LHON

LHON Global LogoInformation on Leber Hereditary Optic Neuropathy (LHON) . LHON is a rare mitochondrial disorder causing blindness.

This site has a non-technical description of LHON,  research into the cause and treatment of LHON..  It documents and describes possible treatments. There are also links to Leber’s related sites and scientific papers, and useful information for visually impaired people. 

Leber Hereditary Optic Neuropathy is also called  Leber Optic Atrophy (LOA) or Leber Optic Neuropathy (LON).

Theodore Leber,  a German ophthalmologist, was the first doctor to identify and describe the disorder .  He published a scientific paper on it in 1871.  He defined a distinctive pattern of symptoms and family history.

Dr Leber also described a completely different eye disorder called Leber Congenital Amaurosis (LCA) .  If you are reading or talking about an eye disorder, be sure which one you mean.

The term “Leber’s Disease” can mean either LHON or LCA.

Doctors knew that LHON was inherited, but could not work out exactly how until the discovery of mitochondrial DNA and mitochondrial inheritance over a hundred years later.

This site is for general information only. Always consult with a qualified medical professional on health matters.

Old medical textbooks used to refer to Leber Hereditary Optic Neuropathy in a couple of sentences such as:  “Sudden bilateral loss of central vision affecting young adult males”.  We now know that LHON is more varied than that, as researchers have studied many more cases of LHON, and family trees affected by LHON, in the past twenty years.

 

LHON summary

Leber Hereditary Optic Neuropathy can affect someone at any age, from infancy to over 70.  In most, but not all, cases, the patient first loses eyesight sometime between the late teens and early thirties.(20675733)(23433437)

 

Rough graph showing that people can be affected from childhood to over 70 years, but most are affected as early adults.

 

Leber Hereditary Optic Neuropathy affects both men and women, although the ratio of male to female patients is about 9:1. That means a doctor specializing in LHON will probably see about 9 times more LHON affected men than women.

It also means that a young man carrying a LHON gene mutation (see the LHON 101 page for an explanation) is a lot more likely to develop LHON than a young woman carrying the same LHON gene mutation.

 

LHON Male-Female Ratio 9 to 1

For more information read the page on LHON in Women and Children.

The main symptom of LHON is a large dark or blurred patch in the center of the field of view.   Doctors call this a “Central Scotoma”.

This happens in one eye first, with no warning signs.  Vision loss starts in the very center, and quickly spreads outwards.  Within a few weeks the patch of lost vision stops growing.

Sometimes a person affected by LHON loses some sight in one eye without noticing at first.  That is because the brain combines the eyesight from the good and bad eye.

Then the same thing happens in the second eye.  At first a small spot of blurred vision in the center, growing quickly outwards.

In most people the center of the field of vision is lost within a few weeks, and they are left being able to see less clearly using their peripheral vision.  That is the sight you use when looking “out of the corner of your eye”.

The majority of patients affected by Leber Hereditary Optic Neuropathy lose central sight in both eyes, but there are rare cases where only one eye is affected.

Unlike some other eye diseases, people losing sight because of LHON don’t usually feel any pain in or behind the eyes at the time.

People with LHON can get eye strain and headaches, especially if he or she is tring something new like learning to use a magnifier.

The most common pattern of symptoms for some one affected by LHON is that one eye is affected first.  Without any warning signs, the patient starts to lose central vision.  There is a bright sparkling or hazy “cloud” in the center of their visual field in one eye. This grows and darkens.  After a couple of weeks the same thing happens in the other eye.  Within a month or two, central vision is lost in both eyes.

Doctors call the time when vision is rapidly getting worse the “Acute” phase of LHON.

Doctors call the time when the first eye starts losing sight the “Onset” of LHON.

After a month or two the eyesight stops getting noticeably worse, and the patient moves into what Doctors call the “Chronic Phase” of LHON.  This means the long-term state.

Most people affected by LHON are left with some eyesight around the edge of the field of vision.  This is called peripheral vision. They can use peripheral vision to walk around, but will not be able to see anything in detail.  They will not be able to see well enough to read, drive or recognise faces.

The “classic” pattern of LHON (Leber Hereditary Optic Neuropathy) is:

Acute Phase

  • Usually some time between the ages of 15 to 30
  • Suddden onset loss of central vision (Central Scotoma) in one eye
  • Swelling of Optic Disc and Retinal Nerve Fiber Layer
  • Painless
  • After a few weeks, sudden onset loss of central vision in the second eye.
  • Eyesight deteriorates rapidly with Scotoma growing in size.
  • Rate of Vision loss stops or dramatically slows after about two months from first onset.
  • Significant thinning of Retinal Nerve Fiber Layer
  • Pale Optic Disc
  • Swollen and distorted retinal blood vessels

Use the navigation menu to find pages with information on different topics such as LHON Triggers,  Contacting other affected families around the world, LHON Plus, LHON Treatments, Assistive Technology and so on. These pages also have links to relevant scientific papers and interesting sites.

