Hypomyelination with Brain stem and Spinal cord involvement and Leg spasticity (HBSL)
A progressive inherited white matter disease (leukoencephalopathy) that affects the brain and spinal cord. Leukoencephalopathies refer to a group of genetic disorders characterised by imperfect myelin, which is the fatty covering that insulates nerve fibres.
The signs and symptoms of this disease usually begin in early infancy; however, the course of the condition appears to be quite variable. Infants with HBSL typically appear normal for the first few months of life and between 6 to 18 months begin having problems with development, including decreased muscle tone (hypotonia), a delay or regression in motor skills such as turning over, crawling, controlling head movement, and sitting without support. In addition, affected individuals develop abnormal muscle stiffness (spasticity) especially of their legs and difficulty with coordinating movements (ataxia). These movement problems affect the legs more than the arms, making walking difficult. Some affected individuals develop recurrent seizures (epilepsy), speech difficulties (dysarthria), learning problems, or mild deterioration of mental functioning. Several children experienced sudden deterioration with minor infections or after vaccination with slow recovery.
Distinct changes in the brains of people with HBSL can be seen using magnetic resonance imaging (MRI). These characteristic abnormalities typically involve particular parts of the white matter of the brain and specific regions (called tracts) within the brain stem and spinal cord, especially the pyramidal tract and the dorsal column.
What genes are related to HBSL?
HBSL is caused by mutations in the cytoplasmic aspartyl-tRNA synthetase DARS gene. These mutations cause non-synonymous changes to seven highly conserved amino acids, and cluster in the DARS C-terminal lobe adjacent to, or within, the active-site pocket. Intriguingly, HBSL bears a striking resemblance to Leukoencephalopathy with Brain stem and Spinal cord involvement and elevated Lactate (LBSL), which is caused by mutations to the mitochondria-specific DARS2, suggesting that these two diseases may share a common underlying molecular pathology.
Despite the fact that DARS and DARS2 encode enzymes with different subcellular localisations and protein binding partners, MRIs of subjects with LBSL and HBSL are, at least for part of the affected structures, strikingly similar. For example they both have abnormalities in the same central nervous system structures, including the superior and inferior cerebellar peduncles, medial lemniscus and pyramidal tracts in the brain stem and the dorsal columns and the lateral corticospinal tracts in the spinal cord. These structures are rarely affected in other leukoencephalopathies, and the combination thereof appears to be unique to HBSL and LBSL.
It remains unclear how mutations in these genes lead to the unique signs and symptoms of HBSL and LBSL. At present researchers do not understand why reduced activity of cytoplasmic and mitochondrial aspartyl-tRNA synthetase specifically affect certain parts of the brain and spinal cord.