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 , , , and 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.
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.
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.