{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T01:25:08Z","timestamp":1787793908091,"version":"build-2784847793"},"reference-count":111,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,4,27]],"date-time":"2025-04-27T00:00:00Z","timestamp":1745712000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Recovery and Resilience Plan (NRRP), Mission 4 Component 2 Investment 1.3-Call for tender No. 341 of 15 March 2022 of Italian Ministry of University and Research funded by the European Union\u2013NextGenerationEU","award":["PE00000003"],"award-info":[{"award-number":["PE00000003"]}]},{"name":"National Recovery and Resilience Plan (NRRP), Mission 4 Component 2 Investment 1.3-Call for tender No. 341 of 15 March 2022 of Italian Ministry of University and Research funded by the European Union\u2013NextGenerationEU","award":["CUP D93C22000890001"],"award-info":[{"award-number":["CUP D93C22000890001"]}]},{"name":"\u201cON Foods-Research and innovation network on food and nutrition Sustainability, Safety and Security\u2013Working ON Foods\u201d","award":["PE00000003"],"award-info":[{"award-number":["PE00000003"]}]},{"name":"\u201cON Foods-Research and innovation network on food and nutrition Sustainability, Safety and Security\u2013Working ON Foods\u201d","award":["CUP D93C22000890001"],"award-info":[{"award-number":["CUP D93C22000890001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: Inherited metabolic disorders (IMDs) are a group of genetic conditions affecting metabolic pathways. The treatment of some IMDs requires the dietary restriction of specific amino acids. IMDs may also necessitate the supplementation of one or more amino acids due to factors such as reduced dietary intake, impaired synthesis, defective transport or absorption, or increased utilization. This literature review aims to evaluate the most recent evidence regarding amino acid supplementation in IMDs, considering not only the prevention of amino acid deficiency and toxic accumulation but also the competition with other toxic metabolites. Methods: A systematic search strategy was developed and applied to PubMed\/Medline and Scopus databases to identify relevant studies. Amino acids were categorized into six groups: branched-chain amino acids, aromatic amino acids, sulfur amino acids, urea cycle amino acids, other essential amino acids, and other non-essential amino acids. Results: A total of 24 rare IMDs were evaluated. A final number of 99 selected articles were assessed based on the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence. Although this work represents a preliminary non-systematic review, it highlights the need for further studies and data collection. Conclusions: Future research must establish the plasma amino acid levels that indicate the need for supplementation, specify the appropriate dosages (g\/day or mg\/kg\/day), determine the optimal treatment duration, and, crucially, define the target plasma ranges to be maintained for effective management of IMDs.<\/jats:p>","DOI":"10.3390\/genes16050502","type":"journal-article","created":{"date-parts":[[2025,4,29]],"date-time":"2025-04-29T11:00:54Z","timestamp":1745924454000},"page":"502","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Single Amino Acid Supplementation in Inherited Metabolic Disorders: An Evidence-Based Review of Interventions"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2111-3111","authenticated-orcid":false,"given":"Elvira","family":"Verduci","sequence":"first","affiliation":[{"name":"Department of Health Sciences, University of Milan, 20142 Milan, Italy"},{"name":"Metabolic Diseases Unit, Department of Pediatrics, Vittore Buzzi Children\u2019s Hospital, 20154 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4859-5288","authenticated-orcid":false,"given":"Martina","family":"Tosi","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, University of Milan, 20142 Milan, Italy"},{"name":"Department of Pediatrics, Vittore Buzzi Children\u2019s Hospital, 20154 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0007-3379","authenticated-orcid":false,"given":"Carlo","family":"Dionisi Vici","sequence":"additional","affiliation":[{"name":"Division of Metabolic Diseases and Hepatology, Bambino Ges\u00f9 Children\u2019s Hospital IRCCS, 00165 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8894-350X","authenticated-orcid":false,"given":"Marco","family":"Spada","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Torino, 10124 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1002\/jimd.12348","article-title":"An International Classification of Inherited Metabolic Disorders (ICIMD)","volume":"44","author":"Ferreira","year":"2021","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Saudubray, J.