Leber optic atrophy

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Description from OMIM

LHON presents in midlife as acute or subacute central vision loss leading to central scotoma and blindness. The disease has been associated with many missense mutations in the mtDNA that can act autonomously or in association with each other to cause the disease. The 18 allelic variants are MTND6*LDYT14459A ({516006.0002); MTND4*LHON11778A ({516003.0001); MTND1*LHON3460A ({516000.0001); MTND6*LHON14484C ({516006.0001); MTCYB*LHON15257A ({516020.0001); MTCO3*LHON9438A ({516050.0001); MTCO3*LHON9804A ({516050.0002 ); MTND5*LHON13730A ({516005.0002); MTND1*LHON4160C ({516000.0002); MTND2*LHON5244A ({516001.0002); MTCOI*LHON7444A ({516030.0001); MTND1*LHON3394C ({516000.0004); MTND5*LHON13708A ({516005.0001); MTCYB*LHON15812A ({516020.0002); MTND2*LHON4917G ({516001.0001); MTND1*LHON4216C ({516000.0003); MTND1*LHON4136G ({516000.0002); MTATP6*LHON9101C ({516060.0003); MTND4L*LHON10663C ({516004.0002). The first 17 of these variants are summarized in Table M1, MIM12. As pointed out by Riordan-Eva and Harding (1995), although the plethora of mtDNA mutations identified in families with LHON had resulted in confusion as to the pathogenic significance of each mutation, it had been established that the 3 primary mutations at basepairs 11778 ({516003.0001), 3460 ({516000.0001), and 14484 ({516006.0001) are present in at least 90% of families. The correlation between the 14484 mutation and a good visual prognosis provides not only hope for affected patients, but also an approach for further research into the pathogenesis of LHON. Yu-Wai-Man et al. (2009) provided a detailed review of LHON and autosomal dominant optic atrophy (OPA1; 165500), with emphasis on the selective vulnerability of retinal ganglion cells to mitochondrial dysfunction in both disorders.



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List of symptoms



Symptom/sign Organ system Percent affected Pubmed id Added on(yyyy-mm-dd) Edit/add reference
Optic atrophy nervous 100 % 2858640 2011-10-18
Optic atrophy nervous 100 % 7735876 2011-10-05
Tremor nervous 30 % 11523562 2011-10-05
Cardiac conduction defect circulatory 25 % 2858640 2011-10-05
Neuropathy nervous 20 % 11523562 2011-10-05
Kyphosis skeletal 15 % 11523562 2011-10-05
Headache nervous 9 % 11523562 2011-10-05
Seizures nervous 7 % 11523562 2011-10-05
Multiple sclerosis nervous 6 % 7735876 2011-10-05
Multiple sclerosis nervous 4 % 11523562 2011-10-05
Parkinsonism nervous 2 % 11523562 2011-10-05



List of references:


Pre-excitation syndrome and Leber's hereditary optic neuroretinopathy.
E Nikoskelainen, O Wanne, M Dahl,



Lancet (London, England) - Mar 1985



The clinical features of Leber's hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation.
P Riordan-Eva, M D Sanders, G G Govan, M G Sweeney, J Da Costa, A E Harding,

One hundred and seven patients from 79 families were defined as having Leber's hereditary optic neuropathy (LHON) by the presence of one of the mitochondrial DNA (mtDNA) mutations at positions 11778 (60 families), 3460 (seven families) or 14484 (12 families). Only half of the 11778 index patients had a history of similarly affected relatives; this proportion was higher with the 3460 (71%) and 14484 (100%) mutations. The ratios of affected male to female patients were 2.5:1 (11778), 2:1 (3460), and 5.7:1 (14484). Detailed clinical data were available for 79 patients from 55 families. Visual loss developed between the ages of 11 and 30 years in 69%, with a range of 6-62 years, and no significant differences between mutation groups or males and females. It was bilateral in all but two patients, to a median of counting fingers with a central scotoma, developing simultaneously in 22% and sequentially in 78%, with a median inter-eye delay of 8 weeks, and progressing in each eye over a period of 4-6 weeks. Nineteen patients had pain in an affected eye or on eye movements, and four experienced Uhthoff's phenomenon. Retinal microangiopathy was uncommon after 6 months from onset and was not detected in 36% of patients examined within 3 months of visual loss; the microangiopathy was particularly uncommon in the 14484 group. There was no difference in the overall visual outcome between the 11778 and 3460 groups with median final visual acuities of 1/60 and 3/60, respectively. Particularly severe visual loss occurred in one-third of women with the 11778 mutation, to vague perception of light or no perception of light in at least one eye. A multiple sclerosis-like illness was observed in 45% of females with the 11778 mutation. Prognosis was substantially better in the 14484 patients, with recovery to a final visual acuity of at least 6/24, in 71% of patients. Good visual outcome was strongly correlated with age at onset, all those with onset before 20 years having a final visual acuity better than 6/24 as opposed to only 2 out of 6 with later onset. Improvement in vision occurred as long as 4 years after onset. High alcohol and tobacco consumption, cranial or ocular trauma, young or old age at presentation, co-existing neurological disease, and recent childbirth with post-partum haemorrhage, all contributed to diagnostic difficulties in this series, usually in the absence of a family history. These problems were resolved by mtDNA analysis.

Brain : a journal of neurology - Apr 1995



Leber hereditary optic neuropathy: clinical and molecular genetic findings.
K Huoponen,

Leber hereditary optic neuropathy (LHON) is a maternally inherited disease characterized by acute or subacute painless central visual loss usually in young adults, predominantly in males. Except for optic atrophy, LHON patients are usually otherwise healthy. Occasionally, LHON is associated with neurological, cardiac, and skeletal changes. The clinical course of LHON has several stages. Peripapillary microangiopathy is present from the beginning. Microangiopathy disappears as the disease progresses towards the end stages. Simultaneously, the retinal nerve fiber layer fades from view, first papillomacular nerve fiber bundles, and months later, the whole nerve fiber layer becomes atrophic. At the end stage the centrocecal scotoma is large and absolute. Loss of vision is usually permanent, but spontaneous recovery can occur. Despite a few attempts, no effective treatment to prevent or halt LHON has been found. Several mitochondrial DNA (mtDNA) mutations are associated with LHON, but the pathogenic processes leading to optic nerve atrophy are largely unknown. About 15% of the families are heteroplasmic, i.e., both mutant and wild type mtDNA coexist within an individual. The level of heteroplasmy between different tissues can vary markedly. mtDNA mutations are not sufficient to cause visual loss in LHON, since not all individuals harboring a pathogenic LHON mutation express the disease. There are additional genetic and/or environmental precipitating factors, but thus far they are unknown.

Neurogenetics - Jul 2001