About LHON

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Leber's hereditary optic neuropathy (LHON) was first described in 1871 by the German ophthalmologist Theodore Leber and was subsequently named after him.

Symptoms

A sudden painless blurring and clouding of vision are usually the first symptoms of LHON. These vision problems may begin in one eye or simultaneously in both eyes. If vision loss starts in one eye, the other eye is usually affected within several weeks or months, this is known as the ‘acute’ phase. The rate of progression can vary from rapid to over 2 years but most people are severely impaired by 3 or 4 months. Over time, vision in both eyes worsens with a severe loss of sharpness (visual acuity) and colour vision. LHON mainly affects the central vision which is required for detailed tasks such as reading, driving, and recognising faces. Peripheral vision generally remains intact so the affected individual can walk around independently. Although central vision gradually improves in a small percentage of cases, for most people the vision loss is permanent and visual acuity rarely changes thereafter. Vision loss is typically the only symptom of LHON however; some families with additional signs and symptoms have been reported. In these individuals, the condition is known as ‘LHON plus’ and some affected individuals develop features similar to multiple sclerosis, with muscle weakness and poor coordination.

 
 
 

Incidence 

The occurrence of LHON in most populations is still unclear. It has been estimated that there are between 1 in 30000 to 1 in 50000 affected individuals in the UK. Although this condition usually begins in a person's teens or twenties, rare cases may appear in early childhood or later in adulthood. LHON vision loss mostly affects men around age 15 - 25.  Women tend to be affected at an older age, often around times of oestrogen loss. For unknown reasons, males are affected much more often than females and there is approximately a 50% chance of losing vision if you are male and a 10% chance if you are female. Male carriers are therefore at a much higher risk of being affected and the reason for this gender bias is still unclear. 

Cause 

LHON is an inherited form of vision loss. This inheritance applies to genes contained in mitochondrial DNA. Mitochondria produce most of the energy that cells need to function and these inherited mutations disrupt the mitochondria and cause cells in the retina to stop working or die. These ganglion cells are required to relay visual information from the eyes to the brain (the optic nerve). Egg cells contribute mitochondria to the developing embryo so only females pass mitochondrial conditions to their children (maternal inheritance). Mitochondrial conditions can appear in every generation of a family and can affect both males and females, but fathers do not pass mitochondrial traits to their children. LHON is the most common mitochondrial condition and about 45 mutations have been linked to LHON.  The most common is the 11778 mutation, accounting for about 50% of all LHON cases.  About 45% of the remaining LHON cases are 14484 or 3460 mutations. Those who have lost their central vision due to LHON are often referred to as ‘affected’ and those with a LHON mutation gene but without vision loss are known as ‘carriers’. In some rare cases, patients do experience a significant recovery of vision and this is more likely to happen if you have the 14484 mutation. About 40% of individuals affected with LHON do not have a clear family history of this condition. A person may carry a mitochondrial DNA mutation without experiencing any signs or symptoms of vision loss therefore it is hard to predict which members of a family who carry a mutation will eventually become affected. However, it is important to realise that most people do not go completely blind and their peripheral vision allows them to lead an independent life. 

Diagram of the human eye
Fuensanta A. Vera-Díaz and Nathan Doble (2012). The Human Eye and Adaptive Optics, Topics in Adaptive Optics, Dr. Bob Tyson (Ed.), ISBN: 978-953-307-949-3, InTech, DOI: 10.5772/31073. Available from: http://www.intechopen.com/books/topics-in-adaptive-optics/the-need-for-adaptive-optics-in-the-human-eye

Triggers 

Patients with LHON mitochondrial DNA mutations usually do not have any symptoms until early adult life, when a trigger process leads to acute loss of vision. This trigger process is still unclear and there are unanswered questions relating to LHON; why does visual loss most often occur during the second and third decade of life, what causes such a sudden loss of vision over weeks or months and why do a small number of patients recover their vision? Answering these questions and understanding the triggers involved in LHON is fundamental to developing treatment options. Work in this area is being carried out at Newcastle University along with other research institutes. Most experts seem to agree that it is sensible to avoid smoking and excessive alcohol intake if you are a carrier of one of the LHON mutations or affected by vision loss. Some drugs are known to have the potential to cause damage to mitochondria and as both carriers and those affected by LHON are known to have weaknesses in their mitochondria, it makes sense to understand and if possible to limit the use of these drugs where alternatives exist. It may be helpful to review this list of medications on the mito action website with your GP or consultant before making these choices:

