title: Acetazolamide-responsive exercise-induced episodic ataxia associated with a novel homozygous DARS2 mutation.
abstract: 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.
authors.affiliation: Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Matthis
authors.initials: M
authors.lastname: Synofzik
authors.forename: Julia
authors.initials: J
authors.lastname: Schicks
authors.forename: Tobias
authors.initials: T
authors.lastname: Lindig
authors.forename: Saskia
authors.initials: S
authors.lastname: Biskup
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schmidt
authors.forename: Jochen
authors.initials: J
authors.lastname: Hansel
authors.forename: Frank
authors.initials: F
authors.lastname: Lehmann-Horn
authors.forename: Ludger
authors.initials: L
authors.lastname: Schöls
mesh_terms: D000086:Acetazolamide / Q000008:administration & dosage*; D000328:Adult; D001226:Aspartate-tRNA Ligase / Q000235:genetics* / Q000378:metabolism; D001923:Brain Chemistry; D002257:Carbonic Anhydrase Inhibitors / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D015444:Exercise; D005260:Female; D020234:Gait Ataxia / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D019344:Lactic Acid / Q000032:analysis / Q000097:blood; D008279:Magnetic Resonance Imaging; D009154:Mutation; D011446:Prospective Studies; D013116:Spinal Cord / Q000737:chemistry
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D019344:Lactic Acid; D001226:Aspartate-tRNA Ligase; C558608:DARS2 protein, human; D000086:Acetazolamide