment, the infant was regularly fed with specialized formula. A protein-restricted diet is recommended for maintaining normal development and achieving long-term survival. Through continuous provision of nutritional intervention, the child showed normal growth and development, and the energy-protein supply was maintained appropriately. This case clearly shows the importance of medical nutrition therapy for patients with citrullinemia.
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Affiliation(s)
- Hyejin Kang
- Food Services and Clinical Nutrition Team, Ajou University Hospital, Suwon 16499, Korea
| | - Mihyang Kim
- Food Services and Clinical Nutrition Team, Ajou University Hospital, Suwon 16499, Korea.,Department of Medical Nutrition, Graduate School of East-West Medical Science, Kyung Hee University, Yongin 17104, Korea
| | - Ji Hyun Lee
- Food Services and Clinical Nutrition Team, Ajou University Hospital, Suwon 16499, Korea
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38
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Kripps KA, Baker PR, Thomas JA, Skillman HE, Bernstein L, Gaughan S, Burns C, Coughlin CR, McCandless SE, Larson AA, Kochar A, Stillman CF, Wymore EM, Hendricks EG, Woontner M, Van Hove JLK. REVIEW: Practical strategies to maintain anabolism by intravenous nutritional management in children with inborn metabolic diseases. Mol Genet Metab 2021; 133:231-241. [PMID: 33985889 DOI: 10.1016/j.ymgme.2021.04.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 04/29/2021] [Accepted: 04/30/2021] [Indexed: 12/31/2022]
Abstract
One of the most vital elements of management for patients with inborn errors of intermediary metabolism is the promotion of anabolism, the state in which the body builds new components, and avoidance of catabolism, the state in which the body breaks down its own stores for energy. Anabolism is maintained through the provision of a sufficient supply of substrates for energy, as well as critical building blocks of essential amino acids, essential fatty acids, and vitamins for synthetic function and growth. Patients with metabolic diseases are at risk for decompensation during prolonged fasting, which often occurs during illnesses in which enteral intake is compromised. During these times, intravenous nutrition must be supplied to fully meet the specific nutritional needs of the patient. We detail our approach to intravenous management for metabolic patients and its underlying rationale. This generally entails a combination of intravenous glucose and lipid as well as early introduction of protein and essential vitamins. We exemplify the utility of our approach in case studies, as well as scenarios and specific disorders which require a more careful administration of nutritional substrates or a modification of macronutrient ratios.
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Affiliation(s)
- Kimberly A Kripps
- Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Aurora, CO, USA; Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, USA
| | - Peter R Baker
- Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Aurora, CO, USA
| | - Janet A Thomas
- Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Aurora, CO, USA
| | - Heather E Skillman
- Department of Clinical Nutrition, Children's Hospital Colorado, Aurora, CO, USA
| | - Laurie Bernstein
- Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Aurora, CO, USA
| | - Sommer Gaughan
- Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Aurora, CO, USA
| | - Casey Burns
- Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Aurora, CO, USA
| | - Curtis R Coughlin
- Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Aurora, CO, USA
| | - Shawn E McCandless
- Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Aurora, CO, USA
| | - Austin A Larson
- Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Aurora, CO, USA
| | - Aaina Kochar
- Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Aurora, CO, USA
| | - Chelsey F Stillman
- Section of Child Neurology, Department of Pediatrics, University of Colorado, Aurora, CO, USA; Neuroscience Institute, Children's Hospital Colorado, Aurora, CO, USA
| | - Erica M Wymore
- Section of Neonatology, Department of Pediatrics, University of Colorado, Aurora, CO, USA
| | - Ellie G Hendricks
- Department of Pharmacy, Children's Hospital Colorado, Aurora, CO, USA
| | - Michael Woontner
- Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Aurora, CO, USA
| | - Johan L K Van Hove
- Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Aurora, CO, USA.
