LHON Possible Triggers

What triggers the eyesight loss?

No-one knows exactly why some people can carry a LHON gene mutation for life and never become affected, and some people do lose their eyesight due to LHON.

If something as bad as losing eyesight happens, it is only human nature for the affected person and his/her family to look for the one clear event that “triggered” the onset of LHON.

Even doctors do this, asking if the affected person has recently suffered an injury, had an illness and so on.

But just because one thing happens after another, it does NOT mean the two events are linked as cause and effect.

Researchers try to find the actual triggers by looking at as many cases as possible, and finding patterns, not relying on one or two “anecdotal” cases.

There are mathematical tools in statistics that researchers use to judge how likely their findings are a real “cause and effect” pattern, or just random chance.

This page lists things researchers have considered as possible triggers for LHON.

Some researchers think that these triggers can combine together, adding up the risk of being affected, until a person is “tipped over” into developing LHON.

There are two kinds of people in LHON Affected families who still stump researchers.

Childhood or Early-Onset Cases

If someone develops LHON before tha age of about 10 years, he/she is very unlikely to have been exposed to environmental factors such as tobacco smoke, alcohol, recreational drugs, industrial solvents and so on.

These cases indicate a person has been born “very susceptible” to LHON, with a very high inherited risk.

Lifetime Heavy Smokers/Drinkers

Even in families of people affected by LHON, there are people who seem to “tick all of the boxes” for high-risk but never develop LHON.  A brother of an affected person who has been a heavy smoker and drinker for decades  but is never affected himself.

These cases indicate a person has been born  “very protected” from LHON, with a very low inherited risk.

 Thousands of people carry a LHON gene without knowing it

As with many disorders, the statistics on how rare or common LHON is are based on studying families with at least one affected person.    Looking at unaffected people in these families does NOT tell us much about the entire population.

If scientists look at the family tree of an affected person, they may find that the family has 10 females and 10 males carrying the LHON gene. If there is 1 affected females and 5 affected males, they may say that the risk of a female carrier being affected is 1 in 10, and the risk of a male carrier being affected is 1 in 2.

BUT THOSE FIGURES ARE ALL FOR PEOPLE IN THE SAME MATERNAL BLOOD LINE!

By definition, they have a lot more in comman, genetically, than just the mitochondrial DNA and LHON gene mutation.

They probably also have a lot of environmental, nutritional and other factors in common.

These risk figures may not apply to the population of the whole country.

What if we find that 1 in 100 people carry a LHON gene without every being affected?  More than 99 percent of families will never be tested for the gene and not even know that they are carriers.

One study in the North West of England studied 2,173,800 people and found that about 8 in 8,500 carried one of the three major LHON gene mutations.  The rate of LHON Affected people in this population was over twice the ‘average’ estimate, at about 1 in 14,000 affected males.

(19001017)

 

Just looking at these figures, with no information on their other risk factors, this puts the risk of a carrier developing LHON at around 150 / 250 or 60%.

Frequency of rare mitochondrial DNA mutations in patients with suspected Leber’s hereditary optic neuropathy J Med Genet. 2003 Jul; 40(7): e85.

The UK population in 2013 was estimated as about 64 million (based on the 2011 census).  Using the estimate of 1 in 8,500 carrying a LHON gene mutation gives an estimate of around 7,500 people in the UK carrying one of the three major LHON gene mutations.

if 60 percent of 7,500 people developed LHON this would be about 5,400 cases in the UK alone.

There must be at least one  big unknown factor reducing the risk a lot.

 

However, once a close blood relative develops symptoms of LHON, the risk of also being affected by LHON rises dramatically.

Doctors have been trying to understand the exact mechanism of LHON for several decades now.  Over the years a number of ideas have been suggested.  Some of these have been discounted, and others have been backed up with more evidence.

Like most information about LHON,  new research is being published every year, so be careful to use up-to-date information  based on medical research.  Even some medical doctors give people out-of-date information because they have not kept up to date with the latest research by the cutting-edge labs working on LHON.

Doctors can’t predict if a specific person will lose eyesight.  What they can do study the cases of people who have been affected by LHON and pull out the common “Risk Fa ctors”.

The big problem stopping scientists from understanding the LHON trigger factors is that none of them are simple black/white or yes/no switches.  It seems to be more likely that an affected person has a build-up of different factors, each one adding to their risk of losing eyesight.

The LHON Gene Mutations

DNA Strand Diagram

Someone is much more likely to be affected by LHON if they carry a Mitochondrial Gene Mutation known to trigger LHON. Almost everyone (over 90 percent) affected by LHON has one of the three main LHON gene mutations.  There are many rarer mutations that can cause LHON.  All of these mutations are in the small piece of DNA in the Mitochondria.

This does not mean that everyone with LHON has one of these mutations.  Doctors can diagnose LHON based on the symptoms.  Nowadays they will often do a set of “yes/no” tests looking for the three major LHON mutations (G11778A, G3460A and T14484C).

If these tests are all Negative, the doctor may order a full analysis of the Mitochondrial DNA for the affected person. This looks at all of the genes in the Mitochondria, listing out the Amino Acids one by one.  The doctors might find that there is one of the rarer LHON mutations, which has already been identified in another family, or they may find that there is a new mutation which has not been seen before.

An Affected Close Relative

Family Group FiguresEven before scientists found the link to Mitochondrial DNA, doctors had worked out that a maternal blood relative of someone with LHON has a higher risk of  being affected as well. That is why it was known as Leber’s Hereditary Optic Neuropathy even in the 19th Century.  But if having a LHON gene were the only factor involved, there would be no LHON Carriers, everyone with a LHON gene mutation would lose their eyesight.

