Leber’s hereditary optic neuropathy (LHON) is one of the most common mitochondrial disorders. The disease was first reported by Von Graefe in 1858, and in 1871 Teodor Leber collected 55 cases in 16 families and confirmed it as an independent hereditary disease. The pathological mechanism of the disease has been unclear, and in 1988 Wallance et al. identified mitochondrial DNA mutations closely related to the disease, which opened a new page for the study of the pathological mechanism of LHON. However, there are still many questions regarding the genetic relationship, epistasis and pathogenesis of the disease that need to be further investigated. In this paper, we would like to review the pathogenesis of LHON and clinical research.
1. Clinical studies.
1.1 Epidemiology.
LHON is a maternally inherited disease, male prevalence, male to female ratio of 3:1 or 9:1 in the West, about 6:4 in China, showing an increase in the incidence of yellow females. The disease occurs mostly in adolescence (18-23 years old) and can be as young as 1 year old and as old as 70 years old. No clear incidence of the disease has been reported in China. There are three recognized primary mutation loci for LHON, 11778, 14484 and 3460, which account for about 90% of all LHON patients, and about 66% of national patients with mutations at 11778. The 11778 mutation accounts for approximately 69% of Caucasian LHON patients, while T14484C and G3460A account for 14% and 13%, respectively. In Europe, the G11778A mutation accounts for about 50%, and the G3460A and T14484C mutations account for 35% and 20%, respectively. In Japan, mutations at the LHON11778 locus can reach 91.7% or 87%, while the remaining two mutated loci are less common. These findings suggest that there are ethnic differences in the incidence and mutation loci of the disease.
1.2 Clinical manifestations.
1.2.1 Clinical symptoms.
LHON patients usually have no obvious cause for the onset of the disease, some have elevated body temperature or fatigue, the main clinical manifestations are acute or subacute central visual field loss in both eyes simultaneously or successively, and loss of color vision mostly before the loss of vision, patients usually have no obvious discomfort at the onset, a few will have eye pain or pulling pain when turning the eyes. Patients with LHON may also have abnormalities such as tremor, ataxia, dystonia, spinal cord cortical tract dysfunction, deafness and skeletal deformities, as well as a syndrome similar to multiple sclerosis. Some patients also have cardiac dysfunction, and some researchers believe that cardiac treatment of these patients is also beneficial for the recovery of ocular lesions. Zuo Wei et al. observed that 53.3% of 30 LHON patients had electrocardiographic abnormalities. It seems that LHON involves many organ systems of the body in addition to ocular symptoms.
1.2.2 Clinical staging.
In 1996, the Ophthalmology by Nikoskelainen divided the disease into three general stages.
(1) Preclinical stage: The optic disc is congested and edematous, with marked microvascular dilatation and curvature on the optic disc and adjacent areas, and edematous clouding of the peripapillary nerve fiber layer; FFA shows rapid venous filling and arteriovenous shunts, but no leakage.
(2) Acute phase: The above signs are more obvious, and sometimes peri-disc hemorrhage is seen; FFA shows faster filling time, with abundant arteriovenous shunting branches mainly in the superior and inferior temporal part of the optic disc, and fluorescence stagnation may appear in the temporal part of the vessel wall, while the vascular bed of the disc spot bundle is reduced and filling is delayed.
(3) Atrophic stage: the small arteries on the temporal side of the optic disc become thin, the capillaries decrease, the band or wedge-shaped missing area of the nerve fibers gradually widens, and the temporal side of the optic disc becomes pale white; as the disease progresses, the above changes become more extensive and involve the whole optic disc and the peripheral nerve fiber layer. There is no clear clinical staging of the disease in China. Early diagnosis of the disease is difficult but important for treatment and prognosis.
1.2.3 Physical examination.
Early visual evoked potentials (VEP) in patients with LHON do not change significantly, and later there may be a decrease in amplitude or a delay in latency. Retinal angiography without fluorescence leakage in the acute phase became one of the indicators to assist clinical diagnosis.Smith believed that the early stage of the disease with dilated capillary microarterial vascular changes around the optic papilla, swelling of the nerve fiber layer around the optic papilla, and no leakage from the optic papilla were the triad of LHON patients. Subsequently confirmed by scholars from various countries, it has been used as the classical concept of LHON. The MRI of the brain and optic nerve is normal, but with transient flipping signal scanning often shows changes of gliosis. giacomo using OCT examination found that all patients with uncomplicated LHON have a thinner optic nerve fiber layer than controls, and the temporal quadrant is the first to be involved in patients with onset, and diffuse damage to optic nerve fibers is more pronounced in men than in women. There is no corresponding report of this examination in China.
