Abstract
Aminoacyl-transfer RNA (tRNA) synthetases (ARSs) are key enzymes for protein translation. The number of identified patients with recessive ARS1 deficiencies is rapidly increasing. Initially, only supportive care was available, but in recent years beneficial effects of targeted amino acid supplementation have been described. To allow early treatment and prevention of symptoms, rapid recognition is necessary, as well as insight into the natural history to evaluate treatment effects. We performed a scoping literature search for clinical characteristics and treatment effects of patients with ARS1 deficiencies. Symptoms were matched to Human Phenotype Ontology terms. We identified 438 patients with 20 different ARS1 deficiencies. Overall mortality was 22%. Neurological symptoms were most prevalent across all ARS1 deficiencies (in 87% of patients), including neurodevelopmental disorder (79%), microcephaly (50%) and seizures (46%). Growth issues and ophthalmological symptoms were also prevalent in many ARS1 deficiencies. Two distinct phenotypical clusters were seen: one with multisystemic disease including liver- and lung disease and another with a predominantly neurological phenotype. Supplementation with cognate amino acids was described in 21 patients, with beneficial effects (e.g., improvements in growth, development, liver and lung disease) in the majority. Treatment did not alleviate the most severe phenotypes. Specific symptoms relate to (a cluster of) specific ARS1 deficiencies; the mechanism is not yet understood. Multi-organ involvement should trigger inclusion of ARS1 genes in the diagnostic work-up. Treatment with cognate amino acids is promising, but it remains challenging to distinguish treatment effects from natural history. Synopsis: Treatment with cognate amino acids in ARS1 deficiencies is promising, but it remains challenging to distinguish treatment effects from natural history.