Acetazolamide-responsive exercise-induced episodic ataxia associated with a novel homozygous DARS2 mutation

J Med Genet. 2011 Oct;48(10):713-5. doi: 10.1136/jmg.2011.090282. Epub 2011 Jul 11.


Background: Leukoencephalopathy with brain stem and spinal cord involvement and brain lactate elevation (LBSL) was recently shown to be caused by mutations in the DARS2 gene, encoding a mitochondrial aspartyl-tRNA synthetase. So far, affected individuals were invariably compound heterozygous for two mutations in DARS2, and drug treatments have remained elusive.

Methods: Prospective 2-year follow-up of the natural history of the main presenting symptoms in a homozygous DARS2 mutation carrier, followed by a 60 day treatment with acetazolamide in two different doses and with two random treatment interruptions.

Results: The patient presented with exercise-induced paroxysmal gait ataxia and areflexia as an atypical phenotype associated with a novel homozygous DARS2 mutation. These features showed an excellent dose-dependent, sustained treatment response to a carbonic anhydrase inhibitor. Pathogenic mutations in episodic ataxia genes were excluded, thus making it highly unlikely that this phenotype was because of episodic ataxia as a second disorder besides LBSL.

Conclusions: This case demonstrates that DARS2 mutation homozygosity is not lethal, as suggested earlier, but compatible with a rather benign disease course. More importantly, it extends the phenotypic spectrum of LBSL and reveals that at least some DARS2-associated phenotypic features might be readily treatable. However, future observations of paroxsymal ataxia and, possibly, areflexia in other DARS2-mutated patients are warranted to further corroborate our finding that DARS2 mutations can lead to a paroxsymal ataxia phenotype.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetazolamide / administration & dosage*
  • Adult
  • Aspartate-tRNA Ligase / genetics*
  • Aspartate-tRNA Ligase / metabolism
  • Brain Chemistry
  • Carbonic Anhydrase Inhibitors / administration & dosage*
  • Dose-Response Relationship, Drug
  • Exercise
  • Female
  • Gait Ataxia / drug therapy*
  • Gait Ataxia / enzymology*
  • Gait Ataxia / metabolism
  • Homozygote
  • Humans
  • Lactic Acid / analysis
  • Lactic Acid / blood
  • Magnetic Resonance Imaging
  • Mutation
  • Prospective Studies
  • Spinal Cord / chemistry


  • Carbonic Anhydrase Inhibitors
  • Lactic Acid
  • Aspartate-tRNA Ligase
  • DARS2 protein, human
  • Acetazolamide