Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation

Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a rare inherited autosomal recessive leukodystrophy characterized by slowly-progressive pyramidal, cerebellar, and dorsal column dysfunction.

Epidemiology

Although considered rare, the exact prevalence is not known.

Clinical presentation

Patients with LBSL typically first become symptomatic in early childhood, most commonly between two and six years of age, but there are early-onset and juvenile-onset forms as well . Typical symptoms include :

• ataxia, particularly gait ataxia
• spasticity, affecting legs more than arms
• proprioceptive loss

A minority of patients may additionally have intellectual disability, epilepsy, or dysarthria . Patients may eventually require walking aids or may be dependent on wheelchairs, with approximately half of all patients needing some sort of mobility aid by 18 years of age .

Pathology

LBSL is inherited in an autosomal recessive fashion and is caused by mutations to the DARS2 gene, which is located on the long arm of chromosome 1 . The DARS2 gene encodes for mitochondrial aspartyl-transfer RNA synthetase, an enzyme required to translate mitochondrial messenger RNA into proteins . Although it is unclear how dysfunction to this process leads to the clinical features of LBSL, interestingly most patients with LBSL are compound heterozygotes, and have two alleles with different mutations in each .

Radiographic features

MRI

LBSL has many characteristic radiographic features that distinguish it from other hereditary leukodystrophies . It is characterized by bilateral and symmetric signal changes of the cerebral white matter with sparing of the subcortical U-fibers, the posterior limbs of the internal capsules, the tracts and trajectories of the trigeminal nerves, cerebellum, and the dorsal columns and lateral corticospinal tracts of the medulla oblongata or spinal cord . In early-onset forms, the cerebral white matter is more extensively affected when compared to LSBL that manifests later in childhood .

In these affected regions, the following signal changes are appreciated :

• T1: hypointense
• T2/FLAIR: hyperintense
• MR spectroscopy: increased lactate in the abnormal white matter, but this is not always the case

One 2012 study proposed an MRI diagnostic criteria based upon the regions of the central nervous system most commonly affected by LBSL . In order to make the diagnosis, MRI brain and full spine are needed and patients should fulfill all major criteria and at least one minor criterion :

• major criteria, signal changes of the :
  • cerebral white matter with relative sparing of the subcortical U-fibers
  • dorsal columns and lateral corticospinal tracts of the spinal cord (just being present in the cervical spinal cord suffices)
  • pyramids at the level of the medulla oblongata, or decussation of the medial lemniscus, or both
• minor criteria, signal changes of the :
  • splenium of the corpus callosum
  • posterior limb of the internal capsule
  • superior cerebellar peduncles and inferior cerebellar peduncles
  • intraparenchymal trajectory of the trigeminal nerve
  • mesencephalic trigeminal tracts
  • anterior spinocerebellar tracts in the medulla oblongata
  • cerebellar white matter

Treatment and prognosis

Currently (as of January 2018), there is no disease-modified treatment available for LBSL, thus management is supportive with physiotherapy and allied health input . Life expectancy may be normal for most patients, although, as aforementioned, patients may require mobility aids as the disease progresses .

History and etymology

LBSL was first described by Marjo S van der Knaap (1958-), a Dutch pediatric neurologist, and her international colleagues in 2002 .