Treatment of ARS deficiencies with specific amino acids

Abstract

Purpose Recessive cytosolic aminoacyl-tRNA synthetase (ARS) deficiencies are severe multiorgan diseases, with limited treatment options. By loading transfer RNAs (tRNAs) with their cognate amino acids, ARS are essential for protein translation. However, it remains unknown why ARS deficiencies lead to specific symptoms, especially early life and during infections. We set out to increase pathophysiological insight and improve therapeutic possibilities. Methods In fibroblasts from patients with isoleucyl-RS (IARS), leucyl-RS (LARS), phenylalanyl-RS-beta-subunit (FARSB), and seryl-RS (SARS) deficiencies, we investigated aminoacylation activity, thermostability, and sensitivity to ARS-specific amino acid concentrations, and developed personalized treatments. Results Aminoacylation activity was reduced in all patients, and further diminished at 38.5/40 °C (P LARS and P FARSB ), consistent with infectious deteriorations. With lower cognate amino acid concentrations, patient fibroblast growth was severely affected. To prevent local and/or temporal deficiencies, we treated patients with corresponding amino acids (follow-up: 1/2–2 2/3rd years), and intensified treatment during infections. All patients showed beneficial treatment effects, most strikingly in growth (without tube feeding), head circumference, development, coping with infections, and oxygen dependency. Conclusion For these four ARS deficiencies, we observed a common disease mechanism of episodic insufficient aminoacylation to meet translational demands and illustrate the power of amino acid supplementation for the expanding ARS patient group. Moreover, we provide a strategy for personalized preclinical functional evaluation.

A case of QARS1 associated epileptic encephalopathy and review of epilepsy in aminoacyl-tRNA synthetase disorders

“…No specific antiepileptic strategy has been highlighted as particular efficacious in previously reported QARS1 encephalopathy cases apart from one report of benefit from the ketogenic diet in a severe, early onset case with multi-drug resistant epilepsy [6]. New research suggests supplementation of the deficient amino acid in aaRS deficiencies may be beneficial [7], although oral glutamine supplementation has been reported to worsen seizure control in one QARS1 patient, for whom memantine was subsequently effective [2].…”

The potential and limitations of intrahepatic cholangiocyte organoids to study inborn errors of metabolism

“…Conversely, patient fibroblast growth was sufficient to devise a treatment strategy, which was successfully translated to the clinics. 28 This indicates that, for some IEMs, alternative patient-derived cell models should be explored if patient ICOs do not meet the practical requirements, such as expression of genes of interest and cell growth, to unravel disease mechanisms. Moreover, we anticipate that hyperoxaluria type 1 (PH1, 259900), caused by mutations in the gene alanine-glyoxylate aminotransferase (AGXT, 604285), .…”

Correspondence on “Treatment of ARS deficiencies with specific amino acids” by Kok et al

“…What could be expected in patients with LARS deficiency? We noticed that in the study by Kok et al, 2 only patients with IARS and LARS deficiency were supplemented with additional natural protein fortification. Is it because IARS and LARS are part of MSC whereas FARS and SARS are not?…”

“…1 Although studies on the biochemical structures and functions of these enzymes has begun a few decades earlier, little is known about these groups of diseases and how to treat them. On the basis of the basic function of these enzymes in protein biosynthesis, Kok et al 2 recently published their work "Treatment of ARS deficiencies with specific amino acids" in Genetics in Medicine, in which they explored a personalized treatment strategy based on supplementing specific amino acids and natural proteins.…”

“…These patients had growth retardation (in terms of both weight and height) and mental retardation, and some growth was restored after the therapy. 2 Isoleucine and leucine share very similar structure. In addition, IARS and LARS are both monomers belonging to class I ARSs, indicating that IARS and LARS may also act in similar ways.…”