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Aminoacyl-tRNA synthetases (aaRS) are ubiquitously expressed enzymes responsible for ligating amino acids to their cognate tRNA molecules through an aminoacylation reaction. The resulting aminoacyl-tRNA is delivered to ribosome elongation factors to participate in protein synthesis. Seryl-tRNA synthetase (SARS1) is one of the cytosolic aaRSs and catalyzes serine attachment to tRNASer . SARS1 deficiency has already been associated with moderate intellectual disability, ataxia, muscle weakness, and seizure in one family. We describe here a new clinical presentation including developmental delay, central deafness, cardiomyopathy, and metabolic decompensation during fever leading to death, in a consanguineous Turkish family, with biallelic variants (c.638G>T, p.(Arg213Leu)) in SARS1. This missense variant was shown to lead to protein instability, resulting in reduced protein level and enzymatic activity. Our results describe a new clinical entity and expand the clinical and mutational spectrum of SARS1 and aaRS deficiencies.

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 (PLARS and PFARSB), 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.

Purpose: Pathogenic variations in genes encoding aminoacyl-tRNA synthetases (ARSs) are increasingly associated with human disease. Clinical features of autosomal recessive ARS deficiencies appear very diverse and without apparent logic. We searched for common clinical patterns to improve disease recognition, insight into pathophysiology, and clinical care. Methods: Symptoms were analyzed in all patients with recessive ARS deficiencies reported in literature, supplemented with unreported patients evaluated in our hospital. Results: In literature, we identified 107 patients with AARS, DARS, GARS, HARS, IARS, KARS, LARS, MARS, RARS, SARS, VARS, YARS, and QARS deficiencies. Common symptoms (defined as present in ≥4/13 ARS deficiencies) included abnormalities of the central nervous system and/or senses (13/13), failure to thrive, gastrointestinal symptoms, dysmaturity, liver disease, and facial dysmorphisms. Deep phenotyping of 5 additional patients with unreported compound heterozygous pathogenic variations in IARS, LARS, KARS, and QARS extended the common phenotype with lung disease, hypoalbuminemia, anemia, and renal tubulopathy. Conclusion: We propose a common clinical phenotype for recessive ARS deficiencies, resulting from insufficient aminoacylation activity to meet translational demand in specific organs or periods of life. Assuming residual ARS activity, adequate protein/amino acid supply seems essential instead of the traditional replacement of protein by glucose in patients with metabolic diseases.

The reported QARS deficient patient carries the QARS1 mutation (NM_005051.2) c.793C>T p.(Arg265Cys and not Arg25Cys). In addition, in Fig. 5, the reported p.Lys476* in QARS1 should have been p.Lys496* (Kodera H, Osaka H, Iai M, et al. Mutations in the glutaminyl-tRNA synthetase gene cause early-onset epileptic encephalopathy. J Hum Genet. 2015;60:97–101. https://doi.org/10.1038/ jhg.2014.103). Finally, we have been informed that the patient described by Datta et al. (Datta A, Ferguson A, Simonson C, et al. Case report: QARS deficiency and favorable outcome following treatment of seizures with ketogenic diet. J Child Neurol. 2017;32(4):403–407. https://doi. org/10.1177/0883073816685508) is the same patient previously published by Salvarinova et al. (Salvarinova R, Ye CX, Rossi A, et al. Expansion of the QARS deficiency phenotype with report of a family with isolated supratentorial brain abnormalities. Neurogenetics. 2015;16(2):145–149. https://doi.org/10.1007/s10048-014-0432-y), and this patient is compound heterozygous for the nonsense variant c.1387C>T (p.Arg463*) and the missense variant c.2226G>C (p.Gln742His). These points have now been corrected in both the PDF and HTML versions of the Article.

We live in an age where the sharing of scientific findings and ideas is no longer confined to people with access to academic libraries or scientific journals. Social media have permitted for knowledge and ideas to be shared with an unprecedented speed and magnitude. This has made it possible for research findings to have a greater impact and to be rapidly implemented in society. However, the spread of unfiltered, unreferenced, and non-peer-reviewed articles through social media comes with dangers as well. In this perspective article, we aim to address both the possibilities and pitfalls of social media for translational medicine. We describe how social media can be used for patient engagement, publicity, transparency, sharing of knowledge, and implementing findings in society. Moreover, we warn about the potential pitfalls of social media, which can cause research to be misinterpreted and false beliefs to be spread. We conclude by giving advice on how social media can be harnessed to combat the pitfalls and provide a new avenue for community engagement in translational medicine.