Observation of penetrance and retinal nerve fiber layer and macular thickness in patients with Leber's hereditary optic neuropathy_Chinese Journal of Ocular Fundus Diseases

Authors：

Teng Da ^1,2 , Yang Mo ² , Peng Chunxia ² , Zhou Haunfen ² , Liu Hongjuan ² , Song Honglu ² , Sun Mingming ² , Xu Quangang ² ,  Wei Shihui ²

1. Medical College of Nankai University, Tianjin 300071, China;
2. Department of Ophthalmology, The First Medical Centre, Chinese PLA General Hospital, Beijing 100853, China Peng Chunxia is working on the Department of Ophthalmology, Beijing Children's Hospital, Beijing 100853, China;

Corresponding author：

Wei Shihui, Email: weishihui58@126.com

Keywords：

Optic atrophy, hereditary, Leber; Penetrance; Mutation; Retinal nerve fiber layer thickness; macular thickness

DOI：

10.3760/cma.j.issn.1005-1015.2019.03.005

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Objective To observe the effects of penetrance, different time of onset and mutation sites on retinal nerve fiber layer (RNFL) and macular thickness in patients with Leber's hereditary optic neuropathy (LHON).Methods This was a cross-sectional observational study. A total of 88 patients with LHON and 1492 relatives of the maternal relatives (gene carriers) who received treatment in People’s Liberation Army General Hospital from 2015 to 2017 were included in the study. Among the 1492 family members, there were 694 males and 798 females. Peripheral venous blood was extracted from all subjects for mitochondrial DNA testing, and penetrance was calculated. A total of 117 patients underwent BCVA and SD-OCT examinations, including 82 patients and 35 gene carriers. The BCVA examination was performed using the Snellen visual acuity chart, which was converted into logMAR visual acuity. The thickness of RNFL, ganglion cell complex (GCC) and inner limiting membrane (ILM)-RPE were measured with OCT instrument. The mean follow-up was 50.02±86.27 months. The disease course was divided into 6 stages including ≤3 months, 4-6 months, 7-12 months and >12 months. The thickness of RNFL, GCC and ILM-RPE in patients with different time of onset and mutation sites were comparatively analyzed by covariance analysis. Categorical variables were expressed as a percentage, and the χ² test was used for comparison among multiple groups.Results Among the 1492 family members, 285 were diagnosed with LHON and highly suspected clinical manifestations (19.10%), including 190 males (21.98%) and 95 females (11.90%). The total penetrance rates of 11778, 14484 and rare mutation sites were 19.84% (228/1149), 20.50% (33/161), and 13.19% (24/182) respectively; male penetrance rates were 28.87% (153/530), 27.28% (20/72), and 18.48% (17/92) and female penetrance rates were 12.12% (75/619),14.61% (13/89) and 7.78% (7/90). There was no significant difference in total (χ²=4.732), male (χ²=4.263) and female (χ²=4.263) penetrance between different mutation sites (P=0.094, 0.110, 0.349). Compared with non-pathogenic carriers, the thickness of the RNFL, GCC and ILM-RPE were all different in the four stages ( ≤3months, 4-6 months, 7-12 months and >12 months). The thickness of RNFL, GCC and ILM-RPE decreased with the time of onset (P=0.000). There were significant differences in the thickness of each of the GCC and ILM-RPE layers in the macular area of LHON patients with different mutation sites (P＜0.05). Among them, the site 11778 and 3460 had the most severe damage in all quadrants of macular GCC and ILM-RPE layer, followed by 14484 site, and the rare site had the least damage in all quadrants.Conclusions The penetrance of LHON patients is 19.10%. With the extension of the onset time (within 1 year), the RNFL layer of the optic disc and all quadrants of the macular GCC and ILM-RPE layer gradually thinned. Compared with 11778 and rare site, 14484 site, and the rare site had the lighter damage on the thickness of RNFL, GCC and ILM-RPE.

Citation： Teng Da, Yang Mo, Peng Chunxia, Zhou Haunfen, Liu Hongjuan, Song Honglu, Sun Mingming, Xu Quangang, Wei Shihui. Observation of penetrance and retinal nerve fiber layer and macular thickness in patients with Leber's hereditary optic neuropathy. Chinese Journal of Ocular Fundus Diseases, 2019, 35(3): 235-241. doi: 10.3760/cma.j.issn.1005-1015.2019.03.005 Copy