-M., Baumgartner, M.R., Garc\u00eda-Cazorla, \u00c1., and Walter, J. (2022). Clinical Approach to Inborn Errors of Metabolism in Paediatrics. Inborn Metabolic Diseases: Diagnosis and Treatment, Springer.","DOI":"10.1007\/978-3-662-63123-2"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1007\/s10545-006-0358-0","article-title":"Clinical Approach to Treatable Inborn Metabolic Diseases: An Introduction","volume":"29","author":"Saudubray","year":"2006","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1038\/s41392-023-01569-3","article-title":"Amino Acid Metabolism in Health and Disease","volume":"8","author":"Ling","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1016\/j.numecd.2017.10.020","article-title":"Position Paper on Vegetarian Diets from the Working Group of the Italian Society of Human Nutrition","volume":"27","author":"Agnoli","year":"2017","journal-title":"Nutr. Metab. Cardiovasc. Dis. NMCD"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/s12986-018-0271-1","article-title":"Branched-Chain Amino Acids in Health and Disease: Metabolism, Alterations in Blood Plasma, and as Supplements","volume":"15","year":"2018","journal-title":"Nutr. Metab."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1097\/MCO.0000000000000614","article-title":"Effect of Branched-Chain Amino Acid Supplementation, Dietary Intake and Circulating Levels in Cardiometabolic Diseases: An Updated Review","volume":"23","author":"Zazpe","year":"2020","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"ref_8","first-page":"E21","article-title":"Effects of Intravenous Infusion of 17 Amino Acids on the Secretion of GH, Glucagon, and Insulin in Sheep","volume":"260","author":"Kuhara","year":"1991","journal-title":"Am. J. Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.jprot.2012.10.024","article-title":"An Enteral Leucine Supply Modulates Human Duodenal Mucosal Proteome and Decreases the Expression of Enzymes Involved in Fatty Acid \u03b2-Oxidation","volume":"78","author":"Goichon","year":"2013","journal-title":"J. Proteom."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/1750-1172-9-7","article-title":"Single Amino Acid Supplementation in Aminoacidopathies: A Systematic Review","volume":"9","author":"Derks","year":"2014","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e1000097","DOI":"10.1371\/journal.pmed.1000097","article-title":"PRISMA Group Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement","volume":"6","author":"Moher","year":"2009","journal-title":"PLoS Med."},{"key":"ref_12","unstructured":"(2024, October 27). OCEBM Levels of Evidence. Available online: https:\/\/www.cebm.ox.ac.uk\/resources\/levels-of-evidence\/ocebm-levels-of-evidence."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1002\/jimd.12100","article-title":"Suggested Guidelines for the Diagnosis and Management of Urea Cycle Disorders: First Revision","volume":"42","author":"Burlina","year":"2019","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/j.ymgme.2013.09.003","article-title":"Dietary Management of Urea Cycle Disorders: European Practice","volume":"110","author":"Adam","year":"2013","journal-title":"Mol. Genet. Metab."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"S72","DOI":"10.1016\/j.ymgme.2010.02.019","article-title":"New Insights in Nutritional Management and Amino Acid Supplementation in Urea Cycle Disorders","volume":"100","author":"Scaglia","year":"2010","journal-title":"Mol. Genet. Metab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1093\/hmg\/ddq507","article-title":"Phenylbutyrate Therapy for Maple Syrup Urine Disease","volume":"20","author":"Lanpher","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"ref_17","unstructured":"Adam, M.P., Feldman, J., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., and Amemiya, A. (1993). Maple Syrup Urine Disease. GeneReviews, University of Washington."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.ymgme.2009.12.007","article-title":"Classical Maple Syrup Urine Disease and Brain Development: Principles of Management and Formula Design","volume":"99","author":"Strauss","year":"2010","journal-title":"Mol. Genet. Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/0190-9622(93)70036-S","article-title":"Dermatitis in Treated Maple Syrup Urine Disease","volume":"28","author":"Koch","year":"1993","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1111\/j.1600-0420.1996.tb00386.x","article-title":"Corneal deepithelialization caused by acute deficiency of isoleucine during treatment of a patient with maple syrup urine disease","volume":"74","author":"Tornqvist","year":"1996","journal-title":"Acta Ophthalmol. Scand. Suppl."