1.3 Diagnostic criteria.
There is no clear diagnostic criteria for LHON, the study concluded that the diagnosis of the disease by peripheral blood gene is the simplest, but because the peripheral blood and optic nerve mitochondrial gene mutation rate is different, prone to false negative results, so the diagnosis of the disease should be combined with clinical manifestations at the same time, family genetic history, age of onset and fundus trismus performance is particularly important. Even if the primary three loci of LHON are not detected, or although there is no clear family history, the disease should be highly suspected with the above clinical manifestations. The application of full gene scan has some clinical value, and we have repeatedly seen new mutant loci in our clinic.
2. Pathogenesis.
2.1 Genetic background.
The mitochondrial interstitium, inner membrane, outer membrane, and the space between the inner and outer membranes all store multiple enzymes or groups of enzymes. The matrix contains mitochondrial DNA (mtDNA), proteins necessary for replication and transcription of mtDNA, mitochondrial ribosomes for protein synthesis, and enzymes for other functions (referring to the citric acid cycle and beta-oxidation of fatty acids). Human mitochondrial DNA is a circular, double-stranded, closed-loop molecule containing 16,569 base pairs. mtDNA is capable of replicating itself and is a genetic system independent of chromosomes. It contains two DNA strands, one light and the other heavy, both of which have coding functions. mtDNA encodes two types of rRNAs, 22 tRNAs and mRNAs containing 13 polypeptide chains (cytochrome B, cytochrome C, subunits I, II and III of oxidase, two components of ATPase subunits 6 and 8 and seven subunits of respiratory chain NADH dehydrogenase: ND1, ND2, ND3 and ND4. (ND2, ND3, ND4, NDL4, ND5, ND6). Only complex II (succinate dehydrogenase) is encoded exclusively by nuclear DNA. The mitochondrial genome thus plays a key role in the regulation of oxidative phosphorylation. Most of the mitochondrial proteins are encoded by the nuclear genome, translated in the cytosol and introduced into the mitochondria. Thus nuclear genes also play an important role in mitochondrial function.
Genetic characteristics of mitochondria.
(1) Maternal inheritance: Since mitochondria are located in the cytoplasm and only nuclear genes from the father enter the egg to form gametes, the vast majority of mitochondria in fertilized eggs are from the mother, so most mitochondrial diseases are inherited maternally.
(2) Heterogeneity: mtDNA genes are compactly arranged and some genes can overlap with each other, except for an 87bp region between the super longitudinalons called D tabs, almost every one of which is used for component genes. Unlike nuclear genes, there are 1-10 mtDNAs in a mitochondrion and hundreds of mtDNA copies in each cell, all mtDNA molecules in each cell are uniform, called homogeneity; while when mtDNA is mutated it will lead to the simultaneous existence of both wild-type and mutant mtDNAs in the cell, called heterogeneity.
(3) Phenotypic expression of mtDNA mutation: The phenotypic expression of mtDNA mutation is different from the expression of nuclear genes, mainly determined by the relative proportion of mutant and wild-type mtDNA in a certain tissue and the degree of dependence on mitochondrial ATP production in that tissue. When the number of mutant mtDNA reaches a certain level that can be sufficient to cause functional abnormalities in an organ or tissue, it is called a threshold effect. That is, whether mutant mtDNA produces phenotypic effects in a tissue depends on the relative ratio of mutant mtDNA to normal mtDNA and the degree of dependence of that tissue on ATP production by mitochondria. The differential expression of mutant mtDNA in different tissues is closely related to the degree of mitochondrial energy dependence of these tissues, with higher energy dependence in the central nervous system, retina, heart, skeletal muscle and liver, where defects in oxidative phosphorylation function are often evident.
(4) High frequency of mtDNA mutations: The frequency of mtDNA mutations is more than 16 times higher than that of nuclear genes, and because of their lack of an intact repair system, mtDNA mutations accumulate in somatic cells with increasing age, and oxidative phosphorylation function declines continuously, even if energy production is below the threshold of tissue energy demand, i.e., clinical symptoms appear.
