Leber Hereditary Optic Neuropathy, International Foundation for Optic Nerve Disease

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Leber Hereditary Optic Neuropathy

IFOND NEWS

Fundraising

IFOND gratefully acknowledges all our generous donors. For years a large portion of our funding has been from the IFOND annual golf outing. This happy event will continue. Email us if you are attending. Recently we have also been getting a steady but modest flow of online donations from many sources. McCORMICK& COMPANY, INC. have been generous regular donors with their Matching Gifts Program. In July 2010 we were graced with a large donation from The Welcoming Club of Garden City. See our fundraising section for further details and recognition. Without your generous giving our important research would not happen.

Alfredo A. Sadun, MD, PhD, wins 2012 William F. Hoyt Award

The IFOND Board is very proud to have Professor Aldredo Sadun as a scientific advisor. This November our most distinguished and effective teacher, clinician and researcher was awarded by the American Academy of Ophthalomology and the North American Neuro-Ophthalmology Society their highest honour in Neuro-Ophthalmology, The William F. Hoyt Lecturer Award.

17th Annual Golf Outing success

Don Diehl, Golf Outing Chair, reports that the 17th Annual Golf Outing Fundraising Event held on September,10 2012 was a resounding success with over 125 golfers participating and many other generous sponsors and donors contributing to the effort.

Idebenone treatment for LHON

A randomized placebo controlled study published in the journal Brain showed idebenone to be an effective treatment for LHON. Idebenone is a synthetic benzoquinone, co-enzyme Q10 like substance, potent antioxidant and inhibitor of lipid peroxidation, which also interacts with the mitochondrial electron transport chain and facilitates mitochondrial electron flux through by-passing complex I. It was shown in the study to be well tolerated and have modest effectiveness in about half of LHON patients treated. The result confirms retrospective treatment data soon to be published. People treated early in onset and for prolonged periods were likely to benefit most.

LHON treatment trials

IFOND scientific members are involved in new LHON treatment trials using the Vitamin E metabolite substance, Alpha-tocotrienol-quinone, coded EPI-743, a potent antioxidant. Find Dr Jerry Sherman's presentation of his optometric case findings in this promising open label study in Review of Optometry Case 38 Leber's Hereditary Optic Neuropathy [Note: be patient for the 60 second wait to download the 100 slides.]

Brazil LHON Field Trip Reports

With your support, IFOND sponsors research on the world's largest Leber Hereditary Optic Neuropathy [LHON] pedigree. In our projects section Dr Alfredo Sadun, the study co-ordinator, has summarized the studies to date since 2001 when they began with IFOND sponsorship. We have pushed the frontiers of knowledge about Leber Hereditary Optic Neuropathy. Please donate to IFOND to see this and other worthwhile IFOND work continue.

Leber Hereditary Optic Neuropathy (LHON), also known as Leber Optic Atrophy (LOA), was first described in 1871 as a sudden loss of vision in young men with a family history of blindness. It is the most common of the hereditary Optic Atrophies.

[Note: LHON or LOA should not be confused with either Leber's Congenital Amaurosis or Leber's Miliary Aneurysms which are unrelated eye conditions.]

Symptoms and Signs of LHON

The disease causes a loss of central vision within two to eight weeks, usually affects both eyes, may cause eye pain or discomfort at first, and may cause neurological symptoms such as numbness and tingling. Ophthalmologists detect signs of optic nerve degeneration such as visual field defects, blood vessel changes around the optic disc, optic disc pallor, pupil reflex abnormalities, and color vision abnormalities. Recent work suggests that abnormalities only found on examination usually preceed visual symptoms.[Yu-Wai-Man & Chinnery 2008] [OMIM] [Kerrison & Newman 1997][Sadun et al 2006]

Causes

In 1988 researchers discovered that LHON is one of a group of mitochondrial diseases, genetic diseases that are inherited only through the mother. [Wallace et al 1988] Mitochondria are the bodies within cells where energy needed for the activities of the cell is produced from oxygen. There are now some twenty different genes known to take part in the development of LHON. Three particular mutations account for 85% to 90% of the cases of LHON. However, the mitochondial mutation is clearly not the only genetic factor involved in the disease, as not every carrier is affected and men are at higher risk than women.

