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Hereditary optical neuropathy of Leber


Optical neuropathy of Leber (atrophy of an optic nerve of Leber) — the hereditary disease which is characterized quickly or gradually developing bilateral disturbances of the central sight at somatic healthy young people.

Problem research history. The disease is for the first time described by Theodor Leber in 1871 which reported about 15 patients from four families. In the subsequent many authors published the observations of families from Europe, Asia, America, Africa and Australia at which members in several generations revealed optical neuropathy.

Reasons of hereditary optical neuropathy of Leber:

The attention of most of researchers was concentrated on studying of mechanisms of inheritance of pathology. Artful designs of a problem of a research of mechanisms of inheritance of optical neuropathy of Leber are that the disease is transmitted only on the maternal line and develops preferential at persons men's a floor. In 1963 A. van Senus proved that it is never transferred by men. At the same time at the H-linked recessive diseases the expected frequency of defeat of women does not exceed 1% that it is much lower than the level, Leber observed at optical neuropathy. Based on these contradictory facts, D.C. Wallace (1970) made the following conclusion: "Superficial studying of the struck family makes an impression about linked with hollow inheritance. The researcher completing work can assume cytoplasmatic inheritance. More detailed analysis leads to confusion". In the subsequent works he emphasized importance of extra chromosomal maternal factors. Some authors did not exclude a possibility of transfer of persistent virus-like substances in a maternal ovoplazma or transplacental defeat of an embryo.

Influence of environmental factors on the course of a disease was at the same time studied. J. Wilson (1965) found correlation between weight of clinical displays of optical neuropathy of Leber and smoking. On the basis of the observations he assumed that at patients with optical neuropathy of Leber disturbances of metabolism of cyanides are the cornerstone of visual frustration. Later THAT. Berninger and соавт. (1989) revealed increase in level of cyanides in blood at patients with optical neuropathy in an acute phase. To. Tsao and соавт. (1999) confirmed correlation of an experience and volume of smoking with penetrance and expressivity of optical neuropathy of Leber.

Genetic researches. Now it is proved that development of neuropathy of Leber is caused by the point mutations in mitochondrial DNA leading another to replacement of one amino acid. Predpolakgayemy mitochondrial inheritance of optical neuropathy of Leber was confirmed in 1988 to D.C Wallace and соавт., which the first identified a point of a mutation of mitokhovdrialny DNA in a nukleotvdny position 11778 at patients with optical neuropathy of Leber from nine families. This mutation is resulted by substitution of arginine with a histidine in a codon of the 340th gene of subunit 4 NADF-dehydrogenases. The mutation 11778 is identified in 50 — 60% of all families inspected by geneticists which members were sick with Leber's neuropathy.

Another pathogenetic significant (primary) mutation in the provision of the 3460th mitochondrial DNA at patients with Leber's neuropathy from three families at which members the mutation 11778 is not revealed was established To. Huoponen and соавт. (1991). This mutation in colon 52 genes, coding subunit of 1 NADF-dehydrogenase, leads to alanine replacement with threonine. Is later than N. Howell and соавт. (1991), and also D.R. Johns (1992) identified a mutation in a nucleotide position 3460 in 15 families of patients with optical neuropathy of Leber. The mutation in a point 3460 is defined approximately at 8% of patients with Leber's neuropathy.

Soon byy are found mutations in nucleotide positions 15257 and 15182 in a gene of an apotsitokhrom of b. At inspection of 120 families which members were sick with optical neuropathy of Leber the mutation 15257 is revealed at 8% of family trees.

D.Besch and соавт. (1999) established at the patient with optical neuropathy Leber, his mother and four not struck members of these family on the maternal line primary point mutation of mitochondrial DNA in a nucleotide position 14568. This mutation caused replacement of glycine by series in ND6 gene. At mother of a proband visual frustration are not revealed, but at an oftalmoskopiya the peripapillary mikroangiopatiya is revealed.

It is not all list of the mutations established at patients with optical neuropathy of Leber. Now about 20 point mutations are known. In all cases they mention components of complexes (and the III respiratory chain of oxidizing phosphorylation.

Complex 1 (NADH дегидрогеназный a complex) — the largest proteinaceous component of a respiratory chain containing more than 22 polypeptide chains coded both mitochondrial, and nuclear by genomes. It is established that G3460A mutation in ND1 gene in the cultivated fibroblasts leads to decrease of the activity of a NADH dehydrogenase up to 40% in comparison with norm, at the same time the synthesis of ATP connected with a complex I remains invariable.

