2.1 Hypomyelination with Brainstem and Spinal Cord Involvement and Leg Spasticity

At least 16 mutations in the DARS1 gene have been found to cause a condition called hypomyelination with brainstem and spinal cord involvement and leg spasticity (HBSL). This condition is characterized by abnormalities of the nervous system's white matter, usually involving particular regions of the spinal cord and brainstem (the region of the brain that connects to the spinal cord). The white matter consists of nerve fibers covered by a fatty substance called myelin, which insulates the fibers and promotes the rapid transmission of nerve impulses. In HBSL, the nervous system has a reduced ability to form myelin (hypomyelination). Affected individuals develop muscle stiffness (spasticity) in the legs that worsens over time and impairs walking.

Most of the mutations in the DARS1 gene change single amino acids in the aspartyl-tRNA synthetase enzyme. These alterations occur in a region of the enzyme called the active site, where aspartate and the tRNA come together so the amino acid can be transferred. The altered enzyme has difficulty adding the amino acid to the tRNA, which in turn hinders the addition of aspartate to proteins. It is unclear how the gene mutations lead to the signs and symptoms of HBSL. Researchers do not understand why reduced activity of aspartyl-tRNA synthetase affects myelination or why specific parts of the brainstem and spinal cord are involved.