Mitochondrial DNA copy number differentiates the Leber’s hereditary optic neuropathy affected individuals from the unaffected mutation carriers

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Abstract
Sir, We read with great interest the article by Giordano and colleagues (2014) reporting that cellular activation of compensatory mitochondrial biogenesis, as measured by mitochondrial DNA (mtDNA) copy number, is a major determinant of incomplete penetrance in Leber’s hereditary optic neuropathy (LHON), a mitochondrial disease characterized by bilateral subacute loss of central vision due to optic atrophy (Carelli et al. , 2004; Yu-Wai-Man et al. , 2011). In most known mitochondrial diseases due to mtDNA mutations the penetrance or the severity of the condition depends on the level of heteroplasmy of the mutation (Schon et al. , 2012). However, LHON is due to mtDNA mutations that exemplify a different paradigm. The three primary mutations, namely the m.3460G>A/ND1, m.11778G>A/ND4 and m.14484T>C/ND6, are generally found as homoplasmic. One of the three primary mtDNA mutations is necessary but not sufficient to cause optic neuropathy and disease penetrance can vary in different families harbouring the same mutation, and even within different branches of the same family (Howell and Mackey, 1998). The study by Giordano and colleagues (2014) highlights how in large LHON cohorts of individuals of European descent, higher mtDNA content in blood cells discriminates the unaffected mutation carriers from LHON affected and control subjects. A significantly higher mtDNA copy number was observed in asymptomatic maternal relatives, hereafter called ‘Carriers’, moving progressively towards lower values from carriers to affected subjects to controls. Previously, different data were reported on this …

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