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Acetazolamide-responsive exercise-induced episodic ataxia associated with a novel homozygous DARS2 mutation
  1. Matthis Synofzik1,2,
  2. Julia Schicks1,2,
  3. Tobias Lindig1,2,
  4. Saskia Biskup1,2,3,
  5. Thorsten Schmidt4,
  6. Jochen Hansel5,
  7. Frank Lehmann-Horn6,
  8. Ludger Schöls1,2
  1. 1Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
  2. 2German Research Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany
  3. 3CeGaT GmbH, Center for Genomics and Transcriptomics, Tübingen, Germany
  4. 4Department of Medical Genetics, University of Tübingen, Tübingen, Germany
  5. 5Department of Sports Medicine, Medical Clinic and Policlinic, University of Tübingen, Tübingen, Germany
  6. 6Division of Neurophysiology, Ulm University, Ulm, Germany
  1. Correspondence to Professor Ludger Schöls, Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, Hoppe-Seyler-Strasse 3, University of Tübingen, 72076 Tübingen, Germany; ludger.schoels{at}


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.

  • Cerebellar ataxia
  • leukoencephalopathy
  • lactate
  • paroxysmal movement disorders
  • mitochondrial disease
  • autosomal recessive ataxia
  • mitochondrial ataxia
  • clinical genetics
  • neurology
  • movement disorders (other than Parkinson)

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  • Funding The study was supported by a grant of the German Ministry of Education and Research (BMBF grant 01GM0838) to the Leukonet ( FLH is the endowed Senior Research Professor of Neurophysiology sponsored by the Charitable Hertie Foundation.

  • Competing interests None.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.