THG1L (tRNA-histidine guanylyltransferase 1 like) is a mitochondrial protein with dual functions in tRNA processing and mitochondrial dynamics. The protein catalyzes 3'-5' addition of guanine to the 5'-end of mitochondrial tRNA-histidine, a critical step for tRNA maturation 1. Beyond tRNA processing, THG1L functions as a guanine nucleotide exchange factor (GEF) for mitofusins MFN1 and MFN2, enhancing their GTP-binding capacity and promoting mitochondrial fusion 2. By regulating mitochondrial dynamics and bioenergetic function, THG1L contributes to cell survival following oxidative stress 2. Loss of THG1L function impairs mitochondrial respiratory capacity and ATP production 2. Mutations in THG1L cause autosomal recessive cerebellar ataxia (SCAR28) and related neurodevelopmental disorders. The homozygous p.Val55Ala variant causes cerebellar atrophy with developmental delay, dysarthria, and pyramidal signs, associated with abnormal mitochondrial fragmentation in patient cells 1. Compound heterozygous variants produce more severe phenotypes including intractable epilepsy, microcephaly, and profound developmental delays 3. THG1L variants were also identified in congenital microcephaly 4. The disease mechanism involves impaired mitochondrial fusion and bioenergetics rather than defective tRNA guanylyltransferase activity 1.