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39
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Şengul Emeksiz Z, Özmen S. The case of a child with contact urticaria due to sodium benzoate treatment. Contact Dermatitis 2021; 86:40-41. [PMID: 34137041 DOI: 10.1111/cod.13916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 05/20/2021] [Accepted: 06/13/2021] [Indexed: 11/30/2022]
Affiliation(s)
- Zeynep Şengul Emeksiz
- Division of Pediatric Allergy and Immunology, Department of Pediatrics, Dr. Sami Ulus Maternity and Children Training and Research Hospital, Ankara, Turkey
| | - Serap Özmen
- Division of Pediatric Allergy and Immunology, Department of Pediatrics, Dr. Sami Ulus Maternity and Children Training and Research Hospital, Ankara, Turkey
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40
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Fredericks RM, Wang GS, Vohwinkel CU, Graham JK. An Unusual Case of Severe Anion Gap Metabolic Acidosis in a 3-year-old Girl. Pediatr Rev 2021; 42:S46-S51. [PMID: 33386361 DOI: 10.1542/pir.2019-0111] [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)
- Ryan M Fredericks
- Children's Hospital Colorado, Section of Pediatric Critical Care Medicine,
| | - George Sam Wang
- Section of Emergency Medicine, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO
| | | | - Jessica Kraynik Graham
- Section of Emergency Medicine, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO
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41
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Meijer R, Vivekananda U, Balestrini S, Walker M, Lachmann R, Haeberle J, Murphy E. Ammonia: what adult neurologists need to know. Pract Neurol 2020:practneurol-2020-002654. [PMID: 33310884 DOI: 10.1136/practneurol-2020-002654] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/04/2020] [Indexed: 12/31/2022]
Abstract
Hyperammonaemia is often encountered in acute neurology and can be the cause of acute or chronic neurological symptoms. Patients with hyperammonaemia may present with seizures or encephalopathy, or may be entirely asymptomatic. The underlying causes are diverse but often straightforward to diagnose, although sometimes require specialist investigations. Haemodialysis or haemo(dia)filtration is the first-line treatment for acute severe hyperammonaemia (of any cause) in an adult. Here we discuss our approach to adult patients with hyperammonaemia identified by a neurologist.
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Affiliation(s)
- Rick Meijer
- Department of Internal Medicine, Amsterdam University Medical Centers, Location VU University Medical Center, Amsterdam, The Netherlands
- Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK
| | - Umesh Vivekananda
- Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK
| | - Simona Balestrini
- Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK
- Chalfont Centre for Epilepsy, Buckinghamshire, UK
| | - Matthew Walker
- Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK
| | - Robin Lachmann
- Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK
| | - Johannes Haeberle
- Department of Pediatrics, University Children's Hospital Zurich and Children's Research Centre, Zurich, Switzerland
| | - Elaine Murphy
- Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK
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42
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Muthaffar OY. Treating epilepsy with options other than antiepileptic medications. NEUROSCIENCES (RIYADH, SAUDI ARABIA) 2020; 25:253-261. [PMID: 33130805 PMCID: PMC8015608 DOI: 10.17712/nsj.2020.4.20200010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Epilepsy is a common health burden worldwide. Epilepsy is linked to variety of factors, including infectious, vascular, immune, structural, genetic, and metabolic etiologies. Despite the existence of multiple antiepileptic drugs (AEDs), many patients are diagnosed with intractable epilepsy. Many nonpharmacological options are available for epilepsy. Some types of epilepsy respond to cofactors. Other patients may be candidates for a ketogenic diet. Inflammatory mediators, such as intravenous immunoglobulins (IVIgs) and steroids, are other options for epilepsy. Recently, cannabinoids have been approved for epilepsy treatment. Refractory epilepsy can be treated with surgical interventions. Focal resections, hemispherectomies, and corpus callosotomies are some common epilepsy surgery approaches. Neuromodulation techniques are another option. Thermal ablation is a minimally invasive approach for epilepsy treatment. Epilepsy outcomes are improving, and treatment modalities are expanding. Trials of nonpharmacological options for epilepsy patients are recommended. This article summarizes available nonpharmacological options other than AEDs for the treatment of epilepsy.
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Affiliation(s)
- Osama Y Muthaffar
- Department of Pediatrics, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia. E-mail:
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43
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Solé C, Arriaga M, Cañedo E. High Blood Pressure in a Urea Cycle Disorder: Case Report. AJP Rep 2020; 10:e347-e351. [PMID: 33133764 PMCID: PMC7591362 DOI: 10.1055/s-0040-1716733] [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: 06/11/2020] [Accepted: 06/15/2020] [Indexed: 11/14/2022] Open
Abstract
Introduction Urea cycle disorders (UCDs) form a group of metabolic pathological conditions that might develop serious neurological consequences. Early diagnosis, before irreversible damage is established, is the most important prognostic and morbidity factor. Case Report We present the case of a 5-day newborn with high blood pressure and respiratory distress. Diagnosis was type I citrullinemia. With appropriate citrullinemia guided-treatment blood pressure returned to normal. Conclusion High blood pressure has been rarely described as a lead symptom for the debut of a UCD. We must take this into consideration as an early recognition and treatment of these disorders are of the utmost importance.
