Leber’s Hereditary

1. Leber’s Hereditary Optic Neuropathy (LHON)

2. What is LHON? Leber’s Hereditary– inherited from mitochondrial DNA Optic – affects the eye Neuropathy – disease/abnormality of nervous system

3. Introduction Introduction • Maternally inherited disorder characterized by degeneration of the retinal ganglion cells (RGCs) and atrophy of the optic nerve • Mutations are in the mitochondrial (not nuclear) genome • Usually begins between the ages of 25 and 35 (but can occur at any age) and leads to legal blindness • More common in males than females • It was first described in 1871 by Theodore Leber and is the most common cause of optic atrophy.

4. Mitochondria Mitochondria • Inherited from mother to all offsprings • Only the egg contributes mitochondria to the embryo • 2 billion mitochondria are made every second throughout a person’s life • 250 mitochondria on the average are found in a cell • Life span is around 100 days.

5. Mitochondrial DNA Mitochondrial or mtDNA • Number varies from cell to cell • Circular strand of DNA consisting of 16,569 nucleotide bases • Contains 37 genes • 2 Encode for rRNA and 22 for tRNA • 13 genes encode for proteins required for the biochemical reactions in process that generates ATP high energy molecules • The rest 74 proteins for oxidative phosphorylation are encoded by nuclear DNA Oxidative phosphorylation

6. vs. Homoplasmy Heteroplasmy Heteroplasmy • Heteroplasmy - Some of the mt DNA has mutations some does not - 15% of individuals with LHON are heteroplasmic - The rest are homoplasmic • Homoplasmy All of the mtDNA has at least one of the three types of mutations for or no mutations at all!! • This determines the type of phenotype and the risk transmission. Complex 1

7. There is also a mitochondrial disorder known as LHON (Leber's Hereditary Optic Neuropathy) where the mitochondrial DNA mutations which causes the disease (acquired blindness) are homoplasmic - meaning that all of the mitochondria carry the defect. However, just because a person has one of the LHON mitochondrial DNA mutations does not mean they will become blind, only about 10% will. Confusing? You bet!

8. Phenotypic threshold effectin mtDNA mutatins • Associated with mtDNA heteroplasmy • Critical threshold in proportion of mutations in mtDNA must be exceeded before disease appears • This is normally about 90% • BUT, LHON is generally homoplasmic • Interestingly certain homoplasmicmtDNA mutations do not express LHONphenotype at all!!!

9. Causes of LHON • 85% to 90% of cases of LHONare usually due to one of the three mtDNA point mutations • ND4 ND1andND6subunit genes ofof the oxidative phosphorylationchain in mitochondria, which is the 1st step of the • The rate of mtDNA mutations is 10-times greater than in nuclear DNA Complex 1 Electron transport Chain

10. Oxidative phosphorylation Complex 1 Site effected by the 3 point mutations found in LEBERS

11. Causes of LHON ND4 • 3 point mutations at these sites: 1)G11778A 50-60% LHON population Mutation is located at position 11778 change is G to A 2)T14484C 10% LHON population 3)G3460A: 8-25% LHON population • These mutations decrease production of ATP resulting in cell dysfunction and cell death • Production ofROS Reactive oxygen species– byproduct of oxidative phosphorylation • Environmental factors Found in 85-90% of LHON cases ND6 ND1

12. Other factors in LHON Environmental factors in LHON • Not everyone with one of these mutations will develop LHON • Additional genetic or environmental factors play an important role to development of central vision loss • Males with one of these mutations have a 40% lifetime risk to develop symptoms • Females have a 10% risk, although the actual risk varies slightly from mutation to mutation

13. What are the environmental factors? What are the environmental factors? • Those factors that can reduce the blood supply to the retina and optic nerve • They are suspect to 'trigger' the vision loss in LHON a. Heavy drinking or smoking b. Exposure to poisonous fumes such as carbon monoxide c. High levels of stress d. Medications: Ethambutol – Rx for TB Chloramphenicol – for conjunctivitis e. Many other known toxins that may cause blindness

14. Epidemiology – race dependent ND4 11778 70% Europeans 90% Asians ND1 3460 Koreans ND6 14484 86% Quebec Canadians

15. RGC (retinal ganglial cells) • These cells depend on oxidative phosphorylation due to their: • HugeATP demand • Very sensitive to energy supply and mitochondria defects • Limited regeneration abilities • END RESULT = Vision damage from degeneration of optic nerve due to insufficient ATP supply

16. LHON is found in 80% of young men in their twenties • Female carriers have 85 - 90% chance of staying healthy • Why? • X - chromosome markers have been found which may influence disease outcome in carriers, called protective factors

17. Asymptomatic until visual blurring develops Acute Phase: • Painless, acute onset of central vision loss • Peripheral vision (seeing out of the corner of the eye) remains • Loss of visual acuity/color • Once symptoms appear in one eye, other eye affected within few weeks Sub acute Phase Atrophy of optic disc = Legally blind

18. Additional symptoms Additional symptoms • Cardiac conduction defects • Tremors • Numbness or weakness in arms or leg • Loss of ankle reflexes • Symptoms vary by gender and type of mutation present — the most common mutation and usually the most severe vision loss — usually has the best long term prognosis or outcome — has an intermediate presentation G11778A ND4 T14484C ND6 G3460A ND1

19. Diagnosis • Molecular genetic blood test using polymerase chain reaction (PCR) techniques • The test is 100% accurate for LHON when visual loss has already occurred • Interestingly, significant number of individuals who are suspected to have LHON do not have one of the three primary mtDNA LHON mutations.

20. Treatment Treatment • So far no treatment has been proven effective in controlled trials forLHON • BUT…….. • Idebenone, a synthetic analogue ofcoenzymeQ10has been studies in clinical trials in Canada, Germany and UK • Idebenoneis a strongantioxidantand may be the key to providing stability to nerve cell, decreasing the likelihood of oxidative damage caused by free radicals released when cells are destroyed by chemical toxins

21. Possible Rx options Possible Rx options • Neutralize free radical production by neuronal cells with supplementation ofantioxidants • Vitamins • Natural plant extracts • Vitamin E • Co-enzyme Q • Vitamin C • Vitamin A • Ginkgo biloba • Curcumin

22. Conclusion • Point mutations in complex 1 due play a major role in causing Lebers • Decreased production of ATP underlies cell dysfunction and cell death • Although there is no treatment at this time, family history along with genetic testing and healthy lifestyle may effect the outcome of this disease as with other disease such as Cancer

23. References • http://www.ifond.org/lhon.php3 • http://brain.oxfordjournals.org/cgi/content/full/124/1/209 • http://jnnp.bmj.com/cgi/content/abstract/75/12/1731 • http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1914692 • http://genome.wellcome.ac.uk/doc_WTD020740.html • http://www.slh.wisc.edu/genetics/basics_disease.dot • Thompson & Thompson. Genetics in Medicine. Saunders: 2007