(5) Mutation types: Mitochondrial mutations are classified as, missense mutations, biosynthetic mutations, deletion mutations and copy number mutations. All LHON mutations to date have been missense mutations in the oxidative phosphorylation subunits of complexes I, III and IV.
(6) Genetic trend: mtDNA replication speed is proportional to its length per unit time, mtDNA is exposed to oxidative damage in the cytoplasm to produce various mutations, and at the same time lacks enzyme protection, so the mutated mtDNA has proliferation advantage compared with normal size mtDNA, that is, with the extension of time, the abnormal mtDNA has the tendency to accumulate in the somatic cells The tendency of
The genetic characteristics of mitochondrial genes are closely related to the occurrence of LHON disease, and it is believed that the pathological mechanism of LHON is mainly related to the following factors.
2.2 LHON pathogenesis.
In 1988 Wallance found that LHON patients with mitochondrial deoxyribonucleic acid site 11778 mutation, that is, guanosine (G) was replaced by adenine (A), this mutation makes the respiratory chain on the reduced coI (NADH) deoxygenase subunit 4 (ND4) gene encoding the 340th amino acid from arginine to histidine, this position of the amino acid is human from the flagellate evolution to In 1991, Huoponen et al. identified a new mtDNA mutation: position 3460 of the ND1 gene caused a change from alanine to threonine and was confirmed to be definitely associated with LHON. Johns et al. first identified a mutation at position 14484 of the ND6 gene in 14 LHON patients, and in these 14 families, in addition to this locus In addition to mutations at this locus, mutations at locus 13708 also occurred in these 14 families. Yen et al. classified the mitochondrial mutations in this disease into four groups, including 3460, 11778 and 14484 as the major mutations, 14459 and 14495 as the rare loci, and 14459 and 14495 as the hypothetical possible mutations. mutant loci are 11 and companion mutant loci are 9, totaling 25. These mutated genes are mainly located on NADH dehydrogenase within mtDNA. With the exception of 11778, 14484 and 3460, other mutant loci may also be primary, but their mechanisms are poorly understood. Although some investigators have suggested that the multiplicity of LHON mutations is necessary for vision loss, this has not been proven. In fact, some investigators have found patients carrying two major mutated genes who have not yet developed the disease. It is also possible that the presence of some potential mtDNA haplogroups within LHON cells, although not a major factor in phenotypic expression, influences the presence, phenotype or expression of mtDNA mutation sites.
One study found that all patients with these three major mutant sites had impaired interaction of coenzyme Q10 substrate with complex enzyme I. Therefore, it is thought that mutations in LHON may affect coenzyme Q binding sites and ubiquinone intermediates resulting in decreased stability. Another factor, the mitochondrial respiratory chain is the origin of aerobic cells, 95% superoxide ions. Inhibition of the cellular respiratory chain can cause an increase in free radical metabolism, and oxidative damage can in turn inhibit the respiratory chain. This self-expanding cyclic tendency of oxidative damage and respiratory chain dysfunction can lead to mitochondrial damage, especially in central nervous tissue, which is extremely sensitive to mitochondrial damage. It has also been suggested that the mitochondrial respiratory activity is higher in the unmyelinated portion of the optic nerve in front of the sieve plate. This part of the visual system may be more sensitive to mitochondrial dysfunction, especially abnormalities of coenzyme I.
The primary cause of whether carriers develop the disease is unclear; nuclear encoding factors, mitochondrial products, or mitochondrial metabolism may all influence LHON phenotypic expression. However, the physiological characteristics of mitochondria may be related to the following.
(1) different distribution of mitochondria in various tissues and bottleneck phenomenon: in the early stages of oocytes, the number of mtDNA molecules grows from reduced to a few hundred to about 100,000 in mature oocytes, so oocytes can have different levels of mutations. Therefore, it is difficult to predict the level of mutations or the onset of disease in the offspring through the mother.
(2) Influence of age factor: high frequency of mtDNA mutations, gradual accumulation of mtDNA mutations in somatic cells with increasing age, decreasing oxidative phosphorylation, higher energy demand of optic nerve than general tissues, which may be one of the reasons why optic nerve is the main affected tissue. Tissue energy utilization and storage in the individual also determine the timing and extent of vision loss. With the decline of mitochondrial energy products with age, the time of onset of vision loss in LHON patients may reflect the domain value of the critical level of mitochondrial function deterioration.