A list of drugs reported to have mitochondrial toxicity

This paper provides some more information on environment interactions and LHON:

Gene–environment interactions in Leber hereditary optic neuropathy  

Diagnosis 

If LHON is suspected, a blood test can determine if an individual has one of the primary mutations. However, LHON is a rare condition and most doctors will not have heard of it and even experienced ophthalmologists may have never seen a patient with LHON. This lack of knowledge can lead doctors to suspect and treat for other causes of vision loss. Typically, a series of tests are performed to confirm LHON diagnosis or exclude any other conditions. Tests may include an examination of the optic disc; an electroretinogram (ERG) to measure the electrical responses in the retina; a visual field test to characterise the area of vision loss (scotoma); an MRI or CT scan to rule out any optic nerve inflammation or other causes of optic neuritis. A lumbar puncture may also be carried out if a central nervous system infection is suspected. A course of intravenous or oral steroids may also be prescribed to treat suspected optic neuritis.

If the diagnosis is positive for one of the LHON mutations, you can request to be referred to a consultant who is knowledgeable about LHON, usually a neuro-ophthalmologist. Since LHON causes the optic nerve to atrophy, a specialist in this field is most likely to have had some experience with LHON. You may wish to consider being seen at Newcastle University, where there is a team of researchers with experience of LHON and mitochondrial disorders.

More information can be found on this NHS website: Rare Mitochondrial Disease Service for Adults and Children. This site is aimed at patients and health care professionals. The NCG is a part of the NHS responsible for directing funds to specialist services for rare disorders and has 3 participating centres in Newcastle, London and Oxford for mitochondrial conditions. Referrals for clinical opinion and requests for genetic or biochemical investigations can be made directly to each of these centres (referral forms for health professionals are available on the website).

Treatment and Management

Raxone (Idebenone) is currently the only medicine authorised in the EU for the treatment of LHON. As of September 2015 Raxone is in theory available on prescription for LHON anywhere within the EU. However, actual availability will vary markedly according to which country the patient is residing. Raxone has 'orphan designation' which is given to medicines used to treat rare diseases or those which probably would not be developed without incentives and there were 'exceptional circumstances' regarding the approval of Raxone due to the lack of comprehensive data on efficacy and safety. More information on the authorisation and assessment of Raxone can be found on the European Medicines Agency website. We provide more background information and links to articles on Raxone further on this page.

Anecdotally, some patients are self-medicating with a range of mostly antioxidant food supplements.  Early studies testing a range of antioxidants and other supplements including curcumin, lutein, brimonidine and others have proved inconclusive and most scientific research into this area seems to have ceased. Some of the most beneficial actions that can be taken by LHON affected patients, whether newly affected or long term blind, are actions that are generally accepted to be beneficial anyway. Chief among these is to adopt a healthy lifestyle which eliminates smoking and reduces or eliminates alcohol, incorporates fresh rather than processed foods and regular exercise.

Genetic Counselling

LHON mutations are usually homoplasmic, i.e. there is only mutant mtDNA within an individual. In about 15% of cases the mutations are heteroplasmic, and the individual harbors a mixture of wild type and mutant mtDNA. Genetic counselling in LHON is difficult because genetic testing cannot predict age of onset, severity, or rate of progression in carriers. Also, the amount of mutant mtDNA transmitted by heteroplasmic females cannot be predicted. 

If the mother has one of the LHON mitochondrial genetic mutations then so too will all her children. It will be passed to all children by mothers and none by fathers. Age and sex are important. A young male has a lifetime risk of around 50% of developing the condition after a positive test result but this falls as years go by without manifestation. However, the risk never vanishes, as it can present late in life. 

Image of the LHON inheritance pattern

Raxone (Idebenone) 

Idebenone (trade names Catena, Raxone) is a drug that was initially developed by Takeda Pharmaceutical Company for the treatment of Alzheimer's disease. The Swiss company Santhera Pharmaceuticals started to investigate it for the treatment of neuromuscular diseases. Chemically, Idebenone is an organic compound of the Quinone family. It is also promoted commercially as a synthetic equivalent of coenzyme Q10 (CoQ10). 

