General description

Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a rare autosomal recessive disorder caused by mutations in the DARS2 gene, with at least fifty mutations identified globally. DARS2 encodes mitochondrial aspartyl-tRNA synthetase (mtAspRS), an enzyme responsible for transferring aspartic acid to its mitochondrial tRNA, essential for mitochondrial protein translation. Deficiency in mtAspRS disrupts mitochondrial protein synthesis, leading to impaired mitochondrial energy production and related functions.

LBSL typically presents as a slowly progressive demyelinating disease with symptoms such as cerebellar ataxia, spasticity, and sensory impairment, particularly affecting proprioception and vibration sense due to posterior column involvement. Neurological symptoms are more pronounced in the lower limbs than in the upper limbs, and tendon reflexes are generally preserved. Motor skills decline often begins in childhood or adolescence, though in some cases, symptoms may not appear until adulthood. Speech difficulties, or dysarthria, gradually worsen over time. Additional features that may occasionally be observed include epilepsy, learning disabilities, cognitive decline, worsened neurological symptoms after mild head trauma, and fever-induced symptom exacerbations. Most patients require wheelchair assistance by their teens or twenties.

Radiographic features

LBSL is diagnosed by MRI when all of the following major criteria and at least one minor criterion are satisfied.

Major Criteria: Signal changes in the:

1. Cerebral white matter with relative sparing of the subcortical U-fibers
2. Dorsal columns and lateral corticospinal tracts of the spinal cord (presence in the cervical spinal cord is sufficient)
3. Pyramids at the level of the medulla

Minor Criteria: Signal changes in the:

1. Splenium of the corpus callosum
2. Posterior limb of the internal capsule
3. Superior and inferior cerebellar peduncles
4. Medial lemniscus of the brainstem
5. Intraparenchymal trajectory of the trigeminal nerve
6. Mesencephalic trigeminal tracts
7. Anterior spinocerebellar tracts in the medulla
8. Cerebellar white matter

Typically, the subcortical U-fibers, globus pallidus, thalamus, and transverse fibers of the pons are spared. MRI also shows T2WI hyperintensity in the dentate nuclei.