LHON Inheritance

Will my children have LHON?

For the vast majority of people, even those carrying a LHON gene mutation, the answer to this question is NO.

All of the LHON gene mutations are in the DNA of Mitochondria.

almost every cell in the body has smitochondria, including a woman’s eggs, but a man cannot pass on his mitochondria in his sperm.

Like all of the other mitochondrial disorders, the LHON gene mutation is only passed on through the mother.

The children of a man affected by LHON will not inherit his LHON mutation.  They cannot develop LHON or pass it on themselves, whether they are male or female.

The children of a woman affected by LHON, or carrying a LHON gene mutation, are very likely to inherit her LHON gene mutation.

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

Anyone carrying a LHON gene mutation is at risk of developing LHON.

Scientists do not yet know all of the reasons why one person carrying a LHON gene is affected and another is not affected.

Three generations of a family tracing a LHON gene.

In the first generation, Man A does not have a LHON gene mutation, his wife B does have a LHON gene mutation.

She passes the LHON Gene Mutation on to all of her children, Woman C, Man D, and woman G.

So woman B has

Man D marries, but cannot pass on his LHON Gene Mutation to his children. His children, woman H and man I, are not LHON Carriers and can never be affected.

Woman G is carrying the same LHON Gene mutation as her mother, and she passe it on to her children woman K and man L

 

Woman K and man L are both LHON Carriers and are at tisk of developing LHON.

So woman B has three children, woman C,  man D and woman G.  Man D is much more likely to be affected than his two sisters, as the ratio of affected men to women is 9:1.

woman B has four grandchildren,   woman H, man I, woman K and man L

Woman H and man I have not inherited the LHON gene mutation and cannot develop LHON.

Their cousins woman K and man L are carrying the LHON gene mutation but man L is much more likely to develop LHON than his sister K.

Woman B has 7 descendants in her maternal bloodline, 5 of them are LHON carriers, and of those 5 people, the two males are at highest risk of developing LHON.

It is very important to think of this as a risk and not a certainty.  Even raising the risk by heavy smoking and drinking for many years does not make developing LHON a certainty.

Researchers think that there is some other inherited factor which protects some people from developing LHON.  It may even be that most people have this protective factor,  because so many people carry a LHON gene and are never affected.

Of course this factor is completely unknown, so doctors cannot tell which people carrying a LHON gene will be affected and which will not.

Doctors do know that smoking makes it a lot more likely that a LHON carrier will be affected, and that smokers are affected more severely than non-smokers.

Homoplasmy and Heterplasmy

A cell contains many mitochondria, and each one has its copy of the Mitochondrial Chromosome.

HOMOPLASMY is when all of the mitochondria have the same form of a gene, say the LHON G11778A mutation.

If some of the mitochondria in the cell have the G11778A LHON mutation, and the rest have the normal or “wild-type” version of the gen, then scientists call this HETERPLASMY.

When doctors do a blood test for a LHON gene, they will get an indication of the percentage of mitochondria carrying that gene.

So they may say that the test result was “Homoplasmic for G11778A”.  This would mean that all of the mitochondria had the mutated form of the gene.

They may say that the person is Heteroplasmic for the G11778A mutation, with 80% mutation.

That would mean that 8 out of 10 mitochondria have the LHON mutation, and 2 out of 10 have the wild-type version of the gene.

The first diagram represents a cell where all of the mitochondria have the wild-type gene.

Homoplasmic Cell

This diagram represents a cell which is heteroplasmic for the gene.  4 out of 10 mitochondria carry a mutated form of the gene.

Heteroplasmic cell

Some scientists believe that someone who has inherited a LHON gene must have a minimum percentage of affected mitochondria to develop LHON.  This percentage seems to be arount 80 percent Affected mitochondria. (2575667) (2238193)

See the Threshold Trigger Proposal page.

Once LHON is “triggered”, the outcome does not depend on the percentage of affected mitochondria.  There is no evidence that someone with 90% affected mitochondria has a better outcome than someone with 95%.

One way heteroplasmy complicates the inheritance of LHON is that different tissues in the body might have different levels of affected and unaffected mitochondria. (9143920)

A single cell can have several thousand mitochondria, and a single mitochondrion can have several copies of the Mitochondrial Chromosome.

Researchers have actually extracted the chromosomes from a single mitochondriion and shown that they can have different versions of a gene. This means that the mitochondrion is heteroplasmic , the cell is heteroplasmic and the person is heteroplasmic. (21179558)

 

What are the LHON Genes?

All of the gene mutations linked to LHON are in Mitochondrial DNA.

See the LHON Cause page for information about LHON and the function of Mitochondria.

The mutations make small but damaging changes in proteins essential to the way mitochondria release energy from food.

For more information on how these genes are inherited see the pages on Eggs, Sperm and DNA and Human Inheritance.

Every position or Base Pair in the Mitochondrial Chromosome is identified by its Base Pair Number – from 1 to 16569.  The numbers start at the top and run clockwise in the diagrams below.

The positions on either side of bp 1 are known as the D-Loop and hold control information rather than genes.

ND1, ND2, ND3, ND4, ND4L, ND5 and ND6 are genes coding for subunits of the protein NADH Dehydrogenase, also known as Complex I of the Electron Transport Chain.

CytB is a gene for Cytochrome B, part of Complex II.

COX1, COX2 and COX3 are genes for subunits 1,2 and 3 of Cytochrome C Oxidase or Complex IV.

ATPase6 and ATPase8 are genes for subunits of ATP Synthase or Complex V of the Electron Transport Chain.

The other genes in the Mitochondrial Chromosome are for chemicals used inside the Mitochondria to build proteins. The genes are for chemicals ccalled Transfer RNA (tRNA) and Ribosomal RNA (rRNA)

Most of the genes for chemicals used inside mitochondria are not held in the mitochondrial chromosome.  They are found on the chromosomes inside the Nucleus.

 

 

Over 9 out of 10 cases of LHON involve one of three “primary” mutations.

Diagram of Mitochonrial Chromosome showing 3 commonest LHON mutations

The next diagram shows rarer LHON mutations, including ones linked to LHON Plus.

Mitochondrial Chromosome with rarer LHON mutations

and there are some LHON mutations doctors have only found in one case so far.

Mitochondrial Chromosome with common and rare LHON mutations

These LHON gene mutations were taken from MITOMAP September 1 2015.

 

This page was last updated September 2 2015

Bibliography

Skip to toolbar