LLeber’seber’s

HHereditaryereditary – – inherited from mitochondrial inherited from mitochondrial DNADNA

OOpticptic – – affects the eyeaffects the eye

NNeuropathyeuropathy – – disease/abnormality of nervous disease/abnormality of nervous systemsystem

Maternally inherited disorder Maternally inherited disorder

characterized by degenerationcharacterized by degeneration

of the retinal ganglion cells (of the retinal ganglion cells (RGCsRGCs) )

and atrophy of the optic nerve and atrophy of the optic nerve Mutations are in the mitochondrial Mutations are in the mitochondrial

(not nuclear) genome(not nuclear) genome Usually begins between the ages of 25 and 35 Usually begins between the ages of 25 and 35

(but can occur at any age) and leads to legal (but can occur at any age) and leads to legal blindnessblindness

More common in males than femalesMore common in males than females It was first described in 1871 by Theodore Leber It was first described in 1871 by Theodore Leber

and is the most common cause of optic atrophy. and is the most common cause of optic atrophy.

Inherited from mother to Inherited from mother to

all offsprings all offsprings

Only the egg contributes Only the egg contributes

mitochondria to the embryomitochondria to the embryo

2 billion mitochondria are 2 billion mitochondria are

made every second made every second

throughout a person’s life throughout a person’s life

250 mitochondria on the 250 mitochondria on the

average are found in a cellaverage are found in a cell

Life span is around 100 Life span is around 100

days.days.

Number varies from cell to Number varies from cell to cellcell

Circular strand of DNA Circular strand of DNA consisting of 16,569 consisting of 16,569 nucleotide bases nucleotide bases

Contains 37 genes Contains 37 genes 2 Encode for rRNA and 22 for 2 Encode for rRNA and 22 for

tRNAtRNA 13 genes encode for proteins 13 genes encode for proteins

required for the biochemical required for the biochemical reactions inreactions in

process that generates ATP process that generates ATP high energy moleculeshigh energy molecules

The rest 74 proteins for The rest 74 proteins for oxidative phosphorylationoxidative phosphorylation are are encoded by nuclear DNAencoded by nuclear DNA

HeteroplasmyHeteroplasmy

- Some of the mt DNA has - Some of the mt DNA has

mutationsmutations

some does notsome does not

- 15% of individuals with - 15% of individuals with LHONLHON are are

heteroplasmicheteroplasmic

- The rest are - The rest are homoplasmichomoplasmic

HomoplasmyHomoplasmy

All of the All of the mtDNAmtDNA has at least one of has at least one of

the three types of mutations for the three types of mutations for

or no mutations at all!!or no mutations at all!!

This determines the type of phenotype This determines the type of phenotype

and the risk transmission. and the risk transmission.

There is also a mitochondrial disorder There is also a mitochondrial disorder known as LHON (Leber's Hereditary known as LHON (Leber's Hereditary Optic Neuropathy) where the Optic Neuropathy) where the mitochondrial DNA mutations which mitochondrial DNA mutations which causes the disease (acquired causes the disease (acquired blindness) are homoplasmic - meaning blindness) are homoplasmic - meaning that all of the mitochondria carry the that all of the mitochondria carry the defect. However, just because a person defect. However, just because a person has one of the LHON mitochondrial has one of the LHON mitochondrial DNA mutations does not mean they will DNA mutations does not mean they will become blind, only about 10% will. become blind, only about 10% will. Confusing? You bet!Confusing? You bet!

Phenotypic threshold effectPhenotypic threshold effectin mtDNA mutatinsin mtDNA mutatins

Associated with mtDNA heteroplasmyAssociated with mtDNA heteroplasmy

Critical threshold in proportion of Critical threshold in proportion of

mutations in mtDNA must be exceeded mutations in mtDNA must be exceeded

before disease appearsbefore disease appears This is normally about 90%This is normally about 90% BUT, BUT, LHONLHON is generally homoplasmic is generally homoplasmic Interestingly certain Interestingly certain homoplasmichomoplasmic

mtDNA mutations do not express mtDNA mutations do not express LHONLHON phenotype at all!!!phenotype at all!!!

