Leber Hereditary Optic Neuropathy Possibly Triggered by Exposure to Tire Fire

Sanchez, Romeo; Smith, Allison J.; Carelli, Valerio; Sadun, Alfredo A.; Keltner, John L.

doi:10.1097/01.wno.0000249320.27110.ab

Cited by 35 publications

(15 citation statements)

References 16 publications

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“…The evidence supporting the role of environmental risk factors in precipitating the optic neuropathy in LHON has so far been largely based on anecdotal reports (DuBios and Feldon, 1992; Golnik and Shaible, 1994; Rizzo, 1995; Hwang and Park, 1996; Mackey et al ., 2003; Sanchez et al ., 2006; Carelli et al ., 2007) and small case series (Newman et al ., 1991; Cullom et al ., 1993; Riordan-Eva et al ., 1995). Larger studies specifically investigating the role of tobacco and alcohol have produced conflicting results (Chalmers and Harding, 1996; Tsao et al ., 1999; Kerrison et al ., 2000; Sadun et al ., 2003) (Table 6).…”

Section: Discussionmentioning

confidence: 99%

“…However, the largest study to date involving affected and unaffected siblings from 80 LHON sibships found no relationship between smoking or alcohol and the likelihood of visual failure (Kerrison et al ., 2000). There are also anecdotal reports of trauma, nutritional deprivation, metabolic disturbance, exposure to industrial toxins, anti-retroviral drugs, psychological stress or acute illness precipitating the onset of blindness in LHON, but the strength of the causal relationship is difficult to establish (DuBios and Feldon, 1992; Johns et al ., 1993; Hwang and Park, 1996; Mackey et al ., 2003; Sadun et al ., 2003; Sanchez et al ., 2006; Carelli et al ., 2007). …”

Section: Introductionmentioning

confidence: 99%

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Gene–environment interactions in Leber hereditary optic neuropathy

Kirkman

Yu‐Wai‐Man

Korsten

et al. 2009

Brain

302

238

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Leber hereditary optic neuropathy (LHON) is a genetic disorder primarily due to mutations of mitochondrial DNA (mtDNA). Environmental factors are thought to precipitate the visual failure and explain the marked incomplete penetrance of LHON, but previous small studies have failed to confirm this to be the case. LHON has no treatment, so identifying environmental triggers is the key to disease prevention, whilst potentially revealing new mechanisms amenable to therapeutic manipulation. To address this issue, we conducted a large, multicentre epidemiological study of 196 affected and 206 unaffected carriers from 125 LHON pedigrees known to harbour one of the three primary pathogenic mtDNA mutations: m.3460G>A, m.11778G>A and m.14484T>C. A comprehensive history of exposure to smoking, alcohol and other putative environmental insults was collected using a structured questionnaire. We identified a strong and consistent association between visual loss and smoking, independent of gender and alcohol intake, leading to a clinical penetrance of 93% in men who smoked. There was a trend towards increased visual failure with alcohol, but only with a heavy intake. Based on these findings, asymptomatic carriers of a LHON mtDNA mutation should be strongly advised not to smoke and to moderate their alcohol intake.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Gene–environment interactions in Leber hereditary optic neuropathy

Kirkman

Yu‐Wai‐Man

Korsten

et al. 2009

Brain

302

238

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“…A subsequent multicenter survey of a cohort of 402 LHON patients, carrying the three primary mutations, also found a significant role in disease risk for tobacco, in particular, and alcohol use [18•]. Smoke in general (not just tobacco smoking) may also trigger LHON, as some reported cases have been associated with exposure to smoke from tire fires or malfunctioning stoves [20].…”

