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Mitochondrial DNA variation and heteroplasmy in monozygotic twins clinically discordant for multiple sclerosis

Hum Mutat. 2016 Apr 27. doi: 10.1002/humu.23003. [Epub ahead of print]

Authors/Editors: Souren NY, Gerdes LA, Kümpfel T, Lutsik P, Klopstock T, Hohlfeld R, Walter J.
Publication Date: 2016


We examined the debated link between mtDNA variation and multiple sclerosis (MS) using 49 monozygotic (MZ) twin pairs clinically discordant for MS, which enables to associate de novo mtDNA variants, skewed heteroplasmy and mtDNA copy number with MS manifestation. Ultra-deep sequencing of blood-derived mtDNA revealed 25 heteroplasmic variants with potentially pathogenic features in 18 pairs. All variants were pair-specific and had low and/or similar heteroplasmy levels in both co-twins. In one pair a confirmed pathogenic variant (m.11778G>A, heteroplasmy ∼50%) associated with Leber hereditary optic neuropathy was detected. Detailed diagnostic investigation revealed subclinical MS signs in the prior non-diseased co-twin. Moreover, neither mtDNA deletions nor copy number variations were involved. Furthermore, the majority of heteroplasmic variants were shared among MZ twins and exhibited more similar heteroplasmy levels in the same tissue of MZ twins as compared to different tissues of the same individual. Heteroplasmy levels were also more similar within MZ twins compared to non-identical siblings. Our analysis excludes mtDNA variation as a major driver of the discordant clinical manifestation of MS in MZ twins, and provides valuable insights into the occurrence and distribution of heteroplasmic variants within MZ twins and non-identical siblings, and across different tissues.

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