Loss-of-function alanyl-tRNA Synthetase Mutations Cause an Autosomal-Recessive Early-Onset Epileptic Encephalopathy With Persistent Myelination Defect

Am J Hum Genet. 2015 Apr 2;96(4):675-81. doi: 10.1016/j.ajhg.2015.02.012. Epub 2015 Mar 26.


Mutations in genes encoding aminoacyl-tRNA synthetases are known to cause leukodystrophies and genetic leukoencephalopathies-heritable disorders that result in white matter abnormalities in the central nervous system. Here we report three individuals (two siblings and an unrelated individual) with severe infantile epileptic encephalopathy, clubfoot, absent deep tendon reflexes, extrapyramidal symptoms, and persistently deficient myelination on MRI. Analysis by whole exome sequencing identified mutations in the nuclear-encoded alanyl-tRNA synthetase (AARS) in these two unrelated families: the two affected siblings are compound heterozygous for p.Lys81Thr and p.Arg751Gly AARS, and the single affected child is homozygous for p.Arg751Gly AARS. The two identified mutations were found to result in a significant reduction in function. Mutations in AARS were previously associated with an autosomal-dominant inherited form of axonal neuropathy, Charcot-Marie-Tooth disease type 2N (CMT2N). The autosomal-recessive AARS mutations identified in the individuals described here, however, cause a severe infantile epileptic encephalopathy with a central myelin defect and peripheral neuropathy, demonstrating that defects of alanyl-tRNA charging can result in a wide spectrum of disease manifestations.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Abnormalities, Multiple / pathology
  • Alanine-tRNA Ligase / chemistry
  • Alanine-tRNA Ligase / genetics*
  • Amino Acid Sequence
  • Base Sequence
  • Epilepsy / genetics*
  • Epilepsy / pathology
  • Genes, Recessive / genetics
  • Humans
  • Infant
  • Infant, Newborn
  • Models, Molecular*
  • Molecular Sequence Data
  • Mutation / genetics
  • Myelin Sheath / pathology*
  • Peripheral Nervous System Diseases / genetics*
  • Peripheral Nervous System Diseases / pathology
  • Phenotype*
  • Prospective Studies
  • Sequence Analysis, DNA
  • Syndrome
  • United States


  • Alanine-tRNA Ligase