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Affiliation(s)
- Carolina Solé
- Department of Neonatology, Gregorio Marañon Hospital, Madrid, Spain
| | - María Arriaga
- Department of Neonatology, Gregorio Marañon Hospital, Madrid, Spain
| | - Elvira Cañedo
- Department of Metabolism Diseases and Nutrition, Niño Jesús Hospital, Madrid, Spain
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44
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A Great Catch for Investigating Inborn Errors of Metabolism-Insights Obtained from Zebrafish. Biomolecules 2020; 10:biom10091352. [PMID: 32971894 PMCID: PMC7564250 DOI: 10.3390/biom10091352] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 09/18/2020] [Accepted: 09/19/2020] [Indexed: 12/14/2022] Open
Abstract
Inborn errors of metabolism cause abnormal synthesis, recycling, or breakdown of amino acids, neurotransmitters, and other various metabolites. This aberrant homeostasis commonly causes the accumulation of toxic compounds or depletion of vital metabolites, which has detrimental consequences for the patients. Efficient and rapid intervention is often key to survival. Therefore, it requires useful animal models to understand the pathomechanisms and identify promising therapeutic drug targets. Zebrafish are an effective tool to investigate developmental mechanisms and understanding the pathophysiology of disorders. In the past decades, zebrafish have proven their efficiency for studying genetic disorders owing to the high degree of conservation between human and zebrafish genes. Subsequently, several rare inherited metabolic disorders have been successfully investigated in zebrafish revealing underlying mechanisms and identifying novel therapeutic targets, including methylmalonic acidemia, Gaucher’s disease, maple urine disorder, hyperammonemia, TRAPPC11-CDGs, and others. This review summarizes the recent impact zebrafish have made in the field of inborn errors of metabolism.
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45
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Ozturk K, McKinney AM, Nascene D. Urea Cycle Disorders: A Neuroimaging Pattern Approach Using Diffusion and FLAIR MRI. J Neuroimaging 2020; 31:144-150. [PMID: 32920938 DOI: 10.1111/jon.12787] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 08/29/2020] [Accepted: 08/31/2020] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND AND PURPOSE This study aimed to assess characteristic regions of MRI involvement utilizing diffusion weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) at urea cycle disorder (UCD) diagnosis to determine the possible association between initial MRI patterns within 10 days of the first hyperammonemia episode, serum ammonia levels, and severity of neurological outcome based on clinical follow-up of >30 days. METHODS Ten patients with UCDs (4 females; median age: 5.4 years, age range: 6 days-54 years) were included who underwent MRI during a first episode of hyperammonemia. The topographical distribution of the DWI and FLAIR abnormalities in the cerebral cortex, deep gray matter, white matter, posterior limb of internal capsule, cerebral peduncle, and cerebellum was evaluated. Possible correlations between the brain injury patterns on DWI/FLAIR images, serum ammonia levels, and severity of neurological outcome were investigated by a trend correlation. RESULTS The UCD cohort (n = 10) involved four ornithine transcarbamoylase deficiencies, four argininosuccinic aciduria, one carbomoylphosphate synthetase deficiency, and one citrullinemia type-1. The observed trend in the distribution of DWI abnormalities as the severity of neurological sequela outcome increased was with diffuse cerebral cortex or corpus striatum involvement. Patients with initial peak serum ammonia ≥450 µmol/L had a grade 2 to 4 outcome, and those with peak ammonia <450 µmol/L had a grade 0 or 1 outcome. CONCLUSIONS The presence of more severe neurological outcome could be associated with diffuse cerebral cortex or corpus striatum involvement on DWI and high serum ammonia levels in patients with UCD.
