CASE REPORT article
Front. Pediatr.
Sec. Genetics of Common and Rare Diseases
Amino acid supplementation in mitochondrial aminoacyl-tRNA synthetase defects: two case reports of tyrosine supplementation in YARS2-associated disease and a review of the literature
Provisionally accepted
- 1Unit of Child Neurology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
- 2Ph.D. Program in Translational Medicine, Universita degli Studi di Milano, Milan, Italy
- 3Unit of Medical Genetics and Neurogenetics-Mariani Centre for Paediatric Mitochondrial Disorders, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
- 4Department of Pathophysiology and Transplantation, Universita degli Studi di Milano, Milan, Italy
- 5Hospital Pharmacy, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
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Background: Mitochondrial diseases (MDs) linked to pathogenic variants in aminoacyl-tRNA synthetase (ARS) genes, either cytosolic (ARS1) or mitochondrial (ARS2), are rare and clinically diverse. YARS2 deficiency causes myopathy, lactic acidosis, and sideroblastic anemia (MLASA2). No treatments exist, though targeted amino acid (AA) supplementation could function as a possible therapy, as many ARS variants retain partial activity. Benefit is reported in several ARS1 disorders, but evidence in ARS2 diseases, including YARS2 deficiency, is scarce. Methods: We report two siblings with genetically confirmed MLASA2 due to homozygous YARS2 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 ARS2 deficiencies was also conducted. Results: Tyrosine was well tolerated. The more severely affected sibling showed improved 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 5 prior ARS2 cases treated with AA supplementation, with variable benefit. Conclusions: YARS2-related MLASA2 is a severe disorder 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, though limited, support the feasibility of this treatment. Our findings suggest tyrosine is a promising candidate therapy in YARS2 deficiency; larger multicenter studies are needed to validate our data.
Keywords: MLASA, YARS2, aminoacyl-tRNA synthetase defect, ARS2, Tyrosine, Treatment, Amino-, Acids
Received: 12 Sep 2025; Accepted: 03 Nov 2025.
Copyright: © 2025 Ferrera, Segre, Lamantea, Ghezzi, Rivelli and Ardissone. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Anna Ardissone, anna.ardissone@istituto-besta.it
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