Extensive investigation of a large Brazilian pedigree of 11778/haplogroup J Leber hereditary optic neuropathy

Sadun, Alfredo A.; Carelli, Valerio; Salomão, Solange Rios; Berezovsky, Adriana; Quirós, Peter A.; Sadun, Federico; DeNegri, Anna Maria; Andrade, Rafael; Moraes, Maria Nathália; Passos, Angelo Ferreira; Kjaer, Patrícia; Pereira, Josenilson Martins; Valentino, Maria Lucia; Schein, Stan; Belfort, Rubens

doi:10.1016/s0002-9394(03)00099-0

Cited by 146 publications

(108 citation statements)

References 28 publications

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“…These features include incomplete penetrance, male predominance, and optic nerve specific disease expression. Currently, genetic backgrounds in the mitochondria and/or in the nucleus are strongly suggested to play a role in disease expression of LHON (Brown et al 2000(Brown et al , 2002Carelli et al 2003;Cock et al 1998;Howell et al 2003;Qi et al 2003;Sadun et al 2002;Sudoyo et al 2002). Despite the different genetic backgrounds, most features that constitute the picture of LHON are quite common between different populations; however, there seem to be a few ethnic-specific differences.…”

Section: Discussionmentioning

confidence: 99%

The unique characteristics of Thai Leber hereditary optic neuropathy: analysis of 30 G11778A pedigrees

et al. 2006

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Leber hereditary optic neuropathy (LHON) is characterized by acute or subacute bilateral visual loss, and affects mostly young males. The most common mitochondrial DNA mutation responsible for LHON worldwide is G11778A. Despite different genetic backgrounds, which are believed to influence the disease expression, most features of LHON are quite common in different populations. However, there seem to be a few ethnic-specific differences. Analyses of our 30 G11778A LHON pedigrees in Thailand showed some characteristics different from those of Caucasians and Japanese. In particular, our pedigrees showed a lower male to female ratio of affected persons (2.6:1) and much higher prevalence of G11778A blood heteroplasmy (37% of the pedigrees contained at least one heteroplasmic G11778A individual). Heteroplasmicity seemed to influence disease manifestation in our patients but did not appear to alter the onset of the disease. The estimated overall penetrance of our G11778A LHON population was 37% for males and 13% for females. When each of our large pedigrees were considered separately, disease penetration varied from 9 to 45% between the pedigrees, and also varied between different branches of the same large pedigree. Survival analysis showed that the secondary LHON mutations G3316A and C3497T had a synergistic deleterious effect with the G11778A mutation, accelerating the onset of the disease in our patients.

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Section: Discussionmentioning

confidence: 99%

The unique characteristics of Thai Leber hereditary optic neuropathy: analysis of 30 G11778A pedigrees

et al. 2006

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“…In Leber hereditary optic neuropathy, pedigrees that are essentially homoplasmic for one of the common causal LHON mtDNA mutations, males are three to four times more likely to manifest mid-life subacute blindness than females. Other factors also affect the onset of blindness including mtDNA haplogroup background and environmental stressors such as smoking and alcohol abuse (Brown et al 1997(Brown et al , 2002Torroni et al 1997;Sadun et al 2003Sadun et al , 2011.…”

Section: Germline Segregation Of Mtdna Heteroplasmymentioning

confidence: 99%

Mitochondrial DNA Genetics and the Heteroplasmy Conundrum in Evolution and Disease

Wallace

Chalkia

2013

Cold Spring Harbor Perspectives in Biology

560

532

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The unorthodox genetics of the mtDNA is providing new perspectives on the etiology of the common "complex" diseases. The maternally inherited mtDNA codes for essential energy genes, is present in thousands of copies per cell, and has a very high mutation rate. New mtDNA mutations arise among thousands of other mtDNAs. The mechanisms by which these "heteroplasmic" mtDNA mutations come to predominate in the female germline and somatic tissues is poorly understood, but essential for understanding the clinical variability of a range of diseases. Maternal inheritance and heteroplasmy also pose major challengers for the diagnosis and prevention of mtDNA disease. THE GENETIC CHALLENGES OF mtDNA DISEASES

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“…The authors emphasized the strong influence of environmental risk factors, with smoking as the most common factor. 9 Eighty-five percent of patients with Leber's hereditary optic neuropathy are homoplasmic for mtDNA mutations; the remaining 15% are heteroplasmic. The relationship between heteroplasmy levels and clinical condition was studied by Chinnery et al, 10 who showed that heteroplasmic patients with higher degrees of mutant mtDNA had a greater probability of developing visual loss.…”

Section: Discussionmentioning

confidence: 99%

Leber's hereditary optic neuropathy: case report and literature review

Teive

Troiano

Raskin³

et al. 2004

Sao Paulo Med. J.

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CONTEXT: Leber's hereditary optic neuropathy is an important cause of progressive painless visual loss among young male patients. OBJECTIVE: To report on a case of a young patient with a clinical and neurophysiological condition suggestive of Leber's hereditary optic neuropathy, confirmed by genetic testing. CASE REPORT: We describe a 17-year-old male with progressive bilateral visual loss. Two maternal uncles had had similar patterns of visual loss. The patient had a history of smoking and alcohol abuse. Neuro-ophthalmological examination revealed visual acuity of 20/800 in both eyes, with decreased direct and consensual pupillary light reflexes. Fundus examination demonstrated pale optic discs. The visual evoked potential test showed signs of conduction disturbances in both optic nerves and campimetric study showed complete visual loss in all fields of both eyes. A diagnosis of bilateral optic neuropathy with a clinical suspicion of Leber's hereditary optic neuropathy was made. A blood sample was submitted to genetic analysis in relation to the principal mutations of this disorder, and homoplasmic mutation in 11778 was detected, thereby confirming the diagnosis of Leber's hereditary optic neuropathy.

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Extensive investigation of a large Brazilian pedigree of 11778/haplogroup J Leber hereditary optic neuropathy

Cited by 146 publications

References 28 publications

The unique characteristics of Thai Leber hereditary optic neuropathy: analysis of 30 G11778A pedigrees

The unique characteristics of Thai Leber hereditary optic neuropathy: analysis of 30 G11778A pedigrees

Mitochondrial DNA Genetics and the Heteroplasmy Conundrum in Evolution and Disease

Leber's hereditary optic neuropathy: case report and literature review

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