Chronic  or Atrophic Phase

The Acute Phase of LHON usually lasts around two or three months.

After that The eyesight usually stops getting worse.

Doctors do not have much scientific information about LHON patients after the Acute phase.

Until very recently, people affected by LHON were not studied or given regular medical check-ups.

Some doctors think that the cells in the retina affected by LHON go dormant and die off gradually in the first year or two after the Acute phase.

People affected by LHON and their families are usually left to recover emotionally, and then adapt to living with very little sight.

Sometimes doctors offer families affected by LHON genetic counseling.  This means discussing the risks of other family members being affected.

(11897814)(9831004)(21527392) (17122117)(14750573)(http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4212093) (20632027)(2209913) (18173420)

 

 LHON Frequently Asked Questions

Is there a cure or treatment for LHON?

We do not yet have any proven cure clinically available for Leber’s Hereditary Optic Neuropathy. However there are some research projects underway looking into possible treatments. As you will see from the text below, there are therapies being developed in Switzerland,  the UK, the USA, Italy and France, as well as work going on in other countries around the world.

This section covers a few of the major points, but use the menu on treatments to read more.

 

Santhera, a Swiss pharmaceutical company, are developing Idebenone for the treatment of LHON and other mitochondrial disorders such as Duchene Muscular Dystrophy. They now use the trade name Raxone® for Idebenone.

For more information see the page on Idebenone aka Raxone

Stealth BioTherapeutics is developing Bendavia as a drug to treat mitochondrial disorders,  and Ocuvia to treat eye conditions such as Diabetic Macular Edema and Age Related Macular Degeneration. It is working to test re-purposing Ocuvia for treatment of LHON.

For more information visit the LHON Treatment page on Bendavia and Ocuvia

Gensight Biologics is developing a Gene Therapy technique to treat LHON due to mutations in the mitochondrial ND4 Gene.  This is aimed at the most common LHON causing mutation, G11778A but will also treat people with the other LHON associated mutations in the ND4 gene. This therapy is called GS010.  Gensight have another version of the treatment in their future pipeline, called GS011, containing the ND1 gene.  This will treat the those with the G3460A mutation.

For more information read the page on LHON Treatments GS010 and GS011 

The Bascom-Palmer Eye Institute at the University of Florida are also developing a Gene Therapy technique, and are in early human trials of a treatment using the ND4 gene, again aimed at treating people with the G11778A mutation.

For more information read the page on Gene Therapy at University of Miama Bascom-Palmer

Edison Pharmeceuticals is developing EPI-743 as a treatment for mitochondrial disorders.  They were involved with two very small trials on LHON patients, but have stopped the most recent trial. They seem to be concentrating on trialling EPI-743 for other mitochondrial disorders.

See the page on EPI-743.

The common factor of all of these programs is treating patients who are already showing the first signs of eyesight loss.  The aim of the treatment is to protect the remaining eyesight.

There is no way yet for a doctor to predict who will lose eyesight due to LHON.  That makes it very difficult to give a preventative treatment.  The best advice for prevention is that anyone carrying one of the LHON Gene mutations should

  • avoid tobacco smoke and any other toxic fumes
  • keep alcohol intake low and never binge-drink
  • avoid some strong antibiotics and other drugs known to affect LHON Carriers.
  • Eat a “healthy” well balanced diet with lots of fresh fruit and vegetables.

LHON doctors currently have the view that LHON causes some swelling of the Retinal Nerve Fiber Layer and Optic Nerve head during the Acute phase. After a few weeks the Retinal Ganglion Cells go dormant and start to die. The smaller RGCs are affected first, gradually spreading outward from the center of the field of view.

Over the next 12 to 24 months,  the Retinal Ganglion Cells die off, so treatment concentrates on trying to protect them.

Doctors think any treatment to recover eyesight more than about a year after onset will have to use Regenerative Medicine, probably based on Stem Cells. They do not think that the cells of the retina can recovery or replace themselves.

That is why all of the research on LHON treatments concentrates on people recently diagnosed, up to about one year ago.

Regenerative Medicine is develping very quickly, but there are no scientifically proven, clinically trialled stem cell treatments for LHON yet.

Read the page on Stem Cells and Regenerative Medicine.

Use the page navigation menu to find more detail about LHON Treatments.

