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LHON

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, temporal optic disc pallor, pupil reflex abnormalities, and color vision abnormalities. Recent work [Sadun et al 2006]suggests that abnormalities only found on examination usually preceed visual symptoms.[Kogachi et al 2016]

Non eye related symptoms are reported in some affected families. These may include heart electrical conduction abnormalities; various central and peripheral nervous system symptoms; or muscle abnormalities of minor to severe nature. The referenced reviews have details of the reports:
[Shemesh et al 2020] [Yu-Wai-Man & Chinnery 2016] [OMIM] [Kerrison & Newman 1997]


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.

Efficient mitochondrial biogenesis drives incomplete penetrance in Leber’s hereditary optic neuropathy. [Giordano et al 2014]. Management of reactive oxygen species is critical to maintain a high mitochondria number. The search for nuclear DNA modifiers which differentiate mutation carriers from affected as so far not been fruitful. Known non genetic risk factors for dysfunctional programmed optic nerve cell death or apoptosis in LHON are smoke inhalation, alcohol excess, other toxins and menopause. Dietary factors and insulin resistance are suspect as well, as these are known risk factors in glaucoma. [Melov et al 1997][Emperador et al 2019][Zarnowski et al 2017] [Zarnowski et al 2012][Harun-Or-Rashid et al 2018]


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 2013] 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, and 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 check this out as the understanding of this disease process is relatively new as is the ability to test and classify the genes. The tests are only performed in certain centres 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. [Hudson et al 2005] Other genetic patterns called mitochondrial DNA-haplogroup background may influence the disorder.[Hudson et al 2007a]

Mature Males Predominate - Males with the LHON mitochondria and are between the ages of 26 to 45 you may be more at 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 tested the term is "heteroplasmic". If all measured mitochondria are affected you may be more at risk due to this "homoplasmic" state. But, many people with documented homoplasmy still have normal vision.[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.[Kogachi et al 2019][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:

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.

Hormonal Factors. Female hormones, progesterone and oestrogen, are currently suspected to play a role in protecting women carriers. This is based on the female protective bias, the slight increase in incidence in post menopausal women, anecdotal reports of disease reversal after hormone replacement therapy [Fantini et al 2018] and in vitro studies of cybrid cell lines.[Giordano et al 2011] [Crespo-Castrillo 2020] The fact that females' exercise metabolism tends to be more based on fat metabolism than males thus relatively mitochondrial sparing could be relevant. [Blaak 2001] [Power 2007] A study on a lymphoblast model showed testosterone decreased cell survival. [Jankauskaitė et al 2020] Clinical studies of oestrogen and other mitochondrial sparing substances are currently being planned. Progesterone has proven neuroprotective benefits in central nervous system injury. [Deutsch et al 2013] In the mean time neuro-ophthalmologist clinicians are suggesting oestrogen hormone replacement [usually with progesterone] be considered for their menopausal LHON carrier patients.


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. Real world data has confirmed efficacy with long term treatment with some reservations about adequacy of data on the natural history of the disease. [Catarino et al 2020] [Newman et al 2020] 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.

Female hormone replacement therapy [HRT], estrogen and progesterone, under appropriate supervision and monitoring are currently recommended by neuro-ophthalmologists for menopausal female LHON carriers as preventative treatment. This is based on the observation of increased incidence of disease after menopause, anectodal evidence of recovered vision after HRT and cybrid studies. Both estrogen and progesterone are known neuroprotectors. An intriging question is how one harnesses this effect in males, avoiding unwanted complications.[Pisano et al 2015][Hernandez-Rabaza 2019]

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 and inhaling smoke of any kind. 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.

Proposed therapy research

The 2020 review by Bahr et al [Bahr 2020] is very broad, thorough and refreshing in its clear outline of the issues at hand. It emphasised the unique nature of the susceptible retinal ganglion cells [RGC] in LHON. It points out the lack of an established proven detailed pathophysiology of LHON in spite of human treatment trials already being performed. Thus, there is a requirement to do research on appropriate models of these particular cells, for example based on induced pluripotential stem cell technology and even on RGCs which are from genetic individuals. A broad range of research questions and approaches is suggested.