The factors that render mitochondria in optic nerve cells unable to produce energy thereby producing cell death, are largely unknown. One hypothesis is that cell death is actually programmed, and is the result of a random distribution of defective mitochondrial DNA during the normal mitotic division and ageing process of cells. [Melov et al 1997]

Diagnosis

The discovery that LHON is a mitochondrial disease has led to a diagnostic molecular genetic blood test. Testing for mutations using polymerase chain reaction techniques is available in a few centers around the world. [Yu-Wai-Man & Chinnery 2008] The test is 100% accurate for LHON when visual loss has already occurred. Family members of someone with LHON who test positive may be at risk for LHON. It is important for family members to be tested because changes in lifestyle and diet may help prevent the onset of LHON. IFOND may be able to help with names of nearby specialists in optic nerve disease for those who have had a sudden visual loss that cannot be corrected by glasses and the diagnosis is unknown.

Incidence

LHON mutations are prevalent in ~1 in 8,500 individuals in the general population.[Man et al 2003] Current research reveals that while LHON occurs 80% of the time in young men in their twenties, it also occurs in men, and in women, of all ages. In one study the onset of LHON was found to have occurred in men and women as young as six and as old as sixty two. Other research finds that LHON may occur in someone who has no family history of LHON or blindness. Expression of the gene varies with the mitochondrial mutation and the family but in general the chances of the eyes of female carriers remaining healthy are over 85% and of males over 50%.

Risk Factors for Onset Of Blindness

Genetic Markers Present - A simple painless test using hair, cheek, or blood cells can be performed to genetically type mitochondria. If there is a family history of sudden onset of blindness, whatever age, it is wise to consider LHON. The tests are only performed in certain centers around the world, and samples may have to be sent some distance.

Genotype - There are many different areas within the mitochondria that may be affected. The area, or site on the mitochondria DNA that contains the mutation is expressed as a number. The particular mitochondrial mutation may affect severity and likelihood of blindness or possible recovery. Up to 80% of the mutations documented are 11778, 3460, and 14484. However research is showing that there are other mutations. [OMIM] Nuclear chromosomal X-linked alleles haplotype may also influence expression of the disease. [Hudson et al 2005] Other genetic patterns called haplogroup may influence the disorder.[Hudson et al 2007a]

Mature Males Predominate - Males with the LHON mitochondria between the ages of 26 to 45 are at highest risk of developing the disease.

Homoplasmy - Of those that have affected mitochondria, some have a greater ratio of "affected" to "normal" mitochondria. This is usually expressed as a percentage. For instance, if 8% normal mitochondria were detected amongst 92% affected cells this is heteroplasmy. If all measured mitochondria are affected, risk may be increased due to this "homoplasmic" state. But, many people with documented homoplasmy still have normal vision. Hetero/homoplasmy does not fully explain risk of penetrance of the condition. [Kerrison & Newman 1997]

Toxic substances - ingested, inhaled or absorbed through the skin, have been shown to cause neurological and optic blindness and it is suggested that those people with genetic or aquired deficiencies of the mitochondria may be more susceptible to small amounts of these sorts of substances.[Sadun et al 2003][Sadun 1998] More work is needed to determine whether mitochondrial deficiency results in increased susceptibility. The toxic substances shown to cause blindness include:

Tobacco smoke
Alcohol
Some antibiotics
Cancer treating drugs
Anti-viral drugs eg. as used for treating AIDS.
Anti malarial drugs
Some anti arrythmic heart drugs
Some anti high blood pressure drugs
Some anti epilepsy drugs
(Possibly) Cyanogens. These are found in some foods such as peas, beans, and other legumes, almonds and other nuts, and apricots. Cigarette smoke also contains quantities of these substances.
Fumes from Paints, Varnishes, hair dyes, especially fat soluble chemicals including Benzene rings in their chemical structure eg Toluene. The cell membrane of the nerve cell has a lipid (fat) layer and these neurotoxins may be aided to penetrate with the benzene components.
Stress related chemicals eg Adrenaline, catecholamines; testosterone and oxidizing chemicals endogenously released by the body.
and others

For those at risk a double check with the doctor and pharmacist is highly recommended before taking a course of drugs for any reason.

