Leber Optic Atrophy

Definition

Definition of Leber Optic Atrophy
Leber's hereditary optic atrophy is a disease of mitochondria. There is usually 1 of 3 point mutations of DNA. These 3 are: G11778A, T14484C and G3460A. Clinical molecular genetic testing for these mutations is available. More recently, new mutations have been identified (G10680A, T3394C) but these are much less common. It may be inherited or, more rarely, a spontaneous mutation. Inheritance is entirely from the maternal side. This has sometimes led to the erroneous belief that it is an X-linked condition but inheritance is not Mendelian.

Symptoms

Symptoms of Leber Optic Atrophy

1. Visual acuity is usually reduced to counting fingers.
2. Visual field testing shows an enlarging central scotoma.
3. Fluorescein angiography may be useful in the acute phase. The disc swells due to pseudo-oedema of the nerve fibre layer, peripapillary telangiectasia appear and there is increased tortuosity of the retinal vessels. Not everyone shows the full picture.
4. Electrophysiology studies, including pattern electroretinogram and visual evoked potentials, may demonstrate optic nerve dysfunction even without retinal disease.
5. CT scan or MRI scan of the brain is necessary to exclude other inflammatory and structural causes of an acute optic neuritis if there is no family history. MRI scan is often normal but may show a high signal within the optic nerves.

Causes

Causes of Leber Optic Atrophy
This disorder results from mutations in mitochondrial genes.  Mitochondrial DNA has 16,500 basepairs and codes for 37 genes, many of which are involved in oxidative phosphorylation.  For example, mutations in those that encode subunits of NADH dehydrogenase, MT-ND1, MT-ND2, MT-ND4, MT-ND5, and MT-ND6, are known to be responsible for LHON but at least 18 allelic variants are suspected to be causative.

Changes in basepairs located at base pairs 3460, 11778, and 14484 account for more than 90% of cases.  In general, there is little clinical difference in the disease resulting from these mutations.  The vision loss seems to be least among patients with mutations at bp 14484 and over 50% of patients recover some vision up to a year later.  Mutations at bp 11778 tends to cause the most severe loss, especially in females.

The disorder is always inherited from the maternal side (males do not contribute mitochondria in their sperm).  Many cases seem to arise de novo but in a majority of families there is a history of a similar disease among maternal relatives.

Diagnosis

Diagnosis of Leber Optic Atrophy
There are many causes of acute bilateral visual failure that must be excluded during the acute phase, including tobacco amblyopia. In the phase of optic atrophy, the inherited deafness-dystonia-optic neuropathy (Mohr-Tranebjaerg syndrome) must be considered. Leber's congenital amaurosis (LCA) was described by the same doctor but is a different disease with several variants.

Treatment

Treatment of Leber Optic Atrophy
There is no value in monitoring asymptomatic people with the gene, as no effective prevention exists. Support, advice about jobs and visual aids will be required.

Small studies have reported a benefit from using the quinone analogues ubiquinone and idebenone during the acute phase. Neither of these drugs is listed in the BNF. It is noted that the optic neuropathy associated with vitamin B12 deficiency is very similar to Leber's congenital optic neuropathy and therefore some have advocated known carriers of the gene defect should take care to have an adequate dietary intake of vitamin B12.

Prognosis

Prognosis of Leber Optic Atrophy
Despite the severe visual impairment, some will gain some recovery of sight. This is highly variable and it is most likely with the 14484 mutation. The penetrance varies between mutations but, by and large, males have a 40% chance of becoming blind some time in their lives and females a 10% chance.

Prevention

Prevention of Leber Optic Atrophy
Consult with your doctor.