YARS1欠損症の治療戦略としての高タンパク質食によるチロシン補給

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.

Nine individuals with YARS1 deficiency received tyrosine (seven with and two without high-protein diet). Aminoacylation was measured in patient-derived fibroblasts.

Since supplementation, cooperation, endurance and motor skills improved in 8/9 children. Two children demonstrated significant progress in active language skills. Weight gain improved in 6/9, and vomiting stopped in all cases. In 4/9 children hematological parameters improved. In vitro, the TyrRS activity determined in three fibroblast cell lines homozygous for p.(Arg367Trp) was significantly reduced (0%, 6%, 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.

Given the positive cost/risk-benefit ratio, we advocate the therapeutic trial 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 to natural history.