Section: Risk Factorsmentioning

confidence: 97%

Leber’s Hereditary Optic Neuropathy

Sadun

Morgia

Carelli

2010

Curr Treat Options Neurol

Self Cite

127

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Leber's hereditary optic neuropathy (LHON) is a maternally inherited blinding disease with variable penetrance. Three primary mitochondrial DNA mutations, affecting the respiratory complex I, are necessary but not sufficient to cause blindness. Reduced efficiency of ATP synthesis and increased oxidative stress are believed to sensitize the retinal ganglion cells to apoptosis. Different therapeutic strategies are considered to counteract this pathogenic mechanism. However, potential treatments for the visual loss are complicated by the fact that patients are unlikely to benefit after optic atrophy occurs. There is no proven therapy to prevent or reverse the optic neuropathy in LHON. Results from a recent trial with idebenone hold promise to limit neurodegeneration and improve final outcome, promoting recovery of visual acuity. Other therapeutic options are under scrutiny, including gene therapy, agents increasing mitochondrial biogenesis, and anti-apoptotic drugs.

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“…However, a recent epidemiologic study of a large cohort of LHON families reached a well-supported conclusion that tobacco smoking is indeed a triggering factor [18]. In a similar manner, exposures to agricultural pesticides, smoke, toxic vapours from industrial solvents have been variously mentioned as possible environmental triggers for LHON [15], [19]. Recently, we also documented one case, a subject carrying the 11778/ND4 mutation [20], for whom the combined exposure to n-hexane and other solvents apparently acted as the trigger for the optic neuropathy.…”

Section: Introductionmentioning

confidence: 99%

The Background of Mitochondrial DNA Haplogroup J Increases the Sensitivity of Leber's Hereditary Optic Neuropathy Cells to 2,5-Hexanedione Toxicity

et al. 2009

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Leber's hereditary optic neuropathy (LHON) is a maternally inherited blinding disease due to mitochondrial DNA (mtDNA) point mutations in complex I subunit genes, whose incomplete penetrance has been attributed to both genetic and environmental factors. Indeed, the mtDNA background defined as haplogroup J is known to increase the penetrance of the 11778/ND4 and 14484/ND6 mutations. Recently it was also documented that the professional exposure to n-hexane might act as an exogenous trigger for LHON. Therefore, we here investigate the effect of the n-hexane neurotoxic metabolite 2,5-hexanedione (2,5-HD) on cell viability and mitochondrial function of different cell models (cybrids and fibroblasts) carrying the LHON mutations on different mtDNA haplogroups. The viability of control and LHON cybrids and fibroblasts, whose mtDNAs were completely sequenced, was assessed using the MTT assay. Mitochondrial ATP synthesis rate driven by complex I substrates was determined with the luciferine/luciferase method. Incubation with 2,5-HD caused the maximal loss of viability in control and LHON cells. The toxic effect of this compound was similar in control cells irrespective of the mtDNA background. On the contrary, sensitivity to 2,5-HD induced cell death was greatly increased in LHON cells carrying the 11778/ND4 or the 14484/ND6 mutation on haplogroup J, whereas the 11778/ND4 mutation in association with haplogroups U and H significantly improved cell survival. The 11778/ND4 mutation on haplogroup U was also more resistant to inhibition of complex I dependent ATP synthesis by 2,5-HD. In conclusion, this study shows that mtDNA haplogroups modulate the response of LHON cells to 2,5-HD. In particular, haplogroup J makes cells more sensitive to its toxic effect. This is the first evidence that an mtDNA background plays a role by interacting with an environmental factor and that 2,5-HD may be a risk element for visual loss in LHON. This proof of principle has broad implications for other neurodegenerative disorders such as Parkinson's disease.

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Leber Hereditary Optic Neuropathy Possibly Triggered by Exposure to Tire Fire

Cited by 35 publications

References 16 publications

Gene–environment interactions in Leber hereditary optic neuropathy

Gene–environment interactions in Leber hereditary optic neuropathy

Leber’s Hereditary Optic Neuropathy

The Background of Mitochondrial DNA Haplogroup J Increases the Sensitivity of Leber's Hereditary Optic Neuropathy Cells to 2,5-Hexanedione Toxicity

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