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1111\/j.1525-1470.2008.00707.x","article-title":"Acrodermatitis Enteropathica-like Syndrome Secondary to Branched-Chain Amino Acid Deficiency in Inborn Errors of Metabolism","volume":"25","year":"2008","journal-title":"Pediatr. Dermatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1542\/peds.109.6.999","article-title":"Diagnosis and Treatment of Maple Syrup Disease: A Study of 36 Patients","volume":"109","author":"Morton","year":"2002","journal-title":"Pediatrics"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1542\/peds.92.2.280","article-title":"Nasogastric Drip Feeding as the Only Treatment of Neonatal Maple Syrup Urine Disease","volume":"92","author":"Parini","year":"1993","journal-title":"Pediatrics"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1001\/archpedi.152.6.593","article-title":"Treatment of the Acute Crisis in Maple Syrup Urine Disease","volume":"152","author":"Nyhan","year":"1998","journal-title":"Arch. Pediatr. Adolesc. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.ymgme.2014.05.006","article-title":"Nutrition Management Guideline for Maple Syrup Urine Disease: An Evidence- and Consensus-Based Approach","volume":"112","author":"Frazier","year":"2014","journal-title":"Mol. Genet. Metab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1002\/jimd.12370","article-title":"Guidelines for the Diagnosis and Management of Methylmalonic Acidaemia and Propionic Acidaemia: First Revision","volume":"44","author":"Forny","year":"2021","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1038\/gim.2015.102","article-title":"A Critical Reappraisal of Dietary Practices in Methylmalonic Acidemia Raises Concerns about the Safety of Medical Foods. Part 1: Isolated Methylmalonic Acidemias","volume":"18","author":"Manoli","year":"2016","journal-title":"Genet. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/s00726-005-0221-x","article-title":"Expression of LAT1 and LAT2 Amino Acid Transporters in Human and Rat Intestinal Epithelial Cells","volume":"29","author":"Fraga","year":"2005","journal-title":"Amino Acids"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1017\/S0954422418000173","article-title":"Optimising Amino Acid Absorption: Essential to Improve Nitrogen Balance and Metabolic Control in Phenylketonuria","volume":"32","author":"MacDonald","year":"2019","journal-title":"Nutr. Res. Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1002\/jimd.12066","article-title":"Evaluation of Dietary Treatment and Amino Acid Supplementation in Organic Acidurias and Urea-Cycle Disorders: On the Basis of Information from a European Multicenter Registry","volume":"42","author":"Molema","year":"2019","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Gugelmo, G., Lenzini, L., Francini-Pesenti, F., Fasan, I., Spinella, P., Valentini, R., Miraval, A., Avogaro, A., and Vitturi, N. (2022). Anthropometrics, Dietary Intake and Body Composition in Urea Cycle Disorders and Branched Chain Organic Acidemias: A Case Study of 18 Adults on Low-Protein Diets. Nutrients, 14.","DOI":"10.3390\/nu14030467"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"47","DOI":"10.3945\/ajcn.110.004341","article-title":"Variable Dietary Management of Methylmalonic Acidemia: Metabolic and Energetic Correlations","volume":"93","author":"Hauser","year":"2011","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/j.ymgme.2019.02.007","article-title":"Nutrition Management Guideline for Propionic Acidemia: An Evidence- and Consensus-Based Approach","volume":"126","author":"Jurecki","year":"2019","journal-title":"Mol. Genet. Metab."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1097\/MCO.0000000000000428","article-title":"Effects of Medical Food Leucine Content in the Management of Methylmalonic and Propionic Acidemias","volume":"21","author":"Myles","year":"2018","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1186\/s13023-024-03373-w","article-title":"The European Reference Network for Metabolic Diseases (MetabERN) Clinical Pathway Recommendations for Pompe Disease (Acid Maltase Deficiency, Glycogen Storage Disease Type II)","volume":"19","author":"Parenti","year":"2024","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1177\/0148607190014002210","article-title":"Treatment of Acid Maltase Deficiency with a Diet High in Branched-Chain Amino Acids","volume":"14","author":"Mobarhan","year":"1990","journal-title":"JPEN J. Parenter. Enteral. Nutr."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1136\/jnnp.52.8.954","article-title":"The Effect of a High Protein Diet on Leucine and Alanine Turnover in Acid Maltase Deficiency","volume":"52","author":"Umpleby","year":"1989","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2202","DOI":"10.1038\/s41436-021-01249-z","article-title":"Treatment of ARS Deficiencies with Specific Amino Acids","volume":"23","author":"Kok","year":"2021","journal-title":"Genet. