scholarly journals Leber’s Hereditary Optic Neuropathy: the roles of mitochondrial transfer RNA variants

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e10651
Author(s):  
Yu Ding ◽  
Guangchao Zhuo ◽  
Qinxian Guo ◽  
Meiya Li
Keyword(s):  
Optic Neuropathy ◽  
Visual Loss ◽  
Incomplete Penetrance ◽  
Leber’S Hereditary Optic Neuropathy ◽  
Inherited Disease ◽  
Leber's Hereditary Optic Neuropathy ◽  
Mtdna Mutations ◽  
Mitochondrial Transfer ◽  
And Function ◽  
Hereditary Optic Neuropathy

Leber’s Hereditary Optic Neuropathy (LHON) was a common maternally inherited disease causing severe and permanent visual loss which mostly affects males. Three primary mitochondrial DNA (mtDNA) mutations, ND1 3460G>A, ND4 11778G>A and ND6 14484T>C, which affect genes encoding respiratory chain complex I subunit, are responsible for >90% of LHON cases worldwide. Families with maternally transmitted LHON show incomplete penetrance with a male preponderance for visual loss, suggesting the involvement of secondary mtDNA variants and other modifying factors. In particular, variants in mitochondrial tRNA (mt-tRNA) are important risk factors for LHON. These variants decreased the tRNA stability, prevent tRNA aminoacylation, influence the post-transcriptionalmodification and affect tRNA maturation. Failure of mt-tRNA metabolism subsequently impairs protein synthesis and expression, folding, and function of oxidative phosphorylation (OXPHOS) enzymes, which aggravates mitochondrial dysfunction that is involved in the progression and pathogenesis of LHON. This review summarizes the recent advances in our understanding of mt-tRNA biology and function, as well as the reported LHON-related mt-tRNA second variants; it also discusses the molecular mechanism behind the involvement of these variants in LHON.

scholarly journals Analysis of Three Primary mtDNA Mutations in 155 Patients with Leber’s Hereditary Optic Neuropathy

2020 ◽  
Author(s):  
Yan-Jiao Yao ◽  
Xue-Mei Zhuang ◽  
Fan Zheng
Keyword(s):  
Optic Neuropathy ◽  
Age At Onset ◽  
Leber’S Hereditary Optic Neuropathy ◽  
Inherited Disease ◽  
Leber's Hereditary Optic Neuropathy ◽  
Clinical Genetic ◽  
Mtdna Mutations ◽  
Functional Variants ◽  
History Of ◽  
Hereditary Optic Neuropathy

Abstract Background: Leber’s Hereditary Optic Neuropathy (LHON) is a maternal inherited disease caused by mitochondrial DNA (mtDNA) mutations. The aim of the current study is to analysis the frequencies of mitochondrial ND1 G3460A, ND4 G11778A and ND6 T14484C mutations in patients with LHON.Methods: Our study enrolled 155 patients with LHON and 83 controls, PCR-Sanger sequencing was performed to screen the presence of these primary mutations. Moreover, we performed clinical, genetic and molecular characterizations of five Chinese families carrying LHON-related three primary mutations.Results: 28 patients with G3460A (18.1%), 86 patients with G11778A (55.5%) and 32 patients carrying T14484C mutation (20.6%) were identified. However, none of these primary mutations were identified in controls. Among them, one patient carrying G3460A, two patients with G11778A and two patients with T14484C mutation had an obvious family history of LHON. Clinical evaluation of these pedigrees showed the variable clinical phenotypes with different age at onset of LHON. Sequence analysis of the complete mtDNA genes from the matrilineal relatives suggested the presence of these primary mutations. However, the lack of any functional variants in mtDNA genes revealed that mitochondrial haplogroups or haplotypes may not play important roles in the clinical phenotypic manifestation of LHON-associated primary mutations.Conclusions: Our data indicated that screening for the mtDNA primary mutations was necessary for early detection, prevention and diagnosis of LHON.

scholarly journals Mitochondrial DNA variation of Leber’s Hereditary Optic Neuropathy (LHON) in Western Siberia