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Affiliation(s)
- Kerem Ozturk
- Department of Radiology, University of Minnesota, Minneapolis, MN
| | - Alexander M McKinney
- Department of Radiology, University of Miami Miller School of Medicine, Miami, FL
| | - David Nascene
- Department of Radiology, University of Minnesota, Minneapolis, MN
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46
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Khoshnejad M, Dia Y, Patel A, Xu Z, Zhu X, Yun K, Wojtak K, Qureshi R, Humeau L, Muthumani K, Weiner DB. DNA-Encoded Glutamine Synthetase Enzyme as Ammonia-Lowering Therapeutic for Hyperammonemia. Nucleic Acid Ther 2020; 30:379-391. [PMID: 32907467 DOI: 10.1089/nat.2020.0886] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Hyperammonemia is a dangerous life-threatening metabolic complication characterized by markedly elevated ammonia levels that can lead to irreversible brain damage if not carefully monitored. Current pharmacological treatment strategies available for hyperammonemia patients are suboptimal and associated with major side effects. In this study, we focus on developing and evaluating the in vivo delivery of novel DNA-encoded glutamine synthetase (GS) enzymes for the treatment of hyperammonemia. Direct in vivo delivered DNA-encoded GS enzyme was evaluated in ammonium acetate-induced hyperammonemia and thioacetamide-induced acute liver injury (ALI) models in C57BL/6 mice. In ammonium acetate-induced hyperammonemia model, we achieved a 30.5% decrease in blood ammonia levels 15 min postadministration of ammonium acetate, with DNA-encoded GS-treated group. Significant increase in survival was observed in ALI model with the treated mice. A comparison of the secreted versus intracellular DNA-encoded GS enzyme demonstrated similar increases in survival in the ALI model, with 40% mortality in the secreted enzymes and 30% mortality in the intracellular enzymes, as compared with 90% mortality in the control group. Direct in vivo delivery of DNA-encoded GS demonstrated important ammonia-lowering potential. These results provide the initial steps toward development of delivered DNA as a potential new approach to ammonia-lowering therapeutics.
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Affiliation(s)
- Makan Khoshnejad
- Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, Pennsylvania, USA
| | - Yaya Dia
- Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, Pennsylvania, USA
| | - Ami Patel
- Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, Pennsylvania, USA
| | - Ziyang Xu
- Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, Pennsylvania, USA.,Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Xizhou Zhu
- Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, Pennsylvania, USA
| | - Kun Yun
- Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, Pennsylvania, USA
| | - Krzysztof Wojtak
- Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, Pennsylvania, USA.,Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Rehman Qureshi
- Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, Pennsylvania, USA
| | - Laurent Humeau
- Inovio Pharmaceuticals, Inc., Plymouth Meeting, Pennsylvania, USA
| | - Kar Muthumani
- Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, Pennsylvania, USA
| | - David B Weiner
- Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, Pennsylvania, USA
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47
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Li M, Zhang M, Qian Y, Shi G, Wang R. Ammonia toxicity in the yellow catfish (Pelteobagrus fulvidraco): The mechanistic insight from physiological detoxification to poisoning. FISH & SHELLFISH IMMUNOLOGY 2020; 102:195-202. [PMID: 32330626 DOI: 10.1016/j.fsi.2020.04.042] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Revised: 04/14/2020] [Accepted: 04/18/2020] [Indexed: 06/11/2023]
Abstract
Ammonia is toxic to fishes. Different fish have different defense strategies against ammonia, so the mechanism of ammonia poisoning is different. In this study, yellow catfish were exposed to three levels of ammonia (0, 5.70 and 57.00 mg L-1) for 96 h. The results showed that ammonia poisoning could lead to free amino acid imbalance (ornithine and citrulline contents declined; arginine content elevated), urea cycle enzymes deficiency (carbamyl phosphate synthetase and arginase contents declined), oxidative stress (superoxide dismutase, catalase and glutathione peroxidase activities declined), immunosuppression (lysozyme activity, 50% hemolytic complement and total immunoglobulin contents and phagocytic index declined) and cytokines release (TNF, IL 1 and IL 8 contents elevated). In addition, ammonia poisoning could induce up-regulation of antioxidant enzymes (Cu/Zn-SOD, Mn-SOD, CAT and GPx), cytokines (TNFα, IL 1 and IL 8) and apoptosis (p53, Bax, cytochrome c, Caspase 3 and Caspase 9) genes transcription. This study suggesting that the urea cycle and glutamine synthesis both were involved in the ammonia detoxification of yellow catfish, and the immunosuppression, inflammation and apoptotic induced by ammonia poisoning in yellow catfish are related to oxidative stress.