V.Carelli and соавт. (1999) investigated influence of mutations 14459 and 14484 in subunit of ND6 (Met 64 Val) on a complex I. The mutation 14459 is revealed at patients with the optical neuropathy of Leber which is combined with muscular dystonia. This mutation induces recovery of specific activity NADH дегидрогеназного of a complex and increases its sensitivity to a detsilubikhinol — substrate of the £-S complex | a respiratory chain (complex II). Thus, the complex I is inhibited by a product of the reaction catalyzed by it. The mutation 14484 does not exert similar impact on specific activity of a complex I, however causes higher sensitivity of this fermental complex in comparison with not mutated forms to inhibitors — analogs of an ubikhinon.

The analysis of 70 various sequences of ND6 subunit showed that 14484 the most conserved region of a proteinaceous molecule which is locally reminding the site of cytochrome £ interacting with ubikhinony or ubikhinoly in a tsitokhromoksidazny complex (complex III) is subject to a mutation.

Thus, all mutations influence system of oxidizing phosphorylation, breaking thereby cell energy metabolism. According to a hypothesis of A. Sadun (1998), as a result of reduction of number of molecules ATP below a certain threshold level anterograde axonal transport of mitochondrions is blocked that leads to deficit of ATP and as a result to death of neuron.

Identification of the diagnosis by means of the analysis of mitochondrial DNA showed that optical neuropathy of Leber covers broader age range, and women are ill considerably more often than assumed earlier. N of Thicme and соавт. (1999) reported about a family which 9 members had an optical neuropathy of Leber caused by a mutation 11778 subunits of ND4, eight of them — girls aged up to 10 years.

Five mutations (11778, 3460, 14484, 15257 and 14568) together make over 90% of the point mutations revealed in all family trees with a phenotype of optical neuropathy of Leber. Assume that each of them has primary pathogenetic value. Also several secondary mutations which, influencing to a combination as synergists, can cause development of optical neuropathy of Leber are identified.

R.I Oostra and соавт. (1994) investigated distribution of 7 mutations of mitochondrial DNA and their communication with clinical displays of optical neuropathy of Leber at 334 patients from 29 families. The mutations in nucleotide positions 11778, 3460 and 14484 which are found only at optical neuropathy of Leber were found in 15, 2 and 9 families respectively. In 3 families any of these mutations is not revealed. Mutations in nucleotide positions 15257, 13708, 4917 and 4216 which were found as in patients with optical neuropathy of Leber earlier and at healthy people, are identified in 1, 10, 3 and 12 families respectively. Combinations of mutations of mitochondrial DNA are found in members of the majority of the inspected families. At patients from 11 families in which only one mutation — 11778 was revealed the disease demonstrated on average at the age of 29,2 years, and final visual acuity averaged 0,113. Weight of phenotypical displays of optical neuropathy Lebera at patients with mutations in other nucleotide positions depended on a mitochondrial genotype.

In families of patients with optical neuropathy of Leber the geteroplazmiya phenomenon is described: the amount of mutant mitokhovdrialny DNA varies from 5 to 300% of all available mitokhovdrialny DNA at different patients. The disease develops when percentage of mutant DNA reaches threshold value. The amount of mutant DNA in cells of an organism correlates with weight of clinical symptoms. In the course of evolution the geteroplazmiya of mitochondrial DNA can effectively be supported throughout several generations. At the same time at a part of persons fixing of one of forms of mitochondrial DNA as a result of accidental full elimination of other form is possible during an oogenesis. So, in certain cases thanks to a geteroplazmiya at mother mutant DNA is not transferred to children. M. T. Lott and соавт. (1990) reported about family trees in which the amount of mutant DNA increased from generation to generation, correlating with weight of phenotypical manifestations. Authors also found out that the content of mutant DNA in blood and hair variously at the same subject. Thus, identification and quantitative assessment of a geteroplazmiya has paramount importance for diagnosis, forecasting and definition of a phenotypical expression.

Though the atrophy of an optic nerve of Leber is traditionally considered a family hereditary disease, now rather often clinical physicians observe patients, disease manifestation at whom can be considered as sporadic. Family cases of optical neuropathy of Leber make 43% of total number of patients for a mutation 11778, 78% - for a mutation 3460, 65% — for a mutation of 14484 and 57% — for a mutation 15257.