2019 ◽  
Author(s):  
E.B. Starikovskaya ◽  
S.A. Shalaurova ◽  
S.V. Dryomov ◽  
A.M. Nazhmidenova ◽  
N.V. Volodko ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Optic Neuropathy ◽  
Western Siberia ◽  
Vision Loss ◽  
Leber’S Hereditary Optic Neuropathy ◽  
Inherited Disease ◽  
Leber's Hereditary Optic Neuropathy ◽  
Mtdna Mutations ◽  
Pathogenic Mutations ◽  
Hereditary Optic Neuropathy

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.

scholarly journals 048 Harding’s disease: an important MS mimic

2019 ◽  
Vol 90 (e7) ◽  
pp. A16.2-A16
Author(s):  
Stuti Joshi ◽  
Allan Kermode
Keyword(s):  
Multiple Sclerosis ◽  
Genetic Testing ◽  
Optic Neuropathy ◽  
Visual Loss ◽  
List Type ◽  
Leber’S Hereditary Optic Neuropathy ◽  
Leber's Hereditary Optic Neuropathy ◽  
Leber Hereditary Optic Neuropathy ◽  
Mtdna Mutations ◽  
Hereditary Optic Neuropathy

IntroductionLeber’s hereditary optic neuropathy is a mitochondrially-inherited disorder characterized by bilateral, painless visual loss, which leads to severe optic atrophy.1 LHON can be associated with an MS-like illness referred to as Harding’s disease.2We report two siblings, who both harbour the 11778 mtDNA mutation, but manifest markedly different clinical phenotypes; a male with classical LHON and a female with Harding’s disease.Methods and ResultsA 61-year-old female, who was diagnosed with MS 22 years ago was referred to our service for a second opinion. She developed unilateral painless visual loss in her 20’s, was diagnosed with optic neuritis and treated with corticosteroids with some recovery. A second episode of more severe visual loss at age 39 left her with visual impairment to less than finger counting. 4 years later, she had an episode of dysarthria and gait ataxia. MRI showed multifocal white matter lesions involving the juxta-cortical and periventricular regions, cerebellar peduncle and cervical cord. Targeted views of the optic pathways showed hyperintensity of the left optic nerve, with involvement extending into the optic canal.The patient has one brother who was diagnosed with LHON at age 37 after presenting with severe painless bilateral sequential visual loss. Genetic testing of the index patient confirmed the presence of the same mutation identified in her brother. ConclusionLHON and Harding’s disease demonstrate a great degree of variability in clinical phenotype and penetrance between males and females as well as individuals within the same family.3 While there is no evidence for screening MS cohorts for the LHON, consider genetic testing in patients with severe and persistent bilateral visual loss or with a suggestive family history.4ReferencesHarding AE, Sweeney MG, Miller DH, Mumford CJ, Kellar-Wood H, Menard D,McDonald WI, Compston DA. Occurrence of a multiple sclerosis-like illness in women who have a Leber’s hereditary optic neuropathy mitochondrial DNA mutation. Brain. 1992 August;115 ( Pt 4):979–89.Palace J. Multiple sclerosis associated with Leber’s Hereditary Optic Neuropathy. J Neurol Sci. 2009 November 15;286(1–2):24–7. Review.Pfeffer G, Burke A, Yu-Wai-Man P, Compston DAS, Chinnery PF. Clinical features of MS associated with Leber hereditary optic neuropathy mtDNA mutations. Neurology. 2013;81(24):2073–2081.Yu-Wai-Man P, Chinnery PF. Leber hereditary optic neuropathy. In: Pagon RA MP, Adam Ardinger HH eds. GeneReviews. Seattle, WA: University of Washington, Seattle; 2013. Accessed May 7, 2018.

scholarly journals Exploiting hiPSCs in Leber's Hereditary Optic Neuropathy (LHON): Present Achievements and Future Perspectives

2021 ◽  
Vol 12 ◽  
Author(s):  
Camille Peron ◽  
Alessandra Maresca ◽  
Andrea Cavaliere ◽  
Angelo Iannielli ◽  
Vania Broccoli ◽  
...  
Keyword(s):  
Optic Neuropathy ◽  
Ganglion Cells ◽  
Deep Understanding ◽  
Specific Cell ◽  
Leber’S Hereditary Optic Neuropathy ◽  
Inherited Disease ◽  
Leber's Hereditary Optic Neuropathy ◽  
Mtdna Mutations ◽  
Hereditary Optic Neuropathy

