Phenotypic diversity of brain MRI patterns in mitochondrial aminoacyl-tRNA synthetase mutations

Abstract Background and purpose Mitochondrial aminoacyl-tRNA synthetases—encoded by ARS2 genes—are evolutionarily conserved enzymes that catalyse the attachment of amino acids to their cognate tRNAs, ensuring the accuracy of the mitochondrial translation process. ARS2 gene mutations are associated with a wide range of clinical presentations affecting the CNS. Methods Two senior neuroradiologists analysed brain MRI of 25 patients (age range: 3 d–25 yrs.; 11 males; 14 females) with biallelic pathogenic variants of 11 ARS2 genes in a retrospective study conducted between 2002 and 2019. Results Though several combinations of brain MRI anomalies were highly suggestive of specific aetiologies (DARS2, EARS2, AARS2 and RARS2 mutations), our study detected no MRI pattern common to all patients. Stroke-like lesions were associated with pathogenic SARS2 and FARS2 variants. We also report early onset cerebellar atrophy and calcifications in AARS2 mutations, early white matter involvement in RARS2 mutations, and absent involvement of thalami in EARS2 mutations. Finally, our findings show that normal brain MRI results do not exclude the presence of ARS2 mutations: 5 patients with normal MRI images were carriers of pathogenic IARS2, YARS2, and FARS2 variants. Conclusion Our study extends the spectrum of brain MRI anomalies associated with pathogenic ARS2 variants and suggests ARS2 mutations are largely underdiagnosed.