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

Local depletion of the cognate amino acid impairing mitochondrial function; targeted oral cognate amino acid supplementation

Mitochondrial aminoacyl-tRNA synthetase (ARS2) deficiencies are clinically heterogeneous and sometimes severe; cognate amino acid supplementation, promising in cytosolic (ARS1) deficiencies, had been little explored in them. In fibroblasts from 7 patients, cognate amino acid depletion decreased mitochondrial membrane potential and basal and maximal respiratory capacity (Seahorse respirometry, imaging flow cytometry). Nine patients with SARS2, EARS2, LARS2, WARS2, FARS2 or VARS2 deficiencies received well-tolerated oral supplementation with no adverse effects observed, and several showed improved development, growth and/or cardiac function. In two patients, treatment discontinuation coincided with severe neurological regression.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The mitochondrial respiration assay under amino acid depletion is the most robust contribution, as it provides a functional argument for variants of uncertain significance in these genes. Clinical results remain preliminary: 9 patients, six genes, and the abstract mentions neither a control group nor a predefined endpoint, so efficacy cannot be concluded. Good tolerance and the regression signal on discontinuation do, however, justify a structured trial.

Analysis by Dr Thibaut Benquey