Transcript Lebers Hereditary Optic Neuropathy

Leber’s
Hereditary
Optic –
– inherited from mitochondrial DNA
affects the eye
Neuropathy –
disease/abnormality of nervous
system

Maternally inherited disorder
characterized by degeneration
of the retinal ganglion cells (RGCs)
and atrophy of the optic nerve

Mutations are in the mitochondrial
(not nuclear) genome

Usually begins between the ages of 25 and 35 (but can
occur at any age) and leads to legal blindness

More common in males than females

It was first described in 1871 by Theodore Leber and
is the most common cause of optic atrophy.

Inherited from mother to all
offsprings

Only the egg contributes
mitochondria to the embryo

2 billion mitochondria are
made every second
throughout a person’s life

250 mitochondria on the
average are found in a cell

Life span is around 100 days.

Number varies from cell to cell

Circular strand of DNA
consisting of 16,569 nucleotide
bases

Contains 37 genes

2 Encode for rRNA and 22 for
tRNA

13 genes encode for proteins
required for the biochemical
reactions in
process that generates ATP high
energy molecules

The rest 74 proteins for oxidative
phosphorylation are encoded by
nuclear DNA

Heteroplasmy
-
Some of the mt DNA has mutations
some does not
- 15% of individuals with LHON are
heteroplasmic
- The rest are homoplasmic

Homoplasmy
All of the mtDNA has at least one of
the three types of mutations for
or no mutations at all!!

This determines the type of phenotype
and the risk transmission.

There is also a mitochondrial disorder
known as LHON (Leber's Hereditary
Optic Neuropathy) where the
mitochondrial DNA mutations which
causes the disease (acquired blindness)
are homoplasmic - meaning that all of the
mitochondria carry the defect. However,
just because a person has one of the
LHON mitochondrial DNA mutations
does not mean they will become blind,
only about 10% will. Confusing? You bet!
Phenotypic threshold effect
in mtDNA mutatins

Associated with mtDNA heteroplasmy

Critical threshold in proportion of mutations in
mtDNA must be exceeded before disease appears
This is normally about 90%
 BUT, LHON is generally homoplasmic
 Interestingly certain homoplasmic mtDNA
mutations do not express LHON phenotype at
all!!!


85% to 90% of cases of
LHON are usually due to
one of the three mtDNA
point mutations

ND4 ND1 and ND6 subunit
genes of
of the
oxidative phosphorylation
chain in mitochondria, which
is the 1st step of the

The rate of mtDNA mutations
is 10-times greater than in
nuclear DNA
Complex 1
Site effected by the
3 point
mutations
found in LEBERS
Causes of LHON

3 point mutations at these sites:
1) G11778A


50-60% LHON population
Mutation is located at position
11778 change is G to A
2) T14484C
10% LHON population
3) G3460A:
8-25% LHON population
These mutations decrease production of
ATP resulting in cell dysfunction and cell
death
Production of ROS
Reactive oxygen species – byproduct

of oxidative phosphorylation
Environmental factors

Not everyone with one of these
mutations will develop LHON

Additional genetic or environmental
factors play an important role to
development of central vision loss

Males with one of these mutations have a 40% lifetime
risk to develop symptoms

Females have a 10% risk, although the actual risk
varies slightly from mutation to mutation

Those factors that can reduce the blood supply to
the retina and optic nerve

They are suspect to 'trigger' the vision loss in LHON
a. Heavy drinking or smoking
b. Exposure to poisonous fumes
such as carbon monoxide
c. High levels of stress
d. Medications:
Ethambutol – Rx for TB
Chloramphenicol – for conjunctivitis
e. Many other known toxins
that may cause blindness
11778
3460
14484
RGC (retinal ganglial cells)

These cells depend on
oxidative phosphorylation due
to their:

Huge ATP demand
 Very sensitive to energy
supply and mitochondria
defects
 Limited regeneration
abilities
 END RESULT = Vision
damage from degeneration
of optic nerve due to
insufficient ATP supply




LHON is found in 80% of
young men in their
twenties
Female carriers have 85 90% chance of staying
healthy
Why?
X - chromosome markers
have been found which
may influence disease
outcome in carriers, called
protective factors
Asymptomatic until visual
blurring develops
Acute Phase:
Painless, acute onset of central vision loss
 Peripheral vision (seeing out of the corner of the

eye) remains


Loss of visual acuity/color
Once symptoms appear in one eye, other eye affected
within few weeks
Sub acute Phase
Atrophy of optic disc =





Cardiac conduction defects
Tremors
Numbness or weakness in arms or leg
Loss of ankle reflexes
Symptoms vary by gender and type of mutation
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 polymerase
chain reaction (PCR) techniques

The test is 100% accurate for LHON when visual
loss has already occurred

Interestingly, significant number of individuals
who are suspected to have LHON do not have
one of the three primary mtDNA LHON
mutations.
So far no treatment has been
proven effective in controlled
trials for LHON
 BUT……..



Idebenone, a synthetic analogue
of coenzymeQ10 has been studies
in clinical trials in Canada,
Germany and UK
Idebenone is a strong antioxidant
and may be the key to providing
stability to nerve cell, decreasing
the likelihood of oxidative damage
caused by free radicals released
when cells are destroyed by
chemical toxins

Neutralize free radical production by
neuronal cells with supplementation of
antioxidants

Vitamins

Natural plant extracts

Vitamin E

Co-enzyme Q

Vitamin C

Vitamin A

Ginkgo biloba

Curcumin
Conclusion
 Point
mutations in complex 1 due play
a major role in causing Lebers
 Decreased production of ATP
underlies cell dysfunction and cell
death
 Although there is no treatment at this
time, family history along with genetic
testing and healthy lifestyle may effect
the outcome of this disease as with
other disease such as Cancer
References
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http://www.ifond.org/lhon.php3
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http://brain.oxfordjournals.org/cgi/content/full/124/1/20
9
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http://jnnp.bmj.com/cgi/content/abstract/75/12/1731

http://www.pubmedcentral.nih.gov/articlerender.fcgi?arti
d=1914692
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http://genome.wellcome.ac.uk/doc_WTD020740.html

http://www.slh.wisc.edu/genetics/basics_disease.dot

Thompson & Thompson. Genetics in Medicine.
Saunders: 2007