A randomised placebo-controlled trial of Idebenone in LHON which included 85 patients and had a treatment duration of 24 weeks showed that patients with discordant visual acuity were the most likely to benefit from a treatment with Idebenone. Discordant meaning that the visual acuity was different between the two eyes of a patient, which is usually observed in early stages of the condition. Treatment with Idebenone as opposed to the placebo did show an improvement in 20% of the eyes of patients who were not able to read any letter on the chart at the beginning of the study. The patients in this group, if they showed an improvement at all, were able to read at least one row of letters in the chart by the end of the study. Based on the available data it is, however, not possible to make any statement on the probability whether anyone personally could benefit from Idebenone treatment. The study also showed that patients with the most common mtDNA mutations in Europe (the 11778 and 3460 mutations) are more likely to benefit from Idebenone. The treatment effect was less obvious in patients with the 14484 mutation, as there is already a comparably high spontaneous vision recovery in these patients. The findings of the trial indicated that the 900mg daily dose of Idebenone was safe and well tolerated. 

A follow up study demonstrated that the beneficial effect from 6 months of treatment with Idebenone persisted despite discontinuation of therapy for a median time of 30 months. It is thought that the drug can preserve or re-establish retinal ganglion cell function during the acute phase, and thus protect from irreversible retinal ganglion cell loss. Consequently, the therapeutic potential of Idebenone therapy is likely to have the highest impact if therapy is initiated early in the disorder at a time when retinal ganglion cell loss is still minimal. 

For patients who were continuously kept on Idebenone treatment, a mean time to recovery of around 17 months has been observed. The results of these studies indicate that prolonged treatment could result in recovery of vision even in patients with established condition and severe visual acuity loss. A treatment period greater than 6 months therefore may offer additional therapeutic benefit. The published papers on the Idebenone trial and follow-up can be found here:

A randomized placebo-controlled trial of idebenone in Leber’s hereditary optic neuropathy 

Persistence of the treatment effect of idebenone in Leber’s hereditary optic neuropathy 

Santhera submitted an application to market Idebenone to European regulators in July 2011. In January 2013, the request for marketing authorisation was refused by the EMA. In June 2014, the EMA validated a revised application submitted by Santhera. Following the submission of further evidence by Santhera the EMA issued a recommendation for approval in July 2015 under their “Exceptional Circumstances” programme and their recommendation was adopted by the European Commission in September 2015.

In the absence of any other options Idebenone has become the only treatment recommended by some specialist neuro-ophthalmologists. Generally patients have been purchasing this medication over the counter due to the high cost and restricted availability of pharmaceutical grade Idebenone. LHON has been given Orphan status by the EMA and consequently any approved treatment for LHON will receive 10 years patent protection. This effectively means that Idebenone will no longer be available to purchase over the internet.

EPI-743 

This vitamin E derived compound Alpha Tocotrienol Quinone otherwise known as EPI-743, has been developed by Edison Pharmaceuticals to be used as a therapy for the treatment of inherited mitochondrial conditions. In early 2011, a stage 1 clinical trial on a small number of patients showed promise when 4 out of 5 patients treated under clinical conditions demonstrated visual recovery. While further trials of this compound are ongoing for Leigh Syndrome, Friedrich’s Ataxia and Pearson Syndrome, no phase 2 trials have yet been announced for EPI-743 in LHON and long term safety and toxicology is as yet untested. In January 2014 Edison Pharmaceuticals announced that it has entered into a strategic alliance with Dainippon Sumitomo Pharma Co Ltd. (DSP) for the development of drugs targeting cellular energy metabolism. More information on EPI-743 can be found here: 

Effect of EPI-743 on the clinical course of the mitochondrial disease Leber hereditary optic neuropathy 

Newcastle University statement on EPI-743.

Bendavia 

In October 2013 US biotech company Stealth Peptides publicly announced that their successfully trialled cardiovascular medication Bendavia, was to have its efficacy tested for mitochondrial conditions and that the condition selected to test would be LHON. The intention is to prove efficacy in LHON and then move on to other mitochondrial conditions. No trial date has been announced and as with EPI-743 this is likely to be a small-scale stage 1 trial with just a handful of recently affected participants. It is likely, therefore, to be another few years before any meaningful predictions can be made as to its efficacy and safety. Currently there are few details of the chemical composition, mechanism and function of the drug. 

Links to the Edison and Stealth Peptides websites: 

http://edisonpharma.com/

http://stealthpeptides.com/bendavia.

Gene Therapy 

Gene therapy treatment aims to correct the faulty mitochondrial DNA. The work is challenging, not least because the therapy must be delivered to the many mitochondria (hundreds) in each cell. This can be overcome by ‘allotropic expression’ where the cell’s nucleus is targeted, encouraging it to produce proteins which can then be transported to the many mitochondria in the cell. Investigations are taking place in 3 main locations into the use of gene therapy as treatment for LHON; Miami (Bascom Palmer Eye Institute), Dublin (Trinity College) and Paris (GenSight Biologics). Miami have secured funding for a phase I trial which begins in April 2014 and will conclude five years later. 