85% to 90% of cases of85% to 90% of cases of

LHONLHON are usually due to are usually due to

one of the threeone of the three mtDNA mtDNA

point mutationspoint mutations

ND4 ND1ND4 ND1 andand ND6ND6 subunit subunit

genes ofgenes of

of theof the

oxidative phosphorylationoxidative phosphorylation

chain in mitochondria, which chain in mitochondria, which

is the is the 11stst step step of the of the

The rate of The rate of mtDNAmtDNA

mutations is 10-times mutations is 10-times

greater than in nuclear DNAgreater than in nuclear DNA

Complex 1Site effected by the

3 point mutations

found in LEBERS

Causes of LHONCauses of LHON 3 point mutations at these sites3 point mutations at these sites: :

1)1) G11778AG11778A

50-60%50-60% LHON population LHON population

Mutation is located at position Mutation is located at position

11778 change is G to A11778 change is G to A

2)2) T14484CT14484C

10%10% LHON population LHON population

3)3) G3460AG3460A::

8-25%8-25% LHON population LHON population These mutations decrease production These mutations decrease production

of ATP resulting in cell dysfunction and of ATP resulting in cell dysfunction and cell deathcell death

Production ofProduction of ROSROS Reactive oxygen speciesReactive oxygen species – –

byproduct of oxidative phosphorylationbyproduct of oxidative phosphorylation Environmental factorsEnvironmental factors

Not everyone with one of these Not everyone with one of these

mutations will develop mutations will develop LHONLHON

Additional Additional geneticgenetic or or environmental environmental

factors factors play an important role to play an important role to

development of central vision lossdevelopment of central vision loss

Males with one of these mutations have a Males with one of these mutations have a 40% 40% lifetime risklifetime risk to develop symptoms to develop symptoms

Females have a Females have a 10% risk10% risk, although the actual risk , although the actual risk varies slightly from mutation to mutation varies slightly from mutation to mutation

Those factors that can reduce the blood supply to Those factors that can reduce the blood supply to the retina and optic nerve the retina and optic nerve

They are They are suspect suspect to 'trigger' the vision loss in to 'trigger' the vision loss in LHON LHON

a. a. Heavy drinking or smokingHeavy drinking or smoking b. b. Exposure to poisonous fumes Exposure to poisonous fumes such as carbon monoxidesuch as carbon monoxide c. c. High levels of stressHigh levels of stress d. d. Medications: Medications: Ethambutol – Ethambutol – Rx for TBRx for TB

Chloramphenicol – Chloramphenicol – for conjunctivitisfor conjunctivitis

e. e. Many other known toxins Many other known toxins that may cause blindnessthat may cause blindness

117783460

14484

RGCRGC (retinal ganglial (retinal ganglial cells)cells)

These cells depend on These cells depend on oxidative phosphorylation due oxidative phosphorylation due to their:to their: HugeHuge ATP demandATP demand Very sensitive to energy Very sensitive to energy

supply and mitochondria supply and mitochondria defects defects

Limited regenerationLimited regeneration abilitiesabilities

END RESULTEND RESULT = Vision = Vision damage from degeneration damage from degeneration of optic nerve due to of optic nerve due to insufficient ATP supplyinsufficient ATP supply

LHON is found in LHON is found in 80% 80% of young men in their of young men in their twentiestwenties

Female carriers have 85 Female carriers have 85 - 90% chance of staying - 90% chance of staying healthyhealthy

WhyWhy? ? X - chromosome X - chromosome

markers have been markers have been found which may found which may influence disease influence disease outcome in carriers, outcome in carriers, called protective factorscalled protective factors

