Leber Hereditary Optic Neuropathy (LHON) 6/14/12 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 6/14/12 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 . 6/14/12 . Descriptio n of the metabolic pathway Click to edit Master subtitle style 6/14/12 . Oxidative Phosphoryla tion 6/14/12 . 6/14/12 . NADH Dehydrogenase • The reaction of NADH dehydrogenase is: NADH + H+ + CoQ + 4H+in → NAD+ + CoQH2 + 4H+out 6/14/12 . Mechanism of NADH dehydrogenase 6/14/12 . Causes Click to edit Master subtitle style 6/14/12 . 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) • – 6/14/12 help assemble protein building blocks (amino acids) into functioning proteins .• Major cause: . 6/14/12 o o . and MT-ND6 gene genes code for the NADH dehydrogenase protein involved in the normal mitochondrial function of oxidative phosphorylation. MT-ND4L. MT-ND4. Mutations in the MT-ND1.o distinct mitochondrial genome composed of mtDNA. 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 6/14/12 . MTND4L MTND6 6/14/12 . necessary for oxidative phosphorylation affect the generation of ATP within mitochondria 6/14/12 • • • .• 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 . This difference in electrical charge provides the energy for ATP production. the transfer – • . responsible for the first step in the 6/14/12 electron transport process.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. • Mutations of the genes : . 6/14/12 .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. 6/14/12 • .• 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. contribute to the development of signs and symptoms. although studies of these factors have produced conflicting results • Researchers are investigating whether changes in additional genes. 6/14/12 .Environmental Factors • Smoking & alcohol use – may be involved. particularly genes on the X chromosome. Diagnosi s 6/14/12 . Measure by reading letter on chart Slit Lamp Examination .Light microscope Automated Visual Field 6/14/12 • • .computerizes machine .• Diagnosi known family historys LHON : of – – neuro-ophthalmological evaluation blood testing for DNA assessment • Visual Acuity . It displays a picture of the structures inside the eye. 6/14/12 Fundus .• Optical Coherence Tomography (OCT): . • Fundus Photography: -Photographs of the optic nerve and retina. Click to edit Master subtitle style Genetic counseling -Provide information on the nature. inheritance and implication of disorder . Florida is launching a study into the possible treatment of LHON using Gene Therapy • .Treatmen So far no treatment has been proven t for LHON effective in controlled trials • The Bascom Palmer Eye Institute in Miami.Use genetic risk assessment and family history to clarify genetic status 6/14/12 . Major Factor In Getting AND Maintaining Good Vision 6/14/12 . 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 Click to edit Master subtitle style 6/14/12 . do at least 20 minutes of aerobic exercise daily. Supplement your diet Limit the amount of medications Exercise daily .v Eliminate smoking-Smoking among other things produces cyanide. a retinal toxin. v v v 6/14/12 . 6/14/12 .