To report a novel AARS2 gene sequence variant with associated clinical, paraclinical, radiologic, and whole genome sequence (WGS) findings in a patient presenting as a demyelinating disease mimic.

Genetic adult onset leukodystrophies (AOLD) often pose a diagnostic challenge. Recent retrospective cohort studies show a diagnostic delay of up to 9 years with nearly 25% of AOLD being initially misdiagnosed as multiple sclerosis or frontotemporal dementia leading to unnecessary treatments. This continued diagnostic uncertainty is in part due to the limited knowledge of the phenotypical spectrum of genetic mutations.  

The AARS2 (OMIM612035) is a nuclear gene on chromosome 6p21.1 encoding the mitochondrial alanyl-tRNA synthetase for mitochondrial protein translation. Reported mutations in this gene span two extremely rare distinct phenotypes – infantile cardiomyopathy and AOLD with premature ovarian failure. To date, less than 50 cases have been reported with AARS2 mutations with an ill-defined phenotypic spectrum.

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We identified a 43-year-old Caucasian female patient who originally presented with clinical syndrome consistent with autoimmune encephalitis. MRI showed multifocal white matter lesions leading to a later diagnosis of atypical demyelinating disease. A history of premature ovarian failure in conjunction with the MRI findings prompted WGS. Patient was then found to carry a novel AARS2 heterozygous variant defined as c.304G>A, predicted to result in the amino acid substitution p.Val102Met that has never been reported. Additionally, she was found to have ~4.1kb deletion corresponding to deletion boundary via NGS of chr 6:44,274,355-44,278,496 (GRCh37/hg19) that has been reported in other neurodegenerative diseases but has not been associated with AARS2 leukodystrophy with premature ovarian failure. 

Our findings highlight the clinical, paraclinical and radiologic findings of genetic AOLD at diagnostic cross junction with demyelinating diseases.  These findings extend the utility of WGS in expanding the mutational spectrum and add to the scarcity of literature regarding adult onset AARS2 leukodystrophy.