Alanyl-tRNA Synthetase 2 (AARS2)-Related Ataxia Without Leukoencephalopathy

• Published in: Cerebellum (London, England) Vol. 19; no. 1; pp. 154 - 160
• Main Authors: Kuo, Molly E., Antonellis, Anthony, Shakkottai, Vikram G.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.02.2020; Springer Nature B.V
• Subjects: Adult; Alanine-tRNA ligase; Alanine-tRNA Ligase - genetics; Amino Acid Sequence; Ataxia; Ataxia - diagnostic imaging; Ataxia - genetics; Biomedical and Life Sciences; Biomedicine; Cerebellar ataxia; Cerebellum; Cognitive ability; Complementation; Female; Humans; Leukoencephalopathies - diagnostic imaging; Leukoencephalopathies - genetics; Leukoencephalopathy; Magnetic resonance imaging; Male; Mitochondria; Neurobiology; Neurology; Neurosciences; Pedigree; Reproductive status; Short Reports; Siblings; tRNA; AARS2; Ovarioleukodystrophy; Leukoencephalopathy; Cerebellar ataxia; Recessive ataxia
• ISSN: 1473-4222; 1473-4230
• DOI: 10.1007/s12311-019-01080-y

Mutations in the mitochondrial alanyl-tRNA synthetase gene, AARS2 , have been reported to cause leukoencephalopathy associated with early ovarian failure, a clinical presentation described as “ovarioleukodystrophy.” We present a sibling pair: one with cerebellar ataxia and one with vision loss and cognitive impairment in addition to ataxia. Neither shows evidence of leukoencephalopathy on MRI imaging. Exome sequencing revealed that both siblings are compound heterozygous for AARS2 variants (p.Phe131del and p.Ile328Met). Yeast complementation assays indicate that p.Phe131del AARS2 dramatically impairs gene function and that p.Ile328Met AARS2 is a hypomorphic allele. This work expands the phenotypic spectrum of AARS2 -associated disease to include ataxia without leukoencephalopathy.