Leber hereditary optic neuropathy

General Information (adopted from Orphanet):

Synonyms, Signs: LHON
Leber optic atrophy
Number of Symptoms 41
OrphanetNr: 104
OMIM Id: 308905
ICD-10: H47.2

Prevalence, inheritance and age of onset:

Prevalence: 2 of 100 000 - PMID: 20454697 [IBIS]
Inheritance: Mitochondrial
- PMID: 11523562 [IBIS]
Age of onset: All ages
- PMID: 26170609 [IBIS]

Disease classification (adopted from Orphanet):

Parent Diseases: Mitochondrial disease with dilated cardiomyopathy
 -Rare cardiac disease
 -Rare genetic disease
Mitochondrial disease with eye involvement
 -Rare eye disease
 -Rare genetic disease
Mitochondrial disease with hypertrophic cardiomyopathy
 -Rare cardiac disease
 -Rare genetic disease
Mitochondrial oxidative phosphorylation disorder due to a point mutation of mitochondrial DNA
 -Rare developmental defect during embryogenesis
 -Rare genetic disease
 -Rare neurologic disease
Optic neuropathy
 -Rare eye disease
 -Rare genetic disease


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 (PMID:11523562). LHON is one of the most common inherited optic neuropathies causing bilateral central vision loss. The disorder results from point mutations in mitochondrial DNA and subsequent mitochondrial dysfunction. All of the mutations occur in genes encoding subunits for complex I in the respiratory chain, particularly in those encoding the ND1 and ND6 subunits (PMID:26170609). Over 95% of LHON cases are primarily the result of one of three mitochondrial DNA (mtDNA) point mutations, G3460A, G11778A, and T14484C, which all involve genes encoding complex I subunits of the respiratory chain. An intriguing feature of LHON is that only approximately 50% of males and approximately 10% of females who harbour a pathogenic mtDNA mutation actually develop the optic neuropathy (PMID:11897814). There have been reports of LHON onset from 2 to 87 years of age. The visual prognosis in LHON is poor. Spontaneous visual recovery is more common in patients with the 14484 mutation, with a partial recovery rate of 37%–58%, while the 11778 mutation has the lowest partial recovery rate of 4%. Patients with the 3460 mutation have an intermediate prognosis, with an approximate 20% partial recovery rate. Earlier age of onset (younger than 20 years), a subacute time course of vision loss, and a larger optic disc are all associated with a better visual prognosis (PMID:26170609). *Leber's "plus" is described as neurological abnormalities in patients with LHON (PMID: 7629530). It could be that some of the symptoms overlap with Leber 'plus' disease as the authors of the annotated papers do not distinguish between LHON and Leber 'plus'. (IBIS). Involved genes: MT-ND1 (PMID:20454697); MT-ND2 (PMID:20454697); MT-ND3 (PMID:20454697); MT-ND4 (PMID:20454697); MT-ND4L (PMID:20454697); MT-ND5 (PMID:20454697); MT-ND6 (PMID:26170609); MT-ATP6 (PMID:20454697); MT-CO1 (PMID:20454697); MT-CO2 (PMID:20454697); MT-CO3 (PMID:20454697); MT-CYB (PMID:20454697);