How do I contact other families affected by LHON?

Because LHON is rare, it is difficult for affected families to meet each other. Even doctors who research LHON cannot put families in contact with each other because of patient confidentiality.

Websites and on-line self-help groups allow people across the world to talk with each other, ask questions and share experiences.

Lissa Poincenot’s LHON.ORG provides a lot of information about LHON, and Lissa sometimes helps people get in touch with other affected families who live in the same area.

Lissa is the United Mitochondrial Disease Foundation LHON Ambassador, and organises their annual LHON Symposium day.

There are several FACEBOOK groups related to LHON, and the main English-language one is Lissa’s Leber Hereditary Optic Neuropathy Facebook Group.

There is more information on the LHON Community page.

This disorder has several names in English, such as Leber’s Optic Atrophy, Leber’s Optic Neuropathy and Leber’s Hereditary Optic Neuropathy.  Sometimes it is known as Leber’s Disease, but this is not a good name to use.  Theodore Leber identified other eye disorders, such as Leber Congenital Amaurosis (LCA).  Although LCA is also a genetic eye disorder, it is completely different to LHON.

That is why on-line sites and documents use the long name or initials like LHON, but even this is difficult if you are talking to someone who is a native French, Italian or Spanish speaker.

In other major languages LHON is:

Dutch: Leber Opticus Atrofie / Leber’s Hereditaire Opticus Atrofie.

French: La Neuropathie Optique de Leber (NOL)

German: Lebersche Hereditäre Optikus Neuropathie

Italian: Neuropatia Ottica di Leber (NOL)

Spanish: Atrofia del Nervio óptico de Leber (ANOL)

What is the cause of LHON? What Triggers the Eyesight Loss?

The underlying cause of LHON is a change or mutation in a gne.  The gene is located in Mitochondria, and tells the body how to make a protein which is vital for releasing energy from food.

You can read more about this in pages on the cause of LHON, Possible LHON Triggers and the LHON Trigger Threshold Proposal.

Will my children have LHON?

For a man affected by LHON the answer to this is NO.

Men cannot pass on the mitochondrial DNA mutation to their children, because every child gets his or her mitochondria from their mother.

A woman who is carrying a LHOn gene mutation will almost certainly pass it on to her children.

This does not mean they will definitely be affected by LHON.

No-one knows exactly what triggers the eyesight loss in someone carrying a LHON gene mutation.  See the pages on LHON Triggers and the Trigger Threshold Proposal for some details.

Genetic testing might help, as doctors think that someone with a low percentage of affected mitochondria is very unlikely to be affected.

If a child has inherited a lot of affected mitochondria, some doctors put the risk of a male child being affected is about 1 in 2, and the risk of a female child being affected is about 1 in 10.

These risk figures might be different for your family.

LHON is a mitochondrial disorder, which means it the LHON gene mutation is inherited through the female line. See the pages on Egg, Sperm and Mitochondria, Human Inheritance and  LHON Inheritance for more information.

Can Women be affected as well as men?

Yes.

A woman carrying a LHON gene mutation has a much lower risk of being affected – about 1 in 10.

Doctors do not know why women are affected by LHON less often than men.

Some women develop symptoms of LHON after a sharp drop in Estrogen levels.

For a long time women affected by LHON have been mis-diagnosed.  This is because the early descriptions of LHON called it a disorder affecting young men. Even in the last few years some women with LHON have had problems getting the correct diagnosis because doctors have out-of-date information.

Read the page on LHON in Women and Children  for more information.

What does someone affected by LHON see?

This is a difficult question to answer, because everyone is affected differently.

LHON damages the part of the retina handling central visioni, so everyone affected by LHON has that in common.

The amount of useful eyesight a person has will vary.  It will depend on the lighting, how tired they are, how experienced they are at using the remaining sight.

The size of the central loss of vision will be different for everyone.

Some people see a dark shadow in the center, others see greyish blurring, or even brightly coloured spots.

Read the page on LHON Sight for some examples.

How Rare is LHON?

Although LHON is one of the commonest mitochondrial disorders, it is very rare.

There have been several studies trying to find out how common it is for someone to lose eyesight due to LHON.  the figures range from around 1 in 31,000 to 1 in 50,000.

LHON affects people in many ethnic groups and many countries around the world.

For more details read the page How Rare is LHON

What can help someone affected by LHON?

The shock of losing eyesight is a huge emotional blow for the affected person and his/her family.

Emotional support and counseling may help, and especially getting in touch with other families with similar experiences.

The affected person will need rehabilitation and orientation support.  This is often given by local Social Servies and/or a local charity for the Blind.