(3) Genetic heterogeneity: Howell et al. studied a British family line of LHON spanning six generations. In this line, two branches with 11778 mutant loci exhibited a complex pattern of racial segregation, another was homozygous wild type, and four had a heterozygous status. Further, there is a joint-racial segregation of allele 11778 and a polymorphism in the family with non-extrinsic G:A at loci 18 and 19 patient nucleoside 5471. This joint-race segregation in the same mtDNA molecule shows that the two substitutions occur simultaneously or almost simultaneously. However, the high rate of divergent mitochondrial alleles in one family implies a complex origin and divergence history in both substitutions. In summary, in one branch of this family, the vector subsequently segregates mutant genotypes to higher levels, and in the other branch, there are doubles of wild-type or mutant phenotypes that become essentially homozygous. The degree of heterogeneity of primary LHON mutations in several onset and non-onset families may be related to the risk of vision loss, yet in the vast majority of patients molecularly identified as LHON, heterogeneity was detected in the blood of only a minority of onset patients.
(4) Intrinsic and extrinsic environmental factors: systemic diseases, nutritional deficiencies, drug effects, or toxins they directly or indirectly inhibit mitochondrial metabolism, thereby triggering or increasing the expression of disease phenotypes. Chronic toxicity and environmental factors have been studied, so far all LHON mutations are missense mutations in the oxidative phosphorylation subunits of complexes I, III and IV. LHON patients may have abnormal oxidative phosphorylation and impaired oxidative and thiocyanate enzyme activity in the mitochondria, when long-term smoking, intake of cyanide-containing substances, environmental pollution, etc., so that the accumulation of cyanide in the patient’s body, over time, can inhibit the cellular cytochrome C oxidase, which further aggravates the oxidative phosphate disorder after mitochondrial gene mutation, thus increasing the chance of morbidity. However, it was found that treatment with cyanide antidotes such as carboxycobalamin and sodium thiosulfate failed to prevent the progression of the disease and the impairment of visual function. Therefore, this study remains to be further developed. In particular, Cuba, a country with a significant nutritional deficiency, did not show an increased incidence of LHON in patients with the 11778 mutation locus. Although no controlled group trials have suggested that tobacco and excessive alcohol can contribute to vision loss, a large sample of controlled studies failed to prove this conclusion. Other factors harmful to LHON, such as ethambutol, and antiviral therapy may also be harmful to patients with LHON mutations, Alfredoa found in a study of risk factors for the development of LHON that smoking was a high risk factor for the disease, but the incidence of hypertension and hypercholesterolemia was lower than in controls. No related studies have been reported in China, and this result remains to be studied in depth. Reported endocrine disorders, such as childbirth, insulin-dependent diabetes, etc. can induce LHON, if this endocrine disorder can be corrected in time can make some patients’ vision to obtain a certain degree of recovery.
(5) Multiple sclerosis: Ancillary tests other than genetic analysis are usually limited in the evaluation of LHON. CT and MRI examinations in patients with LHON are normal except for those suggestive of multiple sclerosis and those with dystonia and basal ganglia damage. 1992 Harding et al. first discovered that mitochondrial DNA mutations that cause LHON are also seen in MS patients, and subsequently researchers in Europe and the United States have conducted numerous studies on the relationship between mitochondrial DNA mutations and MS, The results showed that the three primary mitochondrial DNA mutation loci 11778, 3460, and 14484, which cause LHON, can be found in MS patients, with 11778 being the most common mutation. A boy with visual impairment but no signs or symptoms suggestive of demyelinating disease was found to have extensive T2 high-signal ventricular white matter changes. Two patients with LHON were found to have dilated optic nerve sheaths on CT, MRI, and orbital ultrasonography. MRI was usually normal during the acute visual loss phase in patients with LHON, whereas the intraorbital segment of the optic nerve exhibited T2 high signal on MRI several months later. In contrast, mtDNA mutations are not only rarely reported in Asia (only in Japan), but also have very different results and are not considered to be related to the development of MS. Jueqian Zhou examined 18 MS patients with mitochondrial DNA 11778 mutations in peripheral blood. The results failed to detect mitochondrial DNA mutations in MS patients. The authors speculate that this may be related to the significantly lower incidence of MS patients in Asia compared to Europe.
