Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (commonly referred to as LBSL) is a progressive disorder that affects the brain and spinal cord. Leukoencephalopathy refers to abnormalities in the white matter of the brain, which is tissue containing nerve cell fibers (axons) that transmit nerve impulses.

Most affected individuals begin to develop movement problems during childhood or adolescence. However, in some individuals, these problems do not develop until adulthood. People with LBSL have abnormal muscle stiffness (spasticity) and difficulty with coordinating movements (ataxia). In addition, affected individuals lose the ability to sense the position of their limbs or vibrations with their limbs. These movement and sensation problems affect the legs more than the arms, making walking difficult. Most affected individuals eventually require wheelchair assistance, sometimes as early as their teens, although the age varies.

People with LBSL can have other signs and symptoms of the condition. Some affected individuals develop recurrent seizures (epilepsy), speech difficulties (dysarthria), learning problems, or mild deterioration of mental functioning. Some people with this disorder are particularly vulnerable to severe complications following minor head trauma, which may trigger a loss of consciousness, other reversible neurological problems, or fever.

Distinct changes in the brains of people with LBSL can be seen using magnetic resonance imaging (MRI). These characteristic abnormalities typically involve particular parts of the white matter of the brain and specific regions (called tracts) within the brainstem and spinal cord, especially the pyramidal tract and the dorsal column. In addition, most affected individuals have a high level of a substance called lactate in the white matter of the brain, which is identified using another test called magnetic resonance spectroscopy (MRS).

LBSL is caused by mutations in the DARS2 gene, which provides instructions for making an enzyme called mitochondrial aspartyl-tRNA synthetase. This enzyme is important in the production (synthesis) of proteins in cellular structures called mitochondria, the energy-producing centers in cells. While most protein synthesis occurs in the fluid surrounding the nucleus (cytoplasm), some proteins are synthesized in the mitochondria.

During protein synthesis, in either the mitochondria or the cytoplasm, building blocks (amino acids) are connected together in a specific order, creating a chain of amino acids that forms the protein. Mitochondrial aspartyl-tRNA synthetase plays a role in adding the amino acid aspartic acid at the proper place in mitochondrial proteins.

Mutations in the DARS2 gene result in decreased mitochondrial aspartyl-tRNA synthetase enzyme activity, which hinders the addition of aspartic acid to mitochondrial proteins. It is unclear how the gene mutations lead to the signs and symptoms of LBSL. Researchers do not understand why reduced activity of mitochondrial aspartyl-tRNA synthetase specifically affects certain parts of the brain and spinal cord.

Normal Function

The DARS2 gene provides instructions for making an enzyme called mitochondrial aspartyl-tRNA synthetase. This enzyme is important in the production (synthesis) of proteins in cellular structures called mitochondria, the energy-producing centers in cells. While most protein synthesis occurs in the fluid surrounding the nucleus (cytoplasm), some proteins are synthesized in the mitochondria.

During protein synthesis, in either the mitochondria or the cytoplasm, a type of RNA called transfer RNA (tRNA) helps assemble protein building blocks (amino acids) into a chain that forms the protein. Each tRNA carries a specific amino acid to the growing chain. Enzymes called aminoacyl-tRNA synthetases, including mitochondrial aspartyl-tRNA synthetase, attach a particular amino acid to a specific tRNA. Mitochondrial aspartyl-tRNA synthetase attaches the amino acid aspartic acid to the correct tRNA, which helps ensure that aspartic acid is added at the proper place in the mitochondrial protein.

Health Conditions Related to Genetic Changes

Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation

At least 25 mutations in the DARS2 gene have been identified in people with leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL), a condition that affects the brain and spinal cord and causes difficulty walking. The most common mutation that causes this condition disrupts the way genetic information is pieced together to make a blueprint for producing the mitochondrial aspartyl-tRNA synthetase enzyme. Most copies of the blueprint are pieced together incorrectly, which prevents the enzyme from being produced. However, some copies are pieced together correctly, and a small amount of normal enzyme is made. Other mutations change single amino acids in the enzyme. This type of mutation results in decreased mitochondrial aspartyl-tRNA synthetase enzyme activity. With reduced activity, the enzyme has difficulty adding aspartic acid to the tRNA, which hinders the addition of this amino acid to mitochondrial proteins.

It is unclear how the gene mutations lead to the signs and symptoms of LBSL. Researchers do not understand why reduced activity of mitochondrial aspartyl-tRNA synthetase specifically affects certain parts of the brain and spinal cord.

Other Names for This Gene

• aspartate tRNA ligase 2, mitochondrial
• aspartyl-tRNA synthetase, mitochondrial
• aspartyl-tRNA synthetase, mitochondrial precursor
• ASPRS
• FLJ10514
• LBSL
• MT-ASPRS

Genomic Location

LBSL is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. In this condition, each copy of the gene carries a different mutation (compound heterozygous mutations). An affected individual never has the same mutation in both copies of the gene (a homozygous mutation). The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

LBSL is a rare condition. Its exact prevalence is not known.