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e70017","DOI":"10.1002\/jimd.70017","article-title":"Setting the Stage for Treatment of Aminoacyl-tRNA Synthetase (ARS)1-Deficiencies: Phenotypic Characterization and a Review of Treatment Effects","volume":"48","author":"Rohof","year":"2025","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1186\/s13023-017-0685-2","article-title":"The Complete European Guidelines on Phenylketonuria: Diagnosis and Treatment","volume":"12","author":"MacDonald","year":"2017","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_41","first-page":"CD001507","article-title":"Tyrosine Supplementation for Phenylketonuria","volume":"2021","author":"Remmington","year":"2013","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1172\/JCI5017","article-title":"Large Neutral Amino Acids Block Phenylalanine Transport into Brain Tissue in Patients with Phenylketonuria","volume":"103","author":"Pietz","year":"1999","journal-title":"J. Clin Investig."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1007\/s10545-010-9216-1","article-title":"Large Neutral Amino Acids in the Treatment of PKU: From Theory to Practice","volume":"33","author":"Hoeksma","year":"2010","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/jcbfm.2014.183","article-title":"Phenylketonuria: Brain Phenylalanine Concentrations Relate Inversely to Cerebral Protein Synthesis","volume":"35","author":"Sijens","year":"2015","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1186\/1750-1172-8-133","article-title":"Phenylketonuria: Reduced Tyrosine Brain Influx Relates to Reduced Cerebral Protein Synthesis","volume":"8","author":"Hoeksma","year":"2013","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_46","first-page":"23","article-title":"Dietary Threonine Reduces Plasma Phenylalanine Levels in Patients with Hyperphenylalaninemia","volume":"36","author":"Sanjurjo","year":"2003","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.jpeds.2014.03.061","article-title":"Melatonin and Dopamine as Biomarkers to Optimize Treatment in Phenylketonuria: Effects of Tryptophan and Tyrosine Supplementation","volume":"165","author":"Yano","year":"2014","journal-title":"J. Pediatr."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1055\/a-2008-4230","article-title":"Treatment of Mitochondrial Phenylalanyl-tRNa-Synthetase Deficiency (FARS2) with Oral Phenylalanine","volume":"54","author":"Oswald","year":"2023","journal-title":"Neuropediatrics"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1007\/s10545-016-9979-0","article-title":"Guidelines for the Diagnosis and Management of Cystathionine \u03b2-Synthase Deficiency","volume":"40","author":"Morris","year":"2017","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s10545-006-0452-3","article-title":"A Rationale for Cystine Supplementation in Severe Homocystinuria","volume":"30","author":"Lee","year":"2007","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/s10545-016-9991-4","article-title":"Guidelines for Diagnosis and Management of the Cobalamin-Related Remethylation Disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR Deficiency","volume":"40","author":"Huemer","year":"2017","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s13023-024-03021-3","article-title":"Late-Onset Methylmalonic Acidemia and Homocysteinemia (cblC Disease): Systematic Review","volume":"19","author":"Arhip","year":"2024","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_53","first-page":"51","article-title":"Reversal of Respiratory Failure in Both Neonatal and Late Onset Isolated Remethylation Disorders","volume":"16","author":"Broomfield","year":"2014","journal-title":"JIMD Rep."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1002\/jimd.12448","article-title":"Methionine Synthase Deficiency: Variable Clinical Presentation and Benefit of Early Diagnosis and Treatment","volume":"45","author":"Kripps","year":"2022","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3057","DOI":"10.1002\/ppul.25031","article-title":"Rescue of Respiratory Failure in Pulmonary Alveolar Proteinosis Due to Pathogenic MARS1 Variants","volume":"55","author":"Lenz","year":"2020","journal-title":"Pediatr. Pulmonol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2101554","DOI":"10.1183\/13993003.01554-2021","article-title":"Methionine Supplementation for Multi-Organ Dysfunction in MetRS-Related Pulmonary Alveolar Proteinosis","volume":"59","author":"Hadchouel","year":"2022","journal-title":"Eur. Respir. J."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1016\/j.ajt.2024.03.003","article-title":"Successful Lung Transplantation in Genetic Methionyl-tRNA Synthetase-Related Alveolar Proteinosis\/Lung Fibrosis without Recurrence under Methionine Supplementation: Medium-Term Outcome in 4 Cases","volume":"24","author":"Roy","year":"2024","journal-title":"Am. J. Transplant."