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|Leber's hereditary optic neuropathy|
|Classification and external resources|
Leber’s hereditary optic neuropathy (LHON) or Leber optic atrophy is a mitochondrially inherited (transmitted from mother to 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.
- 1 History
- 2 Signs & Symptoms
- 2.1 LHON Plus
- 3 Genetics
- 4 Epidemiology
- 5 Pathophysiology
- 6 Diagnosis and management
- 7 See also
- 8 References
- 9 External links
This disease was first described by the German ophthalmologist Theodor Leber (1840–1917) in 1871. In this paper Leber described four families in which a number of young men suffered abrupt loss of vision in both eyes either simultaneously or sequentially. This disease was initially thought to be X linked but was subsequently shown to be mitochondrial. The nature of the causative mutation was first identified in 1988 by Wallace et al. who discovered the guanine (G) to adenosine (A) mutation at nucleotide position 11778 in nine families. This mutation converts a highly conserved arginine to histidine at codon 340 in the NADH dehydrogenase subunit 4 of complex I of the mitochondrial respiratory chain. The other two mutations known to cause this condition were identified in 1991 (G to A point mutation at nucleotide position 3460) and 1992 (thymidine (T) to cytosine (C) mutation at nucleotide 14484). These three mutations account for over 95% of cases: the 11778 mutation accounts for 50-70% of cases, the 14484 mutation for 10-15% and the 3460 mutation for 8-25%.
Signs & Symptoms
Clinically, there is an acute onset of visual loss, first in one eye, and then a few weeks to months later in the other. Onset is usually young adulthood, but age range at onset from 7-75 is reported. The age of onset is slightly higher in females (range 19–55 years: mean 31.3 years) than males (range 15–53 years: mean 24.3). The male to female ratio varies between mutations: 3:1 for 3460 G>A, 6:1 for 11778 G>A and 8:1 for 14484 T>C.
This typically evolves to very severe optic atrophy and permanent decrease of visual acuity. Both eyes become affected either simultaneously (25% of cases) or sequentially (75% of cases) with a median inter-eye delay of 8 weeks. Rarely only one eye may be affected. 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). The main features are seen on fundus examination, just before or subsequent to the onset of visual loss. A pupillary defect may be visible in the acute stage as well. 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 arrhythmia. 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 series of four large multienzyme complexes, which are all embedded in the inner mitochondrial membrane 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 Northern 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. As a rule of thumb, a woman who harbors a homoplasmic primary LHON mutation has a ~40% risk of having an affected son and a ~10% risk of having an affected daughter.
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 and management
Without a known family history of LHON the diagnosis usually requires a neuro-ophthalmological evaluation and blood testing for mitochondrial DNA assessment. It is important to exclude other possible causes of vision loss and important associated syndromes such as heart electrical conduction system abnormalities. The prognosis for those affected left untreated is almost always that of continued significant visual loss in both eyes. Regular corrected visual acuity and perimetry checks are advised for follow up of affected individuals. There is beneficial treatment available for some cases of this disease especially for early onset disease. Also, experimental treatment protocols are in progress. Genetic counselling should be offered. Health and lifestyle choices should be reassessed particularly in light of toxic and nutritional theories of gene expression. Vision aides assistance and work rehabilitation should be used to assist in maintaining employment.
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.
Cyanocobalamin (a form of B12) should be avoided as it may lead to blindness in Leber's disease patients.
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. Ethambutol, in particular, has been implicated as triggering visual loss in carriers of LHON. 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.
Idebenone has been shown in a small placebo controlled trial to have modest benefit in about half of patients. People most likely to respond best were those treated early in onset.
α-Tocotrienol-quinone, a vitamin E metabolite, has had some success in small open label trials in reversing early onset vision loss.
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, curcumin, glutathione, near infrared light treatment, and viral vector techniques.
"Three person in vitro fertilisation" is a proof of concept research technique for preventing mitochondrial disease in developing human fetuses. So far, viable macaque monkeys have been produced. But ethical and knowledge hurdles remain before use of the technique in humans is established.
- Dominant optic atrophy
- Ischemic optic neuropathy
- List of eye diseases and disorders
- Optic atrophy
- Toxic and Nutritional Optic Neuropathy
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- cardiac arrythmia
- Mayo Clinic: Multiple Sclerosis
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- GeneTests LHON search
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- Katz, Jason; Patel, Chetan (2006). Parkland Manual of Inpatient Medicine. Dallas, TX: FA Davis. p. 903.