More than 30 years after discovering Leber's hereditary optic neuropathy (LHON) as the first maternally inherited disease associated with homoplasmic mtDNA mutations, we still struggle to achieve effective therapies. LHON is characterized by selective degeneration of retinal ganglion cells (RGCs) and is the most frequent mitochondrial disease, which leads young people to blindness, in particular males. Despite that causative mutations are present in all tissues, only a specific cell type is affected. Our deep understanding of the pathogenic mechanisms in LHON is hampered by the lack of appropriate models since investigations have been traditionally performed in non-neuronal cells. Effective in-vitro models of LHON are now emerging, casting promise to speed our understanding of pathophysiology and test therapeutic strategies to accelerate translation into clinic. We here review the potentials of these new models and their impact on the future of LHON patients.

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

Spectrum of pathogenic mtDNA mutations in Leber’s hereditary optic neuropathy families from Siberia

2006 ◽  
Vol 42 (1) ◽  
pp. 76-83 ◽  
Author(s):  
N. V. Volodko ◽  
M. A. L’vova ◽  
E. B. Starikovskaya ◽  
O. A. Derbeneva ◽  
I. Yu. Bychkov ◽  
...  
Keyword(s):  
Optic Neuropathy ◽  
Leber’S Hereditary Optic Neuropathy ◽  
Leber's Hereditary Optic Neuropathy ◽  
Mtdna Mutations ◽  
Hereditary Optic Neuropathy

scholarly journals A Simple Oligonucleotide Biochip Capable of Rapidly Detecting Known Mitochondrial DNA Mutations in Chinese Patients with Leber’S Hereditary Optic Neuropathy (LHON)

2011 ◽  
Vol 30 (4) ◽  
pp. 181-190 ◽  
Author(s):  
Wei-Dong Du ◽  
Gang Chen ◽  
Hui-Min Cao ◽  
Qing-Hui Jin ◽  
Rong-Feng Liao ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Optic Neuropathy ◽  
Transmitted Disease ◽  
Chinese Patients ◽  
Base Substitution ◽  
Leber’S Hereditary Optic Neuropathy ◽  
Leber's Hereditary Optic Neuropathy ◽  
Mtdna Mutations ◽  
Hereditary Optic Neuropathy ◽  
Oligonucleotide Biochip

Leber's hereditary optic neuropathy (LHON) is a maternally transmitted disease. Clinically, no efficient assay protocols have been available. In this study, we aimed to develop an oligonucleotide biochip specialized for detection of known base substitution mutations in mitochondrial DNA causing LHON and to investigate frequencies of LHON relevant variants in Anhui region of China. Thirty-two pairs of oligonucleotide probes matched with the mutations potentially linked to LHON were covalently immobilized. Cy5-lablled targets were amplified from blood DNA samples by a multiplex PCR method. Two kinds of primary mutations 11778 G > A and 14484 T > C from six confirmed LHON patients were interrogated to validate this biochip format. Further, fourteen Chinese LHON pedigrees and twenty-five unrelated healthy individuals were investigated by the LHON biochip, direct sequencing and pyrosequencing, respectively. The biochip was found to be able efficiently to discriminate homoplasmic and heteroplasmic mtDNA mutations in LHON. Biochip analysis revealed that twelve of eighteen LHON symptomatic cases from the 14 Chinese pedigree harbored the mutations either 11778G > A, 14484T > C or 3460G > A, respectively, accounting for 66.7%. The mutation 11778G > A in these patients was homoplasmic and prevalent (55.5%, 10 of 18 cases). The mutations 3460G > A and 3394T > C were found to co-exist in one LHON case. The mutation 13708G > A appeared in one LHON pedigree. Smaller amount of sampling and reaction volume, easier target preparation, fast and high-throughput were the main advantages of the biochip over direct DNA sequencing and pyrosequencing. Our findings suggested that primary mutations of 11778G > A, 14484T > C or 3460G > A are main variants of mtDNA gene leading to LHON in China. The biochip would easily be implemented in clinical diagnosis.

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. 

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