in mitochondrial leukoencephalopathy and multiple sclerosis

ABSTRACT Background: Leukoencephalopathy with brain stem and spinal cord involvement and high brain lactate (LBSL) was first defined by characteristic MRI and spectroscopic findings. The clinical features include childhood or juvenile-onset slowly progressive ataxia, spasticity, and dorsal column dysfunction, occasionally accompanied by learning difficulties. Mutations in DARS2 , encoding mitochondrial aspartyl-tRNA synthetase, were recently shown to cause LBSL. The signs and symptoms show some overlap with the most common leukoencephalopathy of young adults, multiple sclerosis (MS). Objective: To clarify the molecular background of LBSL patients in Finland, and to look for DARS2 mutations in a group of MS patients. Methods: Clinical evaluation of LBSL patients, DARS2 sequencing and haplotype analysis, and carrier frequency determination in Finland. Results: All eight LBSL patients were compound heterozygotes for DARS2 mutations: all carried R76SfsX5 change, seven had M134_K165del and one had C152F change. Axonal neuropathy was found in five of the eight patients. The carrier frequencies of the R76SfsX5 and M134_K165del mutations were 1:95 and 1:380, respectively. All patients shared common European haplotypes, suggestive of common European LBSL ancestors. No enrichment of the two common DARS2 mutations was found in 321 MS patients. Conclusion: All LBSL patients were compound heterozygotes, which suggests that DARS2 mutation homozygosity may be lethal or manifest as a different phenotype. We show here that despite identical mutations the clinical picture was quite variable in the patients. Axonal neuropathy was an important feature of LBSL. DARS2 mutations cause childhood-to-adolescence-onset leukoencephalopathy, but they do not seem to be associated with MS.