- Clinical Idebenone trial recruiting at Newcastle University UK http://lhon.ncl.ac.uk
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- Sadun,A et al. "EPI-743 alters the natural history of progression of Leber hereditary optic neuropathy". AOS meeting. May 2011
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- Clinical Curcurmin trial recruiting at ClinicalTrials.nlm.nih.gov
- Wisconsin near infrared trial
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- Leber's hereditary optic neuropathy at NLM Genetics Home Reference
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- LHONsociety.org a Charity Registered with the Charity Commission for England & Wales number 1157206 - The LHON Society was established by the Trustees to create a home for those in the British Isles affected by and with an interest in, LHON. Our aspiration is that through the LHON Society you have access to:
•Shared experiences of those living with LHON and their families •Sources of practical and emotional support •Up-to-date information on practical innovation and scientific progress into LHON
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- 1. 視神経症 optic neuropathies
- 2. 全身疾患と関連した遺伝性ニューロパチー hereditary neuropathies associated with generalized disorders
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- Applications of the method of high resolution melting analysis for diagnosis of Leber's disease and the three primary mutation spectrum of LHON in the Han Chinese population.
- Cui G, Ding H, Xu Y, Li B, Wang DW.SourceThe Institute of Hypertension and Department of Internal Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan People's Republic of China.
- Gene.Gene.2013 Jan 1;512(1):108-12. doi: 10.1016/j.gene.2012.09.110. Epub 2012 Oct 9.
- Current screening methods, such as single strand conformational polymorphism (SSCP), denaturing high performance liquid chromatography (dHPLC) and direct DNA sequencing that are used for detecting mutation in Leber's hereditary optic neuropathy (LHON) subjects are time consuming and costly. Here we
- PMID 23063736
- Mathematically Modeling the Involvement of Axons in Leber's Hereditary Optic Neuropathy.
- Pan BX, Ross-Cisneros FN, Carelli V, Rue KS, Salomao SR, Moraes-Filho MN, Moraes MN, Berezovsky A, Belfort R Jr, Sadun AA.SourceDoheny Eye Institute and Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, California.
- Investigative ophthalmology & visual science.Invest Ophthalmol Vis Sci.2012 Nov 9;53(12):7608-17. doi: 10.1167/iovs.12-10452.
- PURPOSE: Leber's hereditary optic neuropathy (LHON), a mitochondrial disease, has clinical manifestations that reflect the initial preferential involvement of the papillomacular bundle (PMB). The present study seeks to predict the order of axonal loss in LHON optic nerves using the Nerve Fiber Layer
- PMID 23060142
- Leber's hereditary optic neuropathy with the 3434, 9011 mitochondrial DNA point mutation
- SHIDARA Kyoko,WAKAKURA Masato
- Japanese journal of ophthalmology 56(2), 175-180, 2012-03-01
- NAID 10030248806
- 症例報告 亜急性期に視神経にMRIで造影効果と腫脹をみとめたLeber's hereditary optic neuropathyの50歳男性例
- 古木 美紗子,大久保 卓哉,太田 浄文 [他]
- 臨床神経学 52(2), 102-105, 2012-02
- NAID 40019200849
- Adjusting to LHON Losing central vision is scary. Figuring out what to do when it happens is confusing, and there are many issues to address all at once. This site was created by a family affected by LHON. By sharing what we ...
- LHON(Leber's hereditary optic neuropathy : Leber病)は主に10才代から20才代にかけて,両眼性に急性または亜急性の視力低下で発症し,通常1年以内に高度の視神経萎縮にいたる予後不良な遺伝性(母系遺伝)の視神経疾患である。LHONは ...
|リンク元||「レーベル遺伝性視神経症」「Leber hereditary optic neuropathy」|
- Leber hereditary optic neuropathy, LHON, Leber's hereditary optic neuropathy
- レーバー遺伝性視神経萎縮症 Leber遺伝性視神経萎縮症 Leber hereditary optic atrophy、レーバー視神経萎縮症 Leber optic neuropathy, レーベル病 Leber disease Leber's disease