Possible Protective Factors

Unfortunately, at present there is no certain cure for LHON. Though early treatment [Klopstock et al 2011] [Carelli et al 2011] may be effective in preserving some vision in some cases. For now prevention, with avoidance of possible toxins, and judicious use of antioxidants when toxins are unavoidable, is the cornerstone of hope. In case of an acute onset of blindness in a recognised family pedigree of Leber's, it is important if at all possible, to be monitored by an ophthalmologist. Hopeful experimental protocols are in progress.

Protective genes. As there are many more cases of male onset of blindness than female, it is postulated that there is some protective factor in the female body. X chromosome markers have been found which may influence disease outcome in carriers.[Hudson et al 2005] It is possible that sex hormone receptors such as androgen receptor may play a role.[Hudson et al 2007b] Mitochondrial halpogroup is known to play a role in penetrance in some mutations.[Hudson et al 2007a] A search for protective genes on other chromosomal and mitochondrial DNA continues.

Treatment

Clinical trials of idebenone [Klopstock et al 2011] [Carelli et al 2011] have shown modest effectiveness in approximately half of cases. Early and prolonged therapy offered most chance of partial recovery. Previously there was some inconsistent ancedotal evidence for this ubiquinone [coenzyme Q10]-like derivative, mildly altering progress or spontaneous recovery in some mutations in some cases. [Mashima et al 2000] [Barnils et al 2007] It is conjectured that inadequate amounts of the substance actually reaching the mitochondria was cause for these early experimental treatment failures.

Various agents and medications have been proposed, not just for LHON but for various other optic neuropathies. IFOND does not recommend any of the agents listed below. We bring you this information for you to stay current on the status of the proposed and somewhat controversial disease modifying therapies. However, the IFOND Scientific Board is intensely involved in research to find potential treatment methods.

Reports of cure with drugs in isolated LHON cases may be spontaneous recoveries which are known to happen in some mutations more than others. Or the intervention may have meant the difference for that individual. The reasons for these "cures" remain a mystery.

Though there is conflicting data about their direct relationship to LHON, [Tsao et al 1999][Kerrison et al 2000][Sadun et al 2003] it is generally regarded as prudent to avoid drinking alcohol and smoking tobacco. Both of these are known to aggravate or cause other eye diseases as well. They may also interact with other environmental or occupational toxins in a harmful way.

Speculative lines of research in LHON therapy include the following:

Antioxidants may be the key to providing stability to the nerve cell and decreasing the likelihood of oxidative damage caused by free radicals released when cells are destroyed by chemical toxins. Antioxidants can be classified according to drug type and include Vitamins and natural plant extracts, for example, Vitamin E, Co-enzyme Q, Vitamin C, Vitamin A, Ginkgo biloba, curcumin. [Ritch 2007] [Clinical Trial Curcurmin 2007]Antioxidants are also part of the body's normal makeup and possibly could be induced to perform better. One proposal in this regard is the use of near infrared light which has had some success in wound and ulcer healing.[Wisconsin trial]

Alpha-tocotrienol-quinone, a Vitamin E metabolite, has had some success in small open label trials in reversing early onset vision loss. Based on this, FDA approved trials are scheduled to begin in July 2011. [Shrader et al 2011]

Various agents are being considered for optic nerve protection. One line of thinking separates axonal from cell body causes of nerve degeneration. It is uncertain how this applies to LHON. [Levin 2007] Brimonidine is one agent thought to have neuroprotective qualities which has been trialed in a small number of early onset LHON cases with mixed results.[Newman et al 2005]

Laboratory research continues on virus vector gene therapy and stem cell therapy. [Qi et al 2007] These lines of treatment have been used experimentally in people with other nerve injuries and diseases, but not in LHON.

The sparse negative anectodal evidence of Hyperbaric Oxygen Therapy [HBO] treatment specifically in LHON is not encouraging. This is not currently a line of active research in LHON. HBO has been suggested as a treatment by delivering increased levels of oxygen to the affected nerve cell during its "starvation" period, or period of onset of blindness. A counter argument is that too much oxygen may be toxic in the context of poor cell antioxidant functioning. Oxygen toxicity to the eye is a known problem in premature babies on oxygen. There has been some success, however, using HBO with with other nerve diseases.

Three person in vitro fertilisation is a proof of concept research technique for preventing mitochondrial disease in developing human fetuses. So far, viable macaque monkeys have been produced. But ethical and knowledge hurdles remain before use of the technique in humans is established. [Craven et al 2010]

Research

Research in LHON is ongoing and of prime importance, as this is a "model" disease. The data gathered may be of importance not only for LHON affected families but for millions of others affected by many other diseases.

