Hypomyelination with brainstem and spinal cord involvement and leg spasticity

Last revised by Rohit Sharma on 20 Feb 2024

Hypomyelination with brainstem and spinal cord involvement and leg spasticity (HBSL) is a very rare inherited autosomal recessive leukodystrophy characterized mainly by progressive early-onset lower limb-predominant spasticity.

HBSL is extremely rare, although the exact incidence and prevalence is not known. There is no sex predilection 1-3. The onset of the condition is usually within infancy or early childhood, with a mean of approximately 4 years 2.

The most common symptom, present in nearly all patients, is progressive spasticity and upper motor neuron signs, affecting legs significantly more than arms 1-3. Other clinical features are generally present in less than half of affected patients, including cerebellar ataxia and nystagmus, myopia, intellectual disability, limb weakness, dysarthria, and seizures 2,3. Notably, vibration and proprioceptive loss is rare, despite radiological involvement of the dorsal columns 2,3.

HBSL is inherited in an autosomal recessive fashion and is caused by a missense mutation to the DARS1 gene, which is located on chromosome 2 1-3. The DARS1 gene encodes for cytoplasmic aspartyl-transfer RNA synthetase 1-3, and is expressed mainly in the central nervous system 2. It is unclear exactly how dysfunction of cytoplasmic aspartyl-tRNA synthetase leads to the clinical phenotype, but hypomyelination secondary to dysfunction of oligodendrocytes is thought to be implicated 2.

In the brain, HBSL is characterized by signal changes of the cerebral white matter, which are typically bilateral, diffuse, symmetric, and sparing subcortical U-fibers 1-4. Additionally, in approximately half of patients, there is signal change in the corpus callosum, posterior limb of the internal capsule, corticospinal tracts in the brainstem, and superior and inferior cerebellar peduncles 1-3. Less commonly, there is signal change in the white matter of the cerebellum and rarely in the medial lemniscus 1-3. In the spinal cord, in nearly all patients there is signal change affecting the dorsal columns and lateral corticospinal tracts 1-4.

In these affected regions, the following signal changes are appreciated 1-3:

  • T1: variable signal intensity (hypointense, isointense, or hyperintense) depending on degree of myelination

  • T2/FLAIR: hyperintense

  • MR spectroscopy: findings have been infrequently reported, but notably no lactate peak has been described

There are no disease-modified treatments available for HBSL, thus, management is supportive, such as with physiotherapy and other allied health input 2. Corticosteroids have been shown to sometimes confer benefit, but usually of a short-term nature 2.

Given its rarity and recency of its discovery, the prognosis and natural history of HBSL is not well established. However, it is felt that an earlier onset of the condition portends a worse prognosis 2.

HBSL and its genetic basis was first described in a seminal case series of ten patients in 2013 1.

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