GenSight Biologics is a privately owned biopharmaceutical company working on gene therapy for eye disorders. LHON gene therapy preclinical phase was completed in 2013 and the first clinical trial started in February 2014.

GenSight will launch Phase 3 clinical trials of its gene therapy product GS010 for patients with LHON carrying the 11778 mitochondrial DNA mutation in early 2016. Recruitment in the UK will be carried out at Moorfields Eye Hospital in London with Mr Patrick Yu Wai Man (Consultant Ophthalmologist) as the lead investigator.

For more information, follow these links:

GenSight Phase 3 Clinical Trials

http://www.gensight-biologics.com/lhon  

http://med.miami.edu/news/clinical-trial-uses-gene-therapy-to-target-mutations-in-mitochon

Mitochondrial Donation

In this treatment, faulty mitochondria are replaced with those from a donor. This is currently in public consultation phase in the UK. This prevents mitochondria conditions from being passed from mother to child but it is not a therapy for carriers or LHON patients. It faces opposition, particularly from religious groups and those who see it as the slippery slope to ‘designer babies’. LHON as a mitochondrial condition can only be passed down the maternal line, as mitochondrial DNA exists only in the female egg.  Approximately 97% of genetic material is carried in the nucleus and so the genetic contribution of the donor to resulting offspring is considered to be relatively insignificant. In vitro and animal models have been successfully tested for inserting the nucleus of one cell containing faulty mitochondrial DNA into another cell containing healthy mitochondrial DNA from which the nucleus has been removed.

The UK became the first country to allow this treatment after Parliament and the House of Lords approved The Human Fertilisation and Embryology (Mitochondrial Donation) Regulations in February 2015, to come into force on 29 October 2015.

To learn more about the issues and science behind mitochondria replacement, visit the HFEA public consultation website.

Oestrogen and LHON

Recent research suggests that oestrogen protects women who carry a LHON mutation. This study investigated the reasons for the higher prevalence of LHON in males, exploring the potential compensatory effects of oestrogens. Female LHON carriers may wish to read this research paper, and discuss its implications with their health care providers:

Oestrogens ameliorate mitochondrial dysfunction in Leber’s hereditary optic neuropathy

Mitochondria Content

A recent research paper suggests that some carriers are protected due to their increased mitochondria content. The authors demonstrated that carriers’ cells have a greater number of mtDNA compared to LHON affected individuals and those who do not have a LHON mutation. The research suggested that when the number of mtDNA exceeds a threshold, the mutation does not cause optic nerve dysfunction. Being able to fully understand the mechanism of this increased mitochondria (biogenesis) in LHON carriers could be of great value to future diagnostic tests and treatment. The published research paper can be found here:

Efficient mitochondrial biogenesis drives incomplete penetrance in Leber’s hereditary optic neuropathy

Stem Cell Treatment 

Stem cell treatment has suffered from bad press due to controversy over ethical issues and scam treatments. No clinical trials are reported into this form of treatment for LHON although a number of private clinics (mostly in China) make claims of successfully treating LHON patients. The only known independent evaluation of these claims has found no evidence of success. It seems likely that any application of this treatment for LHON is some way off. As there is currently no therapy for curing neurodegenerative eye conditions, the idea of using stem cells to replace damaged cells seems very attractive to those desperate for treatment. Unfortunately some clinics prey on this desperation and offer unproven stem cell therapies. Travel to these clinics is often referred to as 'stem cell tourism' and it is common for these clinics to promise great benefits and downplay or ignore the risks. Find out more about the risks of bogus stem cell treatment here.

Various types of stem cells have been transplanted into mouse retinas, but it seems that further study is needed to find the signals within the eye that can differentiate transplanted stem cells and enable repair of damaged tissue. Researchers are trying to use stem cells to replace damaged retinal ganglion cells in conditions such as glaucoma. The challenge is to get the transplanted cells to integrate and to make connections with the cells that bring the visual signal from photoreceptors and the optic nerve carrying the signals to the brain. 

This useful website has lots of information about stem cells including current research, the challenges and potential treatments.

EuroStemCell is funded by the European Commission and provides independent information and educational resources on stem cells and their impact on society.

Click here for a medical definition of LHON