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Affiliation(s)
- Ming Li
- School of Marine Sciences, Ningbo University, Ningbo, 315211, China
| | - Muzi Zhang
- School of Marine Sciences, Ningbo University, Ningbo, 315211, China
| | - Yunxia Qian
- School of Marine Sciences, Ningbo University, Ningbo, 315211, China.
| | - Ge Shi
- College of Marine Science, Zhejiang Ocean University, Zhoushan, 316000, China
| | - Rixin Wang
- School of Marine Sciences, Ningbo University, Ningbo, 315211, China.
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48
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Peoc'h K, Damaj L, Pelletier R, Lefèvre C, Dubourg C, Denis MC, Bendavid C, Odent S, Moreau C. Early care of N-acetyl glutamate synthase (NAGS) deficiency in three infants from an inbred family. Mol Genet Metab Rep 2020; 22:100558. [PMID: 32021803 PMCID: PMC6994713 DOI: 10.1016/j.ymgmr.2019.100558] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 12/20/2019] [Accepted: 12/21/2019] [Indexed: 12/30/2022] Open
Abstract
N-acetyl glutamate synthase (NAGS) deficiency is the rarest urea cycle defect presenting as neonatal onset life-threatening hyperammonemia. We report here a family history of severe NAGS deficiency: after the index-case with severe hyperammonemia, one patient benefited from antenatal diagnosis, and from primary care at birth, another one was diagnosed at 2-days and immediately treated with carbaglumic-acid. Finally, we report excellent tolerance to long-term carbaglumic-acid treatment, with no side effects, and healthy neurological and psychomotor development.
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Affiliation(s)
- Katell Peoc'h
- APHP, HUPNVS, UF de Biochimie Clinique, Hôpital Beaujon, F-91118 Clichy, France.,Université de Paris, U1149 INSERM, F-75018 Paris, France
| | - Léna Damaj
- Service de Pédiatrie, Hôpital Sud, CHU Rennes Boulevard de Bulgarie, 35000 Rennes, France
| | - Romain Pelletier
- Laboratoire de Biochimie-Toxicologie, Hôpital Pontchaillou CHU Rennes, 2 rue Henri Le Guilloux, 35000 Rennes, France
| | - Charles Lefèvre
- Laboratoire de Biochimie-Toxicologie, Hôpital Pontchaillou CHU Rennes, 2 rue Henri Le Guilloux, 35000 Rennes, France
| | - Christèle Dubourg
- Laboratoire de Génétique moléculaire et Génomique Hôpital Pontchaillou CHU Rennes, 2 rue Henri Le Guilloux, 35000 Rennes, France.,UMR6290 IGDR, Univ Rennes, France
| | | | - Claude Bendavid
- Laboratoire de Biochimie-Toxicologie, Hôpital Pontchaillou CHU Rennes, 2 rue Henri Le Guilloux, 35000 Rennes, France.,Univ Rennes, INSERM, INRA, Institut NuMeCan, CHU, Rennes, France
| | - Sylvie Odent
- UMR6290 IGDR, Univ Rennes, France.,Service de Génétique clinique, Hôpital Sud, CHU Rennes Boulevard de Bulgarie, UMR6290 IGDR, Univ Rennes, 35000 Rennes, France
| | - Caroline Moreau
- Laboratoire de Biochimie-Toxicologie, Hôpital Pontchaillou CHU Rennes, 2 rue Henri Le Guilloux, 35000 Rennes, France.,Univ Rennes, INSERM, INRA, Institut NuMeCan, CHU, Rennes, France
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49
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Alhashem AM, Salih RM, Al-Aqeel AI, Mohamed S. Peripheral venous route for administration of ammonul infusion for treatment of acute hyperammonemia. An experience from a tertiary center in Saudi Arabia. Saudi Med J 2020; 41:98-101. [PMID: 31915802 PMCID: PMC7001061 DOI: 10.15537/smj.2020.1.24760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Objectives: To determine the local effects of peripheral Ammonul infusion on the skin and the subcutaneous tissues. Methods: This retrospective study was conducted at Prince Sultan Military Medical City, Riyadh, Saudi Arabia. All children <16 years of age admitted between December 2015 and October 2018 with hyperammonemia and received Ammonul infusion for treatment were recruited. Results: Twenty-one patients received the Ammonul infusion. They were admitted 58 times with acute hyperammonemia during the study period, with an average of 2.8 admissions per patient. The mean age of the included patients was 49.5 months. The most frequent underlying diagnoses were propionic acidemia (n=9), urea cycle disorders (n=5), and intrinsic liver disease (n=3). All participants received Ammonul through peripheral lines except 3 who received it through central lines. No extravasation, burns, or other local side effects were observed in this cohort. Conclusion: This data indicate that the use of Ammonul through a peripheral venous route appears to be safe and not associated with infusion-related local adverse effects.
