An Overview of Leber’s Hereditary Optic Neuropathy

Zina Mobarak

Introduction

Leber’s Hereditary Optic Neuropathy (LHON) is a mitochondrial disorder characterised by severe vision loss, often manifesting in young adulthood (1). It was first described by Theodore Leber in 1871, but the pattern of inheritance was not confirmed until 1988 by Wallace et al. (2). It is one of the most common inherited optic neuropathies, with the hallmark being bilateral, painless central vision loss (3).

Epidemiology

The prevalence of LHON has been reported at 1 in 31,000 in the northern UK (4), 1 in 39,000 (5) in the Netherlands and 1 in 50,000 in Finland (6). However, the disease is underreported, as many patients may be given a diagnosis of optic atrophy without clearly defining LHON (1). It has been reported to affect males in 80 – 90% of cases (7), but this can be attributed to the much higher penetrance of the disease in males (8). A Brazilian study found that 45% of males in comparison to 10% of females actually lost their vision (8). Onset of the disease is typically in the second and third decades of life (9).

Pathophysiology

LHON is caused by point mutations in mitochondrial DNA, with three mutations known as the “primary LHON mutations” accounting for 90% of cases worldwide (7). These mutations impair the function of Complex I in the mitochondrial electron transport chain, leading to reduced ATP production and increased oxidative stress (10). The exact mechanism for what leads this dysfunction to the selective death of retinal ganglion cells is a debated topic.

Clinical Presentation

Classically, LHON presents with painless, unilateral loss of central vision. This can then progress to the second eye within days to months (7, 10), with more than 97% of patients developing second eye involvement within one year (7). Vision loss can have a bilateral onset, but these numbers may be inflated due to the patient simply not noticing the vision loss in the first eye (7). The vision loss is usually acute or subacute, with the deterioration stabilising after a few months {11, 12).

Diagnosis

Diagnosis can be made clinically. Fundoscopy includes micropapillary telangiectatic microangiopathy and elevation of the retinal nerve fibre layer around the disc (9). Other findings include hyperaemia of the optic nerve head, dilatation and tortuosity of posterior pole vasculature and retinal haemorrhages (7). Fluorescein angiography will show the absence of leakage from the disk or papillary region and an OCT will show thickening of the nerve fibre layer around the disk (1).

Confirmation of diagnosis can be made through blood testing for the mitochondrial DNA mutations (1). This type of testing is useful in atypical presentations or where there is an unclear family history.

Management

There is currently no treatment for LHON and supportive care and symptom management are offered to patients. However, there are new drugs being developed such as Idebenone, which is an antioxidant that has been shown to be successful in some case series and an ongoing clinical trial (14,15). Patients are advised to stop smoking, as some studies have shown a strong association between visual loss and smoking (13). Visual aids and genetic counselling are also offered to patients.

Prognosis

Visual prognosis for LHON is poor and most patients end up with permanent visual loss and legally registered as visually impaired (16). After the acute phase of the disease, visual loss stabilises and is unlikely to progress further. However, this level of vision loss has a negative impact on quality of life. Spontaneous bilateral recovery can sometimes occur, usually within the first year, and can also occur many years later (7). Vision improvement usually occurs in patients who have a lower mean age at the time of vision loss (6).

References

  1. Sadun, A. A., Morgia, C. L., & Carelli, V. (2011). Leber’s hereditary optic neuropathy. Current treatment options in neurology, 13, 109-117.
  2. Wallace, D. C., Singh, G., Lott, M. T., Hodge, J. A., Schurr, T. G., Lezza, A. M., & Nikoskelainen, E. K. (1988). Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science, 242(4884), 1427-1430.
  3. Meyerson, C., Van Stavern, G., & McClelland, C. (2015). Leber hereditary optic neuropathy: current perspectives. Clinical Ophthalmology, 1165-1176.
  4. Man, P. Y. W., Griffiths, P. G., Brown, D. T., Howell, N., Turnbull, D. M., & Chinnery, P. F. (2003). The epidemiology of Leber hereditary optic neuropathy in the North East of England. The American Journal of Human Genetics, 72(2), 333-339.
  5. Spruijt, L., Kolbach, D. N., de Coo, R. F., Plomp, A. S., Bauer, N. J., Smeets, H. J., & de Die-Smulders, C. E. (2006). Influence of mutation type on clinical expression of Leber hereditary optic neuropathy. American journal of ophthalmology, 141(4), 676-676.
  6. Puomila, A., Hämäläinen, P., Kivioja, S., Savontaus, M. L., Koivumäki, S., Huoponen, K., & Nikoskelainen, E. (2007). Epidemiology and penetrance of Leber hereditary optic neuropathy in Finland. European Journal of Human Genetics, 15(10), 1079-1089.
  7. Newman, N. J. (2005). Hereditary optic neuropathies: from the mitochondria to the optic nerve. American journal of ophthalmology, 140(3), 517-e1.
  8. Sadun, A. A., Carelli, V., Salomao, S. R., Berezovsky, A., Quiros, P. A., Sadun, F., & Belfort, R. (2003). Extensive investigation of a large Brazilian pedigree of 11778/haplogroup J Leber hereditary optic neuropathy. American journal of ophthalmology, 136(2), 231-238.
  9. Fraser, J. A., Biousse, V., & Newman, N. J. (2010). The neuro-ophthalmology of mitochondrial disease. Survey of ophthalmology, 55(4), 299-334.
  10. Carelli, V., Ross-Cisneros, F. N., & Sadun, A. A. (2004). Mitochondrial dysfunction as a cause of optic neuropathies. Progress in retinal and eye research, 23(1), 53-89.
  11. Riordan-Eva, P., Sanders, M. D., Govan, G. G., Sweeney, M. G., Costa, J. D., & Harding, A. E. (1995). The clinical features of Leber’s hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation. Brain, 118(2), 319-337.
  12. Mackey, D. A., & Buttery, R. G. (1992). Leber hereditary optic neuropathy in Australia. Australian and New Zealand journal of ophthalmology, 20(3), 177-184.
  13. Kirkman, M. A., Yu-Wai-Man, P., Korsten, A., Leonhardt, M., Dimitriadis, K., De Coo, I. F., & Chinnery, P. F. (2009). Gene–environment interactions in Leber hereditary optic neuropathy. Brain, 132(9), 2317-2326.
  14. Eng, J. G., Aggarwal, D., & Sadun, A. A. (2009). Idebenone treatment in patients with Leber hereditary optic neuropathy. Investigative Ophthalmology & Visual Science, 50(13), 1440-1440.
  15. Chinnery, P. F., Dimitriadis, K., Rouleau, J., Yu-Wai-Man, P., Heck, S., Griffiths, P. G.,  & Klopstock, T. (2010, January). Results of a 6-Months Randomized, Placebo-Controlled Trial (RHODOS) with Idebenone (Catena (R)) in Leber’s Hereditary Optic Neuropathy (LHON). In ANNALS OF NEUROLOGY (Vol. 68, No. 4, pp. S63-S63). DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA: WILEY-LISS.
  16. Kirkman, M. A., Korsten, A., Leonhardt, M., Dimitriadis, K., Ireneaus, F., Klopstock, T.,  & Yu-Wai-Man, P. (2009). Quality of life in patients with Leber hereditary optic neuropathy. Investigative ophthalmology & visual science, 50(7), 3112-3115.

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