Researchers at the Center for Children with White Matter Disorders, in collaboration with colleagues from the Netherlands, Germany, Iltaly, USA, Belgium and Russia, have found the gene for a new white matter disorder.
Definition of the inherited disease Leukoencephalopathy with brain stem and spinal cord involvement and elevated lactate (LBSL) was based on clinical descriptions and Magnetic Resonance Imaging (MRI) results. LBSL patients suffer from motor problems mainly. The onset and progression vary greaqtly. The most seriously affected patients become wheelchair-dependent as children, while others remain able to walk and live an independent life as adults.
MRI of the central nervous system shows inhomogeneous signal abnormalities in the periventricular and deep cerebral white matter and the involvement of specific white matter tracts. This constellation of white matter abnormalities has not been observed in other white matter disorders and the MRI is diagnostic.
Through collaboration with several doctors around the world we have been able to diagnose 30 families with LBSL, which allowed us to search for the gene that is involved in this disease. Through genome-wide linkage analysis of microsatellite markers we found a region on chromosome 1 that is linked to the disease. Subsequent sequence analysis of several genes in this region showed that LBSL is caused by mutations in a gene called DARS2. This gene encodes mitochondrial aspartyl-tRNA synthetase. This protein is needed for synthesis of protein inside mitochondria, the energy-producing compartments within cells. It is not surprsing that lactate in the white matter is elevated in LBSL patients, because this is a common effect of reduced mitochondrial function. The relatively mild effect of DARS2 mutations on mitochondrial activity and the specific involvement of the white matter, however, is as yet unexplained.
Publication:
Scheper GC, van der Klok T, van Andel RJ, van Berkel CG, Sissler M, Smet J, Muravina TI, Serkov SV, Uziel G, Bugiani M, Schiffmann R, Krageloh-Mann I, Smeitink JA, Florentz C, Van Coster R, Pronk JC, van der Knaap MS.
Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation.
Nat Genet. 2007;39:534-539.