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DARS2 mutations in mitochondrial leukoencephalopathy and multiple sclerosis
  1. P Isohanni (pirjo.isohanni{at}helsinki.fi)
  1. Research Programme of Molecular Neurology, University of Helsinki and Department of Child Neurology, Finland
    1. T Linnankivi (tarja.linnankivi{at}hus.fi)
    1. Department of Child Neurology, Helsinki University Central Hospital, Finland
      1. J Buzkova
      1. Research Programme of Molecular Neurology, University of Helsinki, Finland
        1. T Lönnqvist (tuula.lonnqvist{at}hus.fi)
        1. Department of Child Neurology, Helsinki University Central Hospital, Finland
          1. H Pihko (helena.pihko{at}hus.fi)
          1. Department of Child Neurology, Helsinki University Central Hospital, Finland
            1. L Valanne (leena.valanne{at}hus.fi)
            1. Helsinki Medical Imaging Center, University of Helsinki, Finland
              1. P J Tienari (pentti.tienari{at}hus.fi)
              1. Department of Neurology, Helsinki University Central Hospital, Finland
                1. I Elovaara
                1. Department of Neurology, University of Tampere and Tampere University Hospital, Finland
                  1. T Pirttilä
                  1. Department of Neurology and Neuroscience, University of Kuopio and Kuopio University Hospital, Finland
                    1. M Reunanen
                    1. Department Neurology, University of Oulu and Oulu University Hospital, Finland
                      1. K Koivisto
                      1. Central Hospital of Seinäjoki, Finland
                        1. S Marjavaara (sanna.marjavaara{at}helsinki.fi)
                        1. Research Programme of Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Finland
                          1. A Suomalainen (anu.wartiovaara{at}helsinki.fi)
                          1. Research Programme of Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Finland

                            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.

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