Leber’s hereditary optic neuropathy

Leber’s hereditary optic neuropathy. It is a maternally inherited disease characterized by painless, bilateral, sub-acute loss, although not always in unison, of central vision. It predominates in young men and is caused by point mutations in mitochondrial DNA . This is one of the most frequent and highly disabling hereditary optic neuropathies, whose diagnosis is certainly made by molecular studies.


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  • 1 Epidemiological characteristics
  • 2 Risk factors
  • 3 Clinical manifestations
    • 1 Forms of manifestation
  • 4 Diagnosis
  • 5 Treatment
  • 6 Sources

Epidemiological characteristics

The disease in the world has an approximate incidence of 1/40 000 inhabitants. A prevalence of 1/50 000 inhabitants is reported in Finland , a country with a number of 36 diagnosed NOHL families, comprising almost 1,000 members. Studies in these families indicate that overall NOHL penetrance is lower than previously estimated, and that affected females have a higher incidence of affected offspring compared to unaffected females.

At the Cuban Institute of Neurology and Neurosurgery , Santiesteban et al. Verified the diagnosis of NOHL in 76 subjects from 13 families, using molecular biology studies. In the families studied by this author, the 3 types of primary mutations described in this disease were found, with a distribution by type of primary mutation similar to those described so far in America and Europe . The 11,778 mutation was the most frequent, followed by 3,460 and 14,484, although in a lower percentage for the latter.7

Currently, the Wallace mutation is considered to be responsible for 40 to 80% of cases with NOHL, with the exception of Japan, where it reaches 90% of patients. 3,460 and 14,484, also primary, have been reported between 10 and 15% of these families.9,13 Santiesteban verified and reported an increase in the incidence of the disease during the years of the nutritional toxic optic neuropathy epidemic.

The usual age of onset described by the different authors ranges from 15 to 35 years of age.6,7,12,14,15 In the study carried out by Santiesteban, the average onset was 28 to 30 years of age, older in individuals with the 11,778 mutation in which two patients with that mutation were over 40 years old at debut.

In relation to sex, a predominance of involvement of male patients is observed. Newman et al., In a study of 72 affected from 43 families with 11 778, found that 81.9% were males.15 In general, the involvement of males is between 77 and 90% of pedigrees, except in Japan. In the cases studied by Santiesteban et al., There was a slight predominance of 57% males, with the exception of two families with the 3 460 mutation, in which there was a predominance of the female sex.

Risk factors

Different studies report toxic factors such as cigarette smoking , alcohol , nutritional deficiencies; as well as intercurrent diseases, as factors that promote the appearance of the disease, since they are all capable of damaging oxidative phosphorylation and therefore ATP production . Such is the case of the cyanide of the cigar and tobacco already mentioned, and of the formic acid coming from the methyl alcohol that have in small quantities the alcoholic drinks.

A deficiency of vitamin B12 or folic acid , would lead to the accumulation of formic acid and cyanide, which are inhibitors of cytochrome c oxidase, which is part of the electron transport chain. This can interfere with the production of ATP, in whose absence the optic nerve is very sensitive, because for its correct metabolism it requires large amounts of this nucleotide; therefore it would be easy to understand the magnitude of the damage caused by these external agents.

Clinical manifestations

The presentation of symptoms is subacute, with visual deterioration in days or weeks, which occurs in unison or with an interval of usually weeks or months between one eye and the other. Psychophysical studies such as visual acuity, color vision, and the visual field show alterations that demonstrate damage to the optic nerve. Color vision in the red-green axis is greatly affected, as is typical of most neuropathies.

Ventura et al. Demonstrated involvement of the red-green axis in asymptomatic carriers of this neuropathy. This deficit behaved with greater incidence and severity in male carriers, not being so in women with the mutation. The same intersex difference was found by Santiesteban in the color vision studies in the NOE, which in these cases was partly attributed to the congenital vision defect in the red-green axis that 8% of men suffer from.

The visual field defect in NOHL is the dense cecocentral scotoma. The fundoscopic findings vary depending on the stage in which the patient arrives. In the cases of NOHL, at the beginning of the disease (presymptomatic stage), the triad of telangectatic microangiopathy , edema of fibers around the papilla, and absence of contrast leakage from the vessels on fluorescein angiography are characteristic . Capillary dilatations and telangiectasias have been recognized in the second affected eye even before they begin to refer to it, some visual deficit.

Changes in the fundus may be minimal or absent. Many times the patient is examined when the changes important for the diagnosis have already disappeared and total disc paleness is shown without any locator value. It is suggested that the hyperemic aspect is the first phase of the disease (acute phase), which gives way to the loss of the papillomacular fiber bundle and then to atrophy (atrophic phase), almost total, or total in most of the cases.

