Expansion of the clinical spectrum associated with AARS2-related disorders

Am J Med Genet A. 2019 Aug;179(8):1556-1564. doi: 10.1002/ajmg.a.61188. Epub 2019 May 17.


Biallelic pathogenic variants in AARS2, a gene encoding the mitochondrial alanyl-tRNA synthetase, result in a spectrum of findings ranging from infantile cardiomyopathy to adult-onset progressive leukoencephalopathy. In this article, we present three unrelated individuals with novel compound heterozygous pathogenic AARS2 variants underlying diverse clinical presentations. Patient 1 is a 51-year-old man with adult-onset progressive cognitive, psychiatric, and motor decline and leukodystrophy. Patient 2 is a 34-year-old man with childhood-onset progressive tremor followed by the development of polyneuropathy, ataxia, and mild cognitive and psychiatric decline without leukodystrophy on imaging. Patient 3 is a 57-year-old woman with childhood-onset tremor and nystagmus which preceded dystonia, chorea, ataxia, depression, and cognitive decline marked by cerebellar atrophy and white matter disease. These cases expand the clinical heterogeneity of AARS2-related disorders, given that the first and third case represent some of the oldest known survivors of this disease, the second is adult-onset AARS2-related neurological decline without leukodystrophy, and the third is biallelic AARS2-related disorder involving a partial gene deletion.

Keywords: AARS2; leukodystrophy; movement disorder; polyneuropathy.

Publication types

  • Case Reports

MeSH terms

  • Adult
  • Alanine-tRNA Ligase / genetics*
  • Alleles
  • Brain / diagnostic imaging
  • Brain / pathology
  • DNA Mutational Analysis
  • Female
  • Genetic Association Studies* / methods
  • Genetic Predisposition to Disease*
  • Genetic Testing
  • Genetic Variation*
  • Genotype
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Mutation
  • Nervous System Diseases / diagnosis
  • Nervous System Diseases / genetics
  • Neurologic Examination
  • Phenotype*


  • AARS2 protein, human
  • Alanine-tRNA Ligase