For example, the crucial cellular damage which leads to nerve cell death and blindness in Leber's Hereditary Optic Neuropathy is similar to nerve cell damage that occurs in Parkinson's disease, Alzheimer's disease and glaucoma. These common, slowly progressing neurodegenerative diseases affect millions in the United States alone. The time span of the disease process in LHON is more rapid, two to eight weeks. Though new research has found tests of LHON disease progress prior to blindness. Finding the reason for this intriguing difference in timing may give clues to the eventual cures of these and other eye and nervous system diseases.

Why do some children who have inherited mitochondrial mutations responsible for LHON become blind while their siblings, born with the same mutations do not develop LHON? It is clear that genetic inherited mitochondrial mutations are not sufficient alone to explain blindness. What other factors may play a role?

Do the risk factors now known to cause blindness in some cases, actually stimulate the development of LHON? If so, how? Are there other risk factors? It seems clear from current knowledge that environmental risk factors play an important role in the onset of LHON but much more needs to be learned about the known potential risk factors, and the possible existence of other risk factors.

These questions, concerning the interplay of genetics and environment are important to work going on now to find ways to prevent the onset of LHON,and may well be of importance to furthering research in other optic nerve diseases, and neurodegenerative diseases.

References

Barnils N, Mesa E, Muñoz S, Ferrer-Artola A, Arruga J. 2007. [Response to idebenone and multivitamin therapy in Leber's hereditary optic neuropathy] Arch Soc Esp Oftalmol. Jun;82(6):377-80. PMID 17573650

Carelli V, La Morgia C,Valentino ML, Rizzo G, Carbonelli M, De Negri AM, Sadun F, Carta A, Guerriero S, Simonelli F, Sadun AA, Aggarwal D, Liguori R, Avoni P, Baruzzi A, Zeviani M, Montagna1 P, Barboni P. 2011. Letter to the editor: Idebenone Treatment In Leber's Hereditary Optic Neuropathy. Brain doi:10.1093/brain/awr180

Clinical Curcurmin trial recruiting at ClinicalTrials.nlm.nih.gov

Clinical Idebenone trial recruiting at Newcastle University UK

Clinical Idebenone-like proposed trial IFOND Projects: Brazil 2007

Craven L, Tuppen HA, Greggains GD, Harbottle SJ, Murphy JL, Cree LM, Murdoch AP, Chinnery PF, Taylor RW, Lightowlers RN, Herbert M, Turnbull DM. 2010. Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease. Nature. 2010 May 6;465(7294):82-5. Epub 2010 Apr 14. PMID 20393463

Hudson G, Carelli V, et al. 2007a. Clinical expression of Leber hereditary optic neuropathy is affected by the mitochondrial DNA-haplogroup background. Am J Hum Genet. Aug;81(2):228-33.PMID 17668373 PubMed central free full text

Hudson G, Carelli V, Horvath R, Zeviani M, Smeets HJ, Chinnery PF. 2007b. X-Inactivation patterns in females harboring mtDNA mutations that cause Leber hereditary optic neuropathy. Mol Vis. Dec 21;13:2339-43 PMID 18199976

Hudson G, Keers S, Yu Wai Man P, Griffiths P, Huoponen K, Savontaus ML, Nikoskelainen E, Zeviani M, Carrara F, Horvath R, Karcagi V, Spruijt L, de Coo IF, Smeets HJ, Chinnery PF. 2005. Identification of an X-chromosomal locus and haplotype modulating the phenotype of a mitochondrial DNA disorder. Am J Hum Genet. Dec;77(6):1086-91. Epub 2005 Oct 11. PMID 16380918

Kerrison JB, Miller NR, Hsu F, Beaty TH, Maumenee IH, Smith KH, Savino PJ, Stone EM, Newman NJ. 2000. A case-control study of tobacco and alcohol consumption in Leber hereditary optic neuropathy. Am J Ophthalmol. Dec;130(6):803-12. PMID 11124301

Kerrison JB, Newman NJ. 1997. Clinical Spectrum of Leber's Hereditary Optic Neuropathy. Clinical Neuroscience. 4:295-301 IFOND Reprint