Symptom Information: Sort by abundance 

(HPO:0001112) Leber optic atrophy Very frequent [IBIS] 3201231 IBIS 9 / 7739
(HPO:0200057) Marcus Gunn pupil 26170609 IBIS 3 / 7739
(HPO:0000648) Optic atrophy 3201231 IBIS 238 / 7739
(HPO:0000543) Optic disc pallor Very frequent [IBIS] 100% (n=10) 20454697 IBIS 67 / 7739
(HPO:0001138) Optic neuropathy Very frequent [IBIS] 24568867 IBIS 12 / 7739
(HPO:0001085) Papilledema 26170609 IBIS 31 / 7739
(HPO:0000512) Abnormal electroretinogram 26170609 IBIS 61 / 7739
(HPO:0000538) Pseudopapilledema 26170609 IBIS 4 / 7739
(HPO:0007641) Dyschromatopsia Frequent [IBIS] 26170609 IBIS 19 / 7739
(HPO:0000649) Abnormality of visual evoked potentials 26170609 IBIS 34 / 7739
(HPO:0000603) Central scotoma Frequent [IBIS] 80% (n=10) 20454697 IBIS 18 / 7739
(HPO:0000576) Centrocecal scotoma Occasional [IBIS] 10% (n=10) 20454697 IBIS 6 / 7739
(HPO:0000505) Visual impairment Frequent [IBIS] 26170609 IBIS 297 / 7739
(HPO:0000618) Blindness 11897814 IBIS 124 / 7739
(HPO:0000622) Blurred vision 14620678 IBIS 14 / 7739
(HPO:0000572) Visual loss Very frequent [IBIS] 11523562 IBIS 272 / 7739
(HPO:0011675) Arrhythmia 20454697 IBIS 226 / 7739
(HPO:0001716) Wolff-Parkinson-White syndrome 23549648 IBIS 21 / 7739
(HPO:0001678) Atrioventricular block 12807863 IBIS 59 / 7739
(HPO:0003287) Abnormality of mitochondrial metabolism Very frequent [IBIS] 26170609 IBIS 12 / 7739
(HPO:0003198) Myopathy 20454697 IBIS 151 / 7739
(HPO:0009830) Peripheral neuropathy 20454697 IBIS 206 / 7739
(HPO:0001251) Ataxia 26170609 IBIS 413 / 7739
(HPO:0002066) Gait ataxia 19301602 IBIS 327 / 7739
(HPO:0002311) Incoordination 15657614 IBIS 84 / 7739
(HPO:0001332) Dystonia 26170609 IBIS 197 / 7739
(HPO:0100022) Abnormality of movement 20454697 IBIS 129 / 7739
(HPO:0002174) Postural tremor 20454697 IBIS 22 / 7739
(HPO:0001009) Telangiectasia 26170609 IBIS 46 / 7739
(HPO:0004948) Vascular tortuosity 26170609 IBIS 5 / 7739
(HPO:3000036) Abnormality of head blood vessel 26170609 IBIS 1 / 7739
(HPO:0012795) Abnormality of the optic disc 26170609 IBIS 187 / 7739
(HPO:0030607) Reduced OCT-measured macular thickness 26170609 IBIS 1 / 7739
(MedDRA:10057361) Blood brain barrier defect 26170609 IBIS 1 / 7739
(MedDRA:10062198) Microangiopathy 3201231 IBIS 4 / 7739
(MedDRA:10071196) Optic disc hyperaemia 26170609 IBIS 1 / 7739
(OMIM) Histology shows degeneration of retinal ganglion cells 26170609 IBIS 2 / 7739
(OMIM) Multiple sclerosis-like illness (516003.0001) 1393514 IBIS 3 / 7739
(OMIM) Nonspecific myopathy 20454697 IBIS 2 / 7739
(OMIM) Spastic dystonia 8644732 IBIS 3 / 7739
(OMIM) Swelling of retinal nerve fiber layer (acute phase) 26170609 IBIS 2 / 7739

Associated genes:


ClinVar (via SNiPA)

