title: Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation.
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.
authors: Department of Pediatrics and Child Neurology, Vrije University Medical Center, 1081 HV Amsterdam, The Netherlands. gc.scheper@vumc.nl
authors: Gert C
authors: GC
authors: Scheper
authors: Thom
authors: T
authors: van der Klok
authors: Rob J
authors: RJ
authors: van Andel
authors: Carola G M
authors: CG
authors: van Berkel
authors: Marie
authors: M
authors: Sissler
authors: Joél
authors: J
authors: Smet
authors: Tatjana I
authors: TI
authors: Muravina
authors: Sergey V
authors: SV
authors: Serkov
authors: Graziella
authors: G
authors: Uziel
authors: Marianna
authors: M
authors: Bugiani
authors: Raphael
authors: R
authors: Schiffmann
authors: Ingeborg
authors: I
authors: Krägeloh-Mann
authors: Jan A M
authors: JA
authors: Smeitink
authors: Catherine
authors: C
authors: Florentz
authors: Rudy
authors: R
authors: Van Coster
authors: Jan C
authors: JC
authors: Pronk
authors: Marjo S
authors: MS
authors: van der Knaap
mesh_terms: D001226:Aspartate-tRNA Ligase / Q000235:genetics* / Q000378:metabolism; D008040:Genetic Linkage; D005819:Genetic Markers; D006239:Haplotypes; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism*; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics*; D028361:Mitochondrial Diseases / Q000235:genetics; D011110:Polymorphism, Genetic; D013132:Spinocerebellar Degenerations / Q000235:genetics* / Q000378:metabolism
chemical_list: D005819:Genetic Markers; D019344:Lactic Acid; D001226:Aspartate-tRNA Ligase