Klopstock T,Yu-Wai-Man P, Dimitriadis K, Rouleau J, Heck S, Bailie M, Atawan A, Chattopadhyay S, Schubert M, Garip A, Kernt M, Petraki D, Rummey C, Leinonen M, Metz G, Griffiths PG, Meier T, Chinnery PF. 2011. A randomized placebo-controlled trial of idebenone in Leber's hereditary optic neuropathy. Brain Full text online doi: 10.1093/brain/awr170

Levin LA. 2007. Axonal loss and neuroprotection in optic neuropathies. Can J Ophthalmol.. Jun;42(3):403-8. PMID 17508035

Man PY, Griffiths PG, Brown DT, Howell N, Turnbull DM, Chinnery PF. 2003. The epidemiology of Leber hereditary optic neuropathy in the north east of England. Am J Hum Genet 72:333339 PMID 12518276

Mashima Y, Kigasawa K, Wakakura M, Oguchi Y. 2000. Do idebenone and vitamin therapy shorten the time to achieve visual recovery in Leber hereditary optic neuropathy? J Neuroophthalmol. Sep;20(3):166-70. PMID 11001192

Medical College of Wisconsin near infrared LHON trial http://www.mcw.edu/neurology/research/LHON.htm

Melov S, Hinerfeld D, Esposito L, Wallace DC. 1997. Multi-organ characterization of mitochondrial genomic rearrangements in ad libitum and caloric restricted mice show striking somatic mitochondrial DNA rearrangements with age. Nucleic Acids Res. Mar 1;25(5):974-82. PMID 9023106

Newman NJ, Biousse V, David R, Bhatti MT, Hamilton SR, Farris BK, Lesser RL, Newman SA, Turbin RE, Chen K, Keaney RP. 2005. Prophylaxis for second eye involvement in leber hereditary optic neuropathy: an open-labeled, nonrandomized multicenter trial of topical brimonidine purite. Am J Ophthalmol. Sep;140(3):407-15. PMID 16083844

OMIM 535000

Qi X, Sun L, Hauswirth WW, Lewin AS, Guy J. 2007. Use of mitochondrial antioxidant defenses for rescue of cells with a Leber hereditary optic neuropathy-causing mutation. Arch Ophthalmol. Feb;125(2):268-72. PMID 17296905

Ritch R. 2007. Natural compounds: evidence for a protective role in eye disease. Can J Ophthalmol. 2007 Jun;42(3):425-38. PMID 17508040

Sadun A. 1998 Acquired mitochondrial impairment as a cause of optic nerve disease. Trans Am Ophthalmol Soc. 96:881-923. PMID 10360310

Sadun AA, Carelli V, Salomao SR, Berezovsky A, Quiros PA, Sadun F, DeNegri AM, Andrade R, Moraes M, Passos A, Kjaer P, Pereira J, Valentino ML, Schein S, Belfort R. 2003. Extensive investigation of a large Brazilian pedigree of 11778/haplogroup J Leber hereditary optic neuropathy. Am J Ophthalmol. Aug;136(2):231-8. PMID 12888043

Sadun AA, Salomao SR, Berezovsky A, Sadun F, Denegri AM, Quiros PA, Chicani F, Ventura D, Barboni P, Sherman J, Sutter E, Belfort R Jr, Carelli V. 2006. Subclinical carriers and conversions in Leber hereditary optic neuropathy: a prospective psychophysical study. Trans Am Ophthalmol Soc. 104:51-61. PMID 17471325

Shrader, W. D.; Amagata, A.; Barnes, A.; Enns, G. M.; Hinman, A.; Jankowski, O.; Kheifets, V.; Komatsuzaki, R. et al. 2011. Alpha-Tocotrienol quinone modulates oxidative stress response and the biochemistry of aging. Bioorganic & Medicinal Chemistry Letters 21 (12): 3693-3698. PMID 21600768

Tsao K, Aitken PA, Johns DR. 1999. Smoking as an aetiological factor in a pedigree with Leber's hereditary optic neuropathy [full text] Br J Ophthalmol. May 83:577-581. PMID 10216058

Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM, Elsas LJ 2nd, Nikoskelainen EK. 1988. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science. Dec 9;242(4884):1427-30. PMID 3201231

Yu-Wai-Man P, Chinnery P. 2011. Leber Hereditary Optic Neuropathy. GeneClinics, University of Washington LHON online review October 2000, March 2008, July 2011