Asymptomatic until visual

blurring develops

Acute PhaseAcute Phase:: Painless, acute onset of central vision lossPainless, acute onset of central vision loss Peripheral vision (seeing out of the corner of Peripheral vision (seeing out of the corner of

the eye) remainsthe eye) remains Loss of visual acuity/colorLoss of visual acuity/color Once symptoms appear in one eye, other eye Once symptoms appear in one eye, other eye

affected within few weeksaffected within few weeks

Sub acute Phase Atrophy of optic disc =

Cardiac conduction defectsCardiac conduction defects TremorsTremors Numbness or weakness in arms or legNumbness or weakness in arms or leg Loss of ankle reflexesLoss of ankle reflexes Symptoms vary by gender and type of Symptoms vary by gender and type of

mutation presentmutation present

— the most common mutation and usually the most severe vision loss

— usually has the best long term prognosis or outcome

— has an intermediate presentation

Molecular genetic blood test using Molecular genetic blood test using

polymerase chain reaction (PCR) techniques polymerase chain reaction (PCR) techniques

The test is 100% accurate for The test is 100% accurate for LHONLHON when when

visual loss has already occurred visual loss has already occurred

Interestingly, significant number of Interestingly, significant number of

individuals who are suspected to have individuals who are suspected to have LHONLHON

do not have one of the three primary mtDNA do not have one of the three primary mtDNA

LHON LHON mutations. mutations.

So far So far no treatmentno treatment has been has been proven effective in controlled proven effective in controlled trials fortrials for LHON LHON

BUTBUT……..…….. IdebenoneIdebenone, , a synthetic analogue a synthetic analogue

ofof coenzymeQ10coenzymeQ10 has been has been studies in clinical trials in studies in clinical trials in Canada, Germany and UKCanada, Germany and UK

IdebenoneIdebenone is a strongis a strong antioxidantantioxidant and may be the key and may be the key to providing stability to nerve to providing stability to nerve cell, decreasing the likelihood of cell, decreasing the likelihood of oxidative damage caused by free oxidative damage caused by free radicals released when cells are radicals released when cells are destroyed by chemical toxinsdestroyed by chemical toxins

Possible Rx options Possible Rx options

Neutralize free radical Neutralize free radical production by production by

neuronal cells with supplementation neuronal cells with supplementation

ofof antioxidantsantioxidants

Vitamins Vitamins

Natural plant extractsNatural plant extracts

Vitamin E Vitamin E

Co-enzyme QCo-enzyme Q

Vitamin C Vitamin C

Vitamin AVitamin A

Ginkgo biloba Ginkgo biloba

Curcumin Curcumin

ConclusionConclusion Point mutations in complex 1 due Point mutations in complex 1 due

play a major role in causing Lebersplay a major role in causing Lebers Decreased production of ATP Decreased production of ATP

underlies cell dysfunction and cell underlies cell dysfunction and cell deathdeath

Although there is no treatment at Although there is no treatment at this time, family history along with this time, family history along with genetic testing and healthy lifestyle genetic testing and healthy lifestyle may effect the outcome of this may effect the outcome of this disease as with other disease such disease as with other disease such as Canceras Cancer

ReferencesReferences http://www.ifond.org/lhon.php3http://www.ifond.org/lhon.php3

http://brain.oxfordjournals.org/cgi/content/full/http://brain.oxfordjournals.org/cgi/content/full/

124/1/209124/1/209

http://jnnp.bmj.com/cgi/content/abstract/75/12/1731http://jnnp.bmj.com/cgi/content/abstract/75/12/1731

http://www.pubmedcentral.nih.gov/articlerender.fcgi?http://www.pubmedcentral.nih.gov/articlerender.fcgi?

artid=1914692artid=1914692

http://genome.wellcome.ac.uk/doc_WTD020740.htmlhttp://genome.wellcome.ac.uk/doc_WTD020740.html

http://www.slh.wisc.edu/genetics/basics_disease.dothttp://www.slh.wisc.edu/genetics/basics_disease.dot

Thompson & Thompson. Thompson & Thompson. Genetics in MedicineGenetics in Medicine. .

Saunders: 2007Saunders: 2007