2. LLeber’seber’s
HHereditaryereditary –– inherited from mitochondrial DNAinherited from mitochondrial DNA
OOpticptic –– affects the eyeaffects the eye
NNeuropathyeuropathy –– disease/abnormality of nervousdisease/abnormality of nervous
systemsystem
3. Maternally inherited disorderMaternally inherited disorder
characterized by degenerationcharacterized by degeneration
of the retinal ganglion cells (of the retinal ganglion cells (RGCsRGCs))
and atrophy of the optic nerveand atrophy of the optic nerve
Mutations are in the mitochondrialMutations are in the mitochondrial
(not nuclear) genome(not nuclear) genome
Usually begins between the ages of 25 and 35 (but canUsually begins between the ages of 25 and 35 (but can
occur at any age) and leads to legal blindnessoccur at any age) and leads to legal blindness
More common in males than femalesMore common in males than females
It was first described in 1871 by Theodore Leber andIt was first described in 1871 by Theodore Leber and
is the most common cause of optic atrophy.is the most common cause of optic atrophy.
4. Inherited from mother to allInherited from mother to all
offspringsoffsprings
Only the egg contributesOnly the egg contributes
mitochondria to the embryomitochondria to the embryo
2 billion mitochondria are2 billion mitochondria are
made every secondmade every second
throughout a person’s lifethroughout a person’s life
250 mitochondria on the250 mitochondria on the
average are found in a cellaverage are found in a cell
Life span is around 100 days.Life span is around 100 days.
5. Number varies from cell to cellNumber varies from cell to cell
Circular strand of DNACircular strand of DNA
consisting of 16,569 nucleotideconsisting of 16,569 nucleotide
basesbases
Contains 37 genesContains 37 genes
2 Encode for rRNA and 22 for2 Encode for rRNA and 22 for
tRNAtRNA
13 genes encode for proteins13 genes encode for proteins
required for the biochemicalrequired for the biochemical
reactions inreactions in
process that generates ATP highprocess that generates ATP high
energy moleculesenergy molecules
The rest 74 proteins forThe rest 74 proteins for oxidativeoxidative
phosphorylationphosphorylation are encoded byare encoded by
nuclear DNAnuclear DNA
6. HeteroplasmyHeteroplasmy
- Some of the mt DNA has mutations- Some of the mt DNA has mutations
some does notsome does not
- 15% of individuals with- 15% of individuals with LHONLHON areare
heteroplasmicheteroplasmic
- The rest are- The rest are homoplasmichomoplasmic
HomoplasmyHomoplasmy
All of theAll of the mtDNAmtDNA has at least one ofhas at least one of
the three types of mutations forthe three types of mutations for
or no mutations at all!!or no mutations at all!!
This determines the type of phenotypeThis determines the type of phenotype
and the risk transmission.and the risk transmission.
7. There is also a mitochondrial disorderThere is also a mitochondrial disorder
known as LHON (Leber's Hereditaryknown as LHON (Leber's Hereditary
Optic Neuropathy) where theOptic Neuropathy) where the
mitochondrial DNA mutations whichmitochondrial DNA mutations which
causes the disease (acquired blindness)causes the disease (acquired blindness)
are homoplasmic - meaning that all of theare homoplasmic - meaning that all of the
mitochondria carry the defect. However,mitochondria carry the defect. However,
just because a person has one of thejust because a person has one of the
LHON mitochondrial DNA mutationsLHON mitochondrial DNA mutations
does not mean they will become blind,does not mean they will become blind,
only about 10% will. Confusing? You bet!only about 10% will. Confusing? You bet!
8. Phenotypic threshold effectPhenotypic threshold effect
in mtDNA mutatinsin mtDNA mutatins
Associated with mtDNA heteroplasmyAssociated with mtDNA heteroplasmy
Critical threshold in proportion of mutations inCritical threshold in proportion of mutations in
mtDNA must be exceeded before disease appearsmtDNA must be exceeded before disease appears
This is normally about 90%This is normally about 90%
BUT,BUT, LHONLHON is generally homoplasmicis generally homoplasmic
Interestingly certainInterestingly certain homoplasmichomoplasmic mtDNAmtDNA
mutations do not expressmutations do not express LHONLHON phenotype atphenotype at
all!!!all!!!
