[DARS mutations responsible for hypomyelination with brain stem and spinal cord involvement and leg spasticity: report of two cases and review of literature].

Objective: To analyze the clinical and imaging features of hypomyelination with brain stem and spinal cord involvement and leg spasticity (HBSL) due to mutations in DARS, and to identify DARS mutations responsible for HBSL. Methods: Data on 2 HBSL patients who were admitted to the pediatric department of Peking University First Hospital from January 2009 through December 2016 were reviewed and the 2 patients were followed up. Targeted next generation sequencing, whole exome sequencing and Sanger sequencing were employed to identify potential genetic variations of the children and their parents. The clinical manifestations, MRI features and genotypic characteristics of two patients were reviewed, and the literature was reviewed. HBSL reported cases were searched with"leukoencephalopathies, DARS"on databases of PubMed, Wanfang, China National Knowledge Infrastructure and VIP from 1975 to 2017. The clinical manifestations and molecular features were analyzed. Results: Both patients showed delayed motor development, but had normal cognitive development. At the age of 8 years, case 1 reached the most significant motor development milestone of only standing with help during the last follow-up. At the age of 9, case 2 could walk independently during the last follow-up. On physical examination, both showed leg spastcity, active tendon reflex, positive Babinski sign. Both patients had brain MRI findings of high T2WI signal in bilateral deep cerebral white matter, slightly lower T1WI, and no abnormal DWI signal. Lesions of case 1 were relatively extensive and involved subcortical white matter, corpus callosum and internal capsule. Spinal MRI scans for both patients showed no abnormal signals. Novel mutations in DARS gene-namely, c.1498_1499insTCA (p.500_501insIle) and c.1210A>G (p.Met404Val) , c.1432A>G (p.Met478Val) and c.1210A>G (p.Met404Val) were identified in case 1 and case 2 respectively. On the database, 2 reports involving 13 foreign patients were retrieved. The age of disease onset was from 4 months to 18 years, and their initial symptoms were development delay or regression. Most of them presented with progressive lower extremity spasm, and the brain magnetic resonance imaging was characterized by hypomyelination in white matter. Clinical phenotypes of different age groups were significantly different. Conclusion: We have reported two patients with HBSL in China, and 3 novel mutations in DARS, which is helpful for the diagnosis and genetic counseling of HBSL.