Mitochondrial Genetic Heterogeneity in Leber’s Hereditary Optic Neuropathy: Original Study with Meta-Analysis

Leber’s hereditary optic neuropathy (LHON) is a mitochondrial disorder that causes loss of central vision. Three primary variants (m.3460G>A, m.11778G>A, and m.14484T>C) and about 16 secondary variants are responsible for LHON in the majority of the cases. We investigated the complete mitochondrial DNA (mtDNA) sequences of 189 LHON patients and found a total of 54 disease-linked pathogenic variants. The primary variants m.11778G>A and m.14484T>C were accountable for only 14.81% and 2.64% cases, respectively. Patients with these two variants also possessed additional disease-associated variants. Among 156 patients who lacked the three primary variants, 16.02% harboured other LHON-associated variants either alone or in combination with other disease-associated variants. Furthermore, we observed that none of the haplogroups were explicitly associated with LHON. We performed a meta-analysis of m.4216T>C and m.13708G>A and found a significant association of these two variants with the LHON phenotype. Based on this study, we recommend the use of complete mtDNA sequencing to diagnose LHON, as we found disease-associated variants throughout the mitochondrial genome.

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Antiretroviral therapy-induced Leber’s hereditary optic neuropathy

Southern African Journal of HIV Medicine ◽

10.4102/sajhivmed.v15i2.24 ◽

2014 ◽

Vol 15 (2) ◽

pp. 69-71 ◽

Cited By ~ 2

Author(s):

Anand Moodley ◽

Sudika Bhola ◽

Fierdoz Omar ◽

Jade Mogambery

Keyword(s):

Antiretroviral Therapy ◽

Optic Neuropathy ◽

Visual Loss ◽

Opportunistic Infections ◽

Genetic Disorders ◽

Mitochondrial Disorder ◽

Phenotypic Expression ◽

Leber’S Hereditary Optic Neuropathy ◽

Leber's Hereditary Optic Neuropathy ◽

Hereditary Optic Neuropathy

Optic neuropathy in HIV-infected patients results from the HIV infection itself, post-infectious auto-immune disease, opportunistic infections and drugs. Nucleoside reverse transcriptase inhibitors (NRTIs) such as zidovudine and stavudine have known mitochondrial toxicity and can cause mitochondrial myopathies, neuropathies, hyperlactataemia, and can induce mitochondrial genetic disorders. Individuals with the mutation for Leber’s hereditary optic neuropathy (LHON), a mitochondrial disorder, are usually asymptomatic but develop visual loss when exposed to external triggers such as smoking. We report on two HIV-infected patients with LHON mutations (m.14484T>C and m.11778G>A) who developed profound visual loss with antiretroviral therapy. We postulate that the phenotypic expression of LHON in these genetically predisposed individuals was triggered by NRTI drugs lamivudine and tenofovir when used in combination, despite their relatively weak mitochondrial toxic effects.

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Leber’s hereditary optic neuropathy

Malaysian Journal of Ophthalmology ◽

10.35119/myjo.v2i4.88 ◽

2020 ◽

Vol 2 (4) ◽

pp. 281-287

Author(s):

Adeline Low ◽

Yee Ling Neoh ◽

Siu Wan Foo ◽

Azida J. Kadir

Keyword(s):

Mitochondrial Dna ◽

Optic Neuropathy ◽

Point Mutations ◽

Field Tests ◽

Pathogenic Mutation ◽

Leber’S Hereditary Optic Neuropathy ◽

Leber's Hereditary Optic Neuropathy ◽

Central Vision ◽

The Brain ◽

Hereditary Optic Neuropathy

Leber’s hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial disease caused by several point mutations in mitochondrial DNA. We present the case of a healthy 12-year-old Chinese boy who presented with bilateral, painless, subacute loss of central vision (more severe in the left eye the than right eye) for 1 week. No abnormalities were detected on magnetic resonance imaging of the brain and orbit. Serial Humphrey visual field tests initially showed a centrocaecal scotoma that worsened progressively. Cerebrospinal fluid samples and blood investigations showed normal results. A trial of steroid therapy was commenced with not much improvement in the patient’s vision. A blood sample was then sent for LHON genetic testing and a mitochondrial DNA (mtDNA) G11778A pathogenic mutation was detected. The same mutation was also present in the patient’s mother.

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Leber's Hereditary Optic Neuropathy: A Report on Novel mtDNA Pathogenic Variants

Frontiers in Neurology ◽

10.3389/fneur.2021.657317 ◽

2021 ◽

Vol 12 ◽

Author(s):

Lorenzo Peverelli ◽

Alessia Catania ◽

Silvia Marchet ◽

Paola Ciasca ◽

Gabriella Cammarata ◽

...

