scholarly journals Leber's Hereditary Optic Neuropathy-Gene Therapy: From Benchtop to Bedside

2011 ◽  
Vol 2011 ◽  
pp. 1-16 ◽  
Author(s):  
Rajeshwari D. Koilkonda ◽  
John Guy
Keyword(s):  
Optic Neuropathy ◽  
Ganglion Cells ◽  
Phenotypic Expression ◽  
Point Mutations ◽  
Population Based ◽  
Incomplete Penetrance ◽  
Leber’S Hereditary Optic Neuropathy ◽  
Leber's Hereditary Optic Neuropathy ◽  
Mtdna Mutation ◽  
Hereditary Optic Neuropathy

Leber's hereditary optic neuropathy (LHON) is a maternally transmitted disorder caused by point mutations in mitochondrial DNA (mtDNA). Most cases are due to mutations in genes encoding subunits of the NADH-ubiquinone oxidoreductase that is Complex I of the electron transport chain (ETC). These mutations are located at nucleotide positions 3460, 11778, or 14484 in the mitochondrial genome. The disease is characterized by apoplectic, bilateral, and severe visual loss. While the mutated mtDNA impairs generation of ATP by all mitochondria, there is only a selective loss of retinal ganglion cells and degeneration of optic nerve axons. Thus, blindness is typically permanent. Half of the men and 10% of females who harbor the pathogenic mtDNA mutation actually develop the phenotype. This incomplete penetrance and gender bias is not fully understood. Additional mitochondrial and/or nuclear genetic factors may modulate the phenotypic expression of LHON. In a population-based study, the mtDNA background of haplogroup J was associated with an inverse relationship of low-ATP generation and increased production of reactive oxygen species (ROS). Effective therapy for LHON has been elusive. In this paper, we describe the findings of pertinent published studies and discuss the controversies of potential strategies to ameliorate the disease.

Leber's Hereditary Optic Neuropathy as a Cause of Severe Visual Loss in Childhood

PEDIATRICS ◽  
1993 ◽  
Vol 91 (5) ◽  
pp. 988-989
Author(s):  
C. M. MOORMAN ◽  
J. S. ELSTON ◽  
P. MATTHEWS
Keyword(s):  
Optic Neuropathy ◽  
Visual Loss ◽  
Age Of Onset ◽  
Transmitted Disease ◽  
Point Mutations ◽  
Leber’S Hereditary Optic Neuropathy ◽  
Leber's Hereditary Optic Neuropathy ◽  
Severe Visual Loss ◽  
Sporadic Cases ◽  
Hereditary Optic Neuropathy

Leber's hereditary optic neuropathy (LHON) is a rare, maternally transmitted disease that most commonly causes acute or subacute visual loss in young men, typically between the ages of 17 and 24 years (although perhaps 14% of affected individuals are women), which may be associated with systemic disorders, eg, cardiac dysrhythmias and neurologic problems.1 Onset is usually asymmetric, but intervals between involvement of the two eyes are usually less than a few months. A definitive diagnosis rested on a family history, age of onset, and the characteristic circumpapillary microangiopathy of the optic disc in the acute phase. However, recent demonstration of point mutations of mitochondrial DNA in affected individuals means that confirmation of the diagnosis can now be obtained in atypical or sporadic cases.2

scholarly journals Antiretroviral therapy-induced Leber’s hereditary optic neuropathy

2014 ◽  
Vol 15 (2) ◽  
pp. 69-71 ◽  
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. 

scholarly journals Leber’s hereditary optic neuropathy

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.

scholarly journals Late-onset Leber’s hereditary optic neuropathy: the role of environmental factors in hereditary diseases

2019 ◽  
Vol 12 (3) ◽  
pp. e227977
Author(s):  
Nuno Moura-Coelho ◽  
Rita Pinto Proença ◽  
Joana Tavares Ferreira ◽  
João Paulo Cunha
Keyword(s):  
Environmental Factors ◽  
Optic Neuropathy ◽  
Late Onset ◽  
Young Male ◽  
Hereditary Diseases ◽  
Incomplete Penetrance ◽  
Leber’S Hereditary Optic Neuropathy ◽  
Leber's Hereditary Optic Neuropathy ◽  
Hereditary Optic Neuropathy

Leber’s hereditary optic neuropathy (LHON) is an optic neuropathy of mitochondrial inheritance, characterised by incomplete penetrance and variable expressivity. Typically, young male patients present with sequential, severe, rapidly progressive loss of central vision, with characteristic funduscopic findings. However, LHON may present at any age, in both genders, and fundus examination may be normal. Evidence has emerged to support the role of environmental factors in triggering LHON, by disrupting the normal mechanisms of mitochondrial function. We present two clinical cases of LHON of late onset, and provide a literature review on atypical cases of LHON and the role of environmental triggers.

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

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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