Symptoms of hereditary optical neuropathy of Leber:

Clinically — — the acute beginning of loss of sight, at first in one eye, and then through a period from several weeks to several months — — in another. Begins usually in youth, but there were messages on initial age in the range of 7-75 years. The initial age is a little higher at women, (range of 19-55 years: on average 31,3 years), than men (range of 15-53 years: on average 24,3 years). The ratio between men and women fluctuates depending on mutations: 3: 1 for 3460 G> A, 6: 1 for 11 778 G> A and 8: 1 for 14484 T> C.

It, as a rule, develops in very heavy atrophy of an optic nerve and continuous decrease in visual acuity, being reflected on both eyes at the same time (25% of cases) or is consecutive (75% of cases) with an average interval of 8 weeks. Only in rare instances only one eye can suffer. In the acute stage lasting several weeks, the affected eye shows emergence of hypostasis of a nerve fiber layer, especially in the arc-shaped bunches and the increased or telangiectatic and twisting peripapillary vessels (mikroangiopatiya). The main features are visible at an oftalmoskopiya, before or after sight loss. Defects of a pupil can be also visible in an acute stage. The analysis shows decrease in visual acuity, loss of color sight and tiflotsentralny scotoma when testing a field of vision.

LHON Plus.

"LHON Plus" — the name given to exceptional cases of a disease of eyes in the presence of other conditions.
Symptoms of this highest form of a disease include loss of ability of a brain to control the movements of muscles, a tremor, and cardiac arrhythmia. In many cases of LHON Plus was comparable to multiple sclerosis because of a lack of muscular control.

Treatment of hereditary optical neuropathy of Leber:

Without knowledge of history of a family of LHON the diagnosis, as a rule, demands neuroophthalmologic assessment and blood test for mitochondrial assessment of DNA. Here it is important to exclude influence of other possible reasons of loss of sight and important, connected syndromes, such as cordial electric conductivity of system anomalies. The forecast almost always means continuation of essential decrease in sight in both eyes for the victims remaining incurable. Regular checks of visual acuity and check of perimetry it is recommended for further steps of affected persons. There is a fine therapy for some cases of this disease, especially for an early onset of the illness. Besides, experimental protocols of treatment proceed. Genetic consultation has to be offered. Health and a way of life have to be reconsidered, especially in the light of toxic and food theories of an expression of genes. Able to see assistants and recovery work have to be used for assistance in preservation of jobs.

For those who are LHON mutation carriers preclinical markers can be used for progress monitoring. For example the photo of a bottom can control swelled a nerve fiber layer. The optical coherent tomography can be used for more detailed studying of thickness of a nerve fiber layer of a retina. Testing of red-green color sensation can find losses. Contrast sensitivity can be reduced. The abnormal electroretinogram or visual evoked potential can be revealed. Neyron-enolaza and markers of axons of a heavy chain of neurofilaments of blood can predict the status of transformation for victims.

Cyanocobalamine (B12 vitamin form) it is necessary to avoid as it can lead to a blindness at patients with Leber's disease.

As a rule it is recommended to avoid toxins of an optic nerve, especially tobacco and alcohol. Some drugs which are released according to the recipe, as we know, bear potential risk so to all drugs it is necessary to be suspicious and check a risk degree before use. Ethambutolum, in particular, was involved as an impulse to loss of sight at LHON carriers. Really, toxic and food optical neuropathy can have the symptoms which are crossed with LHON, mitochondrial mechanisms of a disease and management. It should be noted when the patient as a result of LHON or a toxic / food optical neuropathy had hypertensive crisis, uslozhnyuyushchy process of a disease, Sodium nitroprussidum (a trade name: Nipride) should not be used in connection with the increased risk of ischemia of an optic nerve, as a result of reaction to this anti-hypertensive drug.

Idebenon in small placebo - a controlled research, was shown to about a half of patients for achievement of moderate advantage. People who were at the beginning of a disease had the best results.

α-Tokotriyenol-quinone, the vitamin E metabolite, made in small open researches some success in the address back of the begun sight loss.

There are various approaches to treatment which passed preliminary tests or offers, any did not provide convincing proofs of usefulness and safety for treatment or prevention that number yet: бримонидин, Minocycline, curcumine, glutathione, phototherapy of infrared radiation, and methods of a virus vector.

"Extracorporal fertilization in the third party" is the proof of the concept of research methods for prevention of a mitochondrial disease in development of a human fruit. Still, viable macaques were made. But obstacles of ethical and cognitive character stop use of this method in public.

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