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).


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).


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