2.3 LHON and apoptosis.
The correlation between mtDNA and apoptosis has been increasingly studied in recent years. pitkeane et al. found that during cell culture, cells can produce large amounts of superoxide if the NADH dehydrogenase complex in the respiratory chain is defective. Treatment of cell lines causing LHON and mtDNA mutant cell lines associated with complex defects with anti-Fas was more susceptible to apoptosis.Danielson et al. found that LHON patients with mutation loci at 3460 and 11778 were susceptible to apoptosis triggered by Fas, inferring that apoptosis plays an important role in the process of LHON neurological injury, and that this In order to clarify whether oxidative stress and apoptosis can cause clinical changes in patients with the disease, Mashima found that patients with the disease who carry a pure His113 in the EPHX1 gene and a pure Arg 72 in the TP53 gene have an earlier onset than those without these genotypes, thus suggesting that nuclear gene-regulated polymorphisms associated with oxidative stress and apoptosis Floreani et al. found that although there was a decrease in superoxide dismutase in the cytoplasm of all LHON patients and a decrease in GPx and GR activity in the blood cells of LHON patients with severe 3460 and 11778 mutations, however, GR and MnSOD activity were decreased in the cytoplasm of all LHON patients. These results imply that there is a reduction in antioxidant function in cells with mutated loci in LHON, especially in cells with significant clinically phenotypic mutations, and this impairment is more pronounced in environments exposed to oxidative stress such as galactose.Battisti et al, used electron microscopy, blood rheology, agar gel electrophoresis and mitochondrial membrane potential assays to examine 6 LHON patients and 6 normal subjects, and the results were that LHON patients had a higher rate of apoptosis than controls, with mitochondria being involved in the apoptotic process. Thus, it is proposed that there is a linear relationship between different oxidative damage and the important role of redox dynamic balance in the expression of mutations in different individuals.
OzawaT suggested that the oxidative damage to mtDNA and the mutations caused by the mitochondrial gene mutations restricted the respiratory function of some tissues and organs, and therefore the disease was closely related to oxidative damage. This cycle eventually leads to cell death. Free radicals attack mtDNA bases mainly by direct oxidative modification of the bases, and the oxidatively modified bases are prone to mismatches during replication and lead to mutations. Wang Jinyong et al. performed serum nitric oxide (NO) and nitric oxide synthase (NOS) assays on LHON family lines with 11778 point mutations, and the results showed that patients had higher NOS than carriers. In the study of changes in free radicals and antioxidants in the LHON family population, it was found that serum superoxide dismutase (SOD) levels were significantly higher in both patients and normal carriers compared with the normal group, and glutathione (GSH) was significantly higher in patients than in the normal group, while serum glutathione-transferase (GST) and GSH levels were lower in LHON normal carriers than in normal controls, and these studies remain to be further observed.
3, laboratory studies.
To date, no early optic nerve pathology has been reported in LHON, so the localization and original damage are not well understood.Kerrison et al. found optic nerve fibers, optic ganglion cell layer and optic nerve atrophy in an 81-year-old female Australian LHON patient at autopsy. Electron microscopy revealed calcium confined to the bilayer in the ganglion cell contents, suggesting the presence of mitochondrial calcification. Histopathologic and morphologic analysis of three patients with years of acute vision loss resulted in severe and extensive optic nerve fiber loss. Only peripheral and primary larger diameter nerve fiber bundles remained. Fibrous cystic scars, scattered degeneration dust and mild inflammatory manifestations were observed. This investigator proposed the loss of selective ganglion cells (P-cells – primordial cells, immortal cells, persistent cells).
There is no suitable animal model in the study of mitochondrial mutation disease. The transmitochondrial cell model, on the other hand, is the main modern tool for studying mitochondrial mutation diseases. In 1996, Jun used the transmitochondrial cell model to study the mitochondrial complex enzyme I activity in patients with the 14459 locus mutation LHON. Mitochondrial complex enzyme Ⅰ activity, the results found that the enzyme activity decreased by 39%.
