Tyrosine supplementation with high-protein diet as a therapeutic strategy for YARS1 deficiency

Purpose Biallelic pathogenic variants in YARS1 cause tyrosyl-tRNA synthase (TyrRS) deficiency that compromises the loading of tyrosine to its tRNA. YARS1 deficiency is characterized by impairment of neurological development, growth, liver function, and hematopoiesis. For other aminoacyl-tRNA synthetase deficiencies, supplementation of the respective amino acid and high-protein diet improved outcome. Whether tyrosine supplementation is effective in YARS1 deficiency is not known. Methods Nine individuals with YARS1 deficiency received tyrosine (7 with and 2 without a high-protein diet). Aminoacylation was measured in patient-derived fibroblasts. Results Since supplementation, cooperation, endurance, and motor skills improved in 8 of 9 children. Two children demonstrated significant progress in active language skills. Weight gain improved in 6 of 9, and vomiting stopped in all cases. In 4 of 9 children, hematological parameters improved. In vitro, the TyrRS activity determined in 3 fibroblast cell lines homozygous for p.(Arg367Trp) was significantly reduced (0%, 6%, and 24%) at 100 μM tyrosine (physiological blood concentration). At 500 μM tyrosine, TyrRS activity increased to almost normal activity relative to controls at 100 μM. Conclusion Given the positive cost/risk-benefit ratio, we advocate therapeutic trials with tyrosine supplementation and high-protein diet for YARS1 deficiency. Further studies should aim to determine variant-specific differences and long-term outcomes in comparison with natural history.