There are several topics with more information under the Living with LHON menu.

There are many aids that can help someone with little or no sight.  Read the page on useful aids for more information.

 

What helps a family living with LHON?

LHON impacts a whole family.

The affected person suddenly loses eyesight.  This is not just a physical loss, the person will be emotionally devastated.  Different people will show this in different ways, but everyone will be trying to deal with a huge life-changing event.

Read the page on Emotional Support for some comments about how people react to life-changing events.

Right now, there are no LHON treatments available, although some like Idebenone are being developed. The main medical care for the LHON Affected person is to help him or her adapt to living with LHON.

Support and care for a newly LHON Affected Person includes:

  • Emotional Support
  • Possible Mental Health care and support
  • Rehabilitation and Mobility Training
  • Daily Living Skills and Confidence Training
  • Finding Aids and Assistive Technology
  • Rebuilding Hobbies and Social Life
  • Rebuilding Skills, Education and a Working Life

The affected person and his/her loved ones can feel:

  • Isolated
  • Helpless
  • Frustrated
  • Lost

The biggest single thing that helps families impacted by LHON is the growing LHON Community. 

Contacting other families means:

  • No longer feeling isolated and alone.
  • Learning from each other about LHON
  • Learning from each other about places to find information and help
  • Providing emotional and practical support for each other.

There are a handful of medical centers around the world with experts in LHON, so these doctors work closely together and share information.

Most “local” health services will no little or nothing about LHON.  Worse, they might have out-of-date or inaccurate information.

Many families struggle to get the right tests and diagnosis.

Other families impacted by LHON who live in the same area can help with information about the local health services, local social services,  sources of help and assistive technology.

The parents and other family members will be very upset,  and will also need support.  A lot of the conversations on-line, by phone or in person at LHON groups are with parents, family members and partners of people affected by LHON.

As LHON is a genetic disorder, the family has to deal with the issue of a LHON Gene Mutation in the family.

Other Close family members, especially brothers of the affected person, are now at high risk of developing LHON.

Relatives on the Maternal side of the family may have to be told about the disorder.  Researchers might want to get blood samples from them, and they might find that they are at risk of developing LHON.

Some families might get Genetic Counseling.  This means a trained genetics expert describing and discussing the risks of other family members being affected.

What is the cause of LHON?

Leber Hereditary Optic Neuropathy is a genetic disorder.  This means you cannot catch LHON like a cold or the Flu.
Doctors know that LHON is caused by changes or mutations in DNA.  DNA is the very special chemical that passes information from parent to child on how the body is built.
The information in DNA is known as the Genetic Code.  Scientists usually represent this code as a long list of letters.  for example.
ACCGTA………………..100s or 1000s of letters…..TTCAGGACG
The mechanism for handling this code is very complicated, but putting it very simply.
DNA in our bodies is divided up into 47 “clumps” called Chromosomes.
The body is made up of a vast number of cells.  Most cells have a Nucleus, where 46 of the Chromosomes are stored.  These are the chromosomes that define our gender, body shape, hair color, eye color and so on.
The factors inherited from parents are called Genes. Scientists now know that each Gene tells the cell how to make one protein, or a small part of a large protein.
Each cell also has thousands of Mitochondria, where energy the cell needs is released from food.  Every one of these Mitochondria has its own Chromosome.
The DNA in Mitochondria only has around 17,000 “letters” or base pairs.   it tells the Mitochondria how to make some proteins used in the Mitochohndria to release energy safely from food.
All of the LHON-causing mutations are in this Mitochondrial Chromosome.
Each mutation is a single-letter change in the code for one protein.   Each mutation is identified by a number – this is the location or base pair number on the chromosome of the change.
Each mutation is also identified by two letters.  The first is the “Correct” letter in the code at that location.  The second letter is the “incorrect” letter caused by the mutation.
The three commonest LHON causing mutations are:
  • G11778A
  • G3460A
  • T14484C
These mutations are all in genes for the protein NADH Dehydrogenase, or Complex I.
This is a very important protein as it does a key process in release energy from food.
The LHON causing gene mutations make the protein a slightly different shape.  that makes it a lot less good at its job in the mitochondrion.
Doctors do not yet know exactly how these changes lead to LHON. Some researchers have found that nerve cells suffering from low ATP levels could not transmit signals properly because they could not move chemicals around inside the cell. (22709375)(24529383)
Most people with a LHON gene mutation never lose eyesight.  Some people seem to lose sight after a certain event, like exposure to toxins, or a medical treatment.  In most cases doctors do not know what “triggers” LHON.
See the pages on LHON Triggers and the Threshold Proposal.
For some reason, someone with one of these mutations starts losing vision at a certain age.  Doctors do not yet know exactly what starts the eyesight loss.
Once LHON is triggered in a person, the Retinal Ganglion Cells in their eyes are affected, and this in turn affects the Retinal Nerve Fiber Layer and the Optic Nerve.
See other pages on Eyesight,   LHON Symptoms, Mitochondrial DNA, Mitochondrial Function

What is Co-enzyme Q10? How is Idebenone different?