Gene symbol Variation Clinical significance Reference
MT-ATP6 rs199476134 pathogenic RCV000010277.2
MT-CO1 rs199474822 pathogenic RCV000010299.4
MT-CO3 rs200613617 pathogenic RCV000010287.2
MT-CO3 rs267606611 pathogenic RCV000010286.2
MT-CYB rs199795644 pathogenic RCV000055706.1
MT-CYB rs200336777 pathogenic RCV000010313.4
MT-ND1 rs199476118 pathogenic RCV000010370.4
MT-ND1 rs199476119 pathogenic RCV000010372.2
MT-ND1 rs199476121 pathogenic RCV000010378.2
MT-ND1 rs199476122 pathogenic RCV000056168.1
MT-ND1 rs199476122 pathogenic RCV000010386.2
MT-ND1 rs199476125 pathogenic RCV000010389.2
MT-ND1 rs28616230 pathogenic RCV000010384.4
MT-ND1 rs397515507 pathogenic RCV000055707.1
MT-ND1 rs397515508 pathogenic RCV000055708.1
MT-ND1 rs397515509 pathogenic RCV000055709.1
MT-ND1 rs397515612 pathogenic RCV000056167.1
MT-ND1 rs41460449 pathogenic RCV000010375.3
MT-ND2 rs199476115 pathogenic RCV000010365.2
MT-ND2 rs387906426 pathogenic RCV000010366.2
MT-ND3 rs193302927 pathogenic RCV000055695.1
MT-ND3 rs267606891 pathogenic RCV000010363.4
MT-ND4L rs193302933 pathogenic RCV000010353.3
MT-ND4 rs199476112 pathogenic RCV000010354.2
MT-ND4 rs200145866 pathogenic RCV000055696.1
MT-ND4 rs200873900 pathogenic RCV000055697.1
MT-ND4 rs200873900 pathogenic RCV000010356.2
MT-ND5 rs199974018 pathogenic RCV000055698.1
MT-ND5 rs200855215 pathogenic RCV000055699.1
MT-ND5 rs201863060 pathogenic RCV000022893.4
MT-ND5 rs267606895 pathogenic RCV000010341.2
MT-ND5 rs267606899 pathogenic RCV000010350.2
MT-ND5 rs387906425 pathogenic RCV000010337.4
MT-ND6 rs199476104 pathogenic RCV000010325.4
MT-ND6 rs199476105 pathogenic RCV000010326.2
MT-ND6 rs199476105 pathogenic RCV000010327.2
MT-ND6 rs199476106 pathogenic RCV000010330.2
MT-ND6 rs199476108 pathogenic RCV000055701.1
MT-ND6 rs199476108 pathogenic RCV000010332.2
MT-ND6 rs387906424 pathogenic RCV000010329.2
MT-ND6 rs387906424 pathogenic RCV000055704.1
MT-ND6 rs397515505 pathogenic RCV000055700.1
MT-ND6 rs397515506 pathogenic RCV000055703.1

Additional Information:

Description: (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 ...
Clinical Description OMIM LHON patients present with midlife, acute or subacute, painless, central vision loss leading to central scotoma. Neuroophthalmologic examination commonly reveals peripapillary telangiectasia, microangiopathy, disc pseudoedema, and vascular tortuosity; these features are observed in 58% of patients with the ...
Molecular genetics OMIM While LHON is traditionally considered to be familial, many individuals represent isolated cases. The proportion of cases with family histories have been reported to be 43% for np 11778, to be 78% for np 3460, to be 57% ...
Population genetics OMIM Carelli et al. (2006) evaluated the mtDNA of 87 index cases with LHON sequentially diagnosed in Italy, including an exceedingly large Brazilian family of Italian maternal ancestry. The results revealed that the large majority of the LHON mutations ...
Diagnosis GeneReviews Leber hereditary optic neuropathy (LHON) is characterized by bilateral, painless subacute visual failure that develops during young adult life. Males are four to five times more likely than females to be affected [Yu-Wai-Man et al 2009]....
Clinical Description GeneReviews Leber hereditary optic neuropathy (LHON) typically presents in young adults as bilateral, painless, subacute visual failure. The peak age of onset in LHON varies between the second and third decades of life depending on the published case series, with 95% of those who lose their vision doing so before the age of 50 years. Very rarely, individuals first manifest LHON in the seventh and eighth decades of life [Buchan et al 2007]. Males are four to five times more likely to be affected than females, but neither gender nor mutational status significantly influences the timing and severity of the initial visual loss....
Genotype-Phenotype Correlations GeneReviews Distinct phenotypes are associated with specific LHON-causing mutations:...
Differential Diagnosis GeneReviews If the ophthalmologic assessment (including an assessment of acuity, color vision, visual fields, and electrophysiology) and molecular genetic testing leave any uncertainty about the diagnosis of Leber hereditary optic neuropathy (LHON), further evaluation of the anterior visual pathways and brain with contrast MRI and lumbar puncture are appropriate to exclude other potentially treatable optic neuropathies....
Management GeneReviews To establish the extent of disease in an individual diagnosed with Leber hereditary optic neuropathy (LHON), the following evaluations are recommended:...
Molecular genetics GeneReviews Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....