Leber's hereditary optic neuropathy
|Leber's hereditary optic neuropathy|
Editor-In-Chief: C. Michael Gibson, M.S., M.D. 
Leber’s hereditary optic neuropathy (LHON) or Leber optic atrophy is a mitochondrially inherited (mother to all offspring) degeneration of retinal ganglion cells (RGCs) and their axons that leads to an acute or subacute loss of central vision; this affects predominantly young adult males. However, LHON is only transmitted through the mother as it is primarily due to mutations in the mitochondrial (not nuclear) genome and only the egg contributes mitochondria to the embryo. LHON is usually due to one of three pathogenic mitochondrial DNA (mtDNA) point mutations. These mutations are at nucleotide positions 11778 G to A, 3460 G to A and 14484 T to C, respectively in the ND4, ND1 and ND6 subunit genes of complex I of the oxidative phosphorylation chain in mitochondria. Men cannot pass on the disease to their offspring.
Signs & symptoms
Clinically, there is an acute onset of visual loss, first in one eye, and then a few weeks later in the other. This eventually evolves to very severe optic atrophy and permanent decrease of visual acuity. In the acute stage lasting a few weeks, the affected eye demonstrates an edematous appearance of the nerve fiber layer especially in the arcuate bundles and enlarged or telangectatic and tortuous peripapillary vessels (microangiopathy). These main features are seen on fundus examination, just before or subsequent to the onset of visual loss. Examination reveals decreased visual acuity, loss of color vision and a cecocentral scotoma on visual field examination.
"LHON Plus" is a name given to rare strains of the disorder with eye disease together with other conditions.  The symptoms of this higher form of the disease include loss of the brain's ability to control the movement of muscles, tremors, and cardiac arrythmia. Many cases of LHON plus have been comparable to Multiple Sclerosis because of the lack of muscular control.
Leber hereditary optic neuropathy is a condition related to changes in mitochondrial DNA. Although most DNA is packaged in chromosomes within the nucleus, mitochondria have a distinct mitochondrial genome composed of mtDNA.
Mutations in the MT-ND1, MT-ND4, MT-ND4L, and MT-ND6 genes cause Leber hereditary optic neuropathy. These genes code for the NADH dehydrogenase protein involved in the normal mitochondrial function of oxidative phosphorylation. Oxidative phosphorylation uses a large multienzyme complex to convert oxygen and simple sugars to energy. Mutations in any of the genes disrupt this process to cause a variety of syndromes depending on the type of mutation and other factors. It remains unclear how these genetic changes cause the death of cells in the optic nerve and lead to the specific features of Leber hereditary optic neuropathy.
In Northern European populations about one in 9000 people carry one of the three primary LHON mutations. There is a prevalence of between 1:30,000 to 1:50,000 in Europe.
The LHON ND4 G11778A mutation dominates as the primary mutation in most of the world with 70% of European cases and 90% of Asian cases. Due to a founder effect, the LHON ND6 T14484C mutation accounts for 86% of LHON cases in Quebec, Canada.
More than 50 percent of males with a mutation and more than 85 percent of females with a mutation never experience vision loss or related medical problems. The particular mutation type may predict likelihood of penetrance, severity of illness and probability of vision recovery in the affected. Additional factors may determine whether a person develops the signs and symptoms of this disorder. Environmental factors such as smoking and alcohol use may be involved, although studies of these factors have produced conflicting results. Researchers are also investigating whether changes in additional genes, particularly genes on the X chromosome, contribute to the development of signs and symptoms. The degree of heteroplasmy, the percentage of mitochondria which have mutant alleles, may play a role.  Patterns of mitochondrial alleles called haplogroup may also affect expression of mutations. 
The eye pathology is limited to the retinal ganglion cell layer especially the maculopapillary bundle. Degeneration is evident from the retinal ganglion cell bodies to the axonal pathways leading to the lateral geniculate nucleii. Experimental evidence reveals impaired glutamate transport and increased reactive oxygen species (ROS) causing apoptosis of retinal ganglion cells. Also, experiments suggest that normal non LHON affected retinal ganglion cells produce less of the potent superoxide radical than other normal central nervous system neurons.  Viral vector experiments which augment superoxide dismutase 2 in LHON cybrids  or LHON animal models or use of exogenous glutathione in LHON cybrids have been shown to rescue LHON affected retinal ganglion cells from apoptotic death. These experiments may in part explain the death of LHON affected retinal ganglion cells in preference to other central nervous system neurons which also carry LHON affected mitochondria.
