Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation

LBSL is a progressive genetic disorder affecting the brain and spinal cord, characterized by white matter abnormalities and elevated lactate levels that typically manifest as movement and coordination difficulties.

Overview

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 that transmit nerve impulses.

Most affected individuals begin to develop movement problems during childhood or adolescence, though onset can occur in adulthood. People with LBSL have abnormal muscle stiffness (spasticity) and difficulty with coordinating movements (ataxia). Affected individuals also lose the ability to sense the position of their limbs or vibrations, which affects the legs more than the arms and often necessitates wheelchair assistance. Other symptoms may include recurrent seizures (epilepsy), speech difficulties (dysarthria), learning problems, or mild deterioration of mental functioning.

Diagnosis

Distinct changes in the brains of people with LBSL can be seen using magnetic resonance imaging (MRI). These abnormalities typically involve specific regions within the brainstem and spinal cord, such as the pyramidal tract and the dorsal column. Additionally, most affected individuals have a high level of lactate in the white matter of the brain, identified using magnetic resonance spectroscopy (MRS).

Causes

LBSL is caused by mutations in the DARS2 gene, which provides instructions for making an enzyme called mitochondrial aspartyl-tRNA synthetase. This enzyme is essential for protein synthesis within mitochondria, the energy-producing centers of cells. Mutations in the DARS2 gene result in decreased enzyme activity, which hinders the proper creation of mitochondrial proteins. It remains unclear why this reduced activity specifically affects certain parts of the brain and spinal cord.

Inheritance

LBSL is inherited in an autosomal recessive pattern, meaning 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). 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.