Wallace suggests the failure so far of some single agent metabolic approaches in treating mitochondrial disease points to a systems approach. He proposes the revival of the high fat, low carbohydrate "ketogenic diet" long used by neurologists for treating intractable epilepsy and arguably the normal diet for many peoples for thousands of years. This model therapy effects a profound change from carbohydrate metabolism which changes multiple pathways and encourages mitochondrial preservation.[Wallace 2010] [Storoni 2019] [Pflanz 2019] There are anectodal reports of successful treatment in mitochondrial disease using this approach[Kang 2006] [Kang 2007] [Ahola-Erkkilä 2010] [Zhao 2012] The hypothesis is consistent with the observed gender differences in LHON disease expression and increased post menopausal incidence as premenopausal females tend to use mitochondrial sparing fat metabolism in exercise more than males. [Abildgaard 2013][Blaak 2001] [Power 2007] Interesting epidemiological observations show a low incidence of primary open angle glaucoma in Inuit and Asians. [Arkell 1987] [Congdon 1992] [Bourne 2001] These groups traditionally ate high fat diets or intermittently starved and exercised regularly to survive.[Blanchet 2002] Some Inuit are currently undergoing a social / cultural / dietary experiment probably to the detriment to their general health and possibly to their eyes. [Sheehy 2013] Chinese rates of open angle glaucoma are rising with urbanised lifestyles. [Wang 2011] Clinical prospective studies on ketogenic diets and exercise therapy for optic nerve disease are called for. [Risner 2009][Zarnowski 2012] [Storoni 2019]

Antioxidants are a 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] [Davis 2018]Antioxidants are also part of the body's normal makeup and possibly could be induced to perform better. One proposal in this regard was the use of near infrared light which has had some success in wound and ulcer healing.[Wisconsin trial] However, preliminary anecdotal use associated with worsening vision stopped a trial going forward. [direct communication A. Sadun]

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 were scheduled to begin in July 2011, but fell through due to cost issues. [verbal reports] [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]

Gene therapy using virus vectors is on trial. Preliminary human clinical safety and efficacy trial reports have so far shown only modest benefits in restoring central vision in LHON. The technique used in the studies is to inject only one eye with active agent in a double blinded fashion per individual trial subject. Interestingly both treated and non treated eyes have similar outcomes so far. Best results were obtained in patients with early disease.[Zhang et al 2018] [Qi et al 2007] [Koilkonda et al 2014].

Stem cell therapy is not near clinical usefulness.[Zhang et al 2018]

Hypoxia [low oxygen] therapy: Speculation and some experiments may indicate that mildly low oxygen levels could be cell sparing in mitochondrial disease.[Hirano et al 2018] [Jain et al 2016] The sparse negative anectodal evidence of Hyperbaric Oxygen Therapy [high oxygen] treatment specifically in LHON is not encouraging, so not advised. High oxygen had 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. Population studies at high altitudes with lower oxygen partial pressure in Tibet have demonstrated a survival advantage for the mitochondrial mutation variant for NADH dehydrogenase subunit 1 (ND1) nucleotide 3394 T > C (Y30H) . [Fuyun et al 2012] This observation suggests that other LHON mutations may have survival advantages in certain environments. The question is which environments are beneficial for these mutants?

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. The United Kingdom has approved experimental use of the technique in humans. [Craven et al 2010][The Guardian 20130628]

The gut microbiome is affected by the host mitochondria. This implies a possible role of manipulation of gut microbiomne in a way beneficial to the host.[Yarden et al 2019]

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.

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OMIM 535000

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See Also

Wikipedia Leber's hereditary optic neuropathy



Update history

Updated 1 October 2020. Bryan Cebuliak

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