2011/07/11 by Matthis Synofzik, Julia Schicks, Tobias Lindig +7 · 49 citations
Biochemistry, Genetics and Molecular Biology · Medicine · Neuroscience · #Acetazolamide #Ataxia #Biology #Compound heterozygosity #Disease #Gene #Genetics #Internal medicine #Leukoencephalopathy #Medicine #Metabolism and Genetic Disorders #Mitochondrial Function and Pathology #Mutation #Neuroscience #Phenotype #RNA and protein synthesis mechanisms
paper · doi:10.1136/jmg.2011.090282
published in Journal of Medical Genetics 48(10), 713-715 (BMJ)
openalex publication_date 2011/07/11 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/30
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.