DARS1 (aspartyl-tRNA synthetase 1) catalyzes the aminoacylation of aspartate to its cognate tRNA through a two-step reaction: amino acid activation by ATP to form aspartyl-AMP, followed by transfer to the tRNA acceptor end 1. DARS1 functions as a component of the human multi-tRNA synthetase complex (MSC), where it forms a dimeric subcomplex linked to QARS1-RARS1-AIMP1-AIMP2-KARS1 complexes through leucine zipper-mediated interactions 1. This aminoacyl-tRNA synthetase is essential for protein translation in the cytoplasm and cytosolic compartments [GO annotations]. Recessive mutations in DARS1 cause Hypomyelination with Brainstem and Spinal cord involvement and Leg spasticity (HBSL), a leukodystrophy characterized by motor regression, spasticity, ataxia, seizures, and intellectual disabilities with typical childhood onset 2. Homozygous DARS1 deletion is embryonically lethal, while hypomorphic mutations demonstrate that HBSL pathology extends beyond neurological dysfunction to include developmental delay and metabolic abnormalities affecting energy metabolism and peripheral organs 2. Additionally, the DARS1 locus at 2q21.3 shows evidence of positive selection in East Asians from Neanderthal introgression, with variants affecting DARS1 and its antisense RNA (DARS1-AS1) expression associated with immune cell function and white blood cell counts 3. Currently, no approved treatments exist for DARS1-associated HBSL.