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Leukoencephalopathy with brain stem and spinal cord involvement and elevated lactate


We have recently defined a novel disorder 'Leukoencephalopathy with brain stem and spinal cord involvement and elevated white matter lactate' (LBSL) on the basis of characteristic magnetic resonance imaging (MRI) and spectroscopy (MRS) findings (1). The consistent lactate elevation suggested an underlying mitochondrial dysfunction.

Clinical symptoms

LBSL is a disorder clinically characterized by slowly progressive signs of pyramidal, cerebellar and dorsal column dysfunction. The disease has a Friedreich ataxia-like clinical picture with a childhood or adolescent onset of symptoms. The spasticity and ataxia affect the legs more severely than the arms. The degree of handicap varies. Some patients become wheelchair-dependent as a child and have severely decreased manual dexterity, making them dependent on others for all daily activities, while other patients show only mild neurological abnormalities without functional problems until mid-adulthood. Some patients have learning problems or show signs of some mental decline.

Diagnosis - MRI and MRS

The MRI pattern is uniform among LBSL patients and is different from the patterns observed in other leukoencephalopathies, both classical and recently defined. MRI shows inhomogeneous signal abnormalities in the cerebral white matter and selective involvement of specific brain stem and spinal cord tracts. MRS shows increased lactate in the abnormal white matter in most patients (1). Especially the selective tract involvement is striking. The pyramidal tracts extending downwards from the motor cortex through the posterior limb of the internal capsule and the brain stem into the lateral corticospinal tracts of the spinal cord are affected over their entire length. Also the sensory tracts extending from the dorsal columns through the medial lemniscus up to the thalamus are affected over their entire length. Furthermore, there is a remarkable involvement of the intraparenchymal trajectories of the trigeminal nerves, inferior and superior cerebellar peduncles and mesencephalic trigeminal tracts (1-4).



Elevated levels of lactate are not only found in the affected cerebral white matter in MRS, but sometimes also in the CSF and occasionally in blood. Consistent elevations of lactate are suggestive of an underlying mitochondrial defect (respiratory chain / oxidative phosphorylation defect).

click here for enlarged MRI and legend



Since description of the disease in 2003, many new patients have been referred to us and family data strongly suggested that LBSL is inherited in an autosomal recessive manner. Therefore, the responsible gene was most likely nuclear, and not part of the mitochondrial genome. Recently we have published that LBSL patients carry mutations in the gene for a nuclear DNA-encoded mitochondrial tRNA synthetase (DARS2) (5). Several of the mutations that we observed in LBSL patients are predicted to affect the catalytic core of the protein or affect amino acids close to the dimerization interface of the protein. A striking finding is that in none of our 38 LBSL patients we have observed a mutation in the homozygous state.

Function of mtAspRS

DARS2 encodes mitochondrial aspartyl-tRNA synthetase (mtAspRS) (6). Transfer RNA (tRNA) is the 'adaptor' molecule that enables the genetic code contained in the nucleotide sequence of a messenger RNA (mRNA) molecule to be translated into the amino acid sequence of a protein. The tRNA contains an anti-codon (three nucleotides) that recognizes a specific codon (three matching nucleotides) in the mRNA. Each tRNA with a certain specific anticodon is associated with a certain specific amino acid. In this way the sequence of codons in the mRNA determines the sequence of amino acids in the protein. Each amino acid is attached to a tRNA by a specific amino acyl-tRNA synthetase. The key to this process lies in the recognition of the correct tRNA molecule by an amino acyl-tRNA synthetase, which attaches the correct amino acid for the tRNA. The amino acyl-tRNA synthetase also mediates a proof reading process to ensure high fidelity of tRNA charging; if the tRNA is found to be improperly charged, the amino acid-tRNA bond is hydrolyzed.

LBSL is a so-called mitochondrial disease. Diseases caused by mitochondrial dysfunction often selectively affect the central nervous system, most often the neurons, the cells most sensitive to energy failure. The selective involvement of specific white matter tracts in LBSL is unexplained. It is, however, important to realize that amino acyl-tRNA synthetases are known to participate in functions other than translation only, including transcription, splicing, inflammation, angiogenesis and apoptosis. Furthermore, in higher eukaryotes multi-functional proteins associate with amino acyl-tRNA synthetases to form multi-synthetase complexes, which have additional functions unrelated to their role in protein synthesis (7).


1. van der Knaap MS, van der Voorn P, Barkhof F, Van Coster R, Krageloh-Mann I, Feigenbaum A, Blaser S, Vles JS, Rieckmann P, Pouwels PJ. A new leukoencephalopathy with brainstem and spinal cord involvement and high lactate. Ann Neurol 2003; 53: 252-258.
2. Serkov SV, Pronin IN, Bykova OV, Maslova OI, Arutyunov NV, Muravina TI, Kornienko VN, Fadeeva LM, Marks H, Bonnemann C, Schiffmann R, van der Knaap MS. Five patients with a recently described novel leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate. Neuropediatrics 2004; 35: 1-5.
3. Linnankivi T, Lundbom N, Autti T, Hakkinen AM, Koillinen H, Kuusi T, Lonnqvist T, Sainio K, Valanne L, Aarimaa T, Pihko H. Five new cases of a recently described leukoencephalopathy with high brain lactate. Neurology 2004; 63: 688-692.
4. Labauge P, Roullet E, Boespflug-Tanguy O, Nicoli F, Le Fur Y, Cozzone PJ, Ducreux D, Rodriguez D.  Familial, Adult Onset Form of Leukoencephalopathy with Brain Stem and Spinal Cord Involvement: Inconstant High Brain Lactate and Very Slow Disease Progression. Eur Neurol 2007; 58:59-61
5. 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.
6. Bonnefond L, Fender A, Rudinger-Thirion J, Giege R, Florentz C, Sissler M.
Toward the full set of human mitochondrial aminoacyl-tRNA synthetases: characterization of AspRS and TyrRS. Biochemistry 2005; 44: 4805-4816.
7. Park SG, Ewalt KL, Kim S. Functional expansion of aminoacyl-tRNA synthetases and their interacting factors: new perspectives on housekeepers. Trends Biochem Sci 2005; 30: 569-574. Review.