Mitochondrial aminoacyl-tRNA synthetase (ARS)-defects: A review of phenotypes and therapeutic strategies in 899 patients

Purpose Aminoacyl-transfer RNA synthetases (ARSs) are crucial for protein translation. The number of identified patients with mitochondrial (mt) ARS deficiencies is rapidly increasing, but treatment is limited to supportive care. Recently, cognate amino acid supplementation has been explored. Early diagnosis and insights into natural history are necessary to evaluate potential treatment effects. Methods In this study, we performed a scoping literature search for patients with mtARS deficiencies, focusing on phenotype (using Human Phenotype Ontology terms), disease progression, death rate, and targeted treatments. Results We identified 899 patients with 19 different mtARS deficiencies with a wide variation in age at disease presentation (0-63 years), clinical symptoms, and death rate (0%-57%). Although neurologic problems were common across many mtARS deficiencies, symptoms were surprisingly different and highly specific for one or a few ARS deficiencies. Supplementation with cognate amino acids has been explored in 11 patients, but studies were largely observational, and the observed effects were variable. Conclusion mtARS deficiencies are an important subgroup within primary mitochondrial disorders, with 899 patients already being reported. The genotype-phenotype correlation between specific symptoms and mtARS deficiencies is not yet understood. Treatment with cognate amino acids is a theoretically appealing potential disease-modifying treatment modality that needs to be explored further with well-designed controlled studies.