Co-enzyme Q10 is also called Co-Q10 or Ubiquinol.

It is very important in releasing energy from food to make ATP fuel.

That is because it is a key part of the Electron Transport Chain in mitochondria.

Co-enzyme Q10 picks up high-energy electrons and transports them from one protein complex to another.

Idebenone is a man-made chemical with similar properties.

It can do the job of Co-enzyme Q10 but is a smaller molecule.

Read the pages on LHON Cause and Co-enzyme Q10 for more information.

 

The Puzzles of LHON Triggers

Researchers have learned a lot about LHON in the last few years, but there are still puzzles to be answered.

Why are so few LHON Carriers affected?

Researchhers estimate that about 1 in every 8,500 people carries a LHON causing mutation, but only about 1 in 30,000 to 50,000 develop LHON.

One theory is that the cells of LHON Carriers have more mitochondria to compensate for the less efficient mitochondrial protein. This creation of extra mitochondria is called mitochondrial biogenesis. (24369379)(24501072)

Why are the Retinas and Optic Nerves affected?

There is a theory that LHON mutation is present in all tissues, but the only tissues affected are the ones with the highest energy demand.  However, the same theory has been put forward to explain why Parkinson’s Disease affects cells in the brain controlling motion.

Do the LHON mutations make the cells more susceptible to light damage? The tissues affected are the ones that light travels through to reach the rods and cones in the retina.

Why are women carriers affected much less often than men?

Extrogen seems to protect against the effcts of a LHON gene, but not completely.

Why does LHON affect the eyesight at a particular age?

The majority of people affected by LHON first lose eyesight in early adulthood.

Why is the eysight not affected from birth? The energy demands of the retinas and optic nerves are there from birth.

Is this due to an age-related metabolic change, such as the end of the male adolescent growth spurt? Is it due to a change in  fat metabolism, A change in Calcium or Magnesium metabolism?

Mitochondria are not just “the powerhouse of the cell” – researchers are finding that they have a vital role in cell signalling and control of many funcitons. They are linked to the way the cell keeps the right balance of chemicals inside, such as Calcium and Magnesium. (26319097)

Mitochondria are also linked to the “programmed cell death” mechanism called Apoptosis.

We know the general pattern of age from many scientific papers, but is there any consistency in the age affected for a particular family?

If the age affected is driven by a gradual factor such as a build up of affected mitochondria, or a build up of damage due to Reactive Oxygen Species,  why is it so consistent? Why are the eyes not both affected at the same time?

Why  is one eye affected significantly after the other?

Whatever the trigger, why is there a delay between the eyes being affected?  Why are they not both affected at the same time?

Is this related to the dominant eye? If for some reason LHON only affects the dominant eye, and the brain switches to the other eye being dominant because of the LHON damage, this could help explain the difference.

What is different in families with early-onset LHON?

Is there a second genetic factor making these people especially likely to be affected?

Is some protective factor missing?

Why are some people high risk but never lose eyesight?

How can some people have a LHON causing mutation, smoke, drink heavily for years but never be affected?

Do they have an extra protective factor?

Do they lack an extra LHON-causing factor?

Why is LHON present in 100% of cell cultures / animal models but not in all human carriers?

There are cell cultures and mouse models used to study LHON.  The lab tests show that these cultures are affected by the LHON gene.

What is it about these cultures or mouse strains that makes them 100% susceptible to LHON?

The assumption is that the LHON gene is affecting the cell and animal models in the same way it affects humans, but is this true?

This is an experimental site still under development. User Registration, Groups, Forums and other areas of this site are NOT OPEN TO THE PUBLIC. 

References

NCBI Gene Reviews – LHON

NIH Genetics Home Reference – LHON

On-line Mendelian Inheritance in Man – 535000 LHON

Hereditary Optic Neuropathies Eye (2004) 18, 1144–1160. doi:10.1038/sj.eye.6701591

Leber Hereditary Optic Neuropathy Yu-Wai-Man P, Turnbull D, Chinnery P; BMJ Jornal of Medical Genetics 2002 Mar 39(3) 162-9

This page was last updated on September 17 2015

Bibliography

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