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Affiliation(s)
- Amal M Alhashem
- Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Kingdom of Saudi Arabia. E-mail.
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Fan L, Zhao J, Jiang L, Xie L, Ma J, Li X, Cheng M. Molecular, biochemical, and clinical analyses of five patients with carbamoyl phosphate synthetase 1 deficiency. J Clin Lab Anal 2019; 34:e23124. [PMID: 31749211 PMCID: PMC7171324 DOI: 10.1002/jcla.23124] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 10/29/2019] [Accepted: 11/04/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Carbamoyl phosphate synthetase 1 deficiency (CPS1D) is a rare urea cycle disorder. The aim of this study was to present the clinical findings, management, biochemical data, molecular genetic analysis, and short-term prognosis of five children with CPS1D. METHODS The information of five CPS1D patients was retrospectively studied. We used targeted next-generation sequencing to identify carbamoyl phosphate synthetase 1 (CPS1) variants in patients suspected to have CPS1D. Candidate mutations were validated by Sanger sequencing. In silico and structure analyses were processed for the pathogenicity predictions of the identified mutations. RESULTS The patients had typically clinical manifestations and biochemical data of CPS1D. Genetic analysis revealed nine mutations in the CPS1 gene, including recurrence of c.1145C > T, five of which were firstly reported. Seven mutations were missense changes, while the remaining two were predicted to create premature stop codons. In silico and structure analyses showed that these genetic lesions were predicted to affect the function or stability of the enzyme. CONCLUSION We reported five cases of CPS1D. Five novel mutations of CPS1 gene were found. Mutations of CPS1 have private nature, and most of them are missense compound heterozygous. The mutation affecting residue predicted to interfere the catalytic sites, the internal tunnel, or the regulatory domain results in severe phenotype.
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Affiliation(s)
- Lijuan Fan
- Department of NeurologyChildren's Hospital of Chongqing Medical UniversityChongqingChina
- Ministry of Education Key Laboratory of Child Development and DisordersChongqingChina
- China International Science and Technology Cooperation Base of Child Development and Critical DisordersChongqingChina
- Chongqing Key Laboratory of PediatricsChongqingChina
| | - Jing Zhao
- Ministry of Education Key Laboratory of Child Development and DisordersChongqingChina
- China International Science and Technology Cooperation Base of Child Development and Critical DisordersChongqingChina
- Chongqing Key Laboratory of PediatricsChongqingChina
| | - Li Jiang
- Department of NeurologyChildren's Hospital of Chongqing Medical UniversityChongqingChina
- Ministry of Education Key Laboratory of Child Development and DisordersChongqingChina
- China International Science and Technology Cooperation Base of Child Development and Critical DisordersChongqingChina
- Chongqing Key Laboratory of PediatricsChongqingChina
| | - Lingling Xie
- Department of NeurologyChildren's Hospital of Chongqing Medical UniversityChongqingChina
- Ministry of Education Key Laboratory of Child Development and DisordersChongqingChina
- China International Science and Technology Cooperation Base of Child Development and Critical DisordersChongqingChina
- Chongqing Key Laboratory of PediatricsChongqingChina
| | - Jiannan Ma
- Department of NeurologyChildren's Hospital of Chongqing Medical UniversityChongqingChina
- Ministry of Education Key Laboratory of Child Development and DisordersChongqingChina
- China International Science and Technology Cooperation Base of Child Development and Critical DisordersChongqingChina
- Chongqing Key Laboratory of PediatricsChongqingChina
| | - Xiujuan Li
- Department of NeurologyChildren's Hospital of Chongqing Medical UniversityChongqingChina
- Ministry of Education Key Laboratory of Child Development and DisordersChongqingChina
- China International Science and Technology Cooperation Base of Child Development and Critical DisordersChongqingChina
- Chongqing Key Laboratory of PediatricsChongqingChina
| | - Min Cheng
- Department of NeurologyChildren's Hospital of Chongqing Medical UniversityChongqingChina
- Ministry of Education Key Laboratory of Child Development and DisordersChongqingChina
- China International Science and Technology Cooperation Base of Child Development and Critical DisordersChongqingChina
- Chongqing Key Laboratory of PediatricsChongqingChina
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