Leukoencephalopathy hypomyelination with brainstem and spinal cord involvement and leg spasticity caused by DARS1 mutations.
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ABSTRACT:
SUBMITTER: Zhu J
PROVIDER: S-EPMC9878823 | biostudies-literature | 2022
REPOSITORIES: biostudies-literature
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Leukoencephalopathy hypomyelination with brainstem and spinal cord involvement and leg spasticity caused by <i>DARS1</i> mutations.
Zhu Jingyi J Guo Xiaomin X Ran Ningjing N Liang Jingtao J Liu Fuyou F Liu Junyan J Wang Rongyu R Jiang Lianyan L Yang Dongdong D Liu Meijun M
Frontiers in genetics 20230112
Hypomyelination with brainstem and spinal cord involvement and leg spasticity (HBSL), caused by aspartyl-tRNA synthetase (<i>DARS1</i>) gene mutations, is extremely rare, with only a few cases reported worldwide; thus, reports on HBSL treatment are few. In this review, we summarized the clinical manifestations, imaging features, treatment methods, and gene mutations responsible for HBSL based on relevant studies and cases. ...[more]
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Project description:Inherited white-matter disorders are a broad class of diseases for which treatment and classification are both challenging. Indeed, nearly half of the children presenting with a leukoencephalopathy remain without a specific diagnosis. Here, we report on the application of high-throughput genome and exome sequencing to a cohort of ten individuals with a leukoencephalopathy of unknown etiology and clinically characterized by hypomyelination with brain stem and spinal cord involvement and leg spasticity (HBSL), as well as the identification of compound-heterozygous and homozygous mutations in cytoplasmic aspartyl-tRNA synthetase (DARS). These mutations cause nonsynonymous changes to seven highly conserved amino acids, five of which are unchanged between yeast and man, 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 in the mitochondria-specific DARS2, suggesting that these two diseases might share a common underlying molecular pathology. These findings add to the growing body of evidence that mutations in tRNA synthetases can cause a broad range of neurologic disorders.
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