Tailored Amino Acid Treatment for Pediatric Patients With Mitochondrial Aminoacyl-tRNA Synthetase Deficiencies.

Aminoacyl-tRNA synthetases (ARSs) facilitate the loading of transfer RNAs with their cognate amino acids in the cytosol (ARS1), mitochondria (ARS2), or both (dual ARS). ARS deficiencies are clinically heterogeneous and can cause severe, occasionally fatal disease. Supplementation with cognate amino acids to prevent local amino acid depletion has shown promise in ARS1 deficiencies, but its potential in ARS2 deficiencies remains largely unexplored. We investigated the effects of cognate amino acid depletion on mitochondrial function in fibroblasts from seven patients with ARS2 deficiencies using Seahorse respirometry and imaging flow cytometry. During amino acid depletion, patient fibroblasts showed decreased mitochondrial membrane potential and reduced basal and maximal respiratory capacity. We additionally evaluated oral cognate amino acid supplementation in nine patients with SARS2, EARS2, LARS2, WARS2, FARS2, or VARS2 deficiencies. Supplementation was well tolerated, with no adverse effects observed. Several patients showed clinical improvements during treatment, including improved development, increased growth, and/or improved cardiac function. In two patients, treatment discontinuation coincided with severe neurological regression. Together, these findings demonstrate that assessing mitochondrial function during cognate amino acid depletion provides a novel functional assay for ARS2 deficiencies that may aid variant interpretation and supports a biological rationale for cognate amino acid supplementation. Clinical supplementation was well tolerated and showed preliminary beneficial effects. These findings support further investigation of cognate amino acid supplementation as a potential supportive treatment strategy for patients with ARS2 deficiencies.