This means there is some unknown inherited factor which has a strong influence on whether someone carrying a LHON gene will be affected. This could be a protective factor, some ability of the Optic Nerves to better cope with mitochondrial dysfunction, or some negative factor which makes the Optic Nerve fibres more likely to fail.

Gender

Male and Female FiguresThere are many studies producing differing results on different families, but an overall general view is that there are about 8 Male LHON affected patients for every Female.

We do not know why women carrying a LHON gene mutation are so much less likely to be affected, but a strong possibility is that the hormone Estrogen helps to protect the optic nerves from the damage caused by LHON.

Some possible reasons for the difference are:

  • An unknown protective factor on the X chromosome.
  • Female hormones protecting the Retinal Ganglion Cells
  • Female Fat metabolism

Whatever it is that “protects” women from being losing eyesight due to  LHON is not 100% certain. About one in nine people affected by LHON is female.

This could be because a woman’s hormone levels have dropped below a “threshold” level of protection, for example at menopause, and/or it could be because that particular woman has the unknown inherited factor that makes her more likely to be affected.

Changes in Hormone Levels

Diagram of an Estrogen moleculeSome research shows that the female hormone Estrogen can act to protect cell cultures from ROS  damage and cell death (apoptosis) in lab experiments. Although no-one knows why men are more often affected than women, this could be because female hormones protect the optic nerve from the damage caused by LHON. (20943885)  There are also cases where a woman has developed LHON as her Estrogen level falls.(20943885)(23748049). (22201999)

 

Age

Calendar imageMost people affected by LHON lose eyesight between the ages of 15 and 30, but cases of LHON have been reported in infants and people over 70.

It is very rare for someone carrying a LHON gene mutation to lose eyesight due to LHON after the age of 50.

Scientists can’t explain why someone doesn’t lose eyesight for many years, then within a few weeks loses most of their central vision.  This could be driven by the mitochondrial damage – it builds up gradually until it hits some “threshold” level where the Optic Nerve fibres can’t cope any more.  It could also be driven by some age-related body mechanism, like hormone levels or fat metabolism.

Smoking and Passive Smoking

No Smoking SignResearchers have found that tobacco smoke dramatically increases someone’s chance of losing eyesight from LHON.  Even among affected people, those with a lot of exposure to smoke, such as heavy smokers, end up with worse vision than non-smokers.

This makes a lot of sense, as exposure to smoke floods the body with a lot of poisons, affecting the nerves and the bloodstream.

Some doctors say that any kind of smoke is harmful and should be avoided as much as possible, including bonfires, camp fires etc.

Certainly anyone carrying a LHON gene mutation should never smoke and should avoid any kind of “passive smoking”.

The LHON Day scientific presentations in 2014 and 2015 both stressed the damaging effect smoke can have on someone carrying a LHON gene.

No Smoking Cigarette photoEven someone already affected by LHON should follow the same rules, as the poisons in smoke could kill off more of the Optic Nerve Fibres.

(19525327)(22194643)(11124301)(25338955)(23506382)

 

 

 

Alcohol

No Alcohol

The link between the onset of LHON and drinking alcohol is less clear-cut than the link with smoking, but doctors definitely recommend that people carrying a LHON gene should avoid heavy drinking.

 

All of the body cells, especially the nerves, are already being affected by the LHON gene, so causing further damage with alcohol is much more likely to give health problems.

(22405409)(22194643)(11124301)(25338955)(23506382)(23506347)

Exposure to toxic chemicals

Toxic Chemical Hazard SignAs well as exposure to tobacco smoke and alcohol, any exposure to toxic chemicals such as n-Hexane could be especially dangerous for someone carrying a LHON gene mutation. (25159832)(19936068)(17366829)

Severe Illness

Cartoon of sick personjDoctors have reported patients developing LHON during  or shortly after severe illness.

 

 

Lyme Disease (Borreliosis) treated with Ceftriaxone antibiotic and Ubidecarenone (Co-enzyme Q10) (16395203)

Hyperthyroidism (18051821)

This may be due to the illness itself or a side-effect of the treatment for the illness, for example  some powerful antibiotics.  See the comments on Medications as a possible trigger and the page on LHON and Drugs to Avoid

 

Medications

Medicine CapsulesPlease refer to the separate page on LHON and Drugs to Avoid for comments on medications such as some Erythromycin based Antibiotics, Ethambutol and Viagra.

 

 

Vitamin B12 Deficiency

Some cases of LHON may have been triggered by below-normal levels of Vitamin B12.  This can be caused by a medical condition preventing absorption, or a particularly bad diet leading to severe malnutrition.  A low level of Vitamin B12 may also be related to alcohol abuse or taking some medications.(19458584)(16523300)(23572439)(23506347)(23398673)(16705513)

 

 

Recreational Drugs

No Recreational DrugsClearly the very strong evidence that tobacco smoke can trigger LHON shows that smoking any drug mixed with tobacco is a very bad idea for anyone carrying a LHON gene mutation.

Please refer to the separate page on LHON and Drugs for comments on recreational drugs such as Cocaine and Ecstasy.

Trauma / Blow to the Head

Physical Injury CartoonThere are a few scientific papers describing a case of LHON where the doctors think that trauma (a blow or shock) might have triggered the symptoms.  This may be a coincidence, rather than cause and effect. (15692782)(22019873)

 

This page was last updated on August 12 2015

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