9. 85% to 90% of cases of85% to 90% of cases of
LHONLHON are usually due toare usually due to
one of the threeone of the three mtDNAmtDNA
point mutationspoint mutations
ND4 ND1ND4 ND1 andand ND6ND6 subunitsubunit
genes ofgenes of of theof the
oxidative phosphorylationoxidative phosphorylation
chain in mitochondria, whichchain in mitochondria, which
is theis the 11stst
stepstep of theof the
The rate ofThe rate of mtDNAmtDNA mutationsmutations
is 10-times greater than inis 10-times greater than in
nuclear DNAnuclear DNA
11. Causes of LHONCauses of LHON
3 point mutations at these sites3 point mutations at these sites::
1)1) G11778AG11778A
50-60%50-60% LHON populationLHON population
Mutation is located at positionMutation is located at position
11778 change is G to A11778 change is G to A
2)2) T14484CT14484C
10%10% LHON populationLHON population
3)3) G3460AG3460A::
8-25%8-25% LHON populationLHON population
These mutations decrease production ofThese mutations decrease production of
ATP resulting in cell dysfunction and cellATP resulting in cell dysfunction and cell
deathdeath
Production ofProduction of ROSROS
Reactive oxygen speciesReactive oxygen species – byproduct– byproduct
of oxidative phosphorylationof oxidative phosphorylation
Environmental factorsEnvironmental factors
12. Not everyone with one of theseNot everyone with one of these
mutations will developmutations will develop LHONLHON
AdditionalAdditional geneticgenetic oror environmentalenvironmental
factorsfactors play an important role toplay an important role to
development of central vision lossdevelopment of central vision loss
Males with one of these mutations have aMales with one of these mutations have a 40% lifetime40% lifetime
riskrisk to develop symptomsto develop symptoms
Females have aFemales have a 10% risk10% risk, although the actual risk, although the actual risk
varies slightly from mutation to mutationvaries slightly from mutation to mutation
13. Those factors that can reduce the blood supply toThose factors that can reduce the blood supply to
the retina and optic nervethe retina and optic nerve
They areThey are suspectsuspect to 'trigger' the vision loss in LHONto 'trigger' the vision loss in LHON
a.a. Heavy drinking or smokingHeavy drinking or smoking
b.b. Exposure to poisonous fumesExposure 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 toxinsMany other known toxins
that may cause blindnessthat may cause blindness
15. RGCRGC (retinal ganglial cells)(retinal ganglial cells)
These cells depend onThese cells depend on
oxidative phosphorylation dueoxidative phosphorylation due
to their:to their:
HugeHuge ATP demandATP demand
Very sensitive to energyVery sensitive to energy
supply and mitochondriasupply and mitochondria
defectsdefects
Limited regenerationLimited regeneration
abilitiesabilities
END RESULTEND RESULT = Vision= Vision
damage from degenerationdamage from degeneration
of optic nerve due toof optic nerve due to
insufficient ATP supplyinsufficient ATP supply
16. LHON is found inLHON is found in 80% of80% of
young men in theiryoung men in their
twentiestwenties
Female carriers have 85 -Female carriers have 85 -
90% chance of staying90% chance of staying
healthyhealthy
WhyWhy??
X - chromosome markersX - chromosome markers
have been found whichhave been found which
may influence diseasemay influence disease
outcome in carriers, calledoutcome in carriers, called
protective factorsprotective factors
17. 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 thePeripheral vision (seeing out of the corner of the
eye) remainseye) remains
Loss of visual acuity/colorLoss of visual acuity/color
Once symptoms appear in one eye, other eye affectedOnce symptoms appear in one eye, other eye affected
within few weekswithin few weeks
Sub acute Phase
Atrophy of optic disc =
18. 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 mutationSymptoms vary by gender and type of mutation
presentpresent
— the most common mutation and usually
the most severe vision loss
— usually has the best long term
prognosis or outcome
— has an intermediate
presentation
19. Molecular genetic blood test using polymeraseMolecular genetic blood test using polymerase
chain reaction (PCR) techniqueschain reaction (PCR) techniques
The test is 100% accurate forThe test is 100% accurate for LHONLHON when visualwhen visual
loss has already occurredloss has already occurred
Interestingly, significant number of individualsInterestingly, significant number of individuals
who are suspected to havewho are suspected to have LHONLHON do not havedo not have
one of the three primary mtDNAone of the three primary mtDNA LHONLHON
mutations.mutations.
20. So farSo far no treatmentno treatment has beenhas been
proven effective in controlledproven effective in controlled
trials fortrials for LHONLHON
BUTBUT……..……..
IdebenoneIdebenone,, a synthetic analoguea synthetic analogue
ofof coenzymeQ10coenzymeQ10 has been studieshas been studies
in clinical trials in Canada,in clinical trials in Canada,
Germany and UKGermany and UK
IdebenoneIdebenone is a strongis a strong antioxidantantioxidant
and may be the key to providingand may be the key to providing
stability to nerve cell, decreasingstability to nerve cell, decreasing
the likelihood of oxidative damagethe likelihood of oxidative damage
caused by free radicals releasedcaused by free radicals released
when cells are destroyed bywhen cells are destroyed by
chemical toxinschemical toxins
21. Neutralize free radicalNeutralize free radical production byproduction by
neuronal cells with supplementation ofneuronal cells with supplementation of
antioxidantsantioxidants
VitaminsVitamins
Natural plant extractsNatural plant extracts
Vitamin EVitamin E
Co-enzyme QCo-enzyme Q
Vitamin CVitamin C
Vitamin AVitamin A
Ginkgo bilobaGinkgo biloba
CurcuminCurcumin
22. ConclusionConclusion
Point mutations in complex 1 due playPoint mutations in complex 1 due play
a major role in causing Lebersa major role in causing Lebers
Decreased production of ATPDecreased production of ATP
underlies cell dysfunction and cellunderlies cell dysfunction and cell
deathdeath
Although there is no treatment at thisAlthough there is no treatment at this
time, family history along with genetictime, family history along with genetic
testing and healthy lifestyle may effecttesting and healthy lifestyle may effect
the outcome of this disease as withthe outcome of this disease as with
other disease such as Cancerother disease such as Cancer