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1186\/s13023-023-02800-8","article-title":"Citrulline in the Management of Patients with Urea Cycle Disorders","volume":"18","author":"Imbard","year":"2023","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/s13023-015-0242-9","article-title":"The Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome","volume":"10","author":"Martinelli","year":"2015","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1002\/jimd.12768","article-title":"The Therapeutic Landscape of Citrin Deficiency","volume":"47","author":"Kuek","year":"2024","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Pinto, A., Ashmore, C., Batzios, S., Daly, A., Dawson, C., Dixon, M., Evans, S., Green, D., Gribben, J., and Hunjan, I. (2020). Dietary Management, Clinical Status and Outcome of Patients with Citrin Deficiency in the UK. Nutrients, 12.","DOI":"10.3390\/nu12113313"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/S1386-6346(02)00331-5","article-title":"Effectiveness of Carbohydrate-Restricted Diet and Arginine Granules Therapy for Adult-Onset Type II Citrullinemia: A Case Report of Siblings Showing Homozygous SLC25A13 Mutation with and without the Disease","volume":"26","author":"Imamura","year":"2003","journal-title":"Hepatol. Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.ymgme.2012.02.010","article-title":"Lysinuric Protein Intolerance (LPI): A Multi Organ Disease by Far More Complex than a Classic Urea Cycle Disorder","volume":"106","author":"Schiff","year":"2012","journal-title":"Mol. Genet. Metab."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"dmm050233","DOI":"10.1242\/dmm.050233","article-title":"Inborn Errors of Amino Acid Metabolism\u2014From Underlying Pathophysiology to Therapeutic Advances","volume":"16","author":"Ziegler","year":"2023","journal-title":"Dis. Model. Mech."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1620\/tjem.142.15","article-title":"Oral Administration of Arginine and Citrulline in the Treatment of Lysinuric Protein Intolerance","volume":"142","author":"Mizutani","year":"1984","journal-title":"Tohoku J. Exp. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1056\/NEJM198501313120506","article-title":"Lysinuric Protein Intolerance Presenting as Childhood Osteoporosis. Clinical and Skeletal Response to Citrulline Therapy","volume":"312","author":"Carpenter","year":"1985","journal-title":"N. Engl. J. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1016\/S0022-3476(80)80422-7","article-title":"Lysinuric Protein Intolerance: A Two-Year Trial of Dietary Supplementation Therapy with Citrulline and Lysine","volume":"97","author":"Rajantie","year":"1980","journal-title":"J. Pediatr."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"5821","DOI":"10.1038\/s41598-019-42183-0","article-title":"Long-Term Benefit of Microbiota Transfer Therapy on Autism Symptoms and Gut Microbiota","volume":"9","author":"Kang","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_69","unstructured":"Adam, M.P., Feldman, J., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., and Amemiya, A. (1993). Lysinuric Protein Intolerance. GeneReviews, University of Washington."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1007\/s10545-011-9289-5","article-title":"Diagnosis and Management of Glutaric Aciduria Type I\u2014Revised Recommendations","volume":"34","author":"Christensen","year":"2011","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"109363","DOI":"10.1016\/j.yebeh.2023.109363","article-title":"Update Current Understanding of Neurometabolic Disorders Related to Lysine Metabolism","volume":"146","author":"Chang","year":"2023","journal-title":"Epilepsy Behav."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1016\/j.ejpn.2014.07.001","article-title":"Novel Therapy for Pyridoxine Dependent Epilepsy Due to ALDH7A1 Genetic Defect: L-Arginine Supplementation Alternative to Lysine-Restricted Diet","volume":"18","author":"Cordeiro","year":"2014","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.ymgme.2015.05.011","article-title":"Triple Therapy with Pyridoxine, Arginine Supplementation and Dietary Lysine Restriction in Pyridoxine-Dependent Epilepsy: Neurodevelopmental Outcome","volume":"116","author":"Coughlin","year":"2015","journal-title":"Mol. Genet. Metab."},{"key":"ref_74","first-page":"7138435","article-title":"An Atypical Presentation of Pyridoxine-Dependent Epilepsy Diagnosed with Whole Exome Sequencing and Treated with Lysine Restriction and Supplementation with Arginine and Pyridoxine","volume":"2022","author":"Kim","year":"2022","journal-title":"Case Rep. Genet."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/j.ymgme.2022.02.005","article-title":"Timing of Therapy and Neurodevelopmental Outcomes in 18 Families with Pyridoxine-Dependent Epilepsy","volume":"135","author":"Tseng","year":"2022","journal-title":"Mol. Genet. Metab."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1097\/YPG.0000000000000372","article-title":"Arginine, Glycine, and Creatine Supplementation Improves Symptoms in a Female with Creatine Transporter Deficiency","volume":"34","author":"Tauer","year":"2024","journal-title":"Psychiatr. Genet."