Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation.
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.
Scheper
Gert C
GC
Department of Pediatrics and Child Neurology, Vrije University Medical Center, 1081 HV Amsterdam, The Netherlands. gc.scheper@vumc.nl
van der Klok
Thom
T
van Andel
Rob J
RJ
van Berkel
Carola G M
CG
Sissler
Marie
M
Smet
Joél
J
Muravina
Tatjana I
TI
Serkov
Sergey V
SV
Uziel
Graziella
G
Bugiani
Marianna
M
Schiffmann
Raphael
R
Krägeloh-Mann
Ingeborg
I
Smeitink
Jan A M
JA
Florentz
Catherine
C
Van Coster
Rudy
R
Pronk
Jan C
JC
van der Knaap
Marjo S
MS
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
D005819:Genetic Markers; D019344:Lactic Acid; D001226:Aspartate-tRNA Ligase