Leber Hereditary Optic Neuropathy (LHON)

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Leber Hereditary Optic Neuropathy (LHON)

Leber Optic Atrophy (LOA) First described in 1871 Can cause loss of central vision Genetic condition Affects predominantly young adult males

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How it passed on

Due to mutation in the mitochondial (not nuclear) genome Transmitted in a nonmendelian or maternal pattern Mitochondrially inherited Only the egg 6/14/12 contributes

Symptoms of LHON

Loss of vision in one/ both eyes

Optic nerve degeneration Over a period lasting year Spontaneously

Vision loss may be gradual

Tremors Lack of coordination Weakness/numbness of arm/ legs 6/14/12

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Descriptio n of the metabolic pathway

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Oxidative Phosphoryla tion

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NADH Dehydrogenase

The reaction of NADH dehydrogenase is:

NADH + H+ + CoQ + 4H+in NAD+ + CoQH2 + 4H+out

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Mechanism of NADH dehydrogenase

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Causes
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Major cause: - changes in mitochondrial DNA

Mitochondrial DNA contains 37 genes, all of which are essential for normal mitochondrial function

13 of it provide instructions for making enzymes involved in oxidative phosphorylation Remaining genes provide instructions for making transfer RNA (tRNA) & ribosomal RNA (rRNA)

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help assemble protein building blocks (amino acids) into functioning proteins

distinct mitochondrial genome composed of mtDNA. Mutations in the MT-ND1, MT-ND4, MT-ND4L, and MT-ND6 gene genes code for the NADH dehydrogenase protein involved in the normal mitochondrial function of oxidative phosphorylation.
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MT-ND1

Mitochondrially encoded NADH dehydrogenase 1 Provide instructions for making NADH dehydrogenase 1 Mitochondrially encoded NADH dehydrogenase 4 Provide instructions for making NADH dehydrogenase 4 Mitochondrially encoded NADH dehydrogenase 4L Provides instructions for making a protein called NADH dehydrogenase 4L Mitochondrially encoded NADH dehydrogenase 6 Provides 6/14/12 instructions for making a protein called NADH

MT-ND4

MT-ND4L

MT-ND6

Location of Genes
MTND1 MTND4

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MTND4L

MTND6

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Provide instructions to make protein for normal mitochondria function Change single protein building blocks (amino acids) in these proteins These group of protein known as complex I , necessary for oxidative phosphorylation affect the generation of ATP within mitochondria
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Complex 1

Create an unequal electrical charge on either side of the inner mitochondrial membrane through a step-by-step transfer of negatively charged particles called electrons. This difference in electrical charge provides the energy for ATP production.
responsible for the first step in the 6/14/12 electron transport process, the transfer

Mutations of the genes : - disrupt this process - cause a variety of syndromes

It remains unclear why the effects of these mutations are often limited to the nerve that relays visual information from the eye to the brain (the optic nerve) or how these genetic changes cause the death of cells in the optic nerve and lead to the specific features of Leber hereditary optic neuropathy.
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genetic changes appear to disrupt the normal activity of complex I in the mitochondrial inner membrane, which may affect the generation of ATP These mutations also may increase the production within mitochondria of potentially harmful molecules called reactive oxygen species.
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Environmental Factors

Smoking & alcohol use

may be involved, although studies of these factors have produced conflicting results

Researchers are investigating whether changes in additional genes, particularly genes on the X chromosome, contribute to the development of signs and symptoms.
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Diagnosi s
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Diagnosi known family historys LHON : of

neuro-ophthalmologicalevaluation blood testing for DNA assessment

Visual Acuity - Measure by reading letter on chart Slit Lamp Examination - Light microscope Automated Visual Field
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- computerizes machine

Optical Coherence Tomography (OCT):

- It displays a picture of the structures inside the eye.

Fundus Photography:

-Photographs of the optic nerve and retina.

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Treatmen So far no treatment has been proven t for LHON effective in controlled trials

The Bascom Palmer Eye Institute in Miami, Florida is launching a study into the possible treatment of LHON using Gene Therapy

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Genetic counseling -Provide information on the nature, inheritance and implication of disorder - Use genetic risk assessment and family history to clarify genetic status
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Major Factor In Getting AND Maintaining Good Vision

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Reduce or eliminate drinking caffeine and sodas- avoid aspartame and man made fats
v

Eliminate deep fat fried foods-monosodium glutanate (MSG) used as a flavor enhancer which is a potential retinal toxin and fat blockers
v v

Limit your alcohol consumption

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Eliminate smoking-Smoking among other things produces cyanide, a retinal toxin. Supplement your diet Limit the amount of medications Exercise daily - do at least 20 minutes of aerobic exercise daily.

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