Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation

Gert C. Scheper, Thom Van Der Klok, Rob J. Van Andel, Carola G M Van Berkel, Marie Sissler, Joél Smet, Tatjana I. Muravina, Sergey V. Serkov, Graziella Uziel, Marianna Bugiani, Raphael Schiffmann, Ingeborg Krägeloh-Mann, Jan A M Smeitink, Catherine Florentz, Rudy Van Coster, Jan C. Pronk, Marjo S. Van Der Knaap

Research output: Contribution to journalArticlepeer-review

Abstract

Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) has recently been defined based on a highly characteristic constellation of abnormalities observed by magnetic resonance imaging and spectroscopy. LBSL is an autosomal recessive disease, most often manifesting in early childhood. Affected individuals develop slowly progressive cerebellar ataxia, spasticity and dorsal column dysfunction, sometimes with a mild cognitive deficit or decline. We performed linkage mapping with microsatellite markers in LBSL families and found a candidate region on chromosome 1, which we narrowed by means of shared haplotypes. Sequencing of genes in this candidate region uncovered mutations in DARS2, which encodes mitochondrial aspartyl-tRNA synthetase, in affected individuals from all 30 families. Enzyme activities of mutant proteins were decreased. We were surprised to find that activities of mitochondrial complexes from fibroblasts and lymphoblasts derived from affected individuals were normal, as determined by different assays.

Original languageEnglish
Pages (from-to)534-539
Number of pages6
JournalNature Genetics
Volume39
Issue number4
DOIs
Publication statusPublished - Apr 2007

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

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