Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation (LBSL)

What is Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation (LBSL)?

Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation (LBSL) is a genetic disorder that was identified on the basis of a characteristic brain magnetic resonance imaging (MRI) pattern. The disease affects the brain and the spinal cord and causes neurologic symptoms.

 

What are the symptoms of LBSL?

LBSL is a disorder with a variable age of onset and severity. Symptoms may appear in the first months of life up to later adulthood, but in the majority the onset is in childhood. The most important signs are spasticity (muscle stiffness, muscle cramps), ataxia (coordination problems) and sensory problems. The legs are more severely affected 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 that interfere with daily life to a small extent. Some patients have learning problems or show signs of some mental decline. The disease course is generally slowly progressive, without sudden episodes of deterioration. Life expectancy can be normal, but there are also severe forms with a fatal course early in life.

 

What causes LBSL?

LBSL is caused by mutations or changes in the DARS2 gene. The DARS2 gene is necessary for the production of an enzyme called mitochondrial aspartyl-tRNA synthetase (mtAspRS). This enzyme is necessary for a certain step in protein production in mitochondria. Mitochondria are responsible for energy production in cells. The DARS2 mutations in LBSL patients result in reduced activity of the mtAspRS enzyme and possibly decreased energy production by mitochondria.

 

How is LBSL inherited?

LBSL is inherited in an autosomal recessive manner. This means that both parents carry one copy of a mutated DARS2 gene and pass it along to their child, who then has two copies of the gene and develops the disease. Parents who have one copy of the mutated gene and a second normal gene are genetic carriers of the abnormal gene, but do not have symptoms. For each pregnancy, carrier parents have a 25% chance of having a child affected by the disorder. Families with a child with LBSL might consult a clinical geneticist for genetic counseling.

 

How is LBSL diagnosed?

LBSL is diagnosed on the basis of the clinical symptoms in combination with specific MRI and magnetic resonance spectroscopy (MRS) findings. The MRI shows a distinctive pattern of white matter abnormalities in the brain together with abnormalities of specific sensory and motor tracts in the brainstem and the spinal cord (see our fact sheet on the MRI for more information). MRS is a special technique to measure the concentration of metabolites in the brain. In LBSL an elevated lactate is most often found, which is indicative of mitochondrial dysfunction. Subsequently, DNA analysis can identify the genetic defect in DARS2.

 

How is LBSL treated?

There is currently no curative treatment for LBSL. Treatment for LBSL is directed at the symptoms as they arise and is largely supportive.

 

How is scientific research on LBSL progressing towards improved treatment or diagnosis?

The identification of DARS2 mutations in LBSL patients was an important step as it facilitated genetic testing and further studies on the underlying disease mechanism. Further studies are focused on strategies that influence the effect of the mutations and aim at restoration of the activity of the mtAspRS enzyme.

 

Are there other names for LBSL?

Other names for LBSL are:

  • Mitochondrial Aspartyl-tRNA Synthetase Deficiency