1.	Fraser JA, Biousse V, Newman NJ. The neuro-ophthalmology of mitochondrial disease[J]. Surv Ophthalmol, 2010, 55(4): 299-334. DOI: 10.1016/j.survophthal.2009.10.002.
2.	Yu-Wai-Man P, Griffiths PG, Brown DT, et al. The epidemiology of Leber hereditary optic neuropathy in the North East of England[J]. Am J Hum Genet, 2003, 72(2): 333-339. DOI: 10.1016/j.ophtha.2009.05.025.
3.	Hudson G, Carelli V, Spruijt L, et al. Clinical expression of Leber hereditary optic neuropathy is affected by the mitochondrial DNA-haplogroup background[J]. Am J Hum Genet, 2007, 81(2): 228-233. DOI: 10.1086/519394.
4.	Yu-Wai-Man P, Griffiths PG, Hudson G, et al. Inherited mitochondrial optic neuropathies[J]. J Med Genet, 2009, 46(3): 145-158. DOI: 10.1136/jmg.2007.054270.
5.	Carelli V, Ross-Cisneros FN, Sadun AA. Mitochondrial dysfunction as a cause of optic neuropathies[J]. Prog Retin Eye Res, 2004, 23(1): 53-89. DOI: 10.1016/j.preteyeres.2003.10.003.
6.	Yu-Wai-Man P, Griffiths PG, Chinnery PF. Mitochondrial optic neuropathies – disease mechanisms and therapeutic strategies[J]. Prog Retin Eye Res, 2011, 30(2): 81-114. DOI: 10.1016/j.preteyeres.2010.11.002.
7.	Carelli V, Sadun AA. Optic neuropathy in Lhon and Leigh syndrome[J]. Ophthalmology, 2001, 108(7): 1172-1173. DOI: 10.1016/S0161-6420(01)00618-2.
8.	Carelli V, Carbonelli M, de Coo IF, et al. International consensus statement on the clinical and therapeutic management of Leber hereditary optic neuropathy[J]. J Neuroophthalmol, 2017, 37(4): 371-381. DOI: 10.1097/WNO.0000000000000570.
9.	Khan NA, Govindaraj P, Soumittra N, et al. Leber's hereditary optic neuropathy-specific mutation m.11778G>A exists on diverse mitochondrial haplogroups in India[J]. Invest Ophthalmol Vis Sci, 2017, 58(10): 3923-3930. DOI: 10.1167/iovs.16-20695.
10.	Carelli V, Giordano C, d'Amati G. Pathogenic expression of homoplasmic mtDNA mutations needs a complex nuclear-mitochondrial interaction[J]. Trends Genet, 2003, 19(5): 257-262. DOI: 10.1016/S0168-9525(03)00072-6.
11.	Carelli V, d'Adamo P, Valentino ML, et al. Parsing the differences in affected with LHON: genetic versus environmental triggers of disease conversion[J]. Brain, 2016, 139(Pt 3): 17. DOI: 10.1093/brain/awv339.
12.	Yu-Wai-Man P, Hudson G, Klopstock T, et al. Reply: parsing the differences in affected with LHON: genetic versus environmental triggers of disease conversion[J]. Brain, 2016, 139(Pt 3): 18. DOI: 10.1093/brain/awv340.
13.	Macmillan C, Kirkham T, Fu K, et al. Pedigree analysis of French Canadian families with T14484C Leber's hereditary optic neuropathy[J]. Neurology, 1998, 50(2): 417-422. DOI: 10.1212/WNL.50.2.417.
14.	张清炯, 郭向明, 贾小云, 等. 线粒体DNA11778突变所致Leber遗传性视神经病变外显率分析[J]. 中华医学遗传学杂志, 2001, 18(6): 415-417. DOI: 10.3760/j.issn.1003-9406.2001.06.006.Zhang QJ, Guo XM, Jia XY, et al. Penetrance of Leber hereditary optic neuropathy in Chineseindividuals with mitochondrial DNA 11778 mutation[J]. Chin J Med Gen, 2001, 18(6): 415-417. DOI: 10.3760/j.issn.1003-9406.2001.06.006.
15.	Harding A, Sweeney M. Pedigree analysis in Leber hereditary optic neuropathy families with a pathogenic mtDNA mutation[J]. Am J Hum Genet, 1995, 57(1): 77-86.
16.	Johns DR, Heher KL, Miller NR, et al. Leber’s hereditary optic neuropathy: clinical manifestations of the 14484 mutation[J]. Arch Ophthalmol, 1993, 111(4): 495-498. DOI: 10.1001/archopht.1993.01090040087038.
17.	Tan O, Chopra V, Lu AT, et al. Detection of macular ganglion cell loss in glaucomaby Fourier-domain optical coherence tomography[J]. Ophthalmology, 2009, 116(12): 2305-2314. DOI: 10.1016/j.ophtha.2009.05.025.
18.	Nikoskelainen E, Hoyt WF, Nummelin K. Ophthalmoscopic findings in Leber’s hereditaryoptic neuropathy. Ⅱ. The fundus findings in the affected family members[J]. Arch Ophthalmol, 1983, 101(7): 1059-1068. DOI: 10.1001/archopht.1983.01040020061011.

