Analysis of secondary mtDNA mutations in families with Leber’s hereditary optic neuropathy: Four novel variants and their association with clinical presentation

Mitochondrion ◽  
2020 ◽  
Vol 50 ◽  
pp. 132-138 ◽  
Author(s):  
Jasna Jancic ◽  
Branislav Rovcanin ◽  
Vesna Djuric ◽  
Ana Pepic ◽  
Janko Samardzic ◽  
...  
Keyword(s):  
Optic Neuropathy ◽  
Clinical Presentation ◽  
Leber’S Hereditary Optic Neuropathy ◽  
Leber's Hereditary Optic Neuropathy ◽  
Mtdna Mutations ◽  
Novel Variants ◽  
Hereditary Optic Neuropathy

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 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 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?

2020 ◽  
Vol 3 ◽  
pp. 251581632093957 ◽  
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.

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.

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

Genes ◽  
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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