Leber's Optic Atrophy

Synonyms: Leber's hereditary optic neuropathy (LHON), optic atrophy, Leber's optic neuropathy and hereditary optic neuroretinopathy

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.¹

It seems likely that the aetiology is multifactorial.²

A study of the north-east of England³ found that 11.8 per 100,000 had the LHON gene but the incidence of the disease was 3.22 per 100,000. The incidence of blindness due to LHON was 1 in 14,000. Mutation of the G11778A gene represents 70% of cases worldwide. There are 18 different phenotypes that have been assessed but 3 account for 95% of cases. Up to 40% give no family history.⁴

Penetrance is about 50-60% in males and 10-15% in females. Many, if not most, cases with no family history are due to incomplete penetrance rather than new mutation.

Risk factors

There are reports of heavy smoking or high alcohol consumption⁵ preceding symptoms. Sometimes there is a history of head trauma or psychological stress.⁵ A retrospective study failed to show that alcohol or heavy smoking had a significant effect on vision⁶ but it is still usual to recommend that patients stop smoking and should moderate alcohol consumption.

• The mean age of onset is between 27 and 34 years with a range of 1 to 70 years.¹
• It usually presents in young adults as painless subacute bilateral visual failure, affecting men more than women (3M:1F).⁷ Women tend to present a little later but the disease can be more severe.
• It starts with blurring of central vision and desaturation of colour in both eyes simultaneously in about ½ of cases.⁷ If it is asymmetrical, both eyes are usually affected within 2-15 months.⁸
• The rate of progression can vary from rapid to over 2 years but most people are severely impaired by 3 or 4 months.¹
• Central vision deteriorates to counting fingers in 80%. There may be temporary improvement before the atrophic phase.
• Optic atrophy develops and clinical investigations are unhelpful in distinguishing it from other causes.
• Visual acuity remains static thereafter. Most will be registered blind for the rest of their lives with a permanent large scotoma.
• Occasionally there is also dystonia and spasticity or a multiple sclerosis-like illness, especially in affected females.⁹
• A subgroup with onset in childhood has been identified in Italy.¹⁰

• Visual acuity is usually reduced to counting fingers.
• Visual field testing shows an enlarging central scotoma.
• 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.
• Electrophysiology studies, including pattern electroretinogram and visual evoked potentials, may demonstrate optic nerve dysfunction even without retinal disease.
• 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.

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)¹¹ must be considered. Leber's congenital amaurosis (LCA) was described by the same doctor but is a different disease with several variants.¹²

A number of studies have found associated conditions. The most common are cardiac pre-excitation syndromes, usually Wolff-Parkinson-White syndrome but also Lown-Ganong-Levine syndrome.¹³ A multiple sclerosis-like disease has also been described.¹⁴ OMIM lists a number of articles.¹

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.

Gene therapy may be a possible option at some time in the future.

The disease is inherited from the mother and not the father. An affected mother invariably passes on the gene although there is limited penetrance. De novo mutations are presumed rare and the 40% with no family history are largely accounted for by incomplete penetrance or failure to know the family. If the mother has the gene, so too will all siblings. It will be passed to all children by mothers and none by fathers. Genetic testing is not useful in predicting age of onset, severity, or rate of progression in asymptomatic carriers. Age and sex are important. An 18-year-old male has a lifetime risk of around 50% for developing the disease after a positive test result but this falls as years go by without manifestation. However, the risk never vanishes, as it can present late in life. If the mutation is heteroplasmic, it may not be present in every family member. Heteroplasmy occurs in 12%.³

Intra-uterine testing is not applicable, as no children of carrier fathers will be affected, although all children of carrier mothers will have the gene. However, it will be manifest in only 50% of male offspring and 15% of females with the risk of blindness being 40% and 10% respectively.

General wisdom holds that children who are at risk of a disorder that strikes in adulthood and for which there is no treatment, should not have testing unless there are symptoms. It is argued that asymptomatic testing removes the choice to know or not know this information, and it raises the possibility of stigma within the family and society, which could have serious implications for education and career.¹⁵

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.¹⁶ 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.

Theodor Karl Gustav von Leber (pronounced LAY-ber) was born in 1840 and died in 1917.¹⁷ He trained as a chemist but turned to medicine on the advice of Robert Bunsen of burner fame. He studied under Carl Ludwig and Albrecht von Graefe. He has lent his name to Franceschetti-Leber phenomenon, LCA, Leber's miliary aneurysm, Leber's plexus and LOA.

He described the disease in 1868 but little progress was made until the 1980s. Many different pedigrees have been described. Wallace and co-workers demonstrated that human mtDNA was maternally inherited and suggested that maternally transmitted diseases might be due to mtDNA mutations.¹⁸