Characterization of the mitochondrial genome in childhood multiple sclerosis. I. Optic neuritis and LHON mutations.

The occurrence of optic neuropathy in patients with MS-like disorders who carry one of the pathogenetically significant LHON mutations as well as the higher incidence of maternal transmission in familial cases of MS support the hypothesis that mitochondrial genes may be implicated in susceptibility to MS. We sequenced the entire mtDNA of six children with MS who developed optic neuritis as early and prominent visual involvement. The analysis revealed a high degree of nucleotide variations relative to the standard mtDNA sequence. After excluding various synonymous nucleotide changes and common neutral polymorphisms, eight discrete novel missense mutations within the protein coding, tRNA or rRNA genes were detected. None of the eight polymorphic sites were found in common between the patients with MS. Of particular interest was the observation that five of six children carried a total of nine secondary LHON mutations at nucleotide positions 4216, 4917 or 13708. We conclude that variation in mtDNA is unlikely to contribute to genetic predisposition for MS. However, secondary LHON mutations may be regarded as additional risk factor for developing prominent optic nerve involvement. The association of individual sets of mtDNA variations with phenotypic presentation in certain subgroups of MS patients remains to be clarified.