Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation

Last revised by Rohit Sharma on 18 Feb 2024

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.

Although considered rare, the exact prevalence is unknown. Patients with LBSL typically first become symptomatic in early childhood, most commonly between two and six years of age, but there are early-onset (early infantile-onset and antenatal-onset) and juvenile-onset forms as well 1,6,7.

Typical symptoms include 1:

  • cerebellar ataxia, particularly gait ataxia

  • spasticity and weakness, affecting legs more than arms

  • proprioceptive loss

A minority of patients may additionally have intellectual disability or developmental delay, peripheral neuropathy, epilepsy, and dysarthria 1,6. 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 1.

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 1,2. The DARS2 gene encodes for mitochondrial aspartyl-transfer RNA synthetase, an enzyme required to translate mitochondrial messenger RNA into proteins 1,2. Although it is unclear how a 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 1.

LBSL has many characteristic radiographic features that distinguish it from other hereditary leukodystrophies 1,3-6. 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, splenium of the corpus callosum, and the dorsal columns and lateral corticospinal tracts of the medulla oblongata or spinal cord 1,3-6. In these affected regions, the following signal changes are appreciated 1,3-5:

  • T1: hypointense

  • T2/FLAIR: hyperintense

  • MR spectroscopy: increased lactate in the abnormal white matter, but this is not always the case

In early-onset forms of LSBL, the cerebral white matter is more extensively affected when compared to LSBL which manifests later in childhood, and there may be microcephaly and cerebral hypoplasia and atrophy 4,7.

One 2012 study proposed an MRI diagnostic criteria based upon the regions of the central nervous system most commonly affected by LBSL 4. 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 4:

There are no disease-modified treatments available for LBSL, thus, management is supportive, such as with physiotherapy and other allied health input 1.

Life expectancy may be normal for most patients, although, as aforementioned, patients may require mobility aids as the disease progresses 1. Patients with early-onset are likely to have a worse prognosis 6.

LBSL was first described by Marjo S van der Knaap (1958-), a Dutch pediatric neurologist, and her international colleagues in 2002 3.

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