Keyword(s):

Optic Neuropathy ◽

Tissue Specificity ◽

Point Mutations ◽

Leber’S Hereditary Optic Neuropathy ◽

Leber's Hereditary Optic Neuropathy ◽

Cellular Models ◽

Pathogenic Variants ◽

Mtdna Sequence ◽

Mtdna Variants ◽

Hereditary Optic Neuropathy

Leber's hereditary optic neuropathy (LHON) is due to missense point mutations affecting mitochondrial DNA (mtDNA); 90% of cases harbor the m.3460G>A, m.11778G>A, and m.14484T>C primary mutations. Here, we report and discuss five families with patients affected by symptomatic LHON, in which we found five novel mtDNA variants. Remarkably, these mtDNA variants are located in complex I genes, though without strong deleterious effect on respiration in cellular models: this finding is likely linked to the tissue specificity of LHON. This study observes that in the case of a strong clinical suspicion of LHON, it is recommended to analyze the whole mtDNA sequence, since new rare mtDNA pathogenic variants causing LHON are increasingly identified.

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Leber's hereditary optic neuropathy plus, case report

Nauchno-prakticheskii zhurnal «Medicinskaia genetika» ◽

10.25557/2073-7998.2020.07.101-102 ◽

2020 ◽

pp. 101-102

Author(s):

Д.Г. Короткова ◽

М.И. Карпова ◽

Г.В. Буянова ◽

Т.Н. Кашко

Keyword(s):

Case Report ◽

Optic Nerve ◽

Optic Neuropathy ◽

Clinical Case ◽

Mitochondrial Disorder ◽

Neurological Symptoms ◽

Leber’S Hereditary Optic Neuropathy ◽

Leber's Hereditary Optic Neuropathy ◽

Optic Nerve Atrophy ◽

Hereditary Optic Neuropathy

Наследственная оптическая невропатия Лебера (LHON) - митохондриальное заболевание с атрофией зрительного нерва. Хотя в большинстве случаев LHON других ассоциированных неврологических отклонений нет, сообщалось о случаях LHON plus. В статье представлен анализ клинического случая с проявлением неврологических симптомов в подростковом возрасте. Leber’s hereditary optic neuropathy (LHON) is a mitochondrial disorder with optic nerve atrophy. Although there are no other associated neurological abnormalities in most cases of LHON, cases of “LHON plus” have been reported. The article presents an analysis of clinical case with the manifestation of neurological symptoms in adolescence.

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Whole Mitochondrial Genome Analysis in Serbian Cases of Leber’s Hereditary Optic Neuropathy

Genes ◽

10.3390/genes11091037 ◽

2020 ◽

Vol 11 (9) ◽

pp. 1037

Author(s):

Phepy G. A. Dawod ◽

Jasna Jancic ◽

Ana Marjanovic ◽

Marija Brankovic ◽

Milena Jankovic ◽

...

Keyword(s):

Optic Neuropathy ◽

Genetic Background ◽

Sequence Variants ◽

Leber’S Hereditary Optic Neuropathy ◽

Leber's Hereditary Optic Neuropathy ◽

Central Vision ◽

Mitochondrial Haplogroup ◽

Mtdna Mutations ◽

Mutational Screening ◽

Hereditary Optic Neuropathy

Leber’s hereditary optic neuropathy (LHON) is a maternally inherited disorder that affects central vision in young adults and is typically associated with mitochondrial DNA (mtDNA) mutations. This study is based on a mutational screening of entire mtDNA in eight Serbian probands clinically and genetically diagnosed with LHON and four of their family members, who are asymptomatic mutation carriers. All obtained sequence variants were compared to human mtDNA databases, and their potential pathogenic characteristics were assessed by bioinformatics tools. Mitochondrial haplogroup analysis was performed by MITOMASTER. Our study revealed two well-known primary LHON mutations, m.11778G>A and m.3460G>A, and one rare LHON mutation, m.8836A>G. Various secondary mutations were detected in association with the primary mutations. MITOMASTER analysis showed that the two well-known primary mutations belong to the R haplogroup, while the rare LHON m.8836A>G was detected within the N1b haplogroup. Our results support the need for further studies of genetic background and its role in the penetrance and severity of LHON.

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The Genetics of Leber’s Hereditary Optic Neuropathy: A Literature Review

University of Ottawa Journal of Medicine ◽

10.18192/uojm.v8i2.3846 ◽

2018 ◽

Vol 8 (2) ◽

pp. 30-34

Author(s):

Henry Liu

Keyword(s):

Optic Neuropathy ◽

Mitochondrial Disease ◽

Incomplete Penetrance ◽

Leber’S Hereditary Optic Neuropathy ◽

Leber's Hereditary Optic Neuropathy ◽

Central Vision ◽

Male Predominance ◽

Clinical Presentations ◽

Hereditary Optic Neuropathy ◽

Made In

Leber’s hereditary optic neuropathy (LHON) is a mitochondrial disease characterized by a painless, acute loss of central vision, with 95% of affected individuals harbouring one of three pathogenic mutations (G11778GA, G3460A, or T14484C). The purpose of this review is to highlight the distinguishing clinical presentations of the disease with respect to the mutation subtype and present our recent understanding of two unique features of the disease: male predominance and incomplete penetrance. We also review recent advancements made in the diagnosis and treatment of this rare mitochondrial disease and their implications for genetic counselling.

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