1. Fraser JA, Biousse V, Newman NJ. The neuro-ophthalmology of mitochondrial disease[J]. Surv Ophthalmol, 2010, 55(4): 299-334. DOI: 10.1016/j.survophthal.2009.10.002.
2. Yu-Wai-Man P, Griffiths PG, Brown DT, et al. The epidemiology of Leber hereditary optic neuropathy in the North East of England[J]. Am J Hum Genet, 2003, 72(2): 333-339. DOI: 10.1016/j.ophtha.2009.05.025.
3. Hudson G, Carelli V, Spruijt L, et al. Clinical expression of Leber hereditary optic neuropathy is affected by the mitochondrial DNA-haplogroup background[J]. Am J Hum Genet, 2007, 81(2): 228-233. DOI: 10.1086/519394.
4. Yu-Wai-Man P, Griffiths PG, Hudson G, et al. Inherited mitochondrial optic neuropathies[J]. J Med Genet, 2009, 46(3): 145-158. DOI: 10.1136/jmg.2007.054270.
5. Carelli V, Ross-Cisneros FN, Sadun AA. Mitochondrial dysfunction as a cause of optic neuropathies[J]. Prog Retin Eye Res, 2004, 23(1): 53-89. DOI: 10.1016/j.preteyeres.2003.10.003.
6. Yu-Wai-Man P, Griffiths PG, Chinnery PF. Mitochondrial optic neuropathies – disease mechanisms and therapeutic strategies[J]. Prog Retin Eye Res, 2011, 30(2): 81-114. DOI: 10.1016/j.preteyeres.2010.11.002.
7. Carelli V, Sadun AA. Optic neuropathy in Lhon and Leigh syndrome[J]. Ophthalmology, 2001, 108(7): 1172-1173. DOI: 10.1016/S0161-6420(01)00618-2.
8. Carelli V, Carbonelli M, de Coo IF, et al. International consensus statement on the clinical and therapeutic management of Leber hereditary optic neuropathy[J]. J Neuroophthalmol, 2017, 37(4): 371-381. DOI: 10.1097/WNO.0000000000000570.
9. Khan NA, Govindaraj P, Soumittra N, et al. Leber's hereditary optic neuropathy-specific mutation m.11778G>A exists on diverse mitochondrial haplogroups in India[J]. Invest Ophthalmol Vis Sci, 2017, 58(10): 3923-3930. DOI: 10.1167/iovs.16-20695.
10. Carelli V, Giordano C, d'Amati G. Pathogenic expression of homoplasmic mtDNA mutations needs a complex nuclear-mitochondrial interaction[J]. Trends Genet, 2003, 19(5): 257-262. DOI: 10.1016/S0168-9525(03)00072-6.
11. Carelli V, d'Adamo P, Valentino ML, et al. Parsing the differences in affected with LHON: genetic versus environmental triggers of disease conversion[J]. Brain, 2016, 139(Pt 3): 17. DOI: 10.1093/brain/awv339.
12. Yu-Wai-Man P, Hudson G, Klopstock T, et al. Reply: parsing the differences in affected with LHON: genetic versus environmental triggers of disease conversion[J]. Brain, 2016, 139(Pt 3): 18. DOI: 10.1093/brain/awv340.
13. Macmillan C, Kirkham T, Fu K, et al. Pedigree analysis of French Canadian families with T14484C Leber's hereditary optic neuropathy[J]. Neurology, 1998, 50(2): 417-422. DOI: 10.1212/WNL.50.2.417.
14. 张清炯, 郭向明, 贾小云, 等. 线粒体DNA11778突变所致Leber遗传性视神经病变外显率分析[J]. 中华医学遗传学杂志, 2001, 18(6): 415-417. DOI: 10.3760/j.issn.1003-9406.2001.06.006.Zhang QJ, Guo XM, Jia XY, et al. Penetrance of Leber hereditary optic neuropathy in Chineseindividuals with mitochondrial DNA 11778 mutation[J]. Chin J Med Gen, 2001, 18(6): 415-417. DOI: 10.3760/j.issn.1003-9406.2001.06.006.
15. Harding A, Sweeney M. Pedigree analysis in Leber hereditary optic neuropathy families with a pathogenic mtDNA mutation[J]. Am J Hum Genet, 1995, 57(1): 77-86.
16. Johns DR, Heher KL, Miller NR, et al. Leber’s hereditary optic neuropathy: clinical manifestations of the 14484 mutation[J]. Arch Ophthalmol, 1993, 111(4): 495-498. DOI: 10.1001/archopht.1993.01090040087038.
17. Tan O, Chopra V, Lu AT, et al. Detection of macular ganglion cell loss in glaucomaby Fourier-domain optical coherence tomography[J]. Ophthalmology, 2009, 116(12): 2305-2314. DOI: 10.1016/j.ophtha.2009.05.025.
18. Nikoskelainen E, Hoyt WF, Nummelin K. Ophthalmoscopic findings in Leber’s hereditaryoptic neuropathy. Ⅱ. The fundus findings in the affected family members[J]. Arch Ophthalmol, 1983, 101(7): 1059-1068. DOI: 10.1001/archopht.1983.01040020061011.

Chinese Journal of Ocular Fundus Diseases

Observation of penetrance and retinal nerve fiber layer and macular thickness in patients with Leber's hereditary optic neuropathy

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