Mitochondrial Dysfunction in Leber’s Hereditary Optic Neuropathy
Mitochondria play an essential role in maintaining cell function and many diseases result from mitochondrial dysfunction. Despite mitochondria being ubiquitous throughout the body, some mitochondrial diseases only affect particular tissues. Describe such a disease and what is known about the basis of its tissue selectivity.
Allowed word count: 1500
Actual word count: 1498
Introduction
Leber’s hereditary optic neuropathy (LHON) is an optical nerve dysfunction caused by mtDNA mutation that generally causes bilateral loss of sight in young adult men between the ages of 18 and 35 due to degradation of the optical nerve and retinal ganglion cells (RGCs). Although LHON generally affects young adults it can affect children as young as 1 and adults over 60.[1] Symptoms begin with a painless blurring of vision in one eye, with the second usually becoming affected simultaneously or within months. Over time both visual acuity and colour perception will deteriorate, with vision loss usually being permanent due to RGCs and the optic nerve being unable to repair under normal circumstances. Prevalence is estimated to be around 1:50,000 in Northern Europe with North England having a rate of 1:25,000.[2] The difficultly with creating treatments for LHON and other mitochondrial diseases is that the genetic mechanisms are not understood due to the complex nature of how mtDNA and nuclear DNA interact, with 18 mtDNA mutations found to be associated with the disease. Various mtDNA mutations also cause different levels of expression; such as 1 of 3 primary point mutations causing expression in 95% of cases; with other mutations having varying or no effect due depending on interaction with other mutations.[1]
Diagram 1 – Expression Pathway
mtDNA Primary mtDNA mutation
Nuclear DNA Genetic factors Mitochondrial Retinal ganglion Dysfunction
Allowed word count: 1500
Actual word count: 1498
Introduction
Leber’s hereditary optic neuropathy (LHON) is an optical nerve dysfunction caused by mtDNA mutation that generally causes bilateral loss of sight in young adult men between the ages of 18 and 35 due to degradation of the optical nerve and retinal ganglion cells (RGCs). Although LHON generally affects young adults it can affect children as young as 1 and adults over 60.[1] Symptoms begin with a painless blurring of vision in one eye, with the second usually becoming affected simultaneously or within months. Over time both visual acuity and colour perception will deteriorate, with vision loss usually being permanent due to RGCs and the optic nerve being unable to repair under normal circumstances. Prevalence is estimated to be around 1:50,000 in Northern Europe with North England having a rate of 1:25,000.[2] The difficultly with creating treatments for LHON and other mitochondrial diseases is that the genetic mechanisms are not understood due to the complex nature of how mtDNA and nuclear DNA interact, with 18 mtDNA mutations found to be associated with the disease. Various mtDNA mutations also cause different levels of expression; such as 1 of 3 primary point mutations causing expression in 95% of cases; with other mutations having varying or no effect due depending on interaction with other mutations.[1]
Diagram 1 – Expression Pathway
mtDNA Primary mtDNA mutation
Nuclear DNA Genetic factors Mitochondrial Retinal ganglion Dysfunction
References: 1. ^Dr Christope Orssaud (August 2002). “Leber Hereditary Optic Neuropathy”. Orphanet Encyclopedia. www.orpha.net/data/patho/GB/uk-LHON.pdf 2. ^Man PY, Griffiths PG, Brown DT, Howell N, Turnbull DM, Chinnery PF (February 2003) 3. ^Ted M. Montgomery (July 2012). “Pathology of the Human Eye.” http://www.tedmontgomery.com/the_eye/optcnrve.html 4. ^Claire Gilmour. Scottish Sensory Center. (February 2005) http://www.ssc.education.ed.ac.uk/courses/vi&multi/cgilmour.html 5. ^Hecht, Eugene, Optics, 2nd Ed, Addison Wesley, 1987 6. ^Jonas, Jost B.; et al (May 1992). "Human optic nerve fiber count and optic disc size". Investigative Opthalmology & Visual Science 33 7. ^Solano A, Playán A, López-Pérez MJ, Montoya J 8. ^Huoponen K, Vilkki J, Aula P, Nikoskelainen EK, Savontaus ML (1991). "A new mtDNA mutation associated with Leber hereditary optic neuroretinopathy". Am J Hum Genet 48 (6): 1147–1153. 9. ^P Y W Man, D M Turnbull, P F Chinnery (2002). “Leber hereditary optic neuropathy” Journal of Medial Genetics 2002; 39:162–169