4. Treatment and prognosis.
There are still many questions regarding the expression of the LHON phenotype, with different mutant loci showing similar clinical manifestations and spontaneous visual recovery in all three major loci mutant phenotypes. However, the recovery rates were different, with only 4% of 136 patients with the 11778 locus mutation having spontaneous recovery; 14484 had 37-65%. In addition 14484 patients had significantly better visual acuity than patients with 11778 and 3460 mutated loci. Oostra [34] studied the prognosis of visual acuity in patients with three primary mutant LHONs, 11778, 3460, and 14484, the best prognosis was found at locus 4484, followed by locus 3460, and the worst prognosis was found in patients with mutations at locus 11778. In Australia, the Netherlands, and the United States, patients with vision loss were followed up for 2 years, and a high rate of vision recovery was found in patients with mutations at locus 14484. Tong Est et al. found that Leber disease with or without the Wallace mutation was not significant in predicting visual recovery, and those with severe neurological complications were often without the 11778 locus mutation. In conclusion, any uncontrolled efficacy report for spontaneous recovery of vision in some LHON patients must be taken with caution. The mechanism of this spontaneous recovery is unclear, while long-term follow-up observations are necessary to clarify whether the recovery is truly spontaneous.
There is no specific treatment for LHON. In the late 1960s, Japan advocated the use of crossed arachnoid adhesion release craniectomy for LHON patients, more than 120 cases about 80% of patients have improved vision, but it is difficult to believe that the use of surgical changes to the optic nerve vascular status can be so effective. It is common to realize that the disease may be related to LHON only after hormonal shock therapy has failed. Some studies have suggested that cofactors with antioxidant functions naturally present in mitochondrial metabolism, such as coenzyme Q10, succinate, vitamins K1, K3, C, B1 and B2, may play a role in vision recovery. According to Yoles in 1999, 14 out of 28 cases of LHON patients were treated by Idebenone (hydroquinone) combined with vitamins B2 and C. There was no difference in the number of eyes on vision recovery. Zuo Wei et al. used a combination of Chinese and Western medicine to treat 28 cases of LHON patients and obtained a total effective rate of 46.5%. Factors thought to have neuroprotective effects or anti-nodal cell apoptosis were used for acute vision loss in LHON, prevention of second eye onset or prophylactic treatment for members of high-risk asymptomatic family lines, but efficacy is subject to further observational studies.
Heterozygous expression gene therapy for LHON and other mitochondrial diseases may be one of the more promising therapeutic approaches in the future. This treatment involves the use of nuclear coding translocation to synthesize (ND4 contains nucleotide 11778 sites) mtDNA encoding a normal gene, insert it into an inactivated adeno-associated viral vector encoding a protein in the cytoplasm, and then import it into the mitochondria. This protein increases the survival rate of cytoplasmic heterozygotes carrying the 11778 locus by a factor of 3 and stores ATP synthesis products to the level of cytoplasmic bodies containing normal mtDNA, a therapy that also needs further investigation.
5. Outlook.
The genetic characteristics of mitochondrial genes can explain part of the pathogenesis of LHON, firstly, all LHON families so far are maternally inherited; the onset of the disease is mostly in young adulthood, which may be related to the mtDNA genetic tendency, due to the existence of intracellular heterogeneity of mitochondria, with the prolongation of time the abnormal mtDNA accumulates in the body and reaches the ” threshold effect” that leads to the onset of the disease in patients. At the same time, the optic nerve becomes the “target” of the disease due to its high demand for oxygen. Although there is a lot of modern research on LHON, there are still many unresolved issues. Some particularly salient issues are the fact that all maternally related family members of LHON patients carry mtDNA mutations, yet some never have clinical symptoms. Thus, although the presence of mtDNA mutations is important for phenotypic expression, it may not be sufficient to cause pathogenesis; why multi-locus mtDNA mutations in different genes encoding different proteins cause the disease to express the same clinical phenotype, while the disease locus is restricted to the optic nerve; and why, by inference from mitochondrial genetic characteristics, the progressive increase in mutated genes with age should result in a progressive worsening of the disease in patients The trend is that this mutation rate should also reach the threshold of oxygen damage in other tissues, resulting in lesions in other tissues, but this is not the pathogenesis pattern of patients with this disease; the incomplete epiphenomenon and the tendency to male pathogenesis suggest that there are other factors, such as nuclear, mitochondrial genes or environmental factors that play a role in the pathogenesis; during the pathogenesis of LHON, vision has been significantly reduced, the optic nerve papillae are pale in color, and usually hormonal shock therapy is ineffective. The pathological mechanism or nature of LHON needs to be further studied from genetic, biochemical, physiological, pathological and clinical aspects of Chinese medicine. therapeutics.