.. A Guide to the Genetics of ..

                    .. Leber's Hereditary Optic Neuropathy 'LHON' ..

                              .. a Mitochondrial Disorder of the Enzyme 'Complex I' ..

Some initial thoughts ..

LHON has been known for over 140 years, having first been described by Theodore Leber in 1871, and his description of a condition occurring in families is as correct today as it was then. But despite a great deal having been learnt since about the condition, LHON remains enigmatic. Certainly the condition is inheritable and mitochondrial mutations are important but just what determines the appearance of symptoms remains unknown. At present it is probably best to reserve the label LHON for instances when there is a demonstrable mitochondrial mutation, either one of the major mutations G3460A, G11778A, or T14484C, or a less common variant. Why is the condition enigmatic? Well, because a person has the mitochondrial mutation present in their cells since conception and yet symptoms do not occur for many years, if at all. But what can be said is: - males are more at risk of developing symptoms than females - females pass the condition to ALL of their children - members of families with the mutation G11778A generally have more severe symptoms - families in mitochondrial Haplogroup J also appear to show more affected members. However ... having noted this, the fact still remains that many persons are asymptomatic throughout their lives, So it would seem that the blindness from LHON is not the inevitable result of having a mitochondrial mutation as presumably there are other underlying genetic and environmental factors that affect a person throughout their life. Recent research shows that the cause lies with Complex I, a mitochondrial OXPHOS complex with 45 subunits. And, it is possible that the assembling of the 45 parts to make a working structure is fragile in the human. So that in a person with a LHON mutation it is the functioning of Complex I in the most susceptible place, the optic nerves, that fails.

Public DNA testing

Until very recently it was really only possible to get one's mitochondrial DNA (mtDNA) tested by attending a hospital or being in a research project. But now .. Anyone can have their mtDNA mutations determined through one of several public companies. For example: Family tree DNA (www.ftdna.com) will do Full mtDNA sequencing for $299 (and lower on occasions) And, 23andMe (www.23andme.com) does a standard test of 500,000+ SNPs (including tests of G11778A, or T14484C) for $99 Note that Family Tree DNA does proper sequencing and any abnormal results can be checked manually. Also significant heteroplasmy will be reported, if present. However, 23andMe uses a 'chip' method to find specific mutations and individual results cannot be checked. The result can only be YES or NO, or if the process fails for whatsoever reason No call is used. Using this method heteroplasmy cannot be found.

Caveats ....

A mtDNA test shows a susceptibility to LHON symptoms, but in no way says they will, or will not, develop. A mtDNA test will confirm the maternal line and demonstrate when a LHON may have originated in a family, as some families carry a mutation through many generations, whilst in other families the mutation can appear recently. 'Heteroplasmy' (where G11778R or T144484Y is reported showing the carriage of the mutation is incomplete) is generally less harmful than being 'homoplastic', but in an individual person this may not be so.

Advice ....

It is generally advised that asymptomatic persons who carry a LHON mutation should avoid SMOKING and EXCESSIVE ALCOHOL CONSUMPTION - but the evidence for this advice is unproven. However, there are good theoretical grounds for suggestion smoking is harmful.

Review article ...

A good simple review is to be found at http://www.acnr.co.uk/09%20ND11/ACNRND11_web.pdf pages 17-19. This is 'Leber Hereditary Optic Neuropathy - Therapeutic Challenges and Early Promise' by Patrick Yu-Wai-Man & Patrick F Chinnery, of Newcastle, UK Link