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"107694","DOI":"10.1016\/j.ymgme.2023.107694","article-title":"X-Linked Creatine Transporter (SLC6A8) Deficiency in Females: Difficult to Recognize, but a Potentially Treatable Disease","volume":"140","author":"Petersen","year":"2023","journal-title":"Mol. Genet. Metab."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Li, J., and Xu, S. (2023). Diagnosis and Treatment of X-Linked Creatine Transporter Deficiency: Case Report and Literature Review. Brain Sci., 13.","DOI":"10.3390\/brainsci13101382"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1007\/s10545-011-9411-8","article-title":"Understanding Pyrroline-5-Carboxylate Synthetase Deficiency: Clinical, Molecular, Functional, and Expression Studies, Structure-Based Analysis, and Novel Therapy with Arginine","volume":"35","author":"Martinelli","year":"2012","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1001\/jamaneurol.2015.5072","article-title":"Recommendations for the Management of Strokelike Episodes in Patients With Mitochondrial Encephalomyopathy, Lactic Acidosis, and Strokelike Episodes","volume":"73","author":"Koenig","year":"2016","journal-title":"JAMA Neurol."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Barros, C.D.S., Coutinho, A., and Tengan, C.H. (2024). Arginine Supplementation in MELAS Syndrome: What Do We Know about the Mechanisms?. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25073629"},{"key":"ref_82","first-page":"e32709","article-title":"Arginine for the Treatment of Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes: A Systematic Review","volume":"14","author":"Argudo","year":"2022","journal-title":"Cureus"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"e2318","DOI":"10.1212\/WNL.0000000000200299","article-title":"L-Arginine in Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like Episodes: A Systematic Review","volume":"98","author":"Stefanetti","year":"2022","journal-title":"Neurology"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1023\/A:1005638004530","article-title":"Oral Lysine Feeding in Gyrate Atrophy with Hyperornithinaemia--a Pilot Study","volume":"23","author":"Peltola","year":"2000","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1023\/A:1010545811361","article-title":"Sustained Oral Lysine Supplementation in Ornithine Delta-Aminotransferase Deficiency","volume":"24","author":"Elpeleg","year":"2001","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"108609","DOI":"10.1016\/j.ymgme.2024.108609","article-title":"A Mini-Review on the International Gyrate Atrophy Symposium 2023: More than Meets the Eye. Focus on Outstanding Research Questions","volume":"143","author":"Brands","year":"2024","journal-title":"Mol. Genet. Metab."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1111\/j.1651-2227.1994.tb13452.x","article-title":"Indications of Changed Amino Acid Homeostasis in Untreated and Treated PKU","volume":"407","author":"Hjelm","year":"1994","journal-title":"Acta Paediatr. Suppl."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"e23106","DOI":"10.1002\/jcla.23106","article-title":"Examining the Blood Amino Acid Status in Pretherapeutic Patients with Hyperphenylalaninemia","volume":"34","author":"Liang","year":"2020","journal-title":"J. Clin. Lab. Anal."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"22079","DOI":"10.1016\/S0021-9258(18)41638-9","article-title":"L-Threonine Transport in Pig Jejunal Brush Border Membrane Vesicles. Functional Characterization of the Unique System B in the Intestinal Epithelium","volume":"267","author":"Maenz","year":"1992","journal-title":"J. Biol. Chem."},{"key":"ref_90","unstructured":"Adam, M.P., Feldman, J., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., and Amemiya, A. (1993). Classic Isovaleric Acidemia. GeneReviews, University of Washington."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2290","DOI":"10.1172\/JCI111657","article-title":"L-Carnitine Therapy in Isovaleric Acidemia","volume":"74","author":"Roe","year":"1984","journal-title":"J. Clin. Investig."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1203\/00006450-197601000-00005","article-title":"Therapeutic Effects of Glycine in Isovaleric Acidemia","volume":"10","author":"Krieger","year":"1976","journal-title":"Pediatr. Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1016\/S0022-3476(78)80164-4","article-title":"Glycine Therapy in Isovaleric Acidemia","volume":"92","author":"Yudkoff","year":"1978","journal-title":"J. Pediatr."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1203\/00006450-198209000-00013","article-title":"Changing Plasma and Urinary Organic Acid Levels in a Patient with Isovaleric Acidemia during an Attack","volume":"16","author":"Shigematsu","year":"1982","journal-title":"Pediatr. Res."