Phenotypes and genotypes of mitochondrial aminoacyl‐tRNA synthetase deficiencies from a single neurometabolic clinic

Abstract

Mitochondrial aminoacyl-tRNA synthetases play a major role in protein translation, synthesis, and oxidative phosphorylation. We reviewed all patients diagnosed with mitochondrial aminoacyl-tRNA synthetase deficiencies diagnosed in a single neurometabolic clinic. We report five patients with mitochondrial aminoacyl-tRNA synthetase deficiencies including <i>DARS2</i>, <i>EARS2</i>, <i>PARS2</i>, and <i>RARS2</i> deficiencies. Siblings with <i>DARS2</i> deficiency presented with global developmental delay within the first year of life. <i>DARS2</i>, <i>EARS2</i>, <i>PARS2</i>, and <i>RARS2</i> deficiencies were identified by whole exome sequencing. We report coagulation factor abnormalities in <i>PARS2</i> deficiency for the first time. We also report symmetric increased signal intensity in globus pallidi in FLAIR images in brain MRI in <i>EARS2</i> deficiency for the first time. One patient with <i>RARS2</i> deficiency had compound heterozygous variants in <i>RARS2</i>. One of those variants was an intronic variant. We confirmed the pathogenicity by mRNA studies. Mitochondrial aminoacyl-tRNA synthetase deficiencies are diagnosed by molecular genetic investigations. Clinically available non-invasive biochemical investigations are non-specific for the diagnosis of mitochondrial aminoacyl-tRNA synthetase deficiencies. A combination of brain MRI features and molecular genetic investigations should be undertaken to confirm the diagnosis of mitochondrial aminoacyl-tRNA synthetase deficiencies.