Leber’s hereditary optic

Complex I deficiency due to mtDNA mutations (seven subunits of complex I are encoded by mtDNA) can be divided into encephalomyopathies and myopathies. The most important encephalomyopathy is Leber s hereditary optic neuropathy, characterized by acute or subacute loss of vision due to severe bilateral optic atrophy, with onset usually between 18 and 30 years and marked predominance in men. Three mutations (in ND1, ND4 and ND6)... 

Beminger, T.A., L.V. Meyer, E. Siess, O. Schon, and F.D. Goebel. 1989. Leber s hereditary optic atrophy further evidence for a defect of cyanide metabolism Brit. Jour. Ophthalmol. 73 314-316. 

The nervous system is the most sensitive target for cyanide toxicity, partly because of its high metabolic demands. High doses of cyanide can result in death via central nervous system effects, which can cause respiratory arrest. In humans, chronic low-level cyanide exposure through cassava consumption (and possibly through tobacco smoke inhalation) has been associated with tropical neuropathy, tobacco amblyopia, and Leber s hereditary optic atrophy. It has been suggested that defects in the metabolic conversion of cyanide to thiocyanate, as well as nutritional deficiencies of protein and vitamin B12 and other vitamins and minerals may play a role in the development of these disorders (Wilson 1965). 

Persons with a metabolic disturbance in the conversion of cyanide to thiocyanate may be at greater risk. A defect in the rhodanese system and vitamin B12 deficiency have been associated with tobacco amblyopia and Leber s hereditary optic atrophy in persons exposed to cyanide in tobacco smoke (Wilson 1983). 

WilsonJ. 1965. Leber s hereditary optic atrophy A possible defect of cyanide metabolism. Clin Sci 29 505-515. 

Wallace DC, Singh G, Lott MT, et al. Mitochondrial DNA mutation associated with Leber s hereditary optic neuropathy. Science 1988 242(4884) 1427-1430. 

Leber s hereditary optic neuropathy (LHON) is caused by a mutation of the ND1 gene encoding an eie-ment of complex I of the eiectron transport chain and other simiiar mutations. 

LHON (Leber s hereditary optic neuropathy) causes blindness arising from mutations in the ND1 gene encoding complex I of the electron transport chain (see Chapter 7). 

The clinical symptoms of mitochondrial diseases are highly varied and include seizures, vomiting, deafness, dementia, stroke-like episodes, and short stature. Although there are many types of mitochondrial disorders, four of the most common types are as follows Kearns-Sayre syndrome, Leber s hereditary optic atrophy, MELAS (mitochondrial encephalopathy, lactic acidosis and stroke-like episodes) and MERRE (myoclonic epilepsy with ragged red fibres). 

D2. Danielson, S. R., Wong, A., Carelli, V., Martinuzzi, A., Schapira, A. H., and Cortopassi, G. A., Cells bearing mutations causing Leber s hereditary optic neuropathy are sensitized to Fas-induced apoptosis. J. Biol. Chem. 277, 5810-5815 (2002). 

V4. Vergani, L., Martinuzzi, A., Carelli, V., Cortelli, P., Montagna, P., Schievano, G., Carrozzo, R., Angelini, C., and Lugaresi, E., MtDNA mutations associated with Leber s hereditary optic neuropathy Studies on cytoplasmic hybrid (cybrid) cells. Biochem. Biophys. Res. Commun. 210, 880-888 (1995). 

Leber s hereditary optic neuropathy (Leber optic atrophy)... 

MS), which is a demyelinating disorder. When optic neuritis occurs without disc swelling, the condition is called retrobulbar neuritis. When disc swelling is associated with optic neuritis, the condition is called papillitis. Papilledema is bilateral disc edema associated with increased intracranial pressure OCP). Optic atrophy, the end stage of many optic neuropathies, is characterized by a pale disc and associated with a relative afferent pupillary defect (RAPD) and possible loss of visual acuity, color vision, and visual field. One example of disc atrophy occurs in cases of Leber s hereditary optic neuropathy... 

Indications Alzheimer s dementia, cardiovascular disease, cerebrovascular disease, demyelination, depression, Friedreich s ataxia, improving memory, Leber s hereditary optic neuropathy Category Coenzyme Q10 analog Half-life N/A... 

Fauser S, Leo-Kottler B, Besch D, Luberichs J. Confirmation of the 14568 mutation in the mitochondrial ND6 gene as causative in Leber s hereditary optic neuropathy. OpthaJ Genet 2002 23 191-7. 

Smith KH, Johns DR, Heher KL, Miller NR. Hetero-plasmy in Leber s hereditary optic neuropathy. Arch Ophthalmol 1993 111 1486-90. 

Mildly deleterious base substitutions 2. Moderately deleterious nucleotide substitutions 3. Severe nucleotide substitutions Familial deafness, Alzheimer s disease, Parkinson s disease Leber s Hereditary Optic Neuropathy (LHON), Myoclonic Epilepsy and Ragged-Red Fiber disease (MERRF) Leigh s Syndrome dystonia... 

Like the mitochondria themselves, some genetic diseases of energy metabolism are maternally inherited. One such disease, Leber s hereditary optic neuropathy (LHON), causes blindness and heart problems. People with LHON have a reduced ability to make ATP. As a result, sensitive tissues that demand a great deal of energy eventually die. LHON sufferers eventually lose their sight because the optic nerve dies from lack of energy. 

---