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1002\/jimd.12364","article-title":"Newborn Screening and Disease Variants Predict Neurological Outcome in Isovaleric Aciduria","volume":"44","author":"Henze","year":"2021","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Spodenkiewicz, M., Diez-Fernandez, C., R\u00fcfenacht, V., Gemperle-Britschgi, C., and H\u00e4berle, J. (2016). Minireview on Glutamine Synthetase Deficiency, an Ultra-Rare Inborn Error of Amino Acid Biosynthesis. Biology, 5.","DOI":"10.3390\/biology5040040"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/1750-1172-7-48","article-title":"Glutamine Supplementation in a Child with Inherited GS Deficiency Improves the Clinical Status and Partially Corrects the Peripheral and Central Amino Acid Imbalance","volume":"7","author":"Shahbeck","year":"2012","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1136\/bjo.69.4.283","article-title":"Clinical Trials of Vitamin B6 and Proline Supplementation for Gyrate Atrophy of the Choroid and Retina","volume":"69","author":"Hayasaka","year":"1985","journal-title":"Br. J. Ophthalmol."},{"key":"ref_99","unstructured":"Adam, M.P., Feldman, J., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., and Amemiya, A. (1993). Serine Deficiency Disorders. GeneReviews, University of Washington."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1007\/s10545-010-9249-5","article-title":"Expanding the Clinical Spectrum of 3-Phosphoglycerate Dehydrogenase Deficiency","volume":"34","author":"Tabatabaie","year":"2011","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1086\/517888","article-title":"Phosphoserine Aminotransferase Deficiency: A Novel Disorder of the Serine Biosynthesis Pathway","volume":"80","author":"Hart","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1093\/hmg\/ddae156","article-title":"Ligand Distances as Key Predictors of Pathogenicity and Function in NMDA Receptors","volume":"34","author":"Montanucci","year":"2025","journal-title":"Hum. Mol. Genet."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/bs.apha.2017.08.010","article-title":"The Neurobiology of D-Serine Signaling","volume":"82","author":"Wolosker","year":"2018","journal-title":"Adv. Pharmacol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"25","DOI":"10.3389\/fpsyt.2019.00025","article-title":"D-Serine: Potential Therapeutic Agent and\/or Biomarker in Schizophrenia and Depression?","volume":"10","author":"MacKay","year":"2019","journal-title":"Front. Psychiatry"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"eaaw0936","DOI":"10.1126\/scisignal.aaw0936","article-title":"L-Serine Dietary Supplementation Is Associated with Clinical Improvement of Loss-of-Function GRIN2B-Related Pediatric Encephalopathy","volume":"12","author":"Soto","year":"2019","journal-title":"Sci. Signal"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1093\/brain\/awae041","article-title":"L-Serine Treatment in Patients with GRIN-Related Encephalopathy: A Phase 2A, Non-Randomized Study","volume":"147","author":"Olivella","year":"2024","journal-title":"Brain"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1203\/00006450-198501000-00023","article-title":"Studies on Requirements for Amino Acids in Infants with Disorders of Amino Acid Metabolism. I. Effect of Alanine","volume":"19","author":"Kelts","year":"1985","journal-title":"Pediatr. Res."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1007\/s10545-006-0238-7","article-title":"The Effect of L-Alanine Therapy in a Patient with Adult Onset Glycogen Storage Disease Type II","volume":"29","author":"Mundy","year":"2006","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1212\/WNL.55.5.710","article-title":"The Effects of L-Alanine Supplementation in Late-Onset Glycogen Storage Disease Type II","volume":"55","author":"Bodamer","year":"2000","journal-title":"Neurology"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/S0887-8994(02)00413-7","article-title":"L-Alanine Supplementation in Late Infantile Glycogen Storage Disease Type II","volume":"27","author":"Bodamer","year":"2002","journal-title":"Pediatr. Neurol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/s13052-022-01249-y","article-title":"L-Alanine Supplementation in Pompe Disease (IOPD): A Potential Therapeutic Implementation for Patients on ERT? A Case Report","volume":"48","author":"Rovelli","year":"2022","journal-title":"Ital. J. Pediatr."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/5\/502\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:22:44Z","timestamp":1760030564000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/5\/502"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,27]]},"references-count":111,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["genes16050502"],"URL":"https:\/\/doi.org\/10.3390\/genes16050502","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,27]]}}}