{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T13:26:50Z","timestamp":1791898010427,"version":"4.3.4"},"reference-count":25,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pediatr."],"abstract":"\n Background<\/jats:title>\n \n Mitochondrial diseases (MDs) caused by pathogenic variants in aminoacyl-tRNA synthetase (\n ARS<\/jats:italic>\n ) genes, either cytosolic (\n ARS1<\/jats:italic>\n ) or mitochondrial (\n ARS2<\/jats:italic>\n ), are rare and clinically diverse.\n YARS2<\/jats:italic>\n deficiency causes myopathy, lactic acidosis, and sideroblastic anemia (MLASA2). No treatments exist, although targeted amino acid (AA) supplementation could function as a possible therapy, as many\n ARS<\/jats:italic>\n variants retain partial activity. While benefits have been reported in several\n ARS1<\/jats:italic>\n disorders, evidence in\n ARS2<\/jats:italic>\n diseases, including\n YARS2<\/jats:italic>\n deficiency, remains limited.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We report two siblings with genetically confirmed MLASA2 due to homozygous\n YARS2<\/jats:italic>\n variants who received oral tyrosine for 12 months. Clinical, biochemical, cardiac, and thyroid safety assessments were performed at baseline and follow-up. Standardized measures tracked motor function, symptoms, and quality of life. A systematic review of AA supplementation in\n ARS2<\/jats:italic>\n deficiencies was also conducted.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Tyrosine was well tolerated. The more severely affected sibling showed improvements in motor function, endurance, and quality of life, with modest prolongation of transfusion intervals. The milder sibling reported increased energy and functional gains. Cardiac function remained stable. Literature review revealed only five prior\n ARS2<\/jats:italic>\n cases treated with AA supplementation, with variable outcomes.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n YARS2-<\/jats:italic>\n related MLASA2 is a severe disorder associated with high morbidity and premature mortality. No spontaneous recovery has been reported, supporting tyrosine as the likely driver of observed improvements. No cardiac or thyroid toxicities were detected during treatment. Prior reports, although limited, support the feasibility of this treatment. Our findings suggest tyrosine is a promising candidate therapy in\n YARS2<\/jats:italic>\n deficiency; larger multicenter studies are needed to validate our data.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fped.2025.1699348","type":"journal-article","created":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T06:26:11Z","timestamp":1764570371000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Amino acid supplementation in mitochondrial aminoacyl-tRNA synthetase defects: two case reports of tyrosine supplementation in YARS2-associated disease and a review of the 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