Lebers Hereditary Optic Neuropathy LHON

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Lebers HereditaryOptic Neuropathy(LHON)

• January 28, 2009
• Anna Huynh (a.huynh_at_utoronto.ca)
• Amy Hu (amyhu_yh_at_yahoo.com)
• Kalena Truong (kalena.truong_at_gmail.com)
• Joseph Chan (choyiuchan2001_at_gmail.com)

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What is LHON?

• Lebers
• Hereditary inherited from mitochondrial DNA
• Optic affects the eye
• Neuropathy disease/abnormality of nervous
  system

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LHON

• Degeneration of retinal ganglion cells and their
  axons
• Inherited from maternal mitochondrial DNA
• Occurs during young adulthood

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Signs and Symptoms

• Asymptomatic until visual blurring develops

• Acute Phase
• Painless, acute onset of central vision loss
• Loss of visual acuity/colour
• once symptoms appear in one eye, other eye
  affected weeks later

• Sub acute Phase
• atrophy of optic disc
• legally blind

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Genetics
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Genetic Basis of LHON

• Maternal inheritance
• Mutation occurs in mitochondrial DNA (mtDNA)
• Only the egg contributes mtDNA to the embryo

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Single Point Mutations3 major pathogenic
mutations

• (1) 11778 50-60 LHON population
• (2) 3460 8-25 LHON population
• (3) 14484 10 LHON population

Genetic Testing is now WIDELY accepted as
diagnosis for LHON
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Males vs. Females

• LHON is predominant in males
• Studies looking at x-linkage have not been
  confirmed nor statistically significant

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Epidemiology race dependent
70 Europeans 90 Asians
11778
3460
Koreans
86 Quebec Canadians Due to Founder Effect
14484
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Heteroplasmy

• presence of mixture of more than one type of
  organellar genome ie mtDNA
• Numerous cell divisions and thus lots of time is
  required for mutant alleles to be expressed in
  mitochondria
• Symptoms dont appear until adulthood
• Also implicated as the reason for variability in
  severity of vision loss

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Mechanism
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In order to SEE
Optic Nerve
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Retina

• Photoreceptors
• Interneurons
• RGC (retinal ganglial cells)
• Neurons
• Axons make up optic nerve

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RGC neurons

• Fire action potentials
• Huge ATP demand
• Very sensitive to energy supply and mitochondria
  defects
• Especially RGCs for central visual field
• Limited regeneration abilities

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All Neurons are Vulnerable

• Other neurons in the body can be affected too
  (CNS PNS)
• This results in Lebers Plus
• Movement disorders
• Tremors
• Cardiac conduction defects
• MS-like features

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ATP Demand
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Complex 1
aka. NADH Dehydrogenase
4e- 4H O2 ? 2H2O
e- prematurely leak to O2
O2-
e- O2 ?
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(No Transcript)
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Things go wrong

• Leber oxidative stress ATP deprivation
• Atrophy wearing away of tissue
• Chronic oxidative stress Apoptosis (cell death)

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Treatment
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Prevention

• Genetic Testing for the maternally inherited
  mitochondrial DNA.
• Avoid potential environmental precipitants such
  as tobacco and excessive alcohol.
• Avoid medications which have been shown to induce
  the disease (Ethambutol, Chloramphenicol)

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Treatment Option I

• Neutralize free radical production by neuronal
  cells with supplementation of antioxidants.
• CoQ10, Vitamin C, Vitamin E, N-acetyl Cysteine

NADH
? Reactive Oxygen Species O2-
Neuronal Degeneration Via Mitochondrial Apoptosis
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Neutralizing Free Radicals
Mitochondrial Respiration
Antioxidant Supplementation to Enhance GSH
levels
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Treatment option II

• Slow down neuronal cell degeneration by
  inhibiting mitochondrial-dependent apoptosis.

Opening of mPTP
ATP depletion Oxidative Stress
? Cytosolic Calcium Overload
?
Minocycline
Cyclosporin A, Creatine
Mitochondrial Apoptosis
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Summary LHON

• Vision damage from degeneration of optic nerve
• Maternally inherited through mtDNA
• 3 point mutations
• Complex I ? ROS (reactive oxygen species)
• Treatment
• Antioxidants
• Inhibit mitochondrial-dependent apoptosis

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References

• www.ncbi.nlm.nih.gov
• http//clinical trials.nlm.nih.gov
• www.ssc.education.ed.ac.uk
• http//jim.leeder.users.btopenworld.com
• Johns, R. Donald. (2002) Treatment of Lebers
  hereditary optic neuropathy theory to practice.
  Seminars in Ophthalmology. Vol 17. p 33-38.
• Haroon, F. Mohammad. (2007) Minocycline, a
  possible neuroprotective agent in Lebers
  hereditary optic neuropathy (LHON). Neurobiology
  of Disease. Vol 28. p 237-250.
• Laberge. AM, et al. (2005) A Fille du Roy
  introduced the T14484C Leber hereditary optic
  neuropathy mutation in French Canadians. Hum.
  Genet. Vol 77(2) p 313-317.
• Qi, X (2007). Use of mitochondrial antioxidant
  defenses for rescue of cells with a Leber
  hereditary optic neuropathy-causing mutation.
  Arch. Ophthalmol. Vol 125 p 216-272.

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