Diagnosis & management
Without a known family history of LHON the diagnosis is difficult and usually requires a neuro-ophthalmological evaluation and/or blood testing for DNA assessment that is available only in a few laboratories. Hence the incidence is probably greater than appreciated. The prognosis for those affected is almost always that of continued very severe visual loss. Regular corrected visual acuity and perimetry checks are advised for follow up of affected individuals. There is no accepted treatment for this disease. Genetic counselling should be offered.
For those who are carriers of a LHON mutation, preclinical markers may be used to monitor progress. For example fundus photography can monitor nerve fiber layer swelling. Optical coherence tomography can be used for more detailed study of retinal nerve fiber layer thickness. Red green color vision testing may detect losses. Contrast sensitivity may be diminished. There could be an abnormal electroretinogram or visual evoked potentials. Neuron-specific enolase and axonal heavy chain neurofilament blood markers may predict conversion to affected status.
Avoiding optic nerve toxins is generally advised, especially tobacco and alcohol. Certain prescription drugs are known to be a potential risk, so all drugs should be treated with suspicion and checked before use by those at risk. In fact, toxic and nutritional optic neuropathies may have overlaps with LHON in symptoms, mitochondrial mechanisms of disease and management.  Of note, when a patient carrying or suffering from LHON or toxic/nutritional optic neuropathy suffers a hypertensive crisis as a possible complication of the disease process, nitroprusside (trade name: Nipride) should not be used due to increased risk of optic nerve ischemia in response to this anti-hypertensive in particular. 
There are various treatment approaches which have had early trials or are proposed, none yet with convincing evidence of usefulness or safety for treatment or prevention including: Brimonidine;  Minocycline;  Idebenone;  ; Curcumin; glutathione; Near infrared light treatment;  and Viral vector techniques. 
Leber's hereditary optic neuropathy is considered an absolute contraindication to the use of the following medications:
Leber’s hereditary optic neuropathy is sometimes confused with Leber's congenital amaurosis, which is a different disease also first described by Theodore Leber in the 19th century.
- Dominant optic atrophy
- Ischemic optic neuropathy
- List of eye diseases and disorders
- Optic atrophy
- Toxic and Nutritional Optic Neuropathy
- ↑ Bandelt HJ, Kong QP, Parson W, Salas A.Bandelt HJ, Kong QP, Parson W, Salas A. More evidence for non-maternal inheritance of mitochondrial DNA? J Med Genet. 2005 Dec;42(12):957-60. PMID 15923271
- ↑ Nikoskelainen EK, Marttila RJ, Huoponen K, Juvonen V, Lamminen T, Sonninen P, Savontaus ML. Leber's "plus": neurological abnormalities in patients with Leber's hereditary optic neuropathy. J Neurol Neurosurg Psychiatry. 1995 Aug;59(2):160-4. PMID 7629530
- ↑ (http://heart-disease.health-cares.net/cardiac-arrhythmia.php)
- ↑ (http://www.mayoclinic.com/health/multiple-sclerosis/DS00188)
- ↑ "OMIM - LEBER OPTIC ATROPHY". Retrieved 2007-11-23.
- ↑ Man PY, Griffiths PG, Brown DT, Howell N, Turnbull DM, Chinnery PF. The epidemiology of Leber hereditary optic neuropathy in the North East of England. Am J Hum Genet. 2003 Feb;72(2):333-9. PMID 12518276
- ↑ Puomila A, Hämäläinen P, Kivioja S, Savontaus ML, Koivumäki S, Huoponen K, Nikoskelainen E. Epidemiology and penetrance of Leber hereditary optic neuropathy in Finland. Eur J Hum Genet. 2007 Oct;15(10):1079-89. PMID 17406640
- ↑ Laberge AM, Jomphe M, Houde L; et al. (2005). "A "Fille du Roy" introduced the T14484C Leber hereditary optic neuropathy mutation in French Canadians". Am. J. Hum. Genet. 77 (2): 313–7. doi:10.1086/432491. PMID 15954041.
