AARS2 compound heterozygous variants in a case of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia

Abstract

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), usually referred to as hereditary diffuse leukoencephalopathy with spheroids or pigmentary orthochromatic leukodystrophy, is genetically caused by CSF1R mutations. AARS2 was recently confirmed to be another causative gene in a series of CSF1R-negative ALSP cases. We report a case of adult-onset leukoencephalopathy with ALSP with AARS2 variants. A 34-year-old woman presented with 2 years of motor and cognitive deterioration with severely impaired cortical functions and rigid spasticity. Brain magnetic resonance imaging showed a confluent, patchy, and predominantly frontoparietal, periventricular pattern of white matter lesions, with relatively preserved subcortical U-fibers. Brain biopsy revealed axonal spheroids, severe demyelination and pigmented macrophages. Genetic analyses revealed compound heterozygous c.1691T>C and c.179C>A variants in the AARS2 gene. CSF1R mutation testing was negative. Our findings proved adult-onset leukoencephalopathy with spheroids and pigmented glia to be a genetically heterogeneous disease entity. The selective brain involvement without ovarian failure might be a new subtype in AARS2 mutations related to ALSP.