Leber Hereditary Optic Neuropathy in 2 of 4 Siblings with 11778 mtDNA Mutation: Clinical Variability or Effect of Toxic Environmental Exposure?

Abstract

Although mitochondrial (mt) DNA mutation at nucleotide position 11778 accounts for most cases of Leber’s hereditary optic neuropathy (LHON), the phenotypic expression may vary greatly even in different members of the same family. The possible influence of exogenous toxicity on phenotypic expression is still debated in LHON. Here we describe 4 siblings carrying the 11778 mtDNA mutation with a different phenotype. The index case developed an atypical optic neuropathy at the age of 60 years after a long history of occupational exposure to polycyclic aromatic hydrocarbons (PAHs). This report underlines a number of unanswered questions about phenotypic variability of LHON including the possible influence of PAH toxicity.

Mitochondria, oxidative stress and neurodegeneration

“…In addition, incomplete penetrance and male predominance suggest that other genetic and environmental factors contribute to signs and symptoms. Smoking and other environmental factors (including hormones, head trauma, occupational exposure, chemical toxins, drugs or pharmacological substances) are known to trigger LHON, supporting the notion that excess ROS production may be an important pathogenetic factor [22][23][24][25].…”

The Role of Mitochondria in the Radiation-Induced Bystander Effect in Human Lymphoblastoid Cells

“…The mammalian mitochondrial genome is a double stranded, covalently closed circular molecule that is composed almost entirely of coding regions. It has some overlapping genes that increase the potential of point mutations or deletions to have dramatic phenotypic effects (Bykhovskaya et al, 2004, Rufa et al, 2005. The mitochondrial DNA (mtDNA) is located close to the inner mitochondrial membrane (Fiskum et al, 1999) and is therefore expected to be highly susceptible to reactive oxygen species that cause mutations.…”

Mitochondrial Gene Expression Changes in Normal and Mitochondrial Mutant Cells after Exposure to Ionizing Radiation

“…Damage to mtDNA can have serious implications and has been shown to play a role in genomic instability. mtDNA has a limited non-coding sequence, which increases the possibility that a point mutation or deletion will have biological consequences (5,6). Mutations in one or more of the 87 genes coding for the nuclear-mitochondrial OXPHOS complex can also lead to clinically recognizable diseases (7)(8)(9)(10)(11), many of which result from single nucleotide substitutions in the mtDNA (12).…”