In the acute stage is when vision is lost, which occurs in a few days. It is observed , in fund eye arteriolar dilatation, edema peripapillary nerve fibers and angiopathy telangiectasia. Improvement in visual function is rare. In asymptomatic carriers with the primary mutation Santiesteban has detected functional damage through more precise studies, such as the contrast sensitivity test and color vision. On fundus examination, she observed capillary dilation in patients before becoming symptomatic.

Forms of manifestation

Leber’s hereditary optic neuropathy can manifest itself in three other but atypical forms, in addition to the classic subacute form of days or weeks of evolution.

  • Subclinical
  • Slowly developing
  • Classic acute stage but with spontaneous recovery.

In subclinical Leber hereditary optic neuropathy, visual acuity is low. The onset of slowly developing disease is usually in childhood and the visual outcome is favorable.

According to Newman and other authors, the mutation that patients carry determines the final visual acuity and the possibility of recovery. The patients most affected by the 11 778 mutation may not perceive light. Those with a severe form of the 3 460 mutation can preserve their perception. Cases with the mutation 15 257 and 14 484 perceive hand movement and finger counts. Only 4% of the 11 778 shows recovery after 36 months of the onset of the disease; 22% of patients with 3,460 after 68 months; 28% of patients with 15 257 and 37% of patients with 14 484 after 16 months.

In relation to visual prognosis, in a recent study Ramos et al. Detected a correlation between the size of the optic disc and the degree of visual recovery, and describe greater recovery in patients with larger diameter optic discs.28 This suggests that the anatomy disc may play a protective or risky role. In this study, important differences were also found in the measurements of the optic disc between carriers and patients, with larger diameters for NOHL carriers and smaller diameters in patients. Why the size of the disc is a protective factor in the case of large discs is understood if we analyze the anatomy of the optic disc.

Structurally, the optic nerve is made up of the axons of retinal nerve fibers that emerge grouped into bundles of fibers, numbering around 1.5 million. In small optic discs these fibers emerge through a narrower cavity and also when passing through the holes in the sieve sheet, which are narrow, asymmetric and misaligned, the probability of suffering damage is increased. In this way, a large optic disk will have a lower risk of axonal damage due to the aggression of exogenous and endogenous agents, as is the case of the risk factors identified for the disease.

A small proportion of patients with NOHL and their families have other accompanying symptoms, some affected have defects in cardiac conduction. Nikoskelainen, Puomila and other authors describe that in Finnish patients and in Japanese families preexitation syndromes such as Wolff-Parkinson-White and Lown-Ganong-Levine are frequent. The mutation of the mitochondrial DNA causing NOHL could contribute to the appearance of these syndromes, as has been reported in patients and relatives (with 11,778 mutation).

Several minor neurological problems have been described, including impaired osteotendinous reflexes and myoclonus. In some families with NOHL, the 11,778 mutation has been associated with multiple sclerosis, a rare comorbidity, which is why NOHL mutations have been considered risk factors in its pathophysiology. The optic neuropathy Leber hereditary also may be associated with dystonia; In a recent study, a new mtDNA mutation, 3697G A / ND1, was detected, capable of producing the disease together with spastic dystonia, an alteration described in one family in the absence of the known primary mutations of this neuropathy.

This mutation can also cause another mitochondrial disease that occurs with myopathy, encephalopathy, lactic acidosis, and cerebrovascular accidents (MELAS). These rare associations have been described in isolation by some authors. Other genetic factors are known to contribute to the clinical expression of the disease.


The diagnosis of certainty of NOHL is made by verification by molecular studies of mutations in the mtDNA, either primary or secondary association. This together with the clinical characteristics described above.

The anamnesis , maternal inheritance in most cases, the psychophysical examination, the fundus, together with other tests such as optical coherence tomography (OCT) and neuroimaging help to confirm the disease clinically.

Barboni describes 38 patients with NOHL and found in the study by OCT increased thickness of the nerve fiber layer (CFN) greater in the upper, lower and nasal sectors in the early stages and a diffuse decrease in all quadrants in stages of atrophy. ; In addition, it was verified that the patients who recovered visual acuity, after the acute phase, had a higher CFN thickness in the upper, lower and nasal quadrants compared to those who did not recover vision.

Seo, in his comparative study using the OCT study of the thickness of the CFN in 30 patients, demonstrated a significant increase in the thickness of the fiber layer in the acute phase in the group with the 11,778 mutation, as well as a greater decrease in late phase of this group in relation to patients with the 14 484 mutation. These new diagnostic means, together with molecular studies, are demonstrating their usefulness in this neuropathy.


To date there is no specific treatment. In a case-control study with patients carrying mutations 14 484, 3 460 and 11 778 received combined treatment with idebenone / vitamin B2 / vitamin C, without visual improvement or stopping the course of the disease. In recent years, much progress has been made in topics such as neuroprotection, apoptosis, neurodegenerative diseases and gene therapy, so in the future this knowledge could be used to find effective therapeutic agents in NOHL; the gene therapy could be a good start.


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