Amino acid supplementation in patients affected by leukoencephalopathies associated with mitochondrial aminoacyl tRNA synthetase pathogenic variants: Pilot clinical trial in adults and review of literature

Background: Mitochondrial aminoacyl tRNA synthetase (mt-ARS) related disorders represent a widely heterogeneous group of diseases affecting the efficiency of mitochondrial protein synthesis.AARS2 and DARS2 biallelic mutations are associated with clinical syndromes prominently characterized by diffuse leukoencephalopathy with a highly variable age of onset, ranging from early infancy to adulthood.Preliminary in vitro results on patients' fibroblasts and some anecdotal reports on patients affected by mt-ARS related disease have suggested a possible benefit of supplementation with the specific substrate amino acid of the defective mt-ARS. Methods: We recruited 6 adult patients affected by AARS2 (n = 2) and DARS2 (n = 4) related leukoencephalopathies and started an oral supplementation with alanine and aspartate, respectively, for a total duration of 2 years. Therapeutic efficacy and safety were assessed through clinical examinations, standardized scales, functional tests, quality of life (QoL) scores, brain MRI, and laboratory analyses. Results: Overall, the treatment was safe and well tolerated by all patients, but efficacy endpoints were not met as no significant improvements were observed in global, cognitive, or motor scores.; nonetheless, all patients but one remained clinically stable. Conclusions: Despite inherent limitations of this pivotal trial, our findings suggest that specific amino acid supplementation is a safe intervention but do not yield a clear symptomatic benefit; nevertheless, we cannot exclude a potential role in stabilizing the clinical condition in adult patients with DARS2-related disorders.