- ↑ Gavin Hudson, Valerio Carelli, Rita Horvath, Massimo Zeviani, Hubert J. Smeets, Patrick F. Chinnery. X-Inactivation patterns in females harboring mtDNA mutations that cause Leber hereditary optic neuropathy. Mol Vis. 2007 Dec 21;13:2339-43 PMID 18199976
- ↑ Hudson G, Keers S, Yu Wai Man P, Griffiths P, Huoponen K, Savontaus ML, Nikoskelainen E, Zeviani M, Carrara F, Horvath R, Karcagi V, Spruijt L, de Coo IF, Smeets HJ, Chinnery PF. Identification of an X-chromosomal locus and haplotype modulating the phenotype of a mitochondrial DNA disorder. Am J Hum Genet. 2005 Dec;77(6):1086-91. Epub 2005 Oct 11. PMID 16380918
- ↑ Chinnery PF, Andrews RM, Turnbull DM, Howell NN. Leber hereditary optic neuropathy: Does heteroplasmy influence the inheritance and expression of the G11778A mitochondrial DNA mutation? Am J Med Genet. 2001 Jan 22;98(3):235-43. PMID 11169561
- ↑ Hudson G, Carelli V, et al. Clinical expression of Leber hereditary optic neuropathy is affected by the mitochondrial DNA-haplogroup background. Am J Hum Genet. 2007 Aug;81(2):228-33.PMID 17668373
- ↑ Hoegger MJ, Lieven CJ, Levin LA. Differential production of superoxide by neuronal mitochondria. BMC Neurosci. 2008 Jan 8;9:4. PMID 18182110
- ↑ 14.0 14.1 Qi X, Sun L, Hauswirth WW, Lewin AS, Guy J. Use of mitochondrial antioxidant defenses for rescue of cells with a Leber hereditary optic neuropathy-causing mutation. Arch Ophthalmol. 2007 Feb;125(2):268-72. PMID 17296905
- ↑ 15.0 15.1 Ghelli A, Porcelli AM, Zanna C, Martinuzzi A, Carelli V, Rugolo M. Protection against oxidant-induced apoptosis by exogenous glutathione in Leber hereditary optic neuropathy cybrids. Invest Ophthalmol Vis Sci. 2008 Feb;49(2):671-6. PMID 18235013
- ↑ GeneTests LHON search
- ↑ Sadun AA, Salomao SR, Berezovsky A, Sadun F, Denegri AM, Quiros PA, Chicani F, Ventura D, Barboni P, Sherman J, Sutter E, Belfort R Jr, Carelli V. Subclinical carriers and conversions in Leber hereditary optic neuropathy: a prospective psychophysical study. Trans Am Ophthalmol Soc. 2006;104:51-61. PMID 17471325
- ↑ Carelli V, Ross-Cisneros F, Sadun A: "Mitochondrial dysfunction as a cause of optic neuropathies." Prog Retinal & Eye Research. 23:53-89, 2004. PMID 14766317
- ↑ Katz, Jason (2006). Parkland Manual of Inpatient Medicine. Dallas, TX: FA Davis. p. 903. Unknown parameter
- ↑ Newman NJ, Biousse V, David R, Bhatti MT, Hamilton SR, Farris BK, Lesser RL, Newman SA, Turbin RE, Chen K, Keaney RP. Prophylaxis for second eye involvement in leber hereditary optic neuropathy: an open-labeled, nonrandomized multicenter trial of topical brimonidine purite. Am J Ophthalmol. 2005 Sep;140(3):407-15.PMID 16083844
- ↑ Haroon MF, Fatima A, Schöler S; et al. (2007). "Minocycline, a possible neuroprotective agent in Leber's hereditary optic neuropathy (LHON): Studies of cybrid cells bearing 11778 mutation". Neurobiol Dis. doi:10.1016/j.nbd.2007.07.021. PMID 17822909.
- ↑ Clinical Idebenone trial recruiting at Newcastle University UK http://lhon.ncl.ac.uk
- ↑ Mashima Y, Kigasawa K, Wakakura M, Oguchi Y. Do idebenone and vitamin therapy shorten the time to achieve visual recovery in Leber hereditary optic neuropathy? J Neuroophthalmol. 2000 Sep;20(3):166-70. PMID 11001192
- ↑ Clinical Curcurmin trial recruiting at ClinicalTrials.nlm.nih.gov
- ↑ Wisconsin near infrared trial
- ↑ Template:WhoNamedIt
- ↑ T. Leber. Über Retinitis pigmentosa und angeborene Amaurose. Albrecht von Graefes. Archiv für Ophthalmologie, Berlin, 1869, 15, 3: 1-25.
- Leber's hereditary optic neuropathy at NLM Genetics Home Reference
- Yu-Wai-Man P, Chinnery P (2008) Leber Hereditary Optic Neuropathy. GeneReviews
- John B. Kerrison and Nancy J. Newman (1997) Clinical Spectrum of Leber's Optic Neuropathy. Clinical Neuroscience. Volume 4, Number 5, pages 295-301. IFOND reprints
- Carelli V, Ross-Cisneros F, Sadun A: "Mitochondrial dysfunction as a cause of optic neuropathies." Prog Retinal & Eye Research. 23:53-89, 2004. PMID 14766317
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