High Mitochondrial DNA Copy Number Is a Protective Factor From Vision Loss in Heteroplasmic Leber's Hereditary Optic Neuropathy (LHON)

AbstractLeber’s hereditary optic neuropathy (LHON) is a form of disorder caused by pathogenic mutations in a mitochondrial DNA. LHON is maternally inherited disease, which manifests mainly in young adults, affecting predominantly males. Clinically LHON has a manifestation as painless central vision loss, resulting in early onset of disability. Epidemiology of LHON has not been fully investigated yet. In this study, we report 44 genetically unrelated families with LHON manifestation. We performed whole mtDNA genome sequencing and provided genealogical and molecular genetic data on mutations and haplogroup background of LHON patients in the Western Siberia population. Known “primary” pathogenic mtDNA mutations (MITOMAP) were found in 32 families: m.11778G>A represents 53,10% (17/32), m.3460G>A – 21,90% (7/32), m.14484T>C – 18,75% (6/32), and rare m.10663T>C and m.3635G>A represent 6,25% (2/32). We describe potentially pathogenic m.4659G>A in one subject without known pathogenic mutations, and potentially pathogenic m.9444C>T, m.6261G>A, m.9921G>A, m.8551T>C, m.8412T>C, m.15077G>A in families with known pathogenic mutations confirmed. We suppose these mutations could contribute to the pathogenesis of optic neuropathy development. Our results indicate that haplogroup affiliation and mutational spectrum of the Western Siberian LHON cohort substantially deviate from those of European populations.

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Can the effects of the mitochondrial DNA mutations found in Leber’s hereditary optic neuropathy be protective against the development of cluster headache in smokers?

Cephalalgia Reports ◽

10.1177/2515816320939571 ◽

2020 ◽

Vol 3 ◽

pp. 251581632093957 ◽

Cited By ~ 1

Author(s):

Todd D Rozen

Keyword(s):

Mitochondrial Dna ◽

Cluster Headache ◽

Protective Effect ◽

Optic Neuropathy ◽

Vision Loss ◽

Leber’S Hereditary Optic Neuropathy ◽

Leber's Hereditary Optic Neuropathy ◽

Tobacco Exposure ◽

Mtdna Mutations ◽

Hereditary Optic Neuropathy

Is it possible that some mitochondrial DNA (mtDNA) mutations enhance the risk of developing a headache disorder while other mutations actually confer a protective effect? Mitochondrial disorders have been linked to migraine but very rarely to cluster headache (CH). The true pathogenesis of CH is unknown but a linkage to cigarette smoking is irrefutable. Leber’s hereditary optic neuropathy is a syndrome of bilateral vision loss that typically manifests in a patient’s 20s and 30s, is male predominant, and its sufferers are heavy smokers and heavy drinkers. Tobacco exposure is so linked to the condition that only smokers appear to develop vision loss while nonsmokers remain unaffected carriers of their mutations. In essence, the Leber’s hereditary optic neuropathy population is the CH population but at present there have been no reported cases of CH in this mitochondrial subgroup. Thus, could the effects of the mtDNA mutations found in Leber’s hereditary optic neuropathy, which involve complex I of the electron transport chain, actually confer a protective effect against the development of CH? This article will delve into this theory.

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Mitochondrial DNA Variation of Leber’s Hereditary Optic Neuropathy in Western Siberia

Cells ◽

10.3390/cells8121574 ◽

2019 ◽

Vol 8 (12) ◽

pp. 1574 ◽

Cited By ~ 1

Author(s):

Elena Starikovskaya ◽

Sofia Shalaurova ◽

Stanislav Dryomov ◽

Azhar Nazhmidenova ◽

Natalia Volodko ◽

...

Keyword(s):

Mitochondrial Dna ◽

Optic Neuropathy ◽

Western Siberia ◽

Vision Loss ◽

Molecular Genetic ◽

Leber’S Hereditary Optic Neuropathy ◽

Leber's Hereditary Optic Neuropathy ◽

Mtdna Mutations ◽

Pathogenic Mutations ◽

Hereditary Optic Neuropathy

Our data first represent the variety of Leber’s hereditary optic neuropathy (LHON) mutations in Western Siberia. LHON is a disorder caused by pathogenic mutations in the mitochondrial DNA (mtDNA), inherited maternally and presents mainly in young adults, predominantly males. Clinically, LHON manifests itself as painless central vision loss, resulting in early onset of disability. The epidemiology of LHON has not been fully investigated yet. In this study, we report 44 genetically unrelated families with LHON manifestation. We performed whole mtDNA genome sequencing and provided genealogical and molecular genetic data on mutations and haplogroup background of LHON patients. Known “primary” pathogenic mtDNA mutations (MITOMAP) were found in 32 families: m.11778G>A represents 53.10% (17/32), m.3460G>A—21.90% (7/32), m.14484T>C–18.75% (6/32), and rare m.10663T>C and m.3635G>A represent 6.25% (2/32). We describe potentially pathogenic m.4659G>A in one subject without known pathogenic mutations, and potentially pathogenic m.6261G>A, m.8412T>C, m.8551T>C, m.9444C>T, m.9921G>A, and m.15077G>A in families with known pathogenic mutations confirmed. We suppose these mutations could contribute to the pathogenesis of optic neuropathy development. Our results indicate that haplogroup affiliation and mutational